WO2015116061A1 - Produits d'addition 1:1 d'hémoglobine s - Google Patents

Produits d'addition 1:1 d'hémoglobine s Download PDF

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Publication number
WO2015116061A1
WO2015116061A1 PCT/US2014/013575 US2014013575W WO2015116061A1 WO 2015116061 A1 WO2015116061 A1 WO 2015116061A1 US 2014013575 W US2014013575 W US 2014013575W WO 2015116061 A1 WO2015116061 A1 WO 2015116061A1
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alkyl
hydrogen
compound
hbs
formula
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PCT/US2014/013575
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English (en)
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Brian W. Metcalf
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Global Blood Therapeutics, Inc.
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Priority to PCT/US2014/013575 priority Critical patent/WO2015116061A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • This invention provides 1 : 1 adducts, of sickle hemoglobin (HbS) and a compound of formula (I), as defined herein, suitable as modulators of HbS, and methods for their use in treating disorders mediated by HbS as well as disorders that would benefit from tissue and/or cellular oxygenation.
  • HbS sickle hemoglobin
  • I formula (I)
  • Sickle cell disease is a disorder of the red blood cells, found particularly among those of African and Mediterranean descent.
  • the basis for sickle cell disease is found in sickle hemoglobin (HbS), which contains a point mutation relative to the prevalent peptide sequence of hemoglobin (Hb).
  • Hemoglobin transports oxygen molecules from the lungs to various tissues and organs throughout the body. Hemoglobin binds and releases oxygen through
  • Sickle hemoglobin contains a point mutation where glutamic acid is replaced with valine, allowing HbS to become susceptible to polymerization to give the HbS containing red blood cells their characteristic sickle shape.
  • the sickled cells are also more rigid than normal red blood cells, and their lack of flexibility can lead to blockage of blood vessels.
  • Some five-membered aldehydes including furfural (FUF) and 5-hydroxymethyl-2- furfural (5HMF), have been shown to increase the oxygen affinity of HbS and inhibit the sickling of homozygous sickle red blood (SS) cells. It has been reported that these aldehydes, such as FUF and 5HMF, act by forming Schiff bases with HbS. Specifically, two molecules of FUF or 5HMF bind to each HbS protein by forming two Schiff base adducts, in a symmetry-related fashion, at the R-cleft at the two N-terminal RVall residues of the HbS protein. See e.g., M. K. Safo et al, J. Med. Chem.
  • HbS adducts with HbS protein are generally administered at doses that are unacceptably high and potentially toxic.
  • This invention relates generally to 1 : 1 adducts comprising sickle hemoglobin (HbS) and a compound of formula (I), as described below.
  • the 1 : 1 adducts are more suitable than 2:1 adducts as allosteric modulators of hemoglobin because the compounds of formula (I) can be administered at effective doses that are lower and potentially safer than doses of compounds that form 2: 1 adducts with HbS.
  • HbS sickle hemoglobin
  • binding of the compound of formula (I) to HbS may be reversible or irreversible. When binding is reversible, each compound of formula (I) generally forms reversible 1 : 1 adducts with multiple HbS proteins. When binding is irreversible, each compound of formula (I) generally forms irreversible 1 : 1 adducts with a single HbS protein.
  • this invention relates to methods for dosing a subject and treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation, where the methods are predicted on the formation of a 1 : 1 adduct comprising sickle hemoglobin (HbS) and a compound of formula (I).
  • HbS sickle hemoglobin
  • X is CH 2 or O
  • Y is CH 2 or O
  • A is:
  • R is hydrogen or C 1 -C 6 alkyl
  • R 1 is hydrogen, C 1 -C 6 alkyl optionally substituted with 3-6 fluoro atoms or with -
  • R 2 is hydrogen or C 1 -C 6 alkyl
  • R 2a is hydrogen or C 1 -C 6 alkyl
  • R 3 is C 1 -C 6 alkyl
  • each R 4 independently is hydrogen or C 1 -C 6 alkyl
  • each R 5 independently is hydrogen or C 1 -C 6 alkyl, or both R 5 are Ci alkyl joined to form a -CH2CH2- moiety that combines with the carbon and oxygen atoms to which they are joined to form a five-membered heterocyclic ring;
  • n 0, 1, 2, 3 or 4;
  • Z is CH or N
  • R 6 is hydrogen or C 1 -C 6 alkyl
  • R 7 is hydrogen, C 1 -C 6 alkyl; OH, or O-C 1 -C 6 alkyl, optionally substituted with a 5- to 6-membered heterocycle containing at least 1 oxygen and/or nitrogen moiety;
  • R 8 is hydrogen, C 1 -C 6 alkyl; OH, or O-C 1 -C 6 alkyl;
  • R 9 is hydrogen, C 1 -C 6 alkyl; OH, or O-C 1 -C 6 alkyl;
  • R 10 is hydrogen, C 1 -C 6 alkyl; OH, or O-C 1 -C 6 alkyl;
  • R 11 is hydrogen, C 1 -C 6 alkyl or N(R 13 ) 2 ;
  • R 12 is hydrogen or C 1 -C 6 alkyl
  • each R 13 independently is hydrogen or C 1 -C 6 alkyl.
  • the 1 :1 adduct is formed in the presence of excess compound of formula (I) that is not bound to HbS. Formation of the conformationally stable 1 : 1 adduct is
  • a method is provided of forming a 1 : 1 adduct of sickle hemoglobin (HbS) and a compound of formula (I), as claimed in any one of claims 1-5, comprising contacting the HbS with the compound of formula (I) under conditions wherein said adduct is formed.
  • a method for inhibiting sickling of HbS in a patient comprises administering to said patient a sufficient amount of a composition comprising a compound of formula (I) so as to form in vivo a 1 : 1 adduct with HbS thereby inhibiting sickling of HbS.
