TW201121965A - Use of a quinolone derivative containing 7-(4-aminomethyl-3-oxime)pyrrolidine group that is capable of inducing granulocyte colony stimulating factor for treatment of neutropenia and recovery of hematopoiesis - Google Patents

Abstract

The present invention relates to a quinolone antibiotic compound of formula (1) capable of promoting the production of G-CSF in the body, and the medicament for treatment of neutropenia and early recovery of immunocytes, comprising the same as an active ingredient.

Description

201121965 'm VI. Description of the invention: [Technical field to which the invention pertains] " The present invention relates to a medicament for treating neutropenia and early recovery of immune cells. The medicament comprises a therapeutically effective amount of 3 (4~aminomethyl-3-indenyl)-α-pyridyl group represented by formula (1), which is a pharmaceutically acceptable salt thereof. Including hydrate solvates, S oximes, isomers or prodrugs (hereinafter, these are simply referred to as compounds of formula (1)) which promote the production of G_CSF (granulocyte community stimulating factor).

R represents hydrogen, a mercapto or an amine group, and Q represents C~H, C-F, C-C1, C-0H, C-CH3, C-0-CH3 or N,

Rl represents hydrogen, cyclopropyl, methyl or ethyl, or phenyl substituted via one or more fluorine atoms, and lanthanide represents one of the following &) to e): a) hydrogen, straight chain or branch a bond Ci-C4 alkyl, cyclopropyl, cyclopropylmethyl, alkynyl, 2-haloethyl, nonyloxyindenyl, methoxycarbonylmethyl, phenyl or allyl, b) Foundation 94999 3 201121965

Wherein X is hydrogen, 2-, 3- or 4-fluoro, cyano, nitro, methoxy, C1-C4 succinyl or 2,4-difluoro ι, c) the base of the formula ^ ^

d) The base of the following formula: ^ < Χ γ > e) The base of the formula ^^(〇Ητ)πΤ^ where η refers to 0 or bu m refers to 〇, i or 2, χ indicates methylene, 0 Or Ν, and h represents -CIMRsR6, wherein 匕 and Re independently of each other represent hydrogen, CrC cycline, or (d) Re may form a ring with the nitrogen atom to which it is bonded, R4 represents hydrogen, or

It is indicated that R3 forms a structure together with the carbon atom to which it is bonded. The structure is combined with the structure in the form of a spiro ring, wherein 94999 4 201121965 nitrogen or Cl_C4 alkyl. In the present invention, the compound of the formula (1) is used as a medicament for the treatment of leukopenia and recovery of hematopoiesis, and is specifically disclosed in EP06887772B1 and KR 10-0566346B1. In the present invention, the preferred antibacterial antibiotic is called gemifloxacin, that is, '7-(4-aminomercapto-3-methoxyimino π is slightly bitten -1- -1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridin-3-carboxylic acid, and pharmaceutically acceptable salts, solvates thereof Including hydrates, esters, isomers or prodrugs (hereinafter, these are referred to briefly as gemifloxacin). The quinolinone antibiotics defined above including gemifloxacin promote and increase the production of G-CSF in the organism, thereby promoting the proliferation and differentiation of progenitor cells of the neutrophil granulocyte cell line. Gemifloxacin and the linalone antibiotic increase the number of neutrophils and promote the activity of mature neutrophils, so they can be used as adjuvants for anticancer therapy for prevention, inhibition, alleviation and treatment. Neutrophilic leukopenia, and as a drug for the promotion of the concentration of immune cells (especially the immune cells inhibited by immune diseases) and its treatment. They can be used as a substitute for G-CSF and PEGylated G~CSF derivatives. [Prior Art] The main system in which the life of a hematopoietic organism is maintained. Multiple immune cell lines are produced starting from the bone marrow by a variety of pathways. Hematopoiesis is regulated by specific glycoproteins commonly referred to as CSFs. cSFs are known as growth factors that promote the formation of monocyte strains, granulocytes or other hematopoietic cells when cultured in semi-solid medium to hematopoietic stem cells or hematopoietic precursor cells 5 94999 201121965. These factors are classified according to the type of cell line they promote and p-names. s, G-CSF (granulocyte-CSF) mainly promotes the formation of neutrophil community, and GM_CSF mainly promotes the formation of macrophage community. CSF (IL-3) mainly promotes the formation of granulocytes, giant sputum cells, megakaryocytes and red blood cells. G-CSF is an interleukin that directs the differentiation and differentiation of bone marrow stem cells and leukocytes outside the bone marrow. It also promotes the division and differentiation of neutrophil-precursor cells and activates mature neutrophils, thereby increasing their phagocytosis, chemotaxis, antibody-dependent cell cytotoxicity, superoxide-producing activity and tendency Responsiveness of the chemical factor (Metcalf, B1〇〇d (1986) 67:257; Yan et al, Blood (1994) 84(3): 795-799; Bensinger et al., Blood (1993) 81(11): 3158- 3163; Roberts et al., Expt' 1 Hematology (1994) 22:1156-1163; Neben et al., Blood (1993) 81(7): 1960-1967). Currently, G-CSF is usually isolated from various cells or produced by genetic recombination techniques, and is effective for the treatment of various anticancer therapies and refractory leukemias. In anticancer therapy, 'typical practitioners are radiation therapy and high-dose chemotherapy, but these treatments destroy the hematopoietic cells of the patient's bone marrow, thus inducing the rapid degradation of white blood cells including neutrophils, thereby weakening the immune system and increasing infection. Risk. Therefore, long-term and repetitive radiation therapy and high dose chemotherapy are limited. Among the side effects of these anticancer therapies, neutropenia is the most common, characterized by a decrease in circulating white blood cells, particularly neutrophils. The absolute neutrophil count (ANC) in the blood of normal healthy adults is 4400/mm 3 (mm3), and the average 6 94999 201121965 normal neutrophil count is in the range of 1800/mm3 to 7700/mm3. When ANC is in the range of l〇〇〇/mm3 to 1500/mm3, it is classified as moderate neutropenia; and when ANC is less than 500/mm3, it is classified as severe neutrophil. Leukopenia. Severe neutropenia causes the patient to have a fatal infection. When a patient receives chemotherapy or an autologous or exogenous transplant, a certain period of time for restoring hematopoiesis is required. During this recovery period, patients have lower concentrations of circulating neutrophils, so they are prone to exposure to infections caused by fungi or bacteria, especially opportunistic infections caused by common microorganisms such as Xanthomonas or Pseudomonas aeruginosa. And such infections significantly affect the survival of the patient.

