Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
  • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
  • C07D311/12—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 3 and unsubstituted in position 7
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
  • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/39—Heterocyclic compounds having sulfur as a ring hetero atom having oxygen in the same ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/06—Antianaemics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
  • C07D285/01—Five-membered rings
  • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
  • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
  • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
  • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/433—Thidiazoles

Definitions

• the present invention relates to methods and compounds for the treatment of blood disorders.
• red blood cells The major function of red blood cells is to transport oxygen to tissues of the body, while minor functions include the transportation of nutrients and cytokines and the absorption of cellular metabolites.
• Anemia defined as a loss of red blood cells or red blood cell capacity resulting in the reduction in the ability of the blood to transport oxygen, may be chronic or acute. Chronic anemia may be caused by extrinsic red blood cell abnormalities, intrinsic abnormalities or impaired production of red blood cells. Extrinsic or extra-corpuscular abnormalities include antibody-mediated disorders such as transfusion reactions and erythroblastosis, mechanical trauma to red cells such as micro-angiopathic hemolytic anemias, thrombotic thrombocytopenic purpura and disseminated intravascular coagulation. In addition, infections by parasites such as Plasmodium, chemical injuries from, for example, lead poisoning, and sequestration in the mononuclear system such as by hyperspienism can result in red blood cell disorders and deficiencies.
• Impaired red blood cell production can occur by disturbing the proliferation and differentiation of the stem cells or committed cells.
• Some of the more common diseases of red cell production include aplastic anemia, sickle cell anemia, ⁇ -thalassemia, hypoplastic anemia, pure red cell aplasia and anemia associated with renal failure or endocrine disorders.
• Disturbances of the proliferation and differentiation of erythroblasts include defects in DNA synthesis such as impaired utilization of vitamin B 12 or folic acid and the megaloblastic anemias, defects in heme or globin synthesis, and anemias of unknown origins such as sideroblastic anemia, anemia associated with chronic infections such as malaria, trypanosomiasis, HIV, hepatitis virus or other viruses, and myelophthisic anemias caused by marrow deficiencies.
• Symptoms of anemia include feelings of weakness or fatigue, pallor, shortness of breath, an increase in cardiac output, which may lead to palpitations and sweatiness. In severe cases, anemia can lead to death by heart failure. Current treatments for anemia depend on the type of anemia the patient suffers from. Monitoring of the diet to increase iron intake may be prescribed, as well as iron supplementation. In some cases, medication or blood transfusions may be necessary.
• Sickle cell disease and ⁇ -thalassemia are two of the most common genetic disorders in the word. These disorders are caused by molecular mutations affecting the ⁇ -globin genes for adult hemoglobin A ( ⁇ 2 ⁇ 2), and it has been established that these disorders can be ameliorated by reactivating production of fetal hemoglobin (HbF, ⁇ 2 ⁇ 2) in the patients' blood. Even small increments in fetal hemoglobin decreases morbidity and mortality in sickle cell disease, while higher levels are necessary to completely ameliorate the symptoms. In ⁇ -thalassemia, increases in fetal globin synthesis, which reduces the excess unbalanced ⁇ -globin chains by 10%, is often enough to decrease the anemia to a level which does not require regular blood transfusions.
• Short chain fatty acids and derivatives of 2-9 carbons induce expression of ⁇ -globin in cultured erythroid cells, animal models and reporter gene assays, which test activity in activating the ⁇ -globin gene promoter.
• Several short chain fatty acids induce the ⁇ -globin promoter and have biologic and clinical activity.
• Pharmacological re-introduction of HbF has been achieved in patients with a prototype short-chain fatty acid, arginine butyrate, resulting in sufficient levels of HbF to ameliorate anemia and reduce clinical complications.
• Patients treated in a Phase II trial with pulsed butyrate have experienced both biochemical and clinical improvement in their diseases, with excellent safety profiles.
• the prototype short chain fatty acids have limitations as therapeutics.
• Arginine butyrate and phenylbutyrate require 100 ⁇ M levels in vitro and are rapidly metabolized in vivo, necessitating large quantities (20 g for sodium phenyl butyrate), an intravenous infusion for arginine butyrate and careful adjustment of dosing to prevent secondary suppression of erythopoiesis.
• the present invention pertains, at least in part, to methods for treating or preventing a blood disorder in a subject by administering to the subject an effective amount of a compound of formula I: wherein
• R 1 is hydroxy or alkoxy
• X is C(O), C(S), SO, SO 2 or PO 2 ;
• R 2 and R 3 are each independently hydrogen, alkyl, halogen, hydroxyl, thiol, alkenyl, alkynyl, aryl, acyl, alkoxy, amino, alkylamino or heterocyclic;
• R 4 is alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, heteroaryl, halogen or
• R 5 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, nitro, halogen or optionally linked to R 6 to form a ring;
• R 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, nitro, halogen or optionally linked to R 5 or R 7 to form a ring;
• R 7 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, nitro, halogen or optionally linked to R 6 or R 8 to form a ring;
• R 8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, nitro, halogen or optionally linked to R 7 or R 9 to form a ring;
• R 9 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, nitro, halogen or optionally linked to R 8 to form a ring;
• R 4 is R 5 , R 6 , R 7 , R 8 , and R 9 are each not hydrogen; and when R 6 , R 7 , R 8 , and R 9 are each hydrogen, R 5 is not methoxy; and when R 5 , R 7 , R 8 , R 9 are hydrogen, R 6 is not methoxy; and when R 5 , R 8 and R 9 are hydrogen, R 6 and R 7 are not methoxy.