  • a method for increasing oxygen affinity of sickle hemoglobin (HbS) comprising contacting the HbS with a compound of formula (I), as claimed in any one of claims 1-5, to convert at a part to substantially all of the HbS to form a 1 : 1 adduct with the compound of formula (I) and allowing that adduct to bind to oxygen.
  • HbS sickle hemoglobin
  • Figure 1 depicts the ESI-MS spectrum of human hemoglobin S.
  • Figure 2 depicts absorption spectra for four ligand states of human adult hemoglobin A.
  • FIG. 3 A illustrates "COHbS crystal clusters" and 3B illustrates "large COHbS monocrystals" as described in the Examples below.
  • Figure 4 illustrates "secondary COHbS protein crystals" incubated in the presence of glycerol, as described in the Examples below.
  • compositions and methods are intended to mean that the compositions and methods include the recited elements, but not excluding others.
  • Consisting essentially of when used to define compositions and methods shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition or process consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
  • C m -C n such as C 1 -C 12 , C 1 -C 8 , or C 1 -C 6 when used before a group refers to that group containing m to n carbon atoms.
  • alkoxy refers to -0-alkyl
  • alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 12 carbon atoms (i.e., C ⁇ -Cn alkyl) or 1 to 8 carbon atoms ⁇ i.e., C ⁇ -C % alkyl), or 1 to 4 carbon atoms.
  • This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), H-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl
  • aryl refers to a monovalent, aromatic mono- or bicyclic ring having 6-10 ring carbon atoms. Examples of aryl include phenyl and naphthyl. The condensed ring may or may not be aromatic provided that the point of attachment is at an aromatic carbon atom. For example, and without limitation, the following is an aryl group:
  • -CO 2 H ester refers to an ester formed between the -CO2H group and an alcohol, preferably an aliphatic alcohol.
  • chiral moiety refers to a moiety that is chiral. Such a moiety can possess one or more asymmetric centers. Preferably, the chiral moiety is enantiomerically enriched, and more preferably a single enantiomer.
  • Non limiting examples of chiral moieties include chiral carboxylic acids, chiral amines, chiral amino acids, such as the naturally occurring amino acids, chiral alcohols including chiral steroids, and the likes.
  • cycloalkyl refers to a monovalent, preferably saturated, hydrocarbyl mono-, bi-, or tricyclic ring having 3-12 ring carbon atoms. While cycloalkyl, refers preferably to saturated hydrocarbyl rings, as used herein, it also includes rings containing 1-2 carbon-carbon double bonds. Nonlimiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamentyl, and the like. The condensed rings may or may not be non-aromatic hydrocarbyl rings provided that the point of attachment is at a cycloalkyl carbon atom. For example, and without limitation, the following is a cycloalkyl group:
  • halo refers to F, CI, Br, and/or I.
  • heteroaryl refers to a monovalent, aromatic mono-, bi-, or tricyclic ring having 2-16 ring carbon atoms and 1-8 ring heteroatoms selected preferably from N, O, S, and P and oxidized forms of N, S, and P, provided that the ring contains at least 5 ring atoms.
  • Nonlimiting examples of heteroaryl include furan, imidazole, oxadiazole, oxazole, pyridine, quinoline, and the like.
  • the condensed rings may or may not be a heteroatom containing aromatic ring provided that the point of attachment is a heteroaryl atom.
  • heterocyclyl refers to a non-aromatic, mono-, bi-, or tricyclic ring containing 2-12 ring carbon atoms and 1-8 ring heteroatoms selected preferably from N, O, S, and P and oxidized forms of N, S, and P, provided that the ring contains at least 3 ring atoms. While heterocyclyl preferably refers to saturated ring systems, it also includes ring systems containing 1-3 double bonds, provided that they ring is non-aromatic.
  • heterocyclyl examples include, azalactones, oxazoline, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, and tetrahydropyranyl.
  • the condensed rings may or may not contain a non-aromatic heteroatom containing ring provided that the point of attachment is a heterocyclyl group.
  • the following is a heterocyclyl group:
  • the term "optionally substituted” refers to a substituted or unsubstituted group.
  • the group may be substituted with one or more substituents, such as e.g., 1, 2, 3, 4 or 5 substituents.
  • the substituents are selected from the group consisting of chloro, fluoro, -OCH 3 , methyl, ethyl, iso-propyl, cyclopropyl, vinyl, ethynyl, -CO 2 H, -CO 2 CH 3 , -OCF 3 , -CF 3 and - OCHF 2 .
  • the term "adduct" refers to a composition formed between a compound and hemoglobin, preferably HbS, which is characterized and/or observed by physico chemical methods, and/or isolated. Such a composition can involve non-covalent interactions and/or covalent bond formation between HbS and the compound participating in the adduct. The adducts can form reversibly or irreversibly.
  • R 101 and R 102 independently is hydrogen; Ci-C 8 alkyl, optionally substituted with -
  • each R 103 independently is hydrogen or C 1 -C 8 alkyl; C 3 -C 12 cycloalkyl; C 3 -C 10 heterocyclyl; C 6 -C 12 aryl; or C2- 2 heteroaryl; wherein each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 alkyl groups or 1-3 halo groups, or R 101 and R 102 together with the nitrogen atom they are attached to form a 5-7 membered heterocycle.
  • pharmaceutically acceptable refers to safe and non-toxic for in vivo, preferably, human administration.
  • pharmaceutically acceptable salt refers to a salt that is pharmaceutically acceptable.
  • salt refers to an ionic compound formed between an acid and a base.
  • salts include, without limitation, alkali metal, alkaline earth metal, and ammonium salts.
  • ammonium salts include, salts containing protonated nitrogen bases and alkylated nitrogen bases.