Lopes et al. reported that G-CSF activates the patient's immune system and thus acts as an adjuvant to anticancer therapies to be more effectively implemented (L ◦ pez et al, J. Immunol. (1983) 131(6): 2983 -2988; Platzer et al, J. Exp. Med. (1985) 162:1788-1801). G-CSF is particularly effective as a drug to improve neutropenia caused by side effects caused by anticancer therapy (Morstyn G. et al., Trends Pharmacol. Sci. (1989) 10: 154-159). It has been reported that G-CSF is involved in the movement of hematopoietic stem cells or hematopoietic precursor cells from the bone marrow to the peripheral blood (G〇〇d Review article, Haylock et al., Blood (1997) 89: 2233-2258). However, G-CSF has the disadvantage of being very unstable, so it can only remain in extreme time in the body. In order to overcome these problems, it is recommended to use G-CSF with, for example, polyethylene glycol (PEG), polyvinyl alcohol and polyvinyl. The biocompatible macromolecule of pyrrolidone binds. These methods address the problem of restlessness; however, they still use exogenous G-CSF such as recombinant G-CSF' and may induce an unwanted immune response to the subject. In addition, more than 20% of patients develop tolerance to genetically modified G-CSF or do not respond to G-CSF 'so 'G-CSF has no effect on them (Sada et al, J. Fermentation Bioengineering (1991) 71: 137-139 ; Flomenberg et al, Blood (2005) 106:1867-1874). SUMMARY OF THE INVENTION The inventors of the present invention have been studied to promote the production and activity of exogenous G-CSF in vivo, instead of using genetically recombinant G-CSF to treat patients. After extensive research, the inventors of the present invention have found that a quinolinone antibiotic having a 7-(4-aminomercapto-3-indenyl)pyrrolidinyl group represented by the following formula (1), a pharmaceutically acceptable salt thereof The solvates, esters, isomers or prodrugs including hydrates can promote the production of G-CSF in vivo, and therefore, they can be used as drugs for treating neutropenia. In addition, they promote the proliferation and differentiation of hematopoietic stem cells in the bone marrow and move these hematopoietic stem cells or hematopoietic precursor cells from the bone marrow to the peripheral blood.

R is hydrogen, methyl or amine, and Q is C-H, C-F, C-Π, C-0H, C-CH3, C-O-CHa or N, 8 94999 201121965

Ri is a hydrogen, cyclopropyl, methyl or ethyl group, or a phenyl group substituted by one or more fluorine atoms, and the ruler 2 represents one of the following a) to e): a) hydrogen, straight chain or branch Chain Ci-decyl, cyclopropyl, cyclopropylindenyl, C3_C6 alkynyl, 2-haloethyl, nonyloxymethyl, decyloxycarbonylmethyl, phenyl or propyl, b) Wherein X is hydrogen, 2-, 3- or 4-fluoro, cyano, nitromethoxy~ 匕^^alkyl or ^-difluoro, c)

