WO2019027890A1 - Méthodes de traitement de la myélosuppression - Google Patents

Méthodes de traitement de la myélosuppression Download PDF

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WO2019027890A1
WO2019027890A1 PCT/US2018/044356 US2018044356W WO2019027890A1 WO 2019027890 A1 WO2019027890 A1 WO 2019027890A1 US 2018044356 W US2018044356 W US 2018044356W WO 2019027890 A1 WO2019027890 A1 WO 2019027890A1
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alkyl
aryl
hydrogen
heteroaryl
alkynyl
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PCT/US2018/044356
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Kevin J. GAFFNEY
Kathleen E. Rodgers
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Gaffney Kevin J
Rodgers Kathleen E
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Publication of WO2019027890A1 publication Critical patent/WO2019027890A1/fr

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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Myelosuppression is a condition in which bone marrow activity is decreased, resulting in fewer hematopoietic cells (erythrocytes, white blood cells, platelets, etc.) and their progenitors.
  • Myelosuppression as a consequence of cytotoxic chemotherapy is well recognized as a dose-limiting factor in cancer treatment.
  • bone marrow is particularly sensitive to the proliferation-specific treatment such as chemotherapy or radiotherapy.
  • chemotherapy or radiotherapy.
  • hematopoietic toxicity frequently limits the opportunity for chemotherapy dose escalation/density. Repeated or high dose cycles of chemotherapy may be responsible for severe stem cell depletion leading to serious long-term hematopoietic sequelea and marrow exhaustion.
  • Myelosuppression can also be caused, for example, by immune deficiencies, off target effects of drugs for other diseases, environmental toxins, crowding of the bone marrow,
  • Myelosuppression may comprise or result in, for example, hematopoietic toxicity, decreased mobilization of hematopoietic progenitor cells from bone marrow into the peripheral blood; anemia, pancytopenia, thrombocytopenia, neutropenia, lymphopenia, leukopenia, and/or deficiencies in bone marrow progenitor cells.
  • methods for treating a subject with myelosuppression comprising administering to the subject in need thereof an effective amount of a compound having the general formula 1 including salts thereof:
  • ring A is a five-membered or six-membered heteroaryl or heterocyclyl ring containing either a combination of two non-adjacent nitrogen or oxygen atoms, or a combination of three or four nitrogen or oxygen atoms;
  • ring B is a five-membered or six-membered heteroaryl ring that contains at least one nitrogen atom;
  • X ! -X 2 is -(R 6 )C-N-, -N-C(R 6 )-, -N-N-, -N-0-, -0-N-, -N-S- or -S-N-;
  • Z is -0-, -N(H or a bond to R 5 ;
  • R a and R b are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido and carboxy,
  • R a and R can also join to form a ring of up to 6 atoms
  • R c and R d are independently selected from a group consisting of hydrogen, alkyl, aryl, or heteroaryl, provided that R c and R d , together with the atoms to which they are attached, form a ring of up to 6 atoms;
  • R e is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl;
  • R 1 , R 3 , R 4 , R 6 , R ', and R 8 are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarvlmethyl, fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyland aryloxyalkyl;
  • R 2 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, alkoxy, trifluoromethoxy, perfluoroalkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl;
  • R D is alkyl, aryl, heteroaryl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, or aryloxyalkyl;
  • R 9 is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl.
  • ring A is selected from the group consisting of:
  • R 10 and R' 1 are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido and carboxy,
  • R 12 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or acylamido;
  • R 13 is hydrogen, alkyl, aryl or heteroaryl
  • R 14 is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl;
  • R f , R g , R b , and R' are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, fluoro, chloro, bromo, iodo, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl;
  • ring B is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • R 1 , R 2 , R 3 , R 4 R 5 , R 6 , R 7 , R 8 , R 9 , R a , R b , R c , R d and Z are defined as in general formula 1;
  • R 10 and R 11 are independently selected from a group consisting of hydrogen, alkyl. alkenyl, alkynyi, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido and carboxy
  • R 12 is hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or acylamido;
  • R 13 is hydrogen, alkyl, aryl or heteroaryl
  • R 14 is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl;
  • R f , R g , R h , and R are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, arylmethyl, heteroaryl methyl, fluoro, chloro, bromo, iodo, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, and aryloxyalkyl;
  • R 2 is trifluoromethoxy and/or Z is O or -N(H)-.