  • Exemplary, and non-limiting cations useful in pharmaceutically acceptable salts include Na, K, Rb, Cs, NH 4 , Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids.
  • salts include, without limitation, salts of organic acids, such as carboxylic acids and sulfonic acids, and mineral acids, such as hydrogen halides, sulfuric acid, phosphoric acid, and the likes.
  • exemplary and non-limiting anions useful in pharmaceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisalfate, mono-, di-, and tribasic phosphate, mesylate, tosylate, and the likes.
  • treat include alleviating, abating or ameliorating a disease or condition or one or more symptoms thereof, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g. , arresting or suppressing the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or suppressing the symptoms of the disease or condition, and are intended to include prophylaxis.
  • the terms also include relieving the disease or conditions, e.g., causing the regression of clinical symptoms.
  • the terms further include achieving a therapeutic benefit and/or a prophylactic benefit.
  • compositions are administered to an individual at risk of developing a particular disease, or to an individual reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
  • preventing refers to a reduction in risk of acquiring a disease or disorder (i.e. , causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).
  • the terms further include causing the clinical symptoms not to develop, for example in a subject at risk of suffering from such a disease or disorder, thereby substantially averting onset of the disease or disorder.
  • an effective amount refers to an amount that is effective for the treatment of a condition or disorder by an intranasal administration of a compound or composition described herein.
  • an effective amount of any of the compositions or dosage forms described herein is the amount used to treat a disorder mediated by hemoglobin or a disorder that would benefit from tissue and/or cellular oxygenation of any of the compositions or dosage forms described herein to a subject in need thereof.
  • an effective amount of the compound utilized herein is contacted with HbS.
  • carrier refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells, e.g., red blood cells, or tissues.
  • carrier refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells, e.g., red blood cells, or tissues.
  • X is CH 2 or O
  • Y is CH 2 or O
  • A is:
  • R is hydrogen or C 1 -C 6 alkyl
  • R 1 is hydrogen, C 1 -C 6 alkyl optionally substituted with 3-6 fluoro atoms or with -
  • R 2 is hydrogen or C 1 -C 6 alkyl
  • R 2a is hydrogen or C 1 -C 6 alkyl
  • R 3 is C 1 -C 6 alkyl
  • each R 4 independently is hydrogen or C 1 -C 6 alkyl
  • each R 5 independently is hydrogen or C 1 -C 6 alkyl, or both R 5 are Ci alkyl joined to form a -CH 2 CH 2 - moiety that combines with the carbon and oxygen atoms to which they are joined to form a five-membered heterocyclic ring;
  • Z is CH or N
  • R 6 is hydrogen or C 1 -C 6 alkyl
  • R 7 is hydrogen, C 1 -C 6 alkyl; OH, or O-C 1 -C 6 alkyl, optionally substituted with a 5- to 6-membered heterocycle containing at least 1 oxygen and/or nitrogen moiety;
  • R 8 is hydrogen, C 1 -C 6 alkyl; OH, or O-C 1 -C 6 alkyl;
  • R 9 is hydrogen, C 1 -C 6 alkyl; OH, or O-C 1 -C 6 alkyl;
  • R 10 is hydrogen, C 1 -C 6 alkyl; OH, or O-C 1 -C 6 alkyl;
  • R" is hydrogen, C 1 -C 6 alkyl or N(R 13 ) 2 ;
  • R 12 is hydrogen or C 1 -C 6 alkyl
  • each R 13 independently is hydrogen or C 1 -C 6 alkyl.
  • X is CH and Y is O. In some embodiments, X is O and Y is CH 2 .
  • R 1 may be hydrogen.
  • R 1 may be C 1 -C 6 alkyl, such as methyl, ethyl, n- propyl, iso-propyl or butyl.
  • R 1 may be C 1 -C 6 alkyl substituted with 3-6 fluoro atoms, such as -CH2CHF2, -CH2CF 3 , or -CH2CH2CF 3 .
  • R' may be -CO 2 R 2a , such as -CH 2 CO 2 H.
  • R 2 may be hydrogen.
  • R 2 may be C 1 -C 6 alkyl such as methyl, ethyl, n-propyl, iso-propyl or butyl.
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • Substituent R 3 may be C 1 -C 6 alkyl, such as methyl, ethyl, n-propyl, iso-propyl or butyl.
  • the variable m may be 0, 1 , 2, 3 or 4.
  • A is N-(2-aminoe[0044] n-[0044] n-[0044] n-[0044] n-[0044] n-[0044] n-[0044] n-[0044] n-[0044] n-[0044] n-[0044] n-[0044] n-[0044] n-[0044] n-[0044]
  • Substituent R may be hydrogen.
  • R may be C1 -C alkyl, such as methyl, ethyl, «-propyl, iso-propyl or butyl.
  • Each R 4 independently may be hydrogen.
  • each R 4 independently may be C 1 -C 6 alkyl, such as methyl, ethyl, n- propyl, iso-propyl or butyl.
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-[0046]
  • Each R 5 for example, may be hydrogen.
  • R 5 may be C 1 -C 6 alkyl, such as methyl, ethyl, n-propyl, iso-propyl or butyl.
  • both R 5 are Ci alkyl joined to form a - CH2CH2- moiety that combines with the carbon and oxygen atoms to which they are joined to
  • B is
  • Z is CH. In some embodiments, Z is N.
  • B is [0051] In some embodiments, B is
  • B is
  • R 6 is hydrogen. In some embodiments, R 6 is C 1 -C 6 alkyl such as methyl, ethyl, n-propyl, iso-propyl or butyl.