^0

e) The basis of the following formula is less (cHiVi·where η refers to 〇 or 1, m refers to 〇, 1 or 2, X represents methylene, 0 or N, and 94999 9 201121965 匕 indicates -CH2NRSR6, where R ;Cl'C3^^j ^ is bad, the helium atoms together form the h system to represent hydrogen, or 1^ and 1^ are combined with the defect 4 r, -n〇J _ sub-form together to form a structure Form and diagnosis R? means hydrogen or G-C4 alkyl. Μ 啶 绂 ,, wherein, the number of hematopoietic stem cells, :: effector increase bone (4) In the present invention, the compound of the formula (1) is preferred Early recovery of the two groups. Pharmaceutically acceptable salts, including hydration, do not be jimifloxacin, its prodrugs. ^, vinegar, isomers or heavy molecular weight synthetic compounds instead of greening the gene weight, and between The molecular weight is G. It has an incredible advantage over the traditional method U gene and the cost of transversion. Passing == pinching: == must pass non-oral route, such as; = heavy dip), continuous SC infusion or continuous (four) liquid It can be carried out easily outside the hospital, so there is significant harm = at the same time, the money ketone antibiotic according to the present invention is delicious Dosing/dose patients can easily carry drugs without having to come to the hospital. In addition, the gene ^ and = G-CSF are very expensive, and even in developed countries, most patients are still unable to receive treatment because of their cost. However, the present invention uses a low-cost synthetic alpha substance. This patient can enjoy the same therapeutic benefit as the genetically recombined g_csf 10 94999 201121965. In addition to the above advantages, since the compound according to the present invention; (1) the compound is treated with an anticancer agent for artificially induced neutrophil-reduction model, the ANC is restored from the fully reduced state to the normal concentration. The time and the time required to reach the so-called normal concentration, ie the duration of neutropenia, is almost the same as the time required for treatment with G-CSF, which shows that it is consistent with G-CSF. The effect, therefore, the compound of formula (1) has a very high industrial advantage. The object of the present invention is to provide an anti-cancer adjuvant, in particular a substitute for G-CSF, a drug for neutropenia, a drug for early recovery of immune cells, and a device for inducing hematopoietic stem cells or hematopoietic precursor cells. a drug that moves from the bone marrow to the peripheral blood, comprising a therapeutically effective amount of a quinolinone derivative antibiotic containing a 7-(4-aminomercapto-3-indolyl)pyrrolidinyl group, or a pharmaceutically acceptable salt thereof, Include solvates, esters, isomers or prodrugs of hydrates. A preferred linaloxone derivative compound according to the present invention is gemifloxacin. Another object of the invention is to provide a method for promoting the production of G-CSF in a mammal comprising administering to the mammal a therapeutically effective amount of 7-(4-aminomercapto-3) of formula (1) - 肟) a pyrrolidine group quinolinone derivative antibiotic, or a pharmaceutically acceptable salt thereof, including a hydrate solvate, ester, isomer or prodrug. Another object of the invention is to provide a method for treating a condition responsive to treatment with G-CSF comprising administering to the mammal a therapeutically effective amount of a formula (1) comprising 7-(4-aminomercapto- 3-indole pyrrolidine group quinolinone 11 94999 201121965 Derivative antibiotic, or a pharmaceutically acceptable salt thereof, including a solvate, ester, isomer or prodrug of a hydrate. Status in response to treatment with G-CSF includes neutropenia, decreased neutrophil motility, decreased peripheral blood cell migration, sepsis, severe chronic neutropenia, myelodysplasia, or bone marrow Inhibition, and acquired immunodeficiency syndrome. Another object of the present invention is to provide a method for increasing immune cells, particularly myeloid immune cells, and collecting such cells by inducing hematopoietic stem cells or hematopoietic precursor cells to move from the bone marrow to the peripheral blood, including the breastfeeding A therapeutically effective amount of a quinolinone derivative antibiotic having a 7-(4-aminomethyl-3-indenyl)pyrrolidinyl group of the formula (1), or a pharmaceutically acceptable salt thereof, including a hydrate thereof a solvate, ester, isomer or prodrug. A particularly preferred linaloxone derivative compound according to the present invention is gemifloxacin, and the therapy includes those administered to a mammal but not a human. In the second article, the present invention will focus on gemifloxacin, which is explained in detail by the present invention. However, it is not limited to riding stars. ^实施例 [Embodiment] The inventors of G-Cst Ming show that the compound of the formula (1) can promote ❹ in the body and can be used as a substitute for the genetically recombinant G-CSF in which the therapeutic towel is used as an adjuvant. Therefore, it can be used as an adjuvant in anticancer therapy. More in vivo and seven in the form of (1) compound therapy ^ heart. Specific acceptance of anti-cancer chemical production: - therapy in patients, the compound (1) promotes G_CSF-induced division and differentiation of hematopoietic stem cells in the bone marrow, hematopoietic stem fine 94999 12 201121965 Migration of cell or hematopoietic precursor cells to peripheral blood and proliferation of bone marrow cells in peripheral blood and spleen. In particular, the inventors of the present invention have found that gem-moxacin systemically promotes the division of myeloid cells and promotes the division of hematopoietic stem cells in the bone marrow. Thus, the present invention encompasses a method of using a compound of the formula (1) as a substitute for g_csf of an anticancer therapy such as an anticancer chemotherapy or an adjuvant for radiation therapy. In particular, the present invention encompasses a method of selectively increasing the production of in vivo sales, and more particularly, wherein the compound of the formula (1) is not promoted or even suppressed by the gm csf drug. Other causes of this external or IL-2 production. Furthermore, the invention encompasses methods for promoting the production of G CSF, including for mammals

