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 六、發明說明： 【發明所屬之技術領域】 "本發明係關於用於治療嗜中性白血球減少症及早期 恢復免疫細胞的藥物。該藥物係包含治療有效量之下式⑴ 表示之3有7 (4~胺基甲基-3-躬·）α比洛唆基團之噎琳_抗 生素化5物、其醫藥可接受之鹽、包括水合物之溶劑合物、 S曰、異構物或前藥（後文巾，這些係簡短地指稱為式⑴化 合物），其係能促進G_CSF(粒細胞群落刺激因子）之產生。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係表示氫、曱基或胺基， Q 係表示 C~H、C-F、C-C1、C-0H、C-CH3、C-0-CH3 或 N，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係表示氫、環丙基、甲基或乙基，或經由一個或多 個氟原子取代之苯基， 匕係表示下列&)至e)之一者： a) 氫、直鏈或分支鍵Ci-C4烧基、環丙基、環丙基甲 基、炔基、2-鹵乙基、曱氧基曱基、甲氧基羰基甲基、 苯基或烯丙基， b) 下式之基 94999 3 201121965Rl 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

其中，X係表示氫、2-、3-或4-之氟、氰基、硝基、 甲氧基、C1-C4炫基或2, 4-二氟ι， c)下式之基 ^ ^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) 下式之基 ：^<Χγ > e) 下式之基 ^^(〇Ητ)πΤ^ 其中，η指稱0或卜m指稱〇、i或2，χ係表示亞甲 基、0或Ν，以及 h係表示-CIMRsR6，其中，匕與Re係彼此獨立表示氫 ，CrC道基，或㈣Re可與其所結合之氮原子—起形成 環， R4係表示氫，或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

係表示 R3與匕與其所結合有之碳原子一起形成結構 該結構係以螺環形式與該^各謂組合，其中， 94999 4 201121965 氮或Cl_C4烧基。 本發明中，該式（1)化合物係作為用於治療嗜令性白 血球減少症及恢復造血的藥物使用，且其係具體揭露於 EP06887772B1 及 KR 10-0566346B1。本發明中，較佳地使 用之啥淋嗣抗生素為名為吉米沙星（gemifloxacin)，亦 即’ 7_(4-胺基曱基-3-甲氧基亞胺基π比略咬-1-基）-1 —環丙 基-6-氟-4-側氧基-1，4-二氫-1，8-萘啶-3-羧酸，及其醫藥 可接受之鹽、溶劑合物（包括水合物）、酯、異構物或前藥（後 文中，這些係簡短地指稱為吉米沙星）。包括吉米沙星之上 述定義之喹啉酮抗生素促進並增加有機體内G-CSF之產 生，從而促進嗜中性白血球粒細胞系之先驅細胞 (progenitor cell)的增殖與分化。吉米沙星及該啥琳酮抗 生素增加嗜中性白血球之數目並促進成熟之嗜中性白血球 的活性，因此，他們可較佳地作為抗癌療法之佐劑用於預 防、抑制、緩解及治療嗜中性白血球減少症，以及作為用 於提升免疫細胞（特別是經免疫疾病抑制之骨趙免疫細胞） 濃度的藥物及其治療。他們可用作G-CSF及PEG化之G~CSF 衍生物的代用品。 【先前技術】 造血係有機體之生命得以維持之主要系統。通過各種 途徑自骨髓起始而產生多個免疫細胞系。造血係藉由一般 稱為CSFs之特異性醣蛋白予以調控。cSFs係因為當於半 固體培養基中培養造血幹細胞或造血先驅細胞時，其作為 生長因子促進單核細胞株、粒細胞或其他造血細胞之形成 5 94999 201121965 而知名。此等因子係依據其促進之細胞系的種類而分類與 p名舉例而s , G-CSF (粒細胞-CSF)主要促進嗜中性白 血球群落之形成，GM_CSF主要促進巨噬細胞群落之形成， 而夕CSF (IL-3)主要促進粒細胞、巨嗤細胞、巨核細胞及 紅血球之群落形成。 