  • ring C is
  • R 7 is hydrogen. In some embodiments, R 7 is C 1 -C 6 alkyl such as methyl, ethyl, n-propyl, iso-propyl or butyl. In some embodiments, R 7 is OH. In some embodiments, R 7 is O-C 1 -C 6 alkyl such as OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCHCH 3 CH 3 or O-butyl, optionally substituted with a 5- to 6-membered heterocycle containing at least 1 oxygen and/or nitrogen moiety. In some preferred embodiments, R 7 is
  • R 7 is [0056] In some embodiments, ring C is
  • R is hydrogen.
  • R is C 1 -C 6 alkyl such as methyl, ethyl, n-propyl, iso-propyl or butyl.
  • R 8 is OH.
  • R 8 is O-C 1 -C 6 alkyl such as OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCHCH 3 CH 3 or O-butyl, optionally substituted with a 5- to 6-membered heterocycle containing at least 1 oxygen and or nitrogen moiety.
  • R 8 is OCH 3 .
  • ring C is
  • R 9 is hydrogen. In some embodiments, R 9 is Ct-Ce alkyl such as methyl, ethyl, n-propyl, iso-propyl or butyl. In some embodiments, R 9 is OH. In some embodiments, R 9 is O-C 1 -C 6 alkyl such as OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCHCH 3 CH 3 or O-butyl, optionally substituted. In some preferred embodiments, R 9 is OCH 3 .
  • R 10 is hydrogen. In some embodiments, R 10 is C 1 -C 6 alkyl such as methyl, ethyl, n-propyl, io-propyl or butyl. In some preferred embodiments, R 10 is OH. In some embodiments, R 8 is O-C 1 -C 6 alkyl such as OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCHCH 3 CH 3 or O-butyl, optionally substituted. In some preferred embodiments, R 10 is OCH 3 . [0061] In some embodiments, ring C is
  • R 11 is hydrogen. In some embodiments, R 11 is C 1 -C 6 alkyl such as methyl, ethyl, n-propyl , iso-propyl or butyl. In some embodiments, R 1 ' is NH 2 . In some embodiments, R 11 is ⁇ e 2 . In some embodiments, R 13 is hydrogen. In some embodiments, R 13 is C 1 -C 6 alkyl such as methyl, ethyl, n-propyl, iso-propyl or butyl.
  • ring C is
  • R 12 is hydrogen. In some embodiments, R 12 is C 1 -C 6 alkyl such as methyl, ethyl, n-propyl, iso-propyl or butyl.
  • R is hydrogen
  • R 1 is methyl, ethyl, iso-propyl, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CF 3 , or -CH 2 CO 2 H;
  • R 2 is methyl or hydrogen
  • R 3 is methyl and m is 1 ;
  • R 4 is methyl
  • both R 5 are joined to form a -CH 2 CH 2 - moiety
  • R 7 is OCH 3 , OH, or
  • R 8 is methyl
  • R 9 is hydrogen
  • R 10 is hydrogen or OH;
  • R 11 is NH 2 ;
  • R 12 is hydrogen
  • R 1 may be hydrogen.
  • R 1 may be C 1 -C 6 alkyl, such as methyl, ethyl, n-propyl, iso-propyl or butyl.
  • R 1 may be CpCe alkyl substituted with 3-6 fluoro atoms, such as -CH 2 CHF 2 , -CH 2 CF 3 , or -CH 2 CH 2 CF 3 .
  • R 1 may be -CO 2 R 2a , such as -CH2CO2H.
  • R 2 may be hydrogen.
  • R 2 may be C 1 -C 6 alkyl such as methyl, ethyl, n-propyl, io-propyl or butyl.
  • R 7 is hydrogen. In some embodiments, R 7 is C 1 -C 6 alkyl such as methyl, ethyl, n-propyl, iso-propyl or butyl. In some embodiments, R 7 is OH. In some embodiments, R 7 is O-C 1 -C 6 alkyl such as OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCHCH 3 CH 3 or O-butyl, optionally substituted with a 5- to 6-membered heterocycle containing at least 1 oxygen and/or nitrogen moiety. In some preferred embodiments, R 7 is
  • R 7 is
  • the compound of formula (I) is of formula (III):
  • R l may be hydrogen.
  • R 1 may be C 1 -C 3 ⁇ 4 alkyl, such as methyl, ethyl, n-propyl, io-propyl or butyl.
  • R 1 may be C 1 -C 6 alkyl substituted with 3-6 fluoro atoms, such as -CH 2 CHF 2> -CH 2 CF 3 , or -CH 2 CH 2 CF 3 .
  • R 1 may be -CO 2 R 2a , such as -CH 2 CO 2 H.
  • R 2 may be hydrogen.
  • R 2 may be Q-Ce alkyl such as methyl, ethyl, n-propyl, io-propyl or butyl.
  • R 8 is hydrogen. In some embodiments, R 8 is Ci-C$ alkyl such as methyl, ethyl, n-propyl, io-propyl or butyl. In some embodiments, R 8 is OH. In some embodiments, R 8 is O-C 1 -C 6 alkyl such as OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 ,
  • R 8 is OCH 3 .
  • the compound of formula (I) is of formula
  • R 1 may be hydrogen.
  • R 1 may be Ci-Cg alkyl, such as methyl, ethyl, «-propyl, io-propyl or butyl.
  • R 1 may be C 1 -C 6 alkyl substituted with 3-6 fluoro atoms, such as -CH 2 CHF 2 , -CH 2 CF 3 , or -CH 2 CH 2 CF 3 .
  • R 1 may be -CC ⁇ R 28 , such as -CH2CO2H.
  • R 2 may be hydrogen.
  • R 2 may be C]-C & alkyl such as methyl, ethyl, n-propyl, io-propyl or butyl.