• the present invention pertains, at least in part, to methods for treating or preventing a blood disorder in a subject by administering to the subject an effective amount of a compound of formula II: wherein
• R 1′ is hydroxy or alkoxy
• Y is C(O);
• n is 0 or an integer from 1 to 5;
• R 10 and R 10′ are each independently hydrogen, alkyl, halogen, hydroxyl, thiol, alkenyl, alkynyl, aryl, acyl, alkoxy, amino, alkylamino, heterocyclic or optionally joined to form a ring;
• R 11 is CR 11′ R 11′′ R 11′′′ , alkenyl, cycloalkyl, alkynyl, arylalkyl, amido, alkylamino, amino, arylamino, carbonylalkyl, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, heteroaryl, hydroxy, halogen or
• R 11′ and R 11′′ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxyl, halogen, or R 11′ and R 11′′ are optionally joined to form a ring;
• R 11′′′ is alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy or halogen;
• R 12 is hydrogen, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic or optionally linked to R 13 to form a ring;
• R 13 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy or optionally linked to R 12 or R 14 to form a ring;
• R 14 is hydrogen, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, halogen or optionally linked to R 13 or R 15 to form a ring;
• R 15 is hydrogen, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, halogen or optionally linked to R 14 or R 16 to form a ring;
• R 16 is hydrogen, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, halogen or optionally linked to R 15 to form a ring;
• R 11 is R 12 , R 13 , R 14 , R 15 , and R 16 are each not hydrogen; and provided when n is 2, R 11 is and R 10 , R 10′ , R 12 , R 15 , and R 16 are hydrogen, then R 14 and R 15 are not methoxy; and provided when n is 1, R 11 is and R 10 , R 10′ , R 13 , R 14 , and R 16 are hydrogen, then R 12 and R 15 are not methoxy.
• the present invention pertains, at least in part, to methods for treating or preventing a blood disorder in a subject by administering to the subject an effective amount of a compound of formula III: wherein
• R 1′′ is hydroxy or alkoxy
• Z is C(S), SO, SO 2 or PO 2 ;
• n is 0 or an integer from 1-5;
• R 17 and R 17′ are each independently hydrogen, alkyl, halogen, hydroxyl, thiol, alkenyl, alkynyl, aryl, acyl, alkoxy, amino, alkylamino or heterocyclic;
• R 18 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, heteroaryl, hydroxyl or halogen;
• the present invention pertains, at least in part, to methods for treating or preventing a blood disorder in a subject by administering to the subject an effective amount of a compound of formula:
• the present invention pertains, at least in part, to pharmaceutical compositions of an effective amount of a compound of formula I, formula II, formula III, or and a pharmaceutically acceptable carrier.
• the present invention pertains, at least in part, to compounds of formula I, formula II, and formula (III) and racemates, isolated enantiomers or diastereomers, and pharmaceutically acceptable salts thereof.
• the present invention pertains, at least in part, to methods
• R 1 is hydroxy or alkoxy
• X is C(O), C(S), SO, SO 2 or PO 2 ;
• R 2 and R 3 are each independently hydrogen, alkyl, halogen, hydroxyl, thiol, alkenyl, alkynyl, aryl, acyl, alkoxy, amino, alkylamino or heterocyclic;
• R 4 is alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, heteroaryl, halogen or
• R 5 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, nitro, halogen or optionally linked to R 6 to form a ring;
• R 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, nitro, halogen or optionally linked to R 5 or R 7 to form a ring;
• R 7 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, nitro, halogen or optionally linked to R 6 or R 8 to form a ring;
• R 8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, nitro, halogen or optionally linked to R 7 or R 9 to form a ring;
• R 9 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, nitro, halogen or optionally linked to R 9 to form a ring;
• R 4 is R 5 , R 6 , R 7 , R 8 , and R 9 are each not hydrogen; and when R 6 , R 7 , R 8 , and R 9 are each hydrogen, R 5 is not methoxy; and when R 5 , R 7 , R 8 , R 9 are hydrogen, R 6 is not methoxy; and when R 5 , R 8 and R 9 are hydrogen, R 6 and R 7 are not methoxy.
• R 1 is hydroxy
• X is C(O)
• R 4 is
• R 2 , R 3 , R 5 , R 6 , R 8 and R 9 are each hydrogen and R 7 is alkoxy (e.g., methoxy).
• R 2 , R 3 , R 5 , R 7 and R 8 are each hydrogen, and R 6 and R 9 are each alkyl (e.g., methyl).
• R 2 , R 3 , R 5 , R 8 are R 9 are each hydrogen and R 6 and R 7 are each hydroxyl.
• R 2 , R 3 , R 5 , R 8 are R 9 are each hydrogen and R 6 and R 7 are linked by —O—CH 2 —O— to form a ring.
• R 2 , R 3 , R 5 , R 6 and R 9 are each hydrogen, R 7 is alkoxy (e.g., methoxy) and R 8 is hydroxyl.
• R 1 is hydroxy
• X is C(O)
• R 4 is heteroaryl, such quinoline or substituted or unsubstituted thiophene (e.g., chlorothiophene).
• the present invention pertains, at least in part, to methods
• the present invention pertains, at least in part, to methods for treating or preventing a blood disorder in a subject by administering to the subject an effective amount of a compound of formula II: wherein
• R 1′ is hydroxy or alkoxy
• Y is C(O);
• n is 0 or an integer from 1 to 5;
• R 10 and R 10′ are each independently hydrogen, alkyl, halogen, hydroxyl, thiol, alkenyl, alkynyl, aryl, acyl, alkoxy, amino, alkylamino, heterocyclic or optionally joined to form a ring;
• R 11 is CR 11′ R 11′′ R 11′′′ , alkenyl, cycloalkyl, alkynyl, arylalkyl, amido, alkylamino, amino, arylamino, carbonylalkyl, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, heteroaryl, hydroxy, halogen or
• R 11′ and R 11′′ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxyl, halogen or R 11′ and R 11′′ are optionally joined to form a ring;
• R 11′′′ is alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy or halogen;
• R 12 is hydrogen, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic or optionally linked to R 13 to form a ring;
• R 13 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy or optionally linked to R 12 or R 14 to form a ring;
• R 14 is hydrogen, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, halogen or optionally linked to R 13 or R 15 to form a ring;
• R 15 is hydrogen, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, halogen or optionally linked to R 14 or R 16 to form a ring;
• R 16 is hydrogen, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, halogen or optionally linked to R 15 to form a ring;
• R 11 is R 12 , R 13 , R 14 , R 15 , and R 16 are each not hydrogen; and provided when n is 2, R 11 is and R 10 , R 10′ , R 12 , R 15 , and R 16 are hydrogen, then R 14 and R 15 are not methoxy; and provided when n is 1, R 11 is and R 10 , R 10′ , R 13 , R 14 , and R 16 are hydrogen, then R 12 and R 15 are not methoxy.