G-CSF係引導骨髓幹細胞及白血球於骨髓外之***與 分化之細胞介素。其亦促進嗜中性白血球-先驅細胞之*** 與分化並活化成熟之嗜中性白血球，從而提升其吞噬作 用、趨化作用、抗體依賴型細胞之細胞毒性、產生超氧化 物之活性及對趨化性因子之響應能力（Metcalf，B1〇〇d (1986) 67:257 ;Yan 等，Blood (1994) 84(3):795-799 ; Bensinger 等，Blood (1993) 81(11):3158-3163 ; Roberts 等，Expt’ 1 Hematology (1994) 22:1156-1163 ;Neben 等，Blood (1993) 81(7):1960-1967)。目前，G-CSF 通常 係自各種細胞分離或藉由基因重組技術生產，其係有效地 用於各種抗癌療法及難治性白血病之治療。於抗癌療法 中’典型實施者係放射療法及高劑量化學療法，但此等治 療方法摧毁患者骨髓之造血細胞，因此誘發包括嗜中性白 血球之白血球的急劇退化，從而弱化免疫系統並增加感染 之風險。因此，限制了長期且重複進行之放射療法及高劑 量化學療法。於此等抗癌療法之副作用之中，嗜中性白血 球減少症係最常見者，其特徵為在循環之白血球，特別是 嗜中性白血球之減少。正常健康成年人血液中具有之絕對 嗜中性白血球計數（ANC)為4400/立方毫米（mm3)，且平均 6 94999 201121965 正常嗜中性白血球計數為1800/mm3至7700/mm3之範圍。當 ANC係於l〇〇〇/mm3至1500/mm3之範圍時，其歸類為中度嗜 中性白血球減少症；而當ANC係低於500/mm3時，其歸類 為嚴重嗜中性白血球減少症。嚴重嗜中性白血球減少症使 得患者易羅患致死感染。 當患者接受化學療法或自源性或外源性移植時，需要 用於恢復造血之一定期間。於該恢復期間中，患者具有較 低濃度之循環性嗜中性白血球，因此，他們容易曝露於真 菌或細菌造成之感染，特別是常見微生物如薰煙色麴菌或 綠膿桿菌造成之機會感染，且該等感染顯著影響患者之存 活。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等人報導了 G-CSF可活化患者之免疫系統，並 因此作為抗癌療法之佐劑以待更有效地予以實施（L ◦ p e z 等，J· Immunol· (1983) 131(6):2983-2988 ; Platzer 等， J· Exp. Med. (1985) 162:1788-1801)。G-CSF 尤其有效 地用作藥物，以改善由抗癌療法造成之副作用的嗜中性白 血球減少症（MorstynG.等，Trends Pharmacol. Sci. (1989) 10:154-159)。據報導，G-CSF參予了使造血幹細 胞或造血先驅細胞自骨髓移動至末梢血液（G〇〇d Review article, Haylock 等，Blood (1997) 89:2233-2258)。 然而，G-CSF由非常不安定之缺點，因此，其僅可於 體内保持極端之時間。為了克服此等問題，建議將G-CSF 與如聚乙二醇（PEG)、聚乙烯醇及聚乙烯基。比咯烷酮之生物 相容性大分子結合。此等方法解決了不安定性之問題；然 7 94999 201121965 而，他們仍然使用外源G-CSF如重組G-CSF ’且可能於給 藥對象誘發非所欲之免疫反應。此外，超過20%之患者發 展對於基因重組G-CSF之耐受度或不響應G-CSF ’因此’ G-CSF對於他們沒有療效（Sada等，J. Fermentation Bioengineering (1991) 71:137-139 ;Flomenberg 等， Blood (2005) 106:1867-1874)。 