  • R 10 is hydrogen. In some embodiments, R 10 is C 1 -C 6 alkyl such as methyl, ethyl, n-propyl, io-propyl or butyl. In some preferred embodiments, R 10 is OH. In some embodiments, R 8 is O-C 1 -C 6 alkyl such as OCH 3 , OCH 2 CH 3 . OCH 2 CH 2 CH 3 , OCHCH 3 CH 3 or O-butyl, optionally substituted. In some preferred embodiments, R 10 is OCH 3 . i0075J m omer embodiments of the 1 : 1 adduct, the compound of formula (I) is selected from the group in Table 1 consisting of:
  • any of the 1 : 1 adducts described herein is formed in a subject in vivo and isolated from the subject.
  • a 1 : 1 adduct of sickle hemoglobin (H S) and a compound of formula (I) is provided by administering the compound of formula (I) to a subject.
  • the compound of formula (I) is provided to the subject as a pharmaceutical composition comprising any of the compounds described herein, and at least a pharmaceutically acceptable excipient.
  • compositions suitable for oral delivery can be formulated for different routes of administration.
  • routes suitable for oral delivery include transdermal, intravenous, intraarterial, pulmonary, rectal, nasal, vaginal, lingual, intramuscular, intraperitoneal, intracutaneous, intracranial, and subcutaneous routes.
  • Suitable dosage forms for administering any of the compounds described herein include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. Sustained release dosage forms may also be used, for example, in a transdermal patch form. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16 th ed., A. Oslo editor, Easton Pa. 1980).
  • compositions in accordance with the invention are prepared by conventional means using methods known in the art.
  • compositions disclosed herein may be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1 ,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerin and the like.
  • Solid pharmaceutical excipients include starch, cellulose, hydroxypropyl cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • the compositions provided herein comprises one or more of a-tocopherol, gum arabic, and or hydroxypropyl cellulose.
  • the compounds and pharmaceutical compositions described herein may be used alone or in combination with other compounds.
  • the co-administration can be in any manner in which the pharmacological effects of both are manifest in the patient at the same time.
  • co-administration does not require that a single pharmaceutical composition, the same dosage form, or even the same route of administration be used for administration of both the compound of this invention and the other agent or that the two agents be administered at precisely the same time.
  • coadministration will be accomplished most conveniently by the same dosage form and the same route of administration, at substantially the same time. Obviously, such administration most advantageously proceeds by delivering both active ingredients simultaneously in a novel pharmaceutical composition in accordance with the present invention.
  • a method for dosing a subject with a compound of formula (I), comprising administering an effective dosage of the compound of formula (I), wherein the effective dosage is predicated on the formation of a 1 :1 adduct between the compound of formula (I) and sickle hemoglobin (HbS) in the subject, rather than being predicated on the formation of a 2: 1 adduct between the compound of formula (I) and HbS in the subject.
  • the method for dosing a subject based on on the formation of the 1 : 1 adduct is safer than methods for dosing based on of the 2: 1 adduct
  • a method is provided of forming a 1 : 1 adduct of sickle hemoglobin (HbS) and a compound of formula (I), as claimed in any one of claims 1 -5, comprising contacting the HbS with the compound of formula (I).
  • a method for increasing oxygen affinity of sickle hemoglobin (HbS) comprising contacting the HbS with a compound of formula (I), as claimed in any one of claims 1-5, to convert at a part to substantially all of the HbS to form a 1 : 1 adduct with the compound of formula (I).
  • the reactions are preferably carried out in a suitable inert solvent that will be apparent to the skilled artisan upon reading this disclosure, for a sufficient period of time to ensure substantial completion of the reaction as observed by thin layer chromatography, ⁇ - NMR, etc. If needed to speed up the reaction, the reaction mixture can be heated, as is well known to the skilled artisan.
  • the final and the intermediate compounds are purified, if necessary, by various art known methods such as crystallization, precipitation, column chromatography, and the likes, as will be apparent to the skilled artisan upon reading this disclosure.
  • Ph 3 PBr 2 s Triphenylphosphine dibromide
  • DIAD Diisopropyl azodicarboxylate
  • the ice cooling bath was allowed to expire over 90 min and the mixture was stirred at RT for 2-48 hours.
  • the mixture was stirred for 10 min, then filtered through a pad of silica.
  • the silica was washed with ethyl acetate 2-20mL.
  • the combined filtrates were evaporated and the residue was dried on highvac.
  • the residue was purified by preparative HPLC or flash silica gel chromatography.
  • Example 2 Preparation of 2-(2-morpholin-4-ylethoxy)-5-[[2-(2-propan-2-ylpyrazol-3- yl)pyridin-3-yl]methoxy
  • Stepl To a 500-mL flask containing the pyrazole boronate (9.0g, 38. lmmol), 2- chloropyridine (5.47g, 38. lmmol), Pd(dppf)Cl2 ([l,l-bis(diphenylphosptono)ferrocene] dichloropalladium) (1.39g, 1.91mmol, 5%mol), and sodium bicarbonate (9.61g, 1 14.4mmol, 3 equiv) was added 100 mL of dioxane and 30 mL of water. The mixture was heated under nitrogen at 100 °C for 12 hrs. Then solvents were removed on a rotavap at 40 oC
  • Step2 To a solution of (2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methanol) (440mg, 2.02mmol) in DCM (4 mL) was added SOCl 2 (2eq) at 0 °C. The reaction mixture was stirred at RT for 1 mins and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give 3-(chloromethyl)-2-(l-isopropyI-lH-pyrazol-5-yl)pyridine hydrochloride (432 mg) as an off-white solid, which was used for next step without further purification.
  • the pH of the aqueous phase was adjusted again to ⁇ 8 with sodium bicarbonate solution and extracted with ethyl acetate (1 x 50 ml).
  • the combined organic phases were washed with an aqueous 10% citric acid solution (80 ml), water (50 ml) and an aqueous saturated sodium chloride solution (50 ml).
  • the extractions were then dried over sodium sulfate, concentrated and purified by silica gel chromatography (10 - 100% ethyl acetate/hexanes) to give 6-hydroxy-l H-indazole-7-carbaldehyde (0.4 g, 33%) as an orange solid.