  • Z is -O- or -N(H ;
  • R 10 and R ! 1 are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido and carboxy,
  • R 12 is hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or acylamido;
  • R 15 is alkyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, trifluoromethyl or pentafluoroethyl;
  • R U is hydrogen, hydroxy, methoxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl. amino, alkylamino, or diaikylamino.
  • the compound has the general formula 4a or a salt thereof:
  • Z is -O- or -N(H)-;
  • R 10 , R 11 and R 12 are hydrogen
  • R 15 is alkyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, trifluoromethyl pentafluoroethyl;
  • R 16 is hydrogen, hydroxy, methoxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, amino, alkylamino, or diaikylamino.
  • the compound has the general formula 4a or a salt
  • Z is -O- or -N(H)-;
  • R 10 and ! 1 are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyi, alkoxy, aryloxy, formyl, acyl, acylamido or carboxy, provided that R 10 and R 11 car also be joined to form a carbocyclic, heterocyclic, aryl or hetoaryl ring;
  • R 12 is hydrogen, alkyl, alkenyi, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or acylamido;
  • R 13 is trifluoromethyl and R 16 is ethyl
  • he compound has the formula 7
  • Compound 7. has the general formula 5a or a salt thereof:
  • R 1 , R 2 , R 3 , R 4 R 5 , R 6 , R 7 , R s , and Z are defined as in general formula 1; and R i4 is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl.
  • R 14 is hydrogen, or alkyl
  • R 2 is alkyl, trifluoromethoxy, or perfluoroalkoxy
  • R 1 , R 3 , R 4 R 5 , R 6 , R', R 8 are independently selected from a group consisting of hydrogen, alkyl, alkenyi, and alkynyl; and'or the compound has the formula 10, or a pharmaceutically acceptable salt thereof.
  • the compound has the formula 10 Compound 10.
  • FIG. 1 Mice were treated with gemcitabine on day 0 (grey arrow) and treated daily starting on day 1 through day 21.
  • White blood cell (WBC) and red blood cell (RBC) counts were quantified on days -1 (baseline), 7, 14, and 21.
  • WBC white blood cell
  • RBC red blood cell
  • B Compound 10 also significantly increased circulating RBC counts at day 21 compared to controls, an effect not seen with Compound 7.
  • C At necropsy, the bone marrow of the mice was harvested and cultured.
  • PCT Application PCT/US 14/30071 provided novel non-peptidic compounds and compositions (including the synthesis thereof). The present invention describes the use of these compounds and compositions for the treatment of myelosuppression
  • this invention provides a method for the treatment of a subject with myelosuppression, comprising the administration to a subject in need thereof an effective amount of a compound h luding salts thereof:
  • ring A is a five-membered or six-membered heteroaryl or heterocyclyl ring containing either a combination of two non-adjacent nitrogen or oxygen atoms, or a combination of three or four nitrogen or oxygen atoms;
  • ring B is a five-membered or six-membered heteroaryl ring that contains at least one nitrogen atom;
  • X -X 2 is -(R 6 )C-N-, -N-QR 6 )-, -N-N-, -N-0-, -0-N-, -N-S- or -S-N-;
  • Z is -0-, -N(H)- or a bond to R 5 ;
  • R a and R b are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido and carboxy,
  • R c and R d are independently selected from a group consisting of hydrogen, alkyl. aryl, or heteroaryl, provided that R c and R d , together with the atoms to which they are attached, form a ring of up to 6 atoms;
  • R c is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl;
  • R 1 , R 3 , R 4 , R 6 , R 7 , and R 8 are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxy alley land aryloxyalkyl;
  • R 2 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, alkoxy, trifluoromethoxy, perfluoroalkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl;
  • R ⁇ is alkyl, aryl, heteroaryl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, or aryloxyalkyl;
  • R 9 is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl.