【發明内容】 本發明之發明人業經研究可促進外源G-CSF於活體内 之產生及活性，代替使用經基因重組之G-CSF治療患者。 經過大量研究，本發明之發明人業經發現，下式（1)表示之 含有7-(4-胺基曱基-3-肟）吡咯啶基團之喹啉酮抗生素， 其醫藥可接受之鹽、包括水合物之溶劑合物、酯、異構物 或前藥可於體内促進G-CSF之產生，因此，他們可用作治 療嗜中性白血球減少症的藥物。此外，他們於骨髓内促進 造血幹細胞之增殖與分化，並將該等造血幹細胞或造血先 驅細胞自骨髓移動至末梢血液。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係表示氫、甲基或胺基， Q 係表示 C-H、C-F、C-Π、C-0H、C-CH3、C-O-CHa 或 N， 8 94999 201121965R 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係表示氫、環丙基、甲基或乙基，或經由一個或多 個氟原子取代之苯基， 尺2係表示下列a)至e)之一者： a)氫、直鏈或分支鏈Ci-匕烷基、環丙基、環丙基曱 基、C3_C6炔基、2-鹵乙基、曱氧基甲基、曱氧基羰基甲基、 苯基或稀丙基， b)下式之基 其中，X係表示氫、2-、3-或4-之氟、氰基、硝基 甲氧基〜匕^^烷基或之^-二氟， c)下式之基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)

^0^0

e)下式之基 少(cHiVi· 其中，η指稱〇或1，m指稱〇、1或2，X係表示亞甲 基、0或N，以及 94999 9 201121965 匕係表示-CH2NRSR6，其中，R ；Cl'C3^^j ^ 壞， 虱原子一起形成 h係表示氫，或 1^與1^與其所結合有缺卩4 r,-n〇J _子一起形成結構 ’該結構係以螺環形式與診 R?係表示氫或G-C4烷基。 Μ ^啶環紱合，其中， 造血幹細胞之數目，::見效生素增加骨㈣ 於本發明中，該式⑴化合物中較佳者二群之早期恢復。 醫藥可接受之鹽、包括水合 、別^吉米沙星，其 前藥。 ^物、醋、異構物或 重分子量之合成化合物代替傳綠經基因 重、，且之间分子量G谓。與傳統方法 U基因 及轉成本方面藉此具有不可思議之優點。傳^=途捏 :==必須通過非經口途徑，如;=重 二峨)、連續SC輸液或連續㈣液進行)， f能於醫院之外將其容易地攜帶，因此存在顯著^患 =同時，根據本發明之钱酮抗生素可口服给藥/因t 患者可容易地攜帶藥物而不必來醫院。此外，經基因^且 = G-CSF非常昂貴，即便在已開發國家，多數患者仍因其 问成本而無法接文治療。然而，本發明使用低成本合成化 α物ϋ此’更>患者可享受與經基因重組之g_csf同等 10 94999 201121965 療效之益處。除了上述優點之外，因為當根據本發明之式 ; (1)化合物治療使用抗癌劑進行人工誘發之嗜中性白血球 - 減少症模型時，ANC自完全縮減狀態恢復至正常濃度之起 k 始時間以及到達所謂正常濃度所需之時間為止，亦即嗜中 性白血球減少症之持續時間幾乎與使用G-CSF治療所需之 時間相同，該式（1)化合物顯示與G-CSF —致之效果，因此 該式（1)化合物具有非常高之產業優勢。 本發明之目標係提供抗癌佐劑，具體為G-CSF之替代 品，用於嗜中性白血球減少症之藥物、用於免疫細胞早期 恢復之藥物、以及用於誘發造血幹細胞或造血先驅細胞自 骨髓向末梢血液移動之藥物，係包含治療有效量之含有 7-(4-胺基曱基-3-肟）吡咯啶基團之喹啉酮衍生物抗生素， 或其醫藥可接受之鹽、包括水合物之溶劑合物、酯、異構 物或前藥。 根據本發明之較佳之啥琳酮衍生物化合物係吉米沙 星。 本發明之另一目標係提供用於哺乳動物促進G-CSF之 產生的方法，係包含對該哺乳動物給藥治療有效量之式（1) 之含有7-(4-胺基曱基-3-肟）吡咯啶基團之喹啉酮衍生物 抗生素，或其醫藥可接受之鹽、包括水合物之溶劑合物、 酯、異構物或前藥。 