  • the reaction mixture was then cooled, and ethyl acetate (100 ml) and water (50 ml) were added.
  • the phases were separated and the aqueous phase was extracted with more ethyl acetate (2 x 50 ml).
  • the combined organic phases were washed with water (50 ml) and aqueous saturated sodium chloride solution (50 ml), and dried over sodium sulfate. After concentration the residue was purified by silica gel chromatography (5 - 70% ethyl acetate/hexanes).
  • Step 1 To a solution of ethyl 5-(l -isopropyl-lH-pyrazol-5-yl)-3,6-dihydro-2H- pyran-4-carboxylate (100 mg, 0.38 mmol) in EtOH (2 mL) was added Pd C (50 mg), then it was charged with 3 ⁇ 4 (latm) and stirred at room temperature for 3 days, Mass spec shows about 50% conversion.
  • Step 3 To a solution of ( ⁇ ) ((3S, 4R)-3-(l-isopropyl-lH-pyrazol-5-yl)tetrahydro- 2H-pyran-4-yl)methanol (50 mg, 0.22 mmol) and 2,6-dihydroxybenzaldehyde (60 mg, 0.44 mmol)in THF (1 mL) was added PPh 3 (120 mg, 0.44 mmol) and DIAD (0.09 mL, 0.44 mmol) at 0 °C.
  • Step 5 To a solution of tert-butyl 4-(bromomethyl)-5-( 1 -isopropyl- lH-pyrazol-5
  • the compound was prepared from ethyl 2-fluoronicotinate and 8-oxa-3- azabicyclo[3.2.1]octane according to reaction scheme below.
  • Step la To a solution of ethyl 2-fluoronicotinate (0.15 g, 0.97 mmol) in NMP (0.5 mL) was added diisopropylethyl amine (0.50 mL, 2.9 mmol), and 8-oxa-3- azabicyclo[3.2.1]octane (0.17 g, 0.72 mmol). The resulting mixture was irradiated with microwaves (100 °C) for lh and loaded directly onto a silica column.
  • Step lb To a cooled (0 °C) solution of 2-(8-oxa-3-azabicyclo[3.2. l]octan-3- yl)nicotinate (0.10 g, 0.40 mmol) in THF (5 mL) was added a solution of lithium aluminum hydride (1.2 mL, 1M in THF). The reaction mixture was stirred for lh and then 20 of H 2 0 was added followed by 20 ⁇ of 15% NaOH (aq) and then 60 ⁇ , of additional H 2 0, The slurry was stirred for lh, filtered and the resulting residue was washed with ether.
  • Step 2 To a cooled (0 °C) solution of (2-(8-oxa-3-azabicyclo[3.2.1]octan-3- yl)pyridin-3-yl)methanol (0.070 g, 0.32 mmol) in dichloromethane was added SOCl 2 (0.23 mL, 3.2 mmol) and the reaction mixture was allowed to warm to ambient temperature. After 1 h, the reaction mixture was concentrated and azeotroped with toluene three times to provide 3-(3-(chloromethyl)pyridin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.075 g, 98%) as a clear oil.
  • Step 3 To a solution of provide 3-(3-(chloromethyl)pyridin-2-yl)-8-oxa-3- azabicyclo[3.2.1]octane (0.080 g, 0.35 mmol) and 5-hydroxy-2,2-dimethyl-4H- benzo[d][l,3]dioxin-4-one (0.061 g, 0.31 mmol) in DMF was added cesium carbonate (0.307 g, .94 mmol) and the reaction mixture was heated (60 °C). After 30 minutes, the reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate and the aqueous layer was extracted two times with EtOAc.
  • Step 4 To a cooled (-78 °C) solution of 5-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8- yl)pyridin-3-yl)memoxy)-2,2-dimethyl-4H-benzo[d][l,3]dioxin-4-one (0.11 g, 0.28 mmol) in CH 2 C1 2 was added DIBAL-H (0.85 mL, 1M in CH 2 C1 ⁇ 2) and reaction mixture was allowed to warm to ambient temperature over 3 hours. The reaction mixture was then cooled (-78 °C) and MeOH was added followed by saturated potassium sodium tartrate solution (300 ⁇ .).
  • Step 1 To a solution of ethyl 3-oxotetrahydro-2H-pyran-4-carboxylate (1.0 g, 5.81 mmol)in DCM (30 mL) was added DIPEA (1.22 mL, 6.97 mmol) and Tf 2 0 (1.08 mL, 6.39 mmol) at -78 °C, then it was warmed up to room temperature and stirred at room
  • Step 2 To a solution of ethyl 5-(((trifluoromethyl)sulfonyI)oxy)-3,6-dihydro-2H- pyran-4-carboxylate (crude from step 1) and l-isopropyI-5-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)-lH-pyrazole (1.37 g, 5.82 mmol) in dioxane (20 ml) was added
  • Step 3 To a solution of ethyl 5-(l-isopropyl-lH-pyrazol-5-yl)-3,6-dihydro-2H- pyran-4-carboxylate (600 mg, 2.27 mmol) in THF (10 mL) was added LiAlH 4 (1M in THF, 2.72 mL, 2.72 mmol) at -20 °C, the reaction was stirred at -20 °C for 30 min, and was quenched with Sat.
  • Step 4 To a solution of (5-(l-isopropyl-lH-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4- yl)methanol (300 mg, 1.35 mmol) in DCM (5 mL) was added dibromotriphenylphosphorane (630 mg, 1.35 mmol) at room temperature, after stirring for 30 min, it was diluted with DCM, organic layer was washed with Sat.