• R 1′ is hydroxyl
• n is 5
• R 10 and R 10′ are hydrogen and R 11 is alkylcarbonyl.
• R 1′ is hydroxyl
• n is 2
• R 10 and R 10′ are each hydrogen and R 11 is CR 11′ R 11′′ R 11′′′ .
• R 11′ and R 11′′ are joined by —(CH 2 ) 5 — to form a cyclohexyl ring and R 11′′′ is a substituted or unsubstituted heterocycle (e.g., chlorothiophene).
• R 1′ is hydroxyl
• n is 0 and R 11 is
• R 13 , R 14 , R 15 , and R 16 are hydrogen and R 12 is arylthioalkyl or alkoxy substituted aryloxy.
• R 12 , R 14 , R 15 and R 16 are hydrogen and R 13 is a substituted or unsubstituted heterocycle, such as, for example, chromen-2-one, nitro-substituted pyrazole, or chloro-substituted pyrazole.
• R 12 , R 13 , R 15 and R 16 are hydrogen and R 13 is alkoxy (e.g., ethoxy).
• R 12 , R 15 and R 16 are hydrogen, and R 13 and R 14 are linked by —N(H)C(O)CH 2 S— to form a ring.
• R 14 , R 15 and R 16 are each hydrogen, and R 12 and R 13 are linked by —CH ⁇ C(CH 3 )O— to form a ring.
• R 1′ is hydroxyl
• n is 0
• R 11 is a substituted or unsubstituted heterocycle (e.g., substituted aryl-substituted furan) or a substituted or unsubstituted cycloalkyl (e.g., tetrahydrobenzothiadiazole or dihydrobenzothiophenone).
• R 1′ is hydroxyl
• n is 1
• R 10 and R 10′ are hydrogen and R 11 is a substituted or unsubstituted cycloalkyl (e.g., dimethylcyclobutane carboxylic acid).
• R 1′ is hydroxyl
• n is 1
• R 10 and R 10′ are hydrogen and R 11 is
• R 12 , R 13 and R 16 are hydrogen, and R 14 and R 15 are linked by —O—CH 2 —O— to form a ring.
• R 1′ is hydroxyl
• n is 1
• R 10 and R 10′ are hydrogen and R 11 is a substituted or unsubstituted heterocycle, such as, for example substituted thiazolidinedione, substituted pyridinone or substituted pyrazole.
• R 1′ is hydroxyl
• n is 1
• R 10 and R 10′ are hydrogen and R 11 is a unsubstituted or substituted arylamino (e.g., trifluorothio-substituted arylamino).
• R 1′ is hydroxyl
• n is 1
• R 10 and R 10′ are hydrogen and R 11 is unsubstituted or substituted arylthio (e.g., methoxyphenylthio) or unsubstituted or substituted heterocyclic thio, such as, for example, substituted triazolethio, substituted thiadiazolethio or substituted thiophenethio.
• arylthio e.g., methoxyphenylthio
• heterocyclic thio such as, for example, substituted triazolethio, substituted thiadiazolethio or substituted thiophenethio.
• R 1′ is hydroxyl
• n is 1
• R 10 and R 10′ are hydrogen and R 11 is R 11 is CR 11′ R 11′′ R 11′′′ and R 11′ is hydrogen, R 11′′ is amino and R 11′′′ is alkoxy-substituted aryl.
• R 1′ is hydroxyl, n is 1, R 10 is hydrogen and R 10′ is alkyl.
• R 10′ is isopropyl and R 11 is substituted or unsubstituted arylthio, such as, for example, alkoxy-substituted phenylthio or alkoxy-substituted pyrimadinylthio.
• R 10′ is ethyl and R 11 is heteroarylamino (e.g., quinazolinylamino).
• R 1′ is hydroxyl
• n is 1
• R 10 and R 10′ are linked by —(CH 2 ) 5 — to form a cyclohexyl ring and R 11 is heterocyclic substituted carbonylalkyl.
• the compounds of formula (II) do not include compounds wherein R 1 is hydroxy, R 10 is alkyl, e.g., ethyl, R 10′ is hydrogen, n is 1, and R 11 is arylamino, e.g., quinazolin-4-ylamino.
• the compounds of formula (II) do not include compounds wherein R 1 is hydroxy, R 10 is hydrogen, R 10′ is alkyl, e.g., ethyl, n is 1, and R 11 is arylamino, e.g., quinazolin-4-ylamino.
• the compounds of formula (II) do not include compounds wherein R 1 is hydroxy, R 10 and R 10′ are each hydrogen, n is 1, and R 11 is aryl amino (e.g., trifluorothio-substituted arylamino).
• the compounds of formula (II) do not include 2-(quinazolin-4-ylamino)butyric acid or [4-[(trifluoromethyl)sulfanyl]-anilino]-acetic acid.
• the present invention pertains, at least in part, to methods
• the present invention pertains, at least in part, to methods for treating or preventing a blood disorder in a subject by administering to the subject an effective amount of a compound of formula III: wherein
• R 1′′ is hydroxy or alkoxy
• Z is C(S), SO, SO 2 or PO 2 ;
• n is 0 or an integer from 1-5;
• R 17 and R 17′ are each independently hydrogen, alkyl, halogen, hydroxyl, thiol, alkenyl, alkynyl, aryl, acyl, alkoxy, amino, alkylamino or heterocyclic;
• R 18 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, heteroaryl, hydroxyl or halogen;
• R 1′′ is hydroxyl
• Z is SO 2
• m is 0, and R 18 is disubstituted aryl substituted by, for example, nitro and fluoro.