The exhibit did not respond to exogenous G-CSF G-CSF. In the present invention, the exogenous G-CSF system includes G-CSF isolated from various cells, G_csp recombined from prokaryotic cells or eukaryotic cells, and various G-CSF variants including saccharification. These include commercially available lenograstim (Granocyte®), filgrastim (Neupogen®) and PEGylated Neulasta®. The compound of formula (1) according to the present invention can be administered to a mammal before, during or after chemotherapy or radiation therapy. When administered prior to chemotherapy or aromatherapy, it can be administered at least 1 day prior to, preferably 2 to 3 days, more preferably 4 days prior. When administered after chemotherapy or radiation therapy, it can be administered on the day of completion of chemotherapy or radiation therapy, within 1 day, or within 2 to 3 days, or at least 4 days from the day of completion of the chemotherapy or radiation therapy. When more than one cycle of chemotherapy or radiation therapy is carried out, the compound of formula (1) can be administered as disclosed above after the respective cycles are complete. 13 94999 201121965 Anticancer agents which can be used in the above anticancer chemotherapy according to its mechanism of action, chemical structure and source include, but are not limited to, the following compounds: alkylating agent, the alkylating agent includes, but is not limited to, Mustard derivatives such as cyclopamine, chlorambucil, ephedamine, mechlorethamine and mildew flanges; ethyl imines such as hexamethylene melamine and beta plug Thietpa; benzoate vinegar such as busulfan; bismuth and triazine such as aitretamine, dacarbazine, procarbazine and temo saliva Amine (temozolomide); a succinyl urea such as carmustine, lomustine and streptozocin; and an inorganic metal complex (such as 'platinum, palladium or iridium metal Complex compounds such as cisplatin, carboplatin and oxaliplatin. These alkylating agents are very potent chemotherapeutic agents for the treatment of most types of cancer, including hematological and solid cancers. Unlike most types of chemotherapeutic agents, nitrosourea crosses the blood-brain barrier and is therefore particularly useful for the treatment of brain cancer. Plant alkaloids Plant alkaloids are a class of chemotherapeutic agents that are isolated from various plants. Yew (from some bark of cedar) and vinca (from vinca) are antimicrotubule agents. Camptothecan analogs (derived from Camptotheca acuminata) and podophyllotoxin (derived from ghost white plants) are topoisomerase inhibitors. These plant bases are cell cycle specific and attack cells in various stages of cell division 94999 14 201121965 cells. Plant alkaloids used in chemotherapy include, but are not limited to, 'antimicrotubules such as yew (for example, docetaxel and paclitaxel) and periwinkle bioassay (for example Verbine, Changchun, Changchun, and vinorelbine; topoisomerase inhibitors such as Hibiscus analogs (for example, irinotecan and topotecan) and Podophyllotoxin (etoposide and epipodophyllotoxin) Ten anti-tumor antibiotics Anti-tumor antibiotics are a class of chemotherapeutic agents produced by various Streptomyces. The mechanism of action of anti-tumor antibiotics involves inhibition of topoisomerase and/or generation of oxygen free radicals which result in cleavage of the DNA strand and inhibition of DNA synthesis. Antitumor antibiotics for chemotherapy include, but are not limited to, anthracyclines such as daunorubicin, doxorubicin, epirubicin, demethoxyl Idarubicin and mitoxantrone; cromomycin such as dactinomycin and cleamycin; and other antitumor antibiotics such as bleomycin and Mitomycin. Antimetabolites Anti-metabolites are inhibitors of molecules involved in cellular metabolism (antagonists). Antimetabolites are usually cell cycle specific and are classified according to the substance they interfere with. Anti-metabolites used in chemotherapy include, but are not limited to, folic acid antagonists such as methotrexate; spray bites; 94999 15 201121965 Anti-agents such as capecitabine, cytarabine (cytarabine), 5 urinary ton (5 FU), fluorouric acid (f〇xuridine) and gemcitabine (gemcitabine); sputum antagonists such as 6-mercaptopurine 6 _ thioguanine; glandamine Enzyme inhibitors such as cladribine, fludarabine, neiarabine, and pentostatin; and ribonucleotide reductase inhibitors such as hydroxyurea. Topoisomerase Inhibitors Topoisomerase inhibitors are a class of molecules that interfere with the action of topoisomerase I and topoisomerase II of topoisomerases and inhibit DNA replication. Topoisomerase inhibitors for chemotherapy include, but are not limited to, topoisomerase I inhibitors such as irinotecan and depototecan; and topoisomerase π inhibitors such as amsacrine , epipodophyllotoxin beta glucopyranoside, pyrophyllotoxin glucopyranoside and epipodophyllotoxin thiophene glycoside. A combination of additional chemotherapeutic agents for chemotherapy includes, but is not limited to, an anti-adrenalin agent such as the adrenal corticosteroid inhibitor mitotane; an enzyme such as aspartic acid phosphatase And polyethylene glycol aspartate glutamate (pegaspargase); retinoids such as bexarotene (bexarotene), isotretinoin (isotretinoin) and retinoic acid (tretinoin) (all-trans retinyl acid). Mammals receiving chemotherapy or radiation therapy usually show moderate or severe neutropenia. The present invention provides a method for preventing, inhibiting, ameliorating or treating neutropenia, in particular, accelerating the recovery of neutrophils, and reducing the degree of neutropenia and maintaining the 94999 16 201121965 renewal method. A mammal is administered a therapeutically effective amount of a compound of formula (1). For such methods, the compound of formula (1) can be administered according to the same method and time interval used to stimulate G-CSF/production. When gemifloxacin is administered as a representative compound of formula (1) to patients with reduced absolute neutrophil count (ANC) after chemotherapy or radiation therapy; the number of neutrophils is restored to normal concentration The time required and the duration of neutrophils are consistent with their therapeutically effective amount of G_CSF. Furthermore, the present invention encompasses a method comprising administering to a patient a therapeutically effective amount of a compound of formula (1) prior to the onset of fever in a patient undergoing chemotherapy or radiation therapy. 'The compound of the formula (1) according to the present invention is a drug for treating neutrophils; it can be advantageously used for the following: (1) Treatment of febrile hooliganism induced by cancer patients receiving myelosuppressive chemotherapy (6) Treatment of neutropenia induced by cancer patients receiving radiation therapy; (3) Treatment of adult patients with acute myeloid leukemia undergoing chemotherapy; (4) Treatment for receiving non-marrow Repressive chemotherapy such as ganciclivir, aciclovir, famciclovir, vidarabine, cytarabine, idoxuridine , 94,999,97821965 neutropenia induced by cancer patients with trifluridine, edoxudine, brivudine, AZT, etc.; (5)/therapy due to infection Caused by neutropenia; (6) Treatment of severe chronic neutropenia, including endogenous, congenital, or periodic neutropenia. In the present invention, the treatment of neutropenia includes prevention, inhibition, alleviation and treatment of neutropenia. In addition, the compound of formula D (promotes the production of G~CSF, thereby increasing the number of neutrophils and treating neutropenia. However, the increase in glucose concentration is independent of this process. Furthermore, the compound of formula (1) can be used Early recovery of immune cells in patients with blood damage due to chemotherapy and/or radiation therapy. For example, 'by gemifloxacin compared to the control group exposed to the lethality of the survival experiment The survival rate of the group is very high (Fig. 1). According to the present invention, the compound of the formula (1) is used as a drug for early recovery of immune cells, which can be advantageously used for the following: (1) Accepting the chemical bribery method and / or early recovery of immune cells from patients with autologous or exogenous bone mineral transplantation; and (2) immunization of patients with metastatic cancer who undergo surgery or chemotherapy to prevent the spread of residual cancer The compound of formula (1) can also be used to (1) move the hematopoietic stem cells of the bone marrow transplant donor from the bone marrow to the peripheral blood and collect them; (2) induce the collection Proliferation of the liquid-free precursor cells; and 94999 18 201121965 (3) Treatment of primary bone marrow failure - Finally, the compound of formula (1) can be used as a transient, hematopoietic reconstitution drug for mammalian hosts, for this purpose, The following methods (a) or (b) may be used: (a) The method comprises: adding a compound of formula (1) to a mixture comprising interleukins and growth factors for culturing a cell population comprising hematopoietic stem cells, Thereby increasing the myeloid precursor cells in the cell population, and (b) the method comprising: adding a compound of formula (1) to a pharmaceutically acceptable medium suitable for administration to a mammalian host, and resuspending the myeloid precursor The compound of the formula (1) according to the present invention can be used as a free compound or as a pharmaceutically acceptable salt, a solvate including a hydrate, an ester, an isomer or a prodrug. "Acceptable salt" means not causing significant irritation to the organism to which it is administered, and does not abolish the biological activity and properties of the compound. Such pharmaceutically acceptable salts are Included are acid addition salts formed by acids having pharmaceutically acceptable anions to form non-toxic acid addition salts, including, for example, mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrogen Bromic acid, hydroiodic acid, etc.; organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trigastric acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc.; The acid continues to be acid, sulphuric acid, benzoic acid, p-phthalic acid, etc. In addition, the pharmaceutically acceptable salt includes alkali metal or alkaline earth metals such as lithium, sodium, potassium, a salt formed by calcium and magnesium; a salt formed with an amino acid such as lysine, arginine, and hydrazine 19 94999 201121965; and an organic test such as dicyclohexylamine, N-methyl-D-glucosamine , ginseng (methyl) methyl ammonium, diethanolamine, biliary test and triethylamine formed salt. The compound of the formula (1) can be converted into its salt by a conventional method known in the art. The hydrates of the compound of the formula (1) are preferred because they are very stable in the pharmaceutical-related drying process and are difficult to run in a wide range of relative humidity without exhibiting hysteresis. For example, 'Gemifloxacin is preferably used in the form of eight times + hydrate or trihydrate. Such waters of the gemifloxacin: are specifically disclosed in WO 98/Face, the contents of which are incorporated herein by reference in its entirety. The hydrates according to the present invention comprise a pharmaceutically acceptable salt of the compound of the formula (1) and a test form of the compound of the formula (1). ^ The compound of the formula (1) has various pharmacological agents as described above, which can be formulated into a drug for convenient administration &, cumin; and gentleman. It can be formulated according to conventional methods and methods known in the art together with other adjuvants of the anti-recording method! Accordingly, the present invention includes a pharmaceutical composition comprising a carrier or agent of formula (1). And the medical treatment of the compound containing the compound of the formula (1) as an active ingredient is administered by various appropriate routes such as σ, non-sigma or β. The compositions may be tablets, capsules:: solutions or suspensions. For oral "volume dosage form, and may contain, for example, a saponin formulated as early sulfhydryl cellulose, propyl cellulose, gum arabic poly: two = 94999 20 201121965 alcohol, tragacanth or polyvinyl σ ratio Alkanone; filler such as microcrystalline cellulose, lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tableting lubricants such as magnesium stearate, talc, polyethylene glycol or cerium oxide a disintegrating agent such as sodium starch glycolate, crosslinked polyvinylpyrrolidone or horse starch starch; or an acceptable wetting agent such as sodium lauryl sulfate. These tablets may be coated according to methods known in the ordinary pharmaceutical practice. For example, an oral liquid preparation may be in the form of an aqueous or oily suspension, solution, emulsion, syrup or elixir, or may be present as a dry product reconstituted with water or other suitable carrier prior to use. These liquid preparations may contain conventional additives such as suspending agents such as sorbitol, decyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats and oils. Emulsifier such as egg Phospholipids, sorbitan monostearate or gum arabic; non-aqueous carriers (which may include edible oils) such as almond oil, oily s, glycerin, propylene glycol or ethanol; preservatives such as hydroxybenzoate Or propyl p-hydroxybenzoate or sorbic acid; and, if desired, a conventional aryl or stain. For parenteral administration, the compound and a sterile carrier, preferably water, are used to prepare a fluid unit dosage form. And they are administered by IV or IV infusion. Depending on the carrier and concentration used, the compound of formula (1) can be suspended or dissolved in the carrier. After the solvent is used, the active compound can be dissolved. Injectable water, and sterile filtration before filling in a suitable vial or ampoule and sealing. Advantageously, reagents such as local anesthetics, preservatives and buffers may be dissolved in the carrier. To enhance stability, The composition was lyophilized, and the dried lyophilized powder was sealed in a vial and an auxiliary vial of water for injection was provided to reconstitute the powder prior to use. In addition to the combination of the formula (1), 21 94999 201121965 Suspension in the bacterium can not be prepared by dissolving it in the same manner, and can be prepared in the same manner. The compound can be exposed by the oral suspension before it is in the essential phase. The compound is suspended in the sterile carrier, and the composition comprises ethene to be sterilized. There is a uniform distribution of the compound (1). 1 'tongue or wetting agent to promote the formula For the veterinary use of the composition of the breast. 篁 / 0 杈 good 10% by weight to 99 5% by weight, more weight % to " 5% by weight, _ amount is a secret active ingredient. When these components When several doses are included, each single reading should contain 5 to 1500 milligrams (mg) of the active ingredient measured as a free base. The dosage for adult treatment depends on the route and frequency of administration, adult patients. (body weight 70 kg (kg)) averages from 160 to 800 lng per person per day, preferably from 200 to 600 mg per day, more preferably from 300 to 500 mg per day, optimally 32 〇 mg per day. Tincture: E can be suitably administered by administering the active ingredient one or more times over a period of 24 hours, e.g., up to 4 mg per day. In practice, the dosage and frequency of administration of the most suitable individual will vary with the age, weight and response of the patient, and the physician may choose a higher or lower dosage and a different frequency of administration, depending on the circumstances. These dosage regimens are within the scope of the invention. G-CSF, which is conventionally used as an adjuvant in anticancer therapy, has a very unstable disadvantage. Therefore, it can be kept in the body for a very short period of time. In order to overcome these problems, it is generally recommended to include a method of combining biocompatible macromolecular sister 94999 22 201121965 to g-csf. According to the present invention, the formula (!) of 啥琳_antibiotics promotes the stability of G-CSF production in the body, and therefore, it is used for all diseases which can be treated or alleviated by G-CSF or Discomfort. Further, G-CSF is an expensive biopharmaceutical obtained from cell culture and is expensive to manufacture. It is very meaningful to replace G-csp with a low-cost synthetic agent. 'The benefits of providing low cost and good therapeutic quality are disclosed in more detail by the following examples, but the invention is not in any way limit. BEST MODE FOR CARRYING OUT THE INVENTION Experimental Animals Male and male C57BL/6 mice (body weight 20 to 27 grams (g)) of 6 to 8 weeks old were purchased from Orient Bio and used in the experiment. The mice were maintained in a standard incubation environment where the temperature was controlled at 7 ° C °' humidity of 55% to 60%' and the illumination and darkness were maintained at 12 ± 2, respectively. Freely supply solid feed and water. Mice were injected intraperitoneally (i PBS or two different doses (50 mg/kg and 1 mg/kg) of gemifloxacin* day' on the 5th day to stain the immune cells and study serum interleukins. Cytometry The following experiments were performed on LSK (lineage-, Sca-1+, c-Kit+) cells containing a large number of mouse hematopoietic stem cells. In order to obtain bone marrow cells, the rats were euthanized with 3% of the gods. Cervical dislocation. Use a syringe to clean bone marrow from the aseptically extracted tibia, femur and ischial bone and separate the bone marrow cells. For isolated bone marrow cells, CD4, CD8, B220, Gr-1 corresponding to lineage cells were performed (Ly -6G), Mac-1 (CDllb) and Ter-119 23 94999 201121965 Labeling of antigen and Sea-b c-Kit antigen antibody, followed by study of the LSK cells. To study from mice by flow cytometry Granulocytes of bone marrow, spleen and peripheral blood 'stained cells from separate organs were stained with antibodies against mouse Gr-l (Ly-6G) and Mac_l (CDllb)-labeled antigens. Collected by using the FACSCalibur system and Using Fi〇wj〇 analysis, via The labeled antigen is subjected to a segmented study of cells such as granulosa cells, lymphocytes, etc. The total number of lymphocytes, granulocytes, red blood cells and platelets is counted by an animal blood counter. Example 1 According to Example 180 of EP 688772 METHODS: Gemifloxacin was prepared. After 4 days of treatment of mice with 50 mg/kg or 100 mg/kg of gemifloxacin, the lymphocytes (CD4+, CD8+, B220+) in the peripheral blood or spleen cells of the mice were prepared. And the number of neutrophils (Gr-1+, CD11b+) compared to those of negative control mice (pBS-treated mice). Measurement of lymphocytes and granulocytes by flow cytometry The changes after treatment with gemifloxacin are shown in Figures 1 and 2. In the group treated with gemifloxacin, the number of neutrophils (Gr_1 +, CD 11 b+) is the dose. The increase in dependence was confirmed by flow cytometry (Fig. 3). The results demonstrate that the use of gemifloxacin in normal mice increases the number of neutrophils in the peripheral blood or spleen. Example 2 24 94999 201121965In the group of mice in Example 1, the protein analysis kit (Pr〇tein array kit) was used to study the change of interleukin in the blood. As shown in Fig. 4, the results showed that treatment with gemifloxacin was used. Induction of G-CSF, MCP-6 (monocyte chemotaxis factor) and TREM_i (which is associated with the activity of bone marrow cells) and the contamination of the hematopoietic stem cells from the bone marrow to the peripheral blood Reduced. The results showed that gemifloxacin increased the number of G-CSF in vivo and played a role in restoring hematopoiesis and increasing neutrophils. Example 3