  • Step 1 Into a 100-mL round-bottom flask, was placed a solution of tert-butyl N-(4- chloropyridin-2-yl)carbamate (3.0 g, 13.12 mmol, 1.00 equiv) in tetrahydrofuran (50 mL). This was followed by the addition of sodium hydride (631 mg, 26.29 mmol, 1.20 equiv) at 0°C. The mixture was stirred for 20 min at 0°C To this was added iodomethane (2.24 g, 15.78 mmol, 1.20 equiv) dropwise with stirring. The resulting solution was stirred for 6 h at room temperature.
  • Step 2 Into a 100-mL three neck round-bottom flask, was placed a solution of tert- butyl N-(4-chloropyridin-2-yl)-N-methylcarbamate (1.5 g, 6.18 mmol, 1.00 equiv) in tetrahydrofuran (50 mL). This was followed by the addition of BuLi (2.5M) (3.0 mL, 1.20 equiv) dropwise with stirring at -78°C. The mixture was stirred for 30 mins at -78°C. To this was added N,N-dimethyIformamide (1.5 mL, 3.00 equiv) dropwise with stirring at -78°C.
  • BuLi (2.5M) 3.0 mL, 1.20 equiv
  • Steps 3 & 4. Into a 100-mL round-bottom flask, was placed a solution of [2-[l- (propan-2-yl)-lH-pyrazol-5-yl]pyridin-3-yl]methanol (1.15 g, 5.29 mmol, 1.00 equiv) in ⁇ , ⁇ -dimethylformamide (40 mL). This was followed by the addition of sodium hydride (530 mg, 13.25 mmol, 2.50 equiv, 60%) at 0°C. The mixture was stirred for 15 min at 0°C.
  • the crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD Column,5um,19*100mm,; mobile phase, water with 0.1%TFA and MeCN (3.0% MeCN up to 20.0% in 5 min, up to 95.0% in 2 min,down to 3.0% in 1 min); Detector, waters2489 254&220nm. This resulted in 107.1 mg (6%) of 2- (memylanuno)-4-([2-[l-(propan-2-yl)-lH-pyrazol-5-yl]pyridm-3-yl]memoxy)pyrid carbaldehyde as a yellow solid.
  • Prep- HPLC-020 Column, SunFire Prep C18 OBD Column,5um,19*100mm,; mobile phase, water with 0.1%TFA and MeCN (3.0% MeCN up to 20.0% in 5 min, up to 95.0% in 2 min,down
  • N-(l-Emyl-lH-pyrazol-5-yl)-2-(2-formyl-3-(methoxvmethoxy)phenoxy)-N- isopropylacetamide (0.38 g, 1.01 mmol) was dissolved in THF (10 ml), purged with N 2 gas and stirred in an ice bath.
  • HC1 concentrated, 0.34 ml, 4.05 mmol
  • Stepl Into a 100-mL round-bottom flask, was placed a solution of 2- (bromomethyl)benzonitrile (1.0 g, 5.10 mmol, 1.00 equiv) in dichloromethane (40 mL). This was followed by the addition of DIBAL-H (5.5 mL, 1.10 equiv) at 0°C. The resulting solution was stirred for 3.5 h at 0°C. The reaction was then quenched by the addition of 10 mL of 5% HBr at 0°C. The resulting solution was extracted with 3x30 mL of dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate.
  • Step 2 Into a 50-mL round-bottom flask, was placed a solution of 2- (bromomethyl)benzaldehyde (150 mg, 0.75 mmol, 1.00 equiv) in CH 3 CN (25 mL). 2-[l- (Propan-2-yl)-lH-pyrazol-5-yl]pyridin-3-ol (150 mg, 0.74 mmol, 1.00 equiv), potassium carbonate (210 rag, 1.52 mmol, 2.00 equiv), and I (40 mg, 0.30 equiv) were added to the reaction. The resulting solution was heated to reflux for 6 h, and then it was cooled to rt.
  • 2- (bromomethyl)benzaldehyde 150 mg, 0.75 mmol, 1.00 equiv
  • 2-[l- (Propan-2-yl)-lH-pyrazol-5-yl]pyridin-3-ol 150 mg, 0.74 mmol, 1.00 equiv
  • oxyHbS was dialyzed against 20 mM HEPES-HC1 (pH 6.8) and concentrated using Millipore centrifugal concentrators. The highly concentrated (around 300 mg/ml) small volume aliquots of pure oxyHbS were flash-frozen in liquid nitrogen and stored in liquid nitrogen until use. All chemicals (biochemical grade or greater quality) unless custom made were purchased from Sigma-Aldrich (St. Louis, MO, USA). Carbon monoxide (pure grade) was obtained from TechAir (White Planes, New York, USA).
  • the ESI-MS spectrum of human hemoglobin S shows that human HbS consists of a typical alpha A globin subunit (molecular mass of 15,126 Da) and a mutant (betaE6V) beta S globin subunit (molecular mass of 15,837 Da).
  • HbS protein sample (-10 mg ml) was diluted 1 : 10 or 1 : 100 in 50% acetonitril e- 0.1% formic acid.
  • Electrospray mass spectrometry (ESI-MS) was performed on a linear trap quadruple (LTQ) ion trap mass spectrometer (Thermo Fisher Scientific, San Jose, CA). The diluted samples were infused at flow rates of 5 ⁇ /min.
  • ESI-MS experimental results are presented in Figure 1.
  • Example 12 Preparation of human carbonmonoxyhemoglobin S (COHbS) and monitoring of iron oxidation.
  • the liganded status of hemoglobin S was further confirmed by determining its crystal structure.
  • the precipitant solution was pre-treated with carbon monoxide (by bubbling CO gas through it for a few minutes), and it was replaced at least every two weeks plus every time the crystallization chamber was opened for manipulations and exposed to air. More concentrated precipitant solutions containing 26-30% PEG 4000 were used to produce protein crystals that grew up fast, in about 3 days. However, the "fast-growing" COHbS crystals were either relatively small or appeared as crystal clusters ( Figure 3A). On the other hand, the "fast-growing" crystals were less likely to contain a detectable amount of methemoglobin and usually diffracted better than crystals "older" than 10-14 days.