• the present invention pertains, at least in part, to methods for treating or preventing a blood disorder in a subject by administering to the subject an effective amount of a compound of formula III, wherein the compound of formula III is:
• the present invention pertains, at least in part, to methods for treating or preventing a blood disorder in a subject by administering to the subject an effective amount of a compound of formula:
• the invention pertains, at least in part, to a compound of formula I: wherein
• R 1 is hydroxy or alkoxy
• X is C(O), C(S), SO, SO 2 or PO 2 ;
• R 2 and R 3 are each independently hydrogen, alkyl, halogen, hydroxyl, thiol, alkenyl, alkynyl, aryl, acyl, alkoxy, amino, alkylamino or heterocyclic;
• R 4 is alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, heteroaryl, halogen or
• R 5 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, nitro, halogen or optionally linked to R 6 to form a ring;
• R 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, nitro, halogen or optionally linked to R 5 or R 7 to form a ring;
• R 7 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, nitro, halogen or optionally linked to R 6 or R 8 to form a ring;
• R 8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, nitro, halogen or optionally linked to R 7 or R 9 to form a ring;
• R 9 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, nitro, halogen or optionally linked to R 8 to form a ring;
• R 4 is R 5 , R 6 , R 7 , R 8 , and R 9 are each not hydrogen; and when R 6 , R 7 , R 8 , and R 9 are each hydrogen, R 5 is not methoxy; and when R 5 , R 7 , R 8 , R 9 are hydrogen, R 6 is not methoxy; and when R 5 , R 8 and R 9 are hydrogen, R 6 and R 7 are not methoxy;
• the present invention also pertains, at least in part, to a compound of formula II: wherein
• R 1′ is hydroxy or alkoxy
• Y is C(O);
• n is 0 or an integer from 1 to 5;
• R 10 and R 10′ are each independently hydrogen, alkyl, halogen, hydroxyl, thiol, alkenyl, alkynyl, aryl, acyl, alkoxy, amino, alkylamino, heterocyclic or optionally joined to form a ring;
• R 11 is CR 11′ R 11′′ R 11′′′ , alkenyl, cycloalkyl, alkynyl, arylalkyl, amido, alkylamino, amino, arylamino, carbonylalkyl, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, heteroaryl, hydroxy, halogen or
• R 11′ and R 11′′ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxyl, halogen or R 11′ and R 11′′ are optionally joined to form a ring;
• R 11′′′ is alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy or halogen;
• R 12 is hydrogen, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic or optionally linked to R 13 to form a ring;
• R 13 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy or optionally linked to R 12 or R 14 to form a ring;
• R 14 is hydrogen, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, halogen or optionally linked to R 13 or R 15 to form a ring;
• R 15 is hydrogen, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, halogen or optionally linked to R 14 or R 16 to form a ring;
• R 16 is hydrogen, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, halogen or optionally linked to R 15 to form a ring;
• R 11 is R 12 , R 13 , R 14 , R 15 , and R 16 are each not hydrogen; and provided when n is 2, R 11 is and R 10 , R 10′ , R 12 , R 15 , and R 16 are hydrogen, then R 14 and R 15 are not methoxy; and provided when n is 1, R 11 is and R 10 , R 10′ , R 13 , R 14 , and R 16 are hydrogen, then R 12 and R 15 are not methoxy;
• the present invention pertains, at least in part, to a compound of formula III: wherein
• R 1′′ is hydroxy or alkoxy
• Z is C(S), SO, SO 2 or PO 2 ;
• n is 0 or an integer from 1-5;
• R 17 and R 17′ are each independently hydrogen, alkyl, halogen, hydroxyl, thiol, alkenyl, alkynyl, aryl, acyl, alkoxy, amino, alkylamino or heterocyclic;
• R 18 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, heteroaryl, hydroxyl or halogen;
• the compounds of the invention do not include the compounds described in S. Casteneda et al., Blood Cells, Molecules, and Diseases, 35 (2005) 217-226.
• alkyl includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
• straight-chain alkyl groups e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,
• alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
• a straight chain or branched chain alkyl has 6 or fewer carbon atoms in its backbone (e.g., C 1 -C 6 for straight chain, C 3 -C 6 for branched chain), and more preferably 4 or fewer.
• preferred cycloalkyls have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
• C 1 -C 6 includes alkyl groups containing 1 to 6 carbon atoms.
• alkyl includes both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
• substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sul
• Cycloalkyls can be further substituted, e.g., with the substituents described above.
• An “alkylaryl” or an “arylalkyl” moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
• the term “alkyl” also includes the side chains of natural and unnatural amino acids.
• aryl includes groups, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
• aryl includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxophenyl, quinoline, isoquinoline, naphthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine.
• aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles”, “heterocycles,” “heteroaryls” or “heteroaromatics”.
• the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and
• alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
• alkenyl includes straight-chain alkenyl groups (e.g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups.
• alkenyl includes straight-chain alkenyl groups (e.g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonen
• alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
• a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
• cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
• C 2 -C 6 includes alkenyl groups containing 2 to 6 carbon atoms.
• alkenyl includes both “unsubstituted alkenyls” and “substituted alkenyls”, the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
• substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
• alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
• alkynyl includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups.
• alkynyl further includes alkynyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
• a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
• the term C 2 -C 6 includes alkynyl groups containing 2 to 6 carbon atoms.
• alkynyl includes both “unsubstituted alkynyls” and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
• substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
• lower alkyl as used herein means an alkyl group, as defined above, but having from one to five carbon atoms in its backbone structure. “Lower alkenyl” and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms.
• acyl includes compounds and moieties which contain the acyl radical (CH 3 CO—) or a carbonyl group. It includes substituted acyl moieties.
• substituted acyl includes acyl groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including
• acylamino includes moieties wherein an acyl moiety is bonded to an amino group.
• the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
• aroyl includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.
• alkoxyalkyl examples include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.
• alkoxy includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom.
• alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups.
• substituted alkoxy groups include halogenated alkoxy groups.
• the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate
• amine or “amino” includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom.
• alkyl amino includes groups and compounds wherein the nitrogen is bound to at least one additional alkyl group.
• dialkyl amino includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups.
• arylamino and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively.
• alkylarylamino “alkylaminoaryl” or “arylaminoalkyl” refers to an amino group which is bound to at least one alkyl group and at least one aryl group.
