News Column

Patent Issued for Methods for Treating Blood Disorders

July 7, 2014



By a News Reporter-Staff News Editor at Clinical Trials Week -- According to news reporting originating from Alexandria, Virginia, by NewsRx journalists, a patent by the inventors Perrine, Susan P (Weston, MA); Bohacek, Regine (Boston, MA), filed on September 17, 2008, was published online on June 24, 2014 (see also Phoenicia Biosciences, Inc.).

The assignee for this patent, patent number 8759378, is Phoenicia Biosciences, Inc. (Weston, MA).

Reporters obtained the following quote from the background information supplied by the inventors: "The present invention relates to methods and compounds for the treatment of blood disorders.

"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, .beta.-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.sub.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 .beta.-thalassemia are two of the most common genetic disorders in the word. These disorders are caused by molecular mutations affecting the .beta.-globin genes for adult hemoglobin A (.alpha.2.beta.2), and it has been established that these disorders can be ameliorated by reactivating production of fetal hemoglobin (HbF, .alpha.2.gamma.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 .beta.-thalassemia, increases in fetal globin synthesis, which reduces the excess unbalanced .alpha.-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 .gamma.-globin in cultured erythroid cells, animal models and reporter gene assays, which test activity in activating the .gamma.-globin gene promoter. Several short chain fatty acids induce the .gamma.-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. However, the prototype short chain fatty acids have limitations as therapeutics. Arginine butyrate and phenylbutyrate require 100 .mu.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.

"While advances have been made in this field, there remains a need for new and/or improved methods for treating and preventing blood disorders generally as well as for compounds and pharmaceutical compositions for the same."

In addition to obtaining background information on this patent, NewsRx editors also obtained the inventors' summary information for this patent: "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:

"##STR00001##

"wherein

"R.sup.1 is hydroxy or alkoxy;

"X is C(O), C(S), SO, SO.sub.2 or PO.sub.2;

"R.sup.2 and R.sup.3 are each independently hydrogen, alkyl, halogen, hydroxyl, thiol, alkenyl, alkynyl, aryl, acyl, alkoxy, amino, alkylamino or heterocyclic;

"R.sup.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

"##STR00002##

"R.sup.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.sup.6 to form a ring;

"R.sup.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.sup.5 or R.sup.7 to form a ring;

"R.sup.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.sup.6 or R.sup.8 to form a ring;

"R.sup.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.sup.7 or R.sup.9 to form a ring;

"R.sup.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.sup.8 to form a ring;

"and racemates, isolated enantiomers or diastereomers, and pharmaceutically acceptable salts thereof;

"provided that when R.sup.4 is

"##STR00003## R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are each not hydrogen; and when R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are each hydrogen, R.sup.5 is not methoxy; and when R.sup.5, R.sup.7, R.sup.8, R.sup.9 are hydrogen, R.sup.6 is not methoxy; and when R.sup.5, R.sup.8 and R.sup.9 are hydrogen, R.sup.6 and R.sup.7 are not methoxy.

"In another embodiment, 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:

"##STR00004##

"Wherein

"R.sup.1' is hydroxy or alkoxy;

"Y is C(O);

"n is 0 or an integer from 1 to 5;

"R.sup.10 and R.sup.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.sup.11 is CR.sup.11'R.sup.11''R.sup.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

"##STR00005##

"R.sup.11' and R.sup.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.sup.11' and R.sup.11'' are optionally joined to form a ring;

"R.sup.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.sup.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.sup.13 to form a ring;

"R.sup.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.sup.12 or R.sup.14 to form a ring;

"R.sup.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.sup.13 or R.sup.15 to form a ring;

"R.sup.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.sup.14 or R.sup.16 to form a ring;

"R.sup.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.sup.15 to form a ring;

"and racemates, isolated enantiomers or diastereomers, and pharmaceutically acceptable salts thereof;

"provided that when R.sup.11 is

"##STR00006## R.sup.12, R.sup.13, R.sup.14, R.sup.15, and R.sup.16 are each not hydrogen; and provided when n is 2, R.sup.11 is

"##STR00007## and R.sup.10, R.sup.10', R.sup.12, R.sup.15, and R.sup.16 are hydrogen, then R.sup.14 and R.sup.15 are not methoxy; and provided when n is 1, R.sup.11 is

"##STR00008## and R.sup.10, R.sup.10', R.sup.13, R.sup.14, and R.sup.16 are hydrogen, then R.sup.12 and R.sup.15 are not methoxy.

"In yet another embodiment, 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:

"##STR00009##

"Wherein

"R.sup.1'' is hydroxy or alkoxy;

"Z is C(S), SO, SO.sub.2 or PO.sub.2;

"m is 0 or an integer from 1-5;

"R.sup.17 and R.sup.17' are each independently hydrogen, alkyl, halogen, hydroxyl, thiol, alkenyl, alkynyl, aryl, acyl, alkoxy, amino, alkylamino or heterocyclic;

"R.sup.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;

"and racemates, isolated enantiomers or diastereomers, and pharmaceutically acceptable salts thereof.

"In another embodiment, 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:

"##STR00010##

"In one embodiment, 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

"##STR00011## and a pharmaceutically acceptable carrier.

"In another embodiment, 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."

For more information, see this patent: Perrine, Susan P; Bohacek, Regine. Methods for Treating Blood Disorders. U.S. Patent Number 8759378, filed September 17, 2008, and published online on June 24, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8759378.PN.&OS=PN/8759378RS=PN/8759378

Keywords for this news article include: Gases, Arginine, Elements, Genetics, Hydrogen, Butyrates, Hemolytic, Blood Cells, Hemeproteins, beta-Globins, Butyric Acids, gamma-Globins, Blood Proteins, Carboxylic Acids, beta-Thalassemia, Basic Amino Acids, Hemoglobinopathies, Diamino Amino Acids, Inorganic Chemicals, Hematologic Diseases, Essential Amino Acids.

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Source: Clinical Trials Week


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