In order to demonstrate that gemifloxacin increases G_CSF in vivo and thereby promotes self-replication of hematopoietic stem cells, the following examples were performed to perform a segmental study on LSK (lineage-, Sca__1+, c_Kit+) cells containing a large number of mouse hematopoietic stem cells. In order to obtain bone marrow cells, the rats were euthanized and euthanized to dislocate the cervical spine. Bone marrow cells are isolated from the bone marrow of the aseptically extracted tibia, femur and ischial bone using a syringe. The CD4, (10), B22G, Gr_lay_6(J)U (CDllb) and Ter-119 labeled antigens and (4), c, t antigen antibodies corresponding to lineage cells were subjected to immunization with the isolated bone cells. The cells expressing &3_c c.t positive cells and the marginal cells were expressed by flow cytometry. As shown in Figure 5, the control group (treated with PBS) was treated with gemoxacin: the frequency of total hematopoietic stem cells in the group increased approximately 2 times (from 〇3眯 to 〇 62% or 0.63%). The results shown in Figure 6 support this step-by-step, and Figure 6 shows the spleen induced by the treatment of f-fimimefloxacin by sputum (hematoxylin and eosin). a) and intraosseous bone _ cell ^ 94999 25 201121965 colonization. Example 4-1 the therapeutic effect of gemifloxacin on the proliferation of bone marrow cells in peripheral blood and the therapeutic effect of the positive control drug ciprof 1 oxacin Comparison. The bone marrow cells were analyzed by flow cytometry. The mice were administered 150 mg/kg of the anticancer agent 5-FU via i.P., and after 24 hours, the method disclosed in Example 1 was administered. Gemifloxacin or PBS is administered twice daily via ip at a dose of 25 mg/kg. As shown in Figure 7, the negative control group (PBS-treated mice) is in the peripheral blood by Ly-6G ( Gr-1 + ) and CDllb+ showed no increase in neutrophils. Compared with the negative control group, the group treated with gemifloxacin White blood cells increased more than 4 times (3.04% vs. (90%), while neutrophils did not increase in ciprofloxacin-treated patients. Figure 7 shows neutrophils The actual number further supports this result obtained by flow cytometry.Example 4-2 For the compound of the following structure (hereinafter referred to as Compound A), its effect on proliferation of bone marrow cells in peripheral blood and a positive control agent Comparison of G-CSF. Compound A was prepared according to the method disclosed in Example 180 of EP688772, except that 7-chloro-6-fluoro-1-indolyl-4-oxo-1,4-diar-[ 1,8]naphthyridine-3-carboxylic acid instead of 1-cyclopropyl-7-chloro-6-fluoro-4-o-oxy-1,4-dihydro-[1,8]naphthyridin-3-carboxylate The acid is used as an intermediate. The use of decylamine in place of cyclopropylamine affords 7-chloro-6-fluoro-1-indolyl-4-yloxy-1,4-dihydro-[1,8] according to the method disclosed in EP 1 678 174 A1. Naphthyridine-3-carboxylic acid. 26 94999 201121965 ο ο