  • R is trifluoromethoxy
  • Z is O or -N(H)-.
  • ring A includes but is not limited to a ring selected from a group consisting of:
  • R 10 and R n are independently selected from a group consisting of hydrogen, alkyl, alkenyl alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido and carboxy. or R i and R l ! , together with ring A to which they are attached, form a carbocyclic, heterocyclic, aryl or hetoaryl ring;
  • R 12 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or acylamido;
  • R B is hydrogen, alkyl, aiyl or heteroaryl
  • R 14 is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl;
  • R f , R , R h , and R 1 are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aiylmethyl, heteroarylmethyl, fluoro, chloro, bromo, iodo, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl;
  • ring B includes but is not limited to a five- or six- memb
  • the compounds administered in connection with the methods and compositions provided herein have the general formula selected from a group consisting of:
  • the compounds have the general formula selected from a group consisting of:
  • R 1 , R 2 , R 3 , R 4 R 5 , R 6 , R 7 , R 8 , R y , R a , R b , R c , R d and Z are defined as in general formula 1 ;
  • R 1 " and R l ! are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryi, halo, hydroxy, hydroxyalkyi, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido and carboxy
  • R !0 and R' 1 together with ring A to which they are attached, form a carbocyciic, heterocyclic, aiyl or hetoaryl ring;
  • R 12 is hydi gen, alkyl, alkenyl, alkynyl, aryl, heteroaryi, halo, hydroxy, hydroxyalkyi, alkoxyalkyl, alkoxy, aryloxy, or acylamido;
  • R lj is hydrogen, alkyl, aryl or heteroaryi
  • R 14 is hydrogen, alkyl, aryl, heteroaryi, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl;
  • R f , R s , R h , and R' are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryi arylmethyl, heteroarylmethyl, fluoro, chloro, bromo, iodo, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, and aryloxyalkyl;
  • the compounds administered in connection with the methods and compositions provided herein have the general formula selected from a group consisting of:
  • R 1 , R 2 , R 4 R 5 , R FI , R 7 , R 8 , R 9 , R 3 , R B , R , R D and Z are defined as in general formula 1.
  • R 10 and R 1 ' are independently selected from a group consisting of hydrogen, alkyl, alkenyl alkynyl, aryl, heteroarvl, halo, hydroxy, hydroxyalkyi, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido or carboxy, provided that R 10 and R 11 can also be joined to form a carbocyclic, heterocyclic, aryl or hetoaryl ring;
  • R 1 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyi, alkoxyalkyl, alkoxy, aryloxy, or acylamido;
  • R 13 is hydrogen, alkyl, aryl or heteroaryl
  • R 14 is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl;
  • R F , R G , R H , and R' are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, fluoro, chloro, bromo, iodo, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl.
  • the compounds administered in connection with the methods provided herein have the general formula 2a,b or 3a,b:
  • R 1 , R 2 , R 3 , R 4 R 5 , R 6 , R 7 , R ⁇ R 9 , R a , R b , R c , R d and Z are defined as in general formula 1.
  • R 10 and R 11 are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido or carboxy, provided that R 10 and R 11 can also be joined to form a carbocyclic, heterocyclic, aryl or hetoaryl ring;
  • R 12 is hydrogen, alkyl. alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl. alkoxyalkyl, alkoxy, aryloxy, or acylamido;
  • R 13 is hydrogen, alkyl, aryl or heteroaryl
  • R 14 is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl;
  • R f , R s , R h , and R' are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, fluoro, chloro, bromo, iodo, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl.