• alkaminoalkyl or “alkyl aminoalkyl” refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group.
• amide or “aminocarbonyl” includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group.
• the term includes “alkaminocarbonyl” or “alkylaminocarbonyl” groups which include alkyl, alkenyl, aryl or alkynyl groups bound to an amino group bound to a carbonyl group. It includes arylaminocarbonyl groups which include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group.
• alkylaminocarbonyl alkenylaminocarbonyl
• alkynylaminocarbonyl arylaminocarbonyl
• alkylcarbonylamino alkenylcarbonylamino
• alkynylcarbonylamino alkynylcarbonylamino
• arylcarbonylamino alkylcarbonylamino
• Amides also include urea groups (aminocarbonylamino) and carbamates (oxycarbonylamino).
• carbonyl or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom.
• the carbonyl can be further substituted with any moiety which allows the compounds of the invention to perform its intended function.
• carbonyl moieties may be substituted with alkyls, alkenyls, alkynyls, aryls, alkoxy, aminos, etc.
• moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
• thiocarbonyl or “thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
• ether includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms.
• alkoxyalkyl which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.
• esters includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group.
• ester includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.
• alkyl, alkenyl, or alkynyl groups are as defined above.
• thioether includes compounds and moieties which contain a sulfur atom bonded to two different carbon or hetero atoms.
• Examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls.
• alkthioalkyls include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group.
• alkthioalkenyls and alkthioalkynyls refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.
• hydroxy or “hydroxyl” includes groups with an —OH or —O ⁇ .
• halogen includes fluorine, bromine, chlorine, iodine, etc.
• perhalogenated generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.
• polycyclyl or “polycyclic radical” refer to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are “fused rings”. Rings that are joined through non-adjacent atoms are termed “bridged” rings.
• Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl, arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkyl carbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and
• heteroatom includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
• ring means cycloalkyl or aryl as these terms are used and defined herein.
• prodrug moiety includes moieties which can be metabolized in vivo and moieties which may advantageously remain esterified or otherwise protected in vivo.
• the prodrugs moieties are metabolized in vivo by esterases or by other mechanisms to hydroxyl groups or other advantageous groups.
• Examples of prodrugs and their uses are well known in the art (See, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).
• the prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent.
• Hydroxyl groups can be converted into esters via treatment with a carboxylic acid.
• prodrug moieties include substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., propionoic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides,
• the structure of some of the compounds of this invention includes asymmetric carbon atoms, and thus may exist as racemic mixtures or as isolated isomeric forms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof.
• the present invention pertains, at least in part, to methods for treating a blood disorder in a subject by administering to the subject an effective amount of a compound of the invention (e.g., a compound of Formula I, II, III or otherwise described herein, including isolated enantiomers or diastereomers).
• a compound of the invention e.g., a compound of Formula I, II, III or otherwise described herein, including isolated enantiomers or diastereomers.
• treating includes curing as well as ameliorating at least one symptom of the state, disease or disorder, e.g., the blood disorder. Therefore, prevention of blood disorders or at least one symptom thereof is also contemplated herein.
• blood disorder includes disorders which can be treated, prevented, or otherwise ameliorated by the administration of a compound of the invention, e.g., a compound of formula I, II, III or otherwise described herein).
• a blood disorder is any disorder of the blood and blood-forming organs.
• the term blood disorder includes nutritional anemias (e.g., iron deficiency anemia, sideropenic dysphasia, Plummer-Vinson syndrome, vitamin B 12 deficiency anemia, vitamin B 12 deficiency anemia due to intrinsic factor, pernicious anemia, folate deficiency anemia, and other nutritional anemias), myelodysplastic syndrome, bone marrow failure or anemia resulting from chemotherapy, radiation or other agents or therapies, hemolytic anemias (e.g., anemia due to enzyme disorders, anemia due to phosphate dehydrogenase (G6PD) deficiency, favism, anemia due to disorders of glutathione metabolism, anemia due to disorders of glycolytic enzymes, anemias due to disorders of nucleotide metabolism and anemias due to unspecified enzyme disorder), thalassemia ⁇ -thalassemia, ⁇ -thalassemia, ⁇ -thalassemia, thalassemia trait, hereditary persistence of fetal
• the compounds of formula I, II, III or otherwise described herein stimulate fetal hemoglobin production, hematopoiesis, erythropoiesis, myelopoiesis and/or neutrophil production upon administration to a subject for the treatment of a blood disorder.
• the compounds of formula I, II, III or otherwise described are administered to the subject for treatment of a blood disorder in combination with one or more cytokines.
• the cytokine is selected from the group consisting of IL-3, GM-CSF, G-CSF, stem cell factor (SCF) and IL-6.
• one or more compounds of the invention may be administered alone to a subject, or more typically a compound of the invention will be administered as part of a pharmaceutical composition in mixture with conventional excipient, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, oral or other desired administration and which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof.
• conventional excipient i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, oral or other desired administration and which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof.
• the invention pertains, at least in part to a pharmaceutical composition of an effective amount of a compound of formula I, formula II, formula III, or and racemates, isolated enantiomers or diastereomers thereof, and a pharmaceutically acceptable carrier.
• pharmaceutically acceptable carrier includes substances capable of being coadministered with the compound(s) of the invention and which allow both to perform their intended function, e.g., treat or prevent a blood disorder.
• Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc.
• the pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds of the invention.
• auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds of the invention.
• the compounds of the invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
• the acids that may be used to prepare pharmaceutically acceptable acid addition salts of the compounds of the invention that are basic in nature are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulf
• salts must be pharmaceutically acceptable for administration to a subject, e.g., a mammal
• the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
• the preparation of other compounds of the invention not specifically described in the foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.
• the compounds of the invention that are acidic in nature are capable of forming a wide variety of base salts.
• the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of the invention that are acidic in nature are those that form non-toxic base salts with such compounds.
• Such non-toxic base salts include, but are not limited to those derived from such pharmaceutically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
• the pharmaceutically acceptable base addition salts of compounds of the invention that are acidic in nature may be formed with pharmaceutically acceptable cations by conventional methods.