F Α Compound Α (50 mg/kg), PBS and G-CSFC 125 μg (#g)/kg were administered to mice, respectively. After 24 hours, the peripheral blood was analyzed by flow cytometry. Bone marrow cells. As shown in Figure 9, the increase in neutrophils in the group treated with Compound A was similar to that in the G-CSF treatment group. Example 5 In order to study the protective effect of genifloxacin on the radiation hazard caused by lethal radiation dose' mice were divided into radiation-only groups (6 rats) and after radiation ------------ --- d 4 radiation rate at a single radiation dose of 10 Gy on the dorsal side of the gemfloxacin dissolved in physiological saline solution, radiation 24 hours field. 2 ml (mL) 5 sea solution via 丨 · mg / kg The moxibustion drug is 7 曰. Since only blushing ..., the group treated with gemifloxacin 〇 mouse). The rats were placed in a radiation chamber and the rats were administered for 7 days using a 6 MV linear accelerator (Siemens, pA, USA): n,,. Λ 3 Gy/min 5 . From only + Qiao Li Xian, J, 4 two-star / alpha therapy group administered gemifloxacin, study the survival rate of two groups of t-killing Maier analysis to the death of radiation, the occupancy rate ln untreated, star treatment group The fatality rate of the group, % 堇 I brother 10 in the picture. In the community _ fruit house § - . Fruit is not the treatment of the body to protect the body π ^ Shuo does not shoot the radiation-induced danger of the macro-hard is not the first mouse in the group after the death of the next day, the defeat of the treatment of gemifloxacin / 'one ... one , stop the sputum hydroxy 2 only, _ y f radiation induced radiation damage, such as February sputum inhibition. 27 ^4999 201121965 This effect is attributed to the action of gemifloxacin, which induces early recovery of hematopoietic cells by increasing neutrophils and hematopoietic stem cells, thereby preventing possible infections. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows changes in the number of peripheral blood cells in mice treated with gemifloxacin; Figure 2 shows changes in the number of spleen cells in mice treated with gemifloxacin; Figure 3 shows Proliferation of osteoblasts in peripheral blood cells of mice treated with gemifloxacin using flow cytometry; Figure 4 shows changes in various interleukins in serum of mice treated with gemifloxacin; Figure 5 shows changes in the frequency of mouse bone marrow hematopoietic stem cells treated with gemifloxacin using flow cytometry; Figure 6 is a graph showing cell proliferation in the spleen red sputum region of mice treated with gemifloxacin Photographs of histochemical analysis (a), and photographs showing histochemical analysis of the proliferation of bone marrow cells in the bone marrow of mice treated with gemifloxacin (b); Figure 7 shows the analysis of Jimmy using flow cytometry Sha Xing is used for the efficacy of neutropenia caused by the anticancer agent 5-FU; Figure 8 shows the change by the target of myeloid cells. Gemifloxacin is used for the treatment of neutropenia caused by the anticancer agent 5-FU; Figure 9 shows the change indicated by the number of neutrophils. 28 94999 201121965 Compound A in peripheral blood The effect on myeloid cells; and - Figure 10 shows the radiation-only group and the gemizae calculated by the Kaplan-Meier survival analysis The fatality rate of the group of star treatments. [Main component symbol description] None 29 94999