  • R 1 , R 2 , R 6 , R 7 , R 8 , R 9 , R I! , R B , R C , R D and Z are defined as in general formula 1.
  • R 10 and R ! L are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkvl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido or carboxy, provided that R 10 and R 1 1 can also be joined to form a carbocyclic, heterocyclic, aryl or hetoaryl ring;
  • R 12 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxy alkyl, alkoxyalkyl, alkoxy, aryloxy, or acylamido;
  • R 14 is hydrogen, alkyl. aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl;
  • R 13 is alkyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, trifluoromethyl or pentafluoroethyl; and R 16 is hydrogen, hydroxy, methoxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, amino, alkylamino, or dialkylamino.
  • the R 10 , R n and R 12 are hydrogen, and R 14 is methyl.
  • R° is trifluoromethyl and R 16 is ethyl.
  • Z is O or NH
  • R 10 and R H are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido or carboxy, provided that R k ' and R n can also be joined to form a carbocyclic, heterocyclic, aryl or hetoaryl ring;
  • R 12 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or acylamido;
  • R 13 is alkyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, trifluoromethyl or pentafluoroethyl;
  • R 16 is hydrogen, hydroxy, methoxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, amino, alkylamino, or dialkylamino.
  • the R !0 , R 1 ! and R 12 are hydrogen.
  • R 15 is trifluoromethyl and R i6 is ethyl.
  • a representative exemplary embodiment of the provided methods disclosed herein comprises the administration of Compound 7 for the treatment of myelosuppression:
  • a representative exemplary embodiment of the provided methods disclosed herein comprises the administration of Compound 10 for the treatment of myelosuppression:
  • the invention further provides pharmaceutical compositions for the treatment of myelosLippression comprising a compound provided in PCT Application PCT/US 14/30071 or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier as described in PCT Application PCT/US 14/30071.
  • the provided methods and compositions are employed in any suitable administrative form, including but not limited to oral, parenteral, or topical administration.
  • treatment refers to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be therapeutic in terms of a partial or complete cure for a disease and/or adverse symptoms attributable to the disease.
  • Treatment covers any treatment of myelosuppression or consequences of myelosuppression, particularly in a human, and includes: (a) increasing circulating hematopoietic cells (erythrocytes (RBCs), white blood cells (WBCs), platelets, etc.) and/or bone marrow progenitor cells, such as mesenchymal stem cells (MSC) and hematopoietic progenitor cells (including but not limited to CFU-GEMM, CFU-GM, BFU-E); (b) limiting the decrease in circulating and/or bone marrow hematopoietic cells and/or bone marrow progenitor cells; (c) causing regression of anemia, pancytopenia, thrombocytopenia, neutropenia, lymphopenia, leukopenia, and/or deficiencies in bone marrow progenitor cells; (d) arresting development of anemia, pancytopenia, thrombocytopenia, neutropenia
  • lymphopenia lymphopenia, leukopenia, and/or deficiencies in bone marrow progenitor cells; and/or (e) reducing the use of colony stimulating factors (including but not limited to granulocyte macrophage colony stimulating factor, granulocyte colon)' stimulating factors, and erythropoietin).
  • colony stimulating factors including but not limited to granulocyte macrophage colony stimulating factor, granulocyte colon
  • stimulating factors including but not limited to granulocyte macrophage colony stimulating factor, granulocyte colon
  • erythropoietin erythropoietin
  • the nomenclature alkyl. alkoxy, carbonyl, etc. is used as is generally understood by those of skill in the chemical art.
  • alkyl groups can include straight-chained, branched and cyclic alkyl radicals containing up to about 20 carbons, or 1 to 16 carbons, and are straight or branched.
  • alkyl groups herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl and isohexyl.
  • lower alkyl refer to carbon chains having from about 1 or about 2 carbons up to about 6 carbons. Suitable alkyl groups may be saturated or unsaturated.