• these salts may be readily prepared by treating the compound of the invention with an aqueous solution of the desired pharmaceutically acceptable cation and evaporating the resulting solution to dryness, preferably under reduced pressure.
• a lower alkyl alcohol solution of the compound of the invention may be mixed with an alkoxide of the desired metal and the solution subsequently evaporated to dryness.
• the compounds of the invention and pharmaceutically acceptable salts thereof can be administered via either the oral, parenteral or topical routes.
• these compounds are most desirably administered in effective dosages, depending upon the weight and condition of the subject being treated and the particular route of administration chosen. Variations may occur depending upon the species of the subject being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out.
• compositions of the invention may be administered alone or in combination with other known compositions for treating blood disorders in a subject, e.g., a mammal.
• Preferred mammals include cats, dogs, pigs, rats, mice, monkeys, chimpanzees, baboons and humans.
• the subject is suffering from a blood disorder.
• the subject is at risk of suffering from a blood disorder.
• composition of the invention in combination with a known composition is intended to include simultaneous administration of the composition of the invention and the known composition, administration of the composition of the invention first, followed by the known composition and administration of the known composition first, followed by the composition of the invention.
• Any of the therapeutically composition known in the art for treating blood disorders can be used in the methods of the invention.
• the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the routes previously mentioned, and the administration may be carried out in single or multiple doses.
• the novel therapeutic agents of this invention can be administered advantageously in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
• Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
• oral pharmaceutical compositions can be suitably sweetened and/or flavored.
• the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
• tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
• disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
• lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
• compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
• preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
• the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
• solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed.
• the aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic.
• These aqueous solutions are suitable for intravenous injection purposes.
• the oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
• suitable preparations include solutions, preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories.
• Therapeutic compounds may be formulated in sterile form in multiple or single dose formats such as being dispersed in a fluid carrier such as sterile physiological saline or 5% saline dextrose solutions commonly used with injectables.
• topical administration examples include transdermal, buccal or sublingual application.
• therapeutic compounds can be suitably admixed in a pharmacologically inert topical carrier such as a gel, an ointment, a lotion or a cream.
• topical carriers include water, glycerol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters, or mineral oils.
• topical carriers are liquid petrolatum, isopropylpalmitate, polyethylene glycol, ethanol 95%, polyoxyethylene monolauriate 5% in water, sodium lauryl sulfate 5% in water, and the like.
• materials such as anti-oxidants, humectants, viscosity stabilizers and the like also may be added if desired.
• tablets, dragees or capsules having talc and/or carbohydrate carrier binder or the like are particularly suitable, the carrier preferably being lactose and/or corn starch and/or potato starch.
• a syrup, elixir or the like can be used wherein a sweetened vehicle is employed.
• Sustained release compositions can be formulated including those wherein the active component is derivatized with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
• compounds of the invention for treatment can be administered to a subject in dosages used in prior therapies.
• a suitable effective dose of one or more compounds of the invention will be in the range of from 0.01 to 100 milligrams per kilogram of body weight of recipient per day, preferably in the range of from 0.1 to 50 milligrams per kilogram body weight of recipient per day, more preferably in the range of 1 to 20 milligrams per kilogram body weight of recipient per day.
• the desired dose is suitably administered once daily, or several sub-doses, e.g. 2 to 5 sub-doses, are administered at appropriate intervals through the day, or other appropriate schedule.
• the invention also pertains to the use of a compound of formula I, II, III or a compound otherwise described herein for the preparation of a medicament.
• the medicament may include a pharmaceutically acceptable carrier and the compound is an effective amount, e.g., an effective amount to treat a blood disorder.
• the pharmacophore was constructed with the TFIT module of the FLO molecular modeling software. It was assumed that the carboxylic acids would bind to the receptor in an analogous fashion, and therefore, the superposition of the carboxylic oxygens was biased by imposing a 5 kJ superimposition energy constraint. Five hundred iterations of TFIT were used in the calculations.
• TFIT produced an ensemble of low energy superimposition. The superimposition with the tightest overlay was taken to be the initial pharmacophore template. This pharmacophore was tested to see if it could distinguish between active and inactive compounds. TFIT was first used to determine the best match between the pharmacophore and four compounds which had been identified as inactive in the ⁇ / ⁇ -globin promoter driven reporter gene assay in previous studies.
• the TFIT was next used to determine how well five additional compounds, which were active in the ⁇ / ⁇ -globin promoter driven reporter gene assay would match the template.
• the template was used to design and select new compounds for testing. Compounds were selected from available compound data bases and evaluated by fitting them onto the template with TFIT.
• a “pseudo” receptor was constructed around the pharmacophore by refining the original pharmacophore template.
• a new template was constructed by adding two of the most active new compounds. The compounds were selected primarily for the additional structural information that they contained.
• the “pseudo” binding site was construction using FLO.
• This “pseudo” binding site was composed of functional groups selected to form hydrogen bonds with the ligands, and functional groups that would mimic the hydrophobic surface of the binding site.
• a guanidinium group was selected form hydrogen bonds with the acidic groups of the ligands.
• a pyrrole group was used to mimic the binding site hydrogen bond donors. These groups were positioned around the template molecules and anchored to the chemically complimentary ligand atoms with a 10 kJ constraint.
• the “pseudo” program of FLO automatically filled the remaining volume with propane to mimic the binding site's hydrophobic surface. This structure was next subject to several rounds of dynamics.
• the shell of propanes, the pyrrole group and the guanidinium groups represented the receptor binding site.
• the atoms of the binding site were allowed to move with a molecular mechanics force field and an additional flat well constraint [radius 0.5 ⁇ , quadratic penalty 20 kJ/ ⁇ 2 ] was imposed.
• FLO+ computed a predicted binding free energy using an empirical scoring function consisting of contact energy, hydrogen bonding energy, polar desolvation, bumping, internal energy and entropy.
• the predicted free energy (reported as pI or the ⁇ logK i ), fell between 6.6 and 6.9, with hydrogen bonding energies between 7.4 and 8.9 kJ/mol.