Claims (1)

201121965 Patent application scope: A medicament for treating a tropophilic flavonoid, comprising a therapeutically effective amount of a compound of the formula (1), a salt thereof, a solvate comprising a hydrate, an isomer or a prodrug As an active ingredient: 0) wherein R represents hydrogen, methyl or amine, and Q represents CH, CF, C-C1, C-OH, C-CH3, C-〇-CH3 or N, and represents hydrogen, cyclopropyl, A mercapto or ethyl group, or a phenyl group substituted by one or more fluorine atoms, and R2 represents one of the following a) to e): a) hydrogen, straight or branched chain Ci-C4 alkyl, cyclopropyl , cyclopropylmethyl, CH: 6 alkynyl, 2-haloethyl, decyloxymethyl, methoxycarbonylmethyl, phenyl or decyl, b) the formula of the formula Non-nitrogen, 2-, 3- or 4-fluoro, gas-based, schlossyl, decyloxy, Ci-C4 alkyl or 2,4-difluoro, 1 94999 201121965 C) d) The base of the following formula: 9 e) The base of the formula wherein η refers to 0 or 1 'm refers to 0, 1 or 2, lanthanide represents anthracenylene, 0 or N, and R3 represents -CMR5R6, wherein Rs And Re are independent of each other to represent hydrogen or G-C3 alkyl, or RS and Re may form a ring with the nitrogen atom to which they are bonded, lanthanide represents hydrogen, or R3 and R4 together with the carbon atom to which they are bonded form a structure R,~ NC^<, the structure is formed by a spiro ring in combination with the pyrrolidine ring, wherein 'R?" represents hydrogen or a C1-C4 alkyl group. The drug according to claim 1, wherein the compound of the formula (1) is gemifloxacin (gemif l〇xacin). The drug according to claim 1 or 2, wherein the vaginal leukocytopenia is induced by febrile neutropenia in a cancer patient undergoing bone marrow suppression chemotherapy. 4. The medicament according to claim 1 or 2, wherein the neutropenia is induced by a cancer patient receiving radiation. 5. The medicament according to claim 1 or 2, wherein the neutrophil reduction is induced in a patient with adult acute myeloid leukemia receiving chemotherapy. 6. The medicament according to claim 1 or 2, wherein the neutropenia is caused by a cancer patient who induces a bone marrow suppression therapy other than chemotherapy. 7. The drug according to claim 6, wherein the non-chemotherapeutic myelosuppressive therapy is selected from the group consisting of ganciclovir, acyclovir, ciclovir, and sputum. Ciclovir, penciclovir, fenciclovir, adenosine, arabin, bitter, moth, urinary, urinary and indifferent. 8. The medicament according to claim 2 or 2, wherein the neutropenia is caused by an infection. 9. The medicament according to claim 1 or 2, wherein the neutropenia is severe chronic neutropenia. 10. The medicament of claim 9, wherein the severe chronic neutropenia is endogenous, congenital, or periodic neutropenia. 11. A medicament for the early recovery of immune cells, comprising a compound of formula (1) as defined in the therapeutically invented scope of claim 3, a pharmaceutically acceptable salt thereof, a solvent comprising a hydrate. Compounds, esters, isomers or prodrugs as active ingredients. • 12. The medicament according to claim 11, wherein the medicament is for early recovery of an immune cell of a self-derived or exogenous bone marrow transplant patient undergoing chemical clear marrow therapy or radiation clearing therapy. 13. The medicament of claim 11, wherein the medicament is for enhancing immunity of a patient suffering from metastatic cancer who is undergoing surgery or chemotherapy and thereby preventing the spread of residual cancer. 14. A medicament for the movement of cells from the bone marrow to the peripheral blood, comprising a therapeutically effective amount of a compound of formula (1) as defined in claim 1 of the patent application, a pharmaceutically acceptable salt thereof, including a hydrate. A solvate, ester, isomer or prodrug is used as the active ingredient. 15. The medicament of claim 14, wherein the medicament is for collecting hematopoietic stem cells of a bone marrow transplant donor. 16. A medicament for collecting cells, comprising a therapeutically effective amount of a compound of formula (1) as defined in claim 1 of the patent application, a pharmaceutically acceptable salt thereof, a solvate comprising the hydrate, an ester, Isomers or prodrugs are used as active ingredients. 17. The medicament according to claim 16, wherein the collection of the cells is achieved by inducing proliferation of peripheral blood precursor cells. 18. A medicament for the treatment of primary bone marrow failure comprising a therapeutically effective amount of a compound of formula (1) as defined in claim 1 of the patent application, a pharmaceutically acceptable salt thereof, a solvate comprising a hydrate A substance, vinegar, isomer or prodrug as an active ingredient. 4 94999 201121965 19. A medicament for transient hematopoietic reconstitution of a mammalian host comprising a therapeutically effective amount of a compound of formula (1) as defined in claim 1 of the patent application, pharmaceutically acceptable salts thereof, including hydrates A solvate, ester, isomer or prodrug as an active ingredient. 20. The medicament according to claim 19, wherein the hematopoietic reconstitution is achieved according to the following method (a) or (b): (a) the method comprises: adding a compound of the formula (1) to a cell-containing medium a medium for mixing a mixture of a gene and a growth factor for culturing a cell group comprising hematopoietic stem cells, thereby increasing a myeloid precursor cell in the cell group, and (b) a method comprising: applying a compound of formula (1) The myeloid precursor cells are resuspended in a pharmaceutically acceptable medium for administration to a mammalian host. The pharmaceutical according to any one of claims 11, 14, 16, 18, and 19, wherein the compound of the formula (1) is gemifloxacin. 22. A method for treating neutropenia in a mammal or achieving early recovery of immune cells in a mammal, comprising administering a therapeutically effective amount to a mammal as defined in claim 1 A compound of the formula (1), a pharmaceutically acceptable salt thereof, a solvate comprising a hydrate, an ester, an isomer or a prodrug. 23. A method for preventing, inhibiting, ameliorating or treating neutropenia caused by chemotherapy or radiation therapy, comprising administering to a mammal receiving the chemotherapy or radiation therapy, Inhibition, alleviation or treatment of neutropenia is an effective amount of the application 5 94999 • 201121965 The formula (1) as defined in Item 1 of the formula I, the pharmaceutically acceptable salt thereof, the solvate of the hydrate A substance, ester, isomer or prodrug. The method of claim 22, wherein the compound of the formula (1) is gemifloxacin. 25. The use of a compound of the formula (1) described in the scope of the patent application, which is used for the manufacture of a neutropenia, especially by chemotherapy or radiation therapy. Leukopenia, as well as early recovery of immune cells. 94999 6