  • an alkyl may also be substituted one or more times on one or more carbons with substituents selected from a group consisting of Cl - C15 alkyl, allyl, allenyl, alkenyl, C3-C7 heterocycle, aryl, halo, hydroxy, amino, cyano, oxo, thio, alkoxy, formyl, carboxy, carboxamido, phosphoryl, phosphonate, phosphonamido, sulfonyl, alkylsulfonate, arylsulfonate, and sulfonamide.
  • an alkyl group may contain up to 10 heteroatoms, in certain embodiments, 1, 2, 3, 4, 5, 6, 7, 8 or 9 heteroatom substituents. Suitable heteroatoms include nitrogen, oxygen, sulfur and phosphorous.
  • cycloalkyl refers to a mono- or multicyclic ring system, in certain embodiments of 3 to 10 carbon atoms, in other embodiments of 3 to 6 carbon atoms.
  • the ring systems of the cycloalkyl group may be composed of one ring or two or more rings which may be joined together in a fused, bridged or spiro-connected fashion.
  • aryl refers to aromatic monocyclic or multicyclic groups containing from 3 to 16 carbon atoms.
  • aryl groups are aryl radicals, which may contain up to 10 heteroatoms, in certain embodiments, 1 , 2, 3 or 4 heteroatoms.
  • An aryl group may also be optionally substituted one or more times, in certain embodiments, 1 to 3 or 4 times with an aryl group or a lower alkyl group and it may be also fused to other aryl or cycloalkyl rings.
  • Suitable aryl groups include, for example, phenyl, naphthyl, tolyl, imidazolyl, pyridyl, pyrroyl, thienyl, pyrimidyl, thiazolyl and furyl groups.
  • a ring is defined as having up to 20 atoms that may include one or more nitrogen, oxygen, sulfur or phosphorous atoms, provided that the ring can have one or more substituents selected from a group consisting of hydrogen, alkyl, allyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo.
  • alkenyl refers to a branched or unbranched hydrocarbon having at least one carbon-carbon double bond.
  • alkynyl refers to a branched or unbranched hydrocarbon having at least one carbon-carbon triple bond.
  • carboxy refers to a -CO 2 H group.
  • hydroxy refers to an -OH group.
  • alkoxy refers to a group of the formula -O- where R is an “alkyl” as defined herein.
  • carrier refers to a non-aromatic stable 3- to 8-membered carbon ring which may be saturated, mono-unsaturated or poly-unsaturated.
  • amino includes primary, secondary or tertiary amino groups.
  • cyano refers to the group -CN.
  • alkenyl and alkynyl carbon chains contain from 2 to 20 carbons, or 2 to 16 carbons, and are straight or branched.
  • Alkenyl carbon chains of from 2 to 20 carbons in certain embodiments, contain 1 to 8 double bonds, and the alkenyl carbon chains of 2 to 16 carbons, in certain embodiments, contain 1 to 5 double bonds.
  • Alkynyl carbon chains of from 2 to 20 carbons in certain embodiments, contain 1 to 8 triple bonds, and the alkynyl carbon chains of 2 to 16 carbons, in certain embodiments, contain 1 to 5 triple bonds.
  • heteroaryl refers to a monocyclic or multicyclic aromatic ring system, in certain embodiments, of about 4 to about 15 members where one or more, in one embodiment 1 to 4, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen or sulfur.
  • the heteroaryl group may be optionally fused to a benzene ring.
  • Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrrolidinyl, pyrimidinyl, triazolyl. tetrazolvl, thienyl, pyridyl, pyrrolyl, N- methylpyrrolyl, quinolinyl and isoquinolinyl.
  • heterocyclyl refers to a monocyclic or multicyclic non-aromatic ring system, in one embodiment of 3 to 10 members, in another embodiment of 4 to 7 members, in a further embodiment of 5 to 6 members, where one or more, in certain embodiments, 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen or sulfur.
  • the nitrogen is optionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl.
  • heterocyciylalkyl, acyl, guanidino, or the nitrogen may be quatemized to form an ammonium group where the substituents are selected as above.