• the pI values for the four inactive compounds ranged from 5.6 to 6.2 with hydrogen bonding energies between 5.6 and 7.0 kJ/mol. A combination of the pI and the hydrogen bonding energy was used to distinguish between active and inactive compounds.
• Table 2 shows the results of the ⁇ / ⁇ -globin promoter driven reporter gene assay for the twenty-six compounds. ‘*’ indicates a 80-100% increase; ‘**’ indicates a 100%- #200% increase; and ‘***’ indicates an over 200% increase of ⁇ globin promoter induction over untreated controls.
• test compounds predicted to be active by reporter gene assays and molecular modeling produce a significant increase in fetal (gamma) globin mRNA in cells cultured in vitro. Furthermore, the concentrations required were significantly lower (5-40 micromolar) than concentrations required for prior generation inducers (100-200 micromolar), making these compounds more suitable for therapeutic and pharmacologic compositions
• ⁇ -globin mRNA was analyzed in control and treated erythroid colonies cultured from cord blood, by RT-PCR.
• the relative in vitro F-cell production was as follows: W>Y>R>M>P.
• the relative potency for F-cell production was as follows: R>M>Y>P>W.
• test compounds predicted to be active by reporter gene assays and molecular modeling produce a significant increase in numbers of erythroid and myeloid colonies or proportion of cells expressing fetal globin in in vitro cultured cells from a variety of sources under a variety of culture conditions. Similar to other in vitro tests described herein, the concentrations required for these biological effects were significantly lower (5-40 micromolar) than concentrations required for prior generation inducers (100-200 micromolar), making these compounds more suitable for therapeutic and pharmacologic compositions.
• Compounds predicted in the molecular model to be ⁇ -globin inducers were evaluated in a series of assays for activity in 1) stimulating activity from the fetal globin gene promoter, (the action which can ameliorate sickle cell disease and beta thalassemia), and 2) for any effects on stimulating erythroid or myeloid cell growth and proliferation, the action which can treat blood cell deficiencies.
• BFU-E Erythroid burst-forming units
• CFU-GM colony-forming units granulocyte-macrophage
• BFU-E cell proliferation was evaluated by enumeration in colonies developing in the presence of reduced amounts of erythropoietin (0.5 U/ml) rather than 3 U (or 3000 mU)/ml, which is standard for these experimental systems), from cord blood or the peripheral blood of several types of humans.
• Experiment 2 Erythroid colonies were cultured from patients with beta thalassemia, either without any test compounds (Control), only an optimal panel of hematopoietic growth factors, or with one of the test compounds M, P, T, 2-methyl-1-benzofuran-4-carboxylic acid, V, W, X, Y, AK, AC, or AI. All of the listed test compounds increased the number of colonies as compared to the matched control cultures that were grown with an optimal panel of growth factors alone. Colony numbers were increased above the control cultures (% BFU-E/Control) by anywhere from 25% to 230%. Each of the listed test compounds was tested in at least 5 different patients' blood and the differences were statistically signficant.
• BFU-E cultured from cord blood was tested with or without compound M, P, R, T, W, Y, Z, AI, F, or 3-(5-chlorothien-3-yl)acrylic acid.
• the test compounds all induced increased numbers of colonies as compared to the controls.
• the test compounds resulted in 50-250% more colonies than in control cultures from the same source.
• Experiment 3 Representative novel compounds M, W, X, Y, and AI also stimulated production of myeloid colonies compared to control, untreated myeloid colonies from the same individual. Control colonies were established in cultures with no added growth factors to support myelopoiesis, in Iscove's Modified Dulbecco's Media (IMDM) methylcellulose media with charcoal-absorbed fetal bovine serum, beta mercaptoethanol, BSA. A 30-75% increase in de novo myeloid colonies was observed in cord blood cultured with the novel compounds at the same concentrations as required for increases in erythroid colonies.
• IMDM Iscove's Modified Dulbecco's Media
• Erythroid cells were generated by culturing purified CD34+ cells in Flt-3 ligand, stem cell factor (SCF) and IL-3 for seven days followed by growth in EPO for 14 days.
• SCF stem cell factor
• IL-3 stem cell factor
• cells were cultured as above in a T75 flask then split into multiple flasks on day 8 and treatment with the test compounds was begun.
• Compound P or other test compounds were diluted from stock solutions with the microliter volumes of stock added to each culture flask for final working concentrations. Cells were enumerated every two days by hemacytometer count.
• RNA was harvested from 10 6 cells every two days using RNeasy Plus Mini Kit (Qiagen) and qRT-PCR performed using IQ SybrGreen Supermix on an Opticon Monitor instrument (MJ Research).
• QPCR primers were designed using known sequences for ⁇ -globin, ⁇ -globin, ⁇ -globin, ⁇ -actin and B3PD. Primers were designed to span at least one exon.
• Hemoglobin F protein levels increased in a compound P dose-dependent manner with a 19-fold increase in expression of fetal globin produced at 100 micromolar compound P as compared to untreated control cultures from the same subject with just one cycle of erythroid differentiation.
• test compounds M, P, 2-methyl-1-benzofuran-4-carboxylic acid, V, W, Y (racemic mixture) or AI resulted in an increase in numbers of erythroid colonies of at least 25% above control conditions.
• Compounds marked with a * are significantly different.
• 2-methyl-1-benzofuran-4-carboxylic acid and compound V require additional samples for statistical evaluation, but had positive effects in 3/3 different patients' cultures.
• experiments described in this example show that representative test compounds produce a significant increase in numbers of erythroid and myeloid colonies or proportion of cells expressing fetal globin in in vitro cultured cells derived from a variety of sources under culture conditions relevant to blood conditions including anemia, sickle cell anemia and beta thalassamia.
• Juvenile baboons were catheterized with venous and arterial catheters, and were phlebotomized a set amount of blood daily to maintain anemia with a hemoglobin level of 7.0-7.5 g/dl, from a baseline normal hemoglobin level of (12-13 g/dl). Normal saline was infused to replace the amount of blood withdrawn. This degree of phlebotomy exchanges the blood volume every 10-20 days.