  • the already grown COHbS crystals were soaked in a precipitant solution supplemented with glycerol (10-30%, v/v), or ethyleneglycol (15-30%, v/v) or dimethylsulfoxide (15-25%, v/v).
  • glycerol which was well-tolerated by COHbS crystals not only as a cryoprotectant but also as an additive in crystallization.
  • Pure paraffin oil did not act as a cryoprotectant but it did not destroy the COHbS crystals during an incubation time of up to 2 hours. This feature was convenient and 2-3 ⁇ of paraffin oil was occasionally used to cover up and thus prevent evaporation of a crystallization drop thus reducing any possibility for gas exchange in the process of soaking COHbS crystals in solutions with different additives.
  • the COHbS crystals were soaked in for a short time (3-10 minutes) or much longer (up to 72 hours).
  • the short soaking time was used for testing cryoconditions and for quick freezing of hemoglobin crystals.
  • the longer soaking time (from 30 minutes to 3 days) was used when the COHbS crystals were incubated in the presence of slow reacting and/or low water-soluble compounds. For the tested compounds that were not very soluble in water and water-based solutions, an overnight or even longer incubation time was used to produce protein-ligand complexes.
  • Example 15 Producing protein-Iigand complexes by soaking COHbS crystals in a ligand suspension or solution and by co-crystallization
  • Each tested compound was suspended either in 20 mM HEPES (for co- crystallization studies) or in a precipitant solution (for crystal soaking experiments) in order to produce a saturated compound solution.
  • a saturated solution or its serial dilutions of each compound was added to the crystallization drops with COHbS crystals (in a ratio of 1 :1 volume/volume).
  • the ligand was gently mixed with COHbS stock solution (20-24 mg ml) before setting up crystallization drops.
  • COHbS stock solution (20-24 mg ml)
  • the hemoglobin crystals grew, they were treated with a cryoprotectant as described above and frozen in liquid nitrogen.
  • the crystals were grown in the presence of glycerol, they were frozen directly without any additional treatment.
  • Example 16 X-Ray diffraction data collection, structure solution and refinement
  • X-ray diffraction data from flash-cooled crystals were collected on the beam line X29A of the National Synchrotron Light Source (Brookhaven National Laboratory, New York) equipped for the rapid data collection studies and using a radiation wavelength ( ⁇ ) of 1.075A and a CBASS data collection software. A few X-ray diffraction data sets were also collected at the beam line 31 ID at the Advanced Photon Source (Argonne National).
  • the room temperature X-ray diffraction experiments were performed on crystals mounted inside the standard MiTeGen plastic capillaries (MiTeGen, Ithaca, New York, USA).
  • the room temperature diffraction data were collected at a wavelength of 1.5418A using a RIGAKU Cu rotating anode as an X- ray generator and an RAXIS IV image plate area detector. (An attempt to collect room temperature diffraction data at X29A was unsuccessful due to extensive crystal damage). All collected X-ray diffraction data were processed and scaled using the H L (2000 or 3000) software packages (Z. Otwinowski, M. Minor.

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Abstract

L'invention a pour objet des produits d'addition 1:1 de l'hémoglobine S (HbS) et d'un composé de formule (I), tel que défini dans l'invention, pouvant être employés en tant que modulateurs de HbS, et des procédés pour les utiliser dans le traitement de troubles médiés par l'hémoglobine et de troubles susceptibles d'être améliorés par une oxygénation tissulaire et/ou cellulaire.
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US11530191B2 (en) 2013-03-15 2022-12-20 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11236109B2 (en) 2013-03-15 2022-02-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11452720B2 (en) 2014-02-07 2022-09-27 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11944612B2 (en) 2015-12-04 2024-04-02 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
CN109152770A (zh) * 2016-05-12 2019-01-04 全球血液疗法股份有限公司 合成2-羟基-6-((2-(1-异丙基-1h-吡唑-5-基)-吡啶-3-基)甲氧基)苯甲醛的方法
US10787430B2 (en) 2016-06-17 2020-09-29 Fronthera U.S. Pharmaceuticals Llc Hemoglobin modifier compounds and uses thereof
US11649242B2 (en) 2017-03-20 2023-05-16 Forma Therapeutics, Inc. Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators
US11396513B2 (en) 2017-03-20 2022-07-26 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
US11014927B2 (en) 2017-03-20 2021-05-25 Forma Therapeutics, Inc. Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators
US10836771B2 (en) 2017-03-20 2020-11-17 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
US11071725B2 (en) 2018-09-19 2021-07-27 Forma Therapeutics, Inc. Activating pyruvate kinase R
US11001588B2 (en) 2018-09-19 2021-05-11 Forma Therapeutics, Inc. Activating pyruvate kinase R and mutants thereof
US10675274B2 (en) 2018-09-19 2020-06-09 Forma Therapeutics, Inc. Activating pyruvate kinase R
US11844787B2 (en) 2018-09-19 2023-12-19 Novo Nordisk Health Care Ag Activating pyruvate kinase R
US11980611B2 (en) 2018-09-19 2024-05-14 Novo Nordisk Health Care Ag Treating sickle cell disease with a pyruvate kinase R activating compound
WO2021224280A1 (fr) * 2020-05-05 2021-11-11 Dipharma Francis S.R.L. Synthèse d'un agent pour le traitement de la drépanocytose et de ses intermédiaires
IT202000025135A1 (it) * 2020-10-23 2022-04-23 Dipharma Francis Srl Procedimento per la preparazione di un farmaco per il trattamento dell’anemia falciforme

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