  • aralkyl refers to an alky! group in which one of the hydrogen atoms of the alky! is replaced by an aryl group.
  • halo refers to F, CI, Br or 1.
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen.
  • groups include, but are not limited to, chloromethyl and trifluoromethyl.
  • aryloxy refers to RO-, in which R is aryl, including lower aryl, such as phenyl.
  • acyl refers to a -COR group, including for example alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, or heteroarylcarbonyls, all of which may be optionally substituted.
  • pharmaceutically acceptable derivatives of a compound include salts, esters, enol ethers, enol esters, acetals. ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs thereof.
  • Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization.
  • the compounds produced may be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs.
  • salts include, but are not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para- chlorobenzyl-2-pyrrolidin- -ylmethylbenzimidazole, diethylamineand other alkylamines, piperazine and tris ⁇ hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and
  • esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl and heterocyclyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfmic acids and boronic acids.
  • Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
  • mice The female C57B1/6 mice (7 per group), 6-8 weeks old, were treated with the formulations described above daily starting 1 day after intravenous injection with chemotherapy, 160 mg/kg gemcitabine. On days -1, 3, 7, 15 and 21 after chemotherapy administration, blood was taken under anesthesia from the saphenous vein to assess white blood cell, and platelet numbers. On day 22, the mice were euthanized and bone marrow collected to assess the number of colony forming units.
  • mice were bled from the saphenous vein.
  • the mice were anesthetized by placing the nose of the animals in a 50 ml conical tube containing cotton balls soaked with isoflurane (an inhaled anesthesia). Once anesthesiawas affected, the animals were taken from the tube and held firmly. Approximately 50 ⁇ of blood were obtained from the saphenous vein and collected using a microcuvette microfuge tube containing 10 mM EDTA and held on ice until further processing.
  • the femurs were collected and the bone marrow was harvested by flushing with PBS containing 2% fetal calf serum and 2X PenStrep. After collection of the bone marrow, the cells were pelleted at 1 ,000 rpm at 4C for 1 0 min, resuspended, and the number of nucleated cells was counted using a Zl Coulter Counter (Beckman Coulter). Aliquots of cells were then resuspended at 5 xlO 6 cells/ml.

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Abstract

L'invention concerne des méthodes de traitement de la myélosuppression par administration d'un composé de formule générale 1 ou d'un sel pharmaceutiquement acceptable de celui-ci, tel que défini dans la description.
PCT/US2018/044356 2017-08-04 2018-07-30 Méthodes de traitement de la myélosuppression WO2019027890A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160016946A1 (en) * 2013-03-15 2016-01-21 Nicos A. Petasis Methods, Compounds, and Compositions for the Treatment of Angiotensin-Related Diseases
US20170119748A1 (en) * 2013-03-15 2017-05-04 University Of Southern California Methods, compounds, and compositions for the treatment of musculoskeletal diseases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160016946A1 (en) * 2013-03-15 2016-01-21 Nicos A. Petasis Methods, Compounds, and Compositions for the Treatment of Angiotensin-Related Diseases
US20170119748A1 (en) * 2013-03-15 2017-05-04 University Of Southern California Methods, compounds, and compositions for the treatment of musculoskeletal diseases

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BIOCHEM., vol. 11, 1972, pages 942 - 944
WANG LI-FANG ET AL: "Clinical observation of Shuanghuang Shengbai Granule (??????) on prevention and treatment of myelosuppression caused by chemotherapy in cancer patients", CHINESE JOURNAL OF INTEGRATED MEDICINE /ZHONGGUO JIEHE YIXUE ZAZHI (ENGLISH), ZHONGGUO ZHONG-XIYI JIEHE YANJIUHUI, CN, vol. 23, no. 2, 2 August 2016 (2016-08-02), pages 105 - 109, XP036174406, ISSN: 1672-0415, [retrieved on 20160802], DOI: 10.1007/S11655-016-2503-4 *

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