• test compound was administered once/day, either intravenously or orally, and blood was withdrawn through the arterial catheter for analysis of globin mRNA or for analysis of the test compound in the plasma by HPLC-MS.
• Pharmacokinetic profiles were established from the plasma levels and oral bioavailability (comparing area under the curve between IV and oral plasma levels) was determined for the test compounds.
• compounds AK, Y and M were evaluated in a baboon and demonstrated significant increases in fetal globin expression at tolerable low doses. As shown in the previous Examples, these 3 compounds all stimulated erythroid cell proliferation in vitro and have favorable pharmacokinetic profiles after oral administration. The compounds were administered to an anemic baboon and studied for pharmacodynamic effects on induction of fetal globin, which is known to ameliorate the pathology of sickle cell anemia and beta thalassemia.
• baseline fetal globin mRNA was 26% of non-alpha globin.
• fetal globin mRNA increased to 48% of non-alpha globin, an 85% increase over the baseline level.
• Treatment with compound AK at 50 mg/kg induced a 51% fetal globin mRNA increase, a 96% increase over the baseline level.
• Compound M treatment at 40 mg/kg induced a 67% fetal globin mRNA increase, a 257% increase over the baseline level.
• the human equivalent dose is 20% of these doses, or 1 mg/kg, 10 mg/kg, or 8 mg/kg respectively.
• compound P was evaluated in a phlebotomized, anemic baboon showing no baseline expression of fetal globin and 100% of globin expression as beta globin. Treatment with compound P resulted in an induction of 7% fetal globin and a concomitant reduction in beta globin expression.
• This example demonstrates that compound W increases expression of human fetal globin mRNA expression and hematocrit in a transgenic mouse model.
• Compound W was administered to mice transgenic for the micro-LCR-201 gamma-globin gene promoter, by IP injection once/day for 5 days/week for 2 weeks, and gamma-globin mRNA was assayed by qPCR. Hematocrit was analyzed once per week. A significant difference in expression of human fetal globin mRNA and in hematocrit between Control and compound W-treated mice was found in initial experiments as summarized in Table 4 below.
• Cesium thiobenzoate To a solution of thiobenzoic acid (50.0 g, 361.8 mmol) in methanol (362 mL) was added Cs 2 CO 3 (130 g, 398 mmol) in portions over 5 min. The resulting mixture was stirred 10 min until all solids were dissolved. The resulting solution was concentrated on the rotovap. The solid residue was diluted with 500 mL of acetone and the white solid (CsHCO 3 ) was filtered off. This process was repeated two times to ensure all CsHCO 3 was removed. The acetone was then concentrated to afford cesium thiobenzoate (Strijtveen, B.; Kellogg, R. M. J. Org. Chem.
• (R)-2-Mercapto-3-methylbutanoic acid To a solution of (R)-2-benzoylthio-3-methylbutanoic acid (4.05 g, 17.0 mmol) in CH 2 Cl 2 (68 mL) was added 3 M aqueous NH 4 OH (68 mL). The mixture was stirred at rt for 3 h. The resulting solution was diluted with 2 M aqueous KOH (68 mL) and washed with CH 2 Cl 2 (6 ⁇ 70 mL) to remove the benzamide. The aqueous layer was then acidified to pH 2 with concentrated aqueous HCl and extracted with CH 2 Cl 2 (4 ⁇ 70 mL).
• (S)-2-Mercapto-3-methylbutanoic acid To a solution of (S)-2-benzoylthio-3-methylbutanoic acid (3.89 g, 16.3 mmol) in CH 2 Cl 2 (65 mL) was added 3 M aqueous NH 4 OH (65 mL). The mixture was stirred at rt for 3 h. The resulting solution was diluted with 2 M aqueous KOH (65 mL) and washed with CH 2 Cl 2 (6 ⁇ 65 mL) to remove the benzamide. The aqueous layer was then acidified to pH 2 with concentrated aqueous HCl and extracted with CH 2 Cl 2 (4 ⁇ 65 mL).
• Compound Y exists naturally in a racemic mixture, and has the highly favorable PK properties described above.
• the experiments described herein demonstrate that the S enantiomer of compound Y stimulates erythroid cell proliferation significantly, while the R enantiomer does not stimulate cell proliferation.
• the R enantiomer of compound Y has activity in stimulating fetal globin expression (see Table 3).
• the proliferative activity of compound Y-S enantiomer was tested in vitro in erythroid colonies cultured from peripheral blood of 3 sources of individuals: sickle cell anemia patients who were taking Hydroxyurea and have suppression of their endogenous erythropoiesis, a normal adult subject, and two cord blood samples.
• the cultures established in high EPO produced 25-45% (mean 35%) more colonies than the cultures established with the racemic mix in low EPO or the R enantiomer in low EPO.
• Addition of the S— enantiomer of compound Y at the same concentration resulted in a mean of 45% more erythroid colonies than in the racemic mixture (range 38-50%).
• the S enantiomer demonstrates the activity of stimulating proliferation of erythroid colonies in vitro.
• the erythroid kruppel-like factor, EKLF is an essential transcription factor for mammalian beta-like globin gene switch, and it specifically activates transcription of the adult beta-globin gene through binding of its zinc fingers to the promoter. It has been shown that transcription factor EKLF is required for activation of the gamma globin gene by the compounds described herein. EKLF was previously considered to activate primarily the beta (adult) globin gene. Transcription factor EKLF is actively recruited to the gamma-globin gene promoter by the compounds described herein.
• the human SWI/WNF complex is a ubiquitous multimeric complex that regulates gene expression by remodeling nucleosomal structure in an ATP-dependent manner.
• the SWI/SNF complex contains one of two core ATPases, BRG1 or BRM. These complexes can interact with sequence specific transcription factors to either promote or repress target gene activation, dependent on promoter context and complex content.
• the SWI/SNF complex chromatin-modifying core ATPase Brg1 is required for gamma globin induction by the compounds described herein.
• Brg1 the co-activator SWI/SNF complex chromatin-modifying ATPase, is actively recruited to the gamma-globin promoter by the compounds described herein, and this recruitment is dependent upon the presence of EKLF.

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