本發明之另一目標係提供用於治療響應使用G-CSF治 療之狀況的方法，係包含對該哺乳動物給藥治療有效量之 式（1)之含有7-(4-胺基曱基-3-肟）吡咯啶基團之喹啉酮 11 94999 201121965 衍生物抗生素、或其醫藥可接受之鹽、包括水合物之溶劑 合物、酯、異構物或前藥。響應使用G-CSF治療之狀況係 包括嗜中性白血球減少症、降低之嗜中性白血球移動、降 低之末梢血液先驅細胞移動、敗血症、嚴重之慢性嗜中性 白血球減少症、骨髓發育不全或骨髓抑制、以及後天性免 疫缺失症候群。 本發明之另一目標係提供用於增加免疫細胞，特別是 骨髓性免疫細胞，以及藉由誘發造血幹細胞或造血先驅細 胞自骨髓向末梢血液移動而收集該等細胞的方法，係包含 對該哺乳動物給藥治療有效量之式（1)之含有7_(4_胺基 曱基-3-肟）吡咯啶基團之喹啉酮衍生物抗生素、或其醫藥 可接又之鹽、包括水合物之溶劑合物、酯、異構物或前藥。 根據本發明之特佳之啥琳酮衍生物化合物係吉米沙 星，且該療法係包括彼等施用於哺乳動物但非人類者。 /二文中本發明將關注吉米沙星，本發明之啥淋酿J衍 生物抗生素之—者’進行詳細解釋；然而 並非限制騎諸星。 ^之^ 【實施方式】 G-Cst明之發明人顯示’式⑴化合物能於體内促進 ❹ 且能使料為纽在減療法巾作為佐劑 之基因重組之G—CSF的替代品。因此， 可於抗癌療法中用作佐劑。更且體而七於垃式⑴化合物 療法^心. 具體 接受抗癌化學 之產:-療法之患者體内，該式⑴化合物促進G_CSF 誘發骨髓内造血幹細胞之***與分化、造血幹細 94999 12 201121965 胞或造血先驅細胞向末梢血液之移動及骨髓性細胞於末梢 -血液及脾臟中的增殖。特別地，本發明之發明人發現，吉 ,·米沙星全身性地促進骨髓性細胞之***以及於骨髓促進造 血幹細胞之***。因此’本發明係包含使用式⑴化合物作 為抗癌療法如抗癌化學療法或放射療法之佐劑之g_csf的 替代品的方法。特別地，本發明包含選擇地增加體内〇售 之產生的方法，更具體而言，其中，不促進甚至壓抑gm csf 藥該式(1)化合物’該哺乳動物係發 之耐受性或由於其他原因對該外^ 或IL-2之產生。此外，本發明包含促進G CSF之產生的方 法，包含對哺乳動物給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

展出對於外源性G-CSF 性G-CSF不做響應。 於本發明中，外源性G-CSF係包括自各種細胞分離之 G-CSF、自原核細胞或真核細胞之基因重組之G_csp、勹括 糖化之各種G-CSF變種。包括可商業購得之來諾拉提 (lenograstim) (Granocyte®)、非格司亭（filgrastim) (Neupogen®)及聚乙二醇化非格司亭（Neulasta®)。 根據本發明之式（1)化合物可於化學療法或放射療法 之前、之中或之後對哺乳動物給藥。當於化學療法或玫射 療法之前給藥時，其可於至少1天前’較佳2至3天前， 更佳4天前給藥。當於化學療法或放射療法之後給藥時， 其可於完成化學療法或放射療法之當天給藥，完成化學療 法或放射療法當天起1天内，或2至3天内，或至少4天 内給藥。當實施超過1次循環之化學療法或放射療法時， 式（1)化合物可於各別循環完全之後如上揭者給藥。 13 94999 201121965 依據其作用機制、化學結構及來源，可用於上述抗癌 化學療法之抗癌劑係包括，但不限於，下列化合物： 烧基化劑 該烷基化劑係包括，但不限於，芥子氣衍生物如環攝 醯胺、氯芥苯丁酸、依弗醯胺、二氯曱基二乙胺 (mechlorethamine)及黴法蘭；伸乙基亞胺類如六曱基三聚 氰胺及β塞替派（thiotepa);續酸烧基醋如白消安 (busulfan);肼及三氮稀如六曱蜜胺（aitretamine)、氮締 嗤胺（dacarbazine)、曱苄肼（procarbazine)及替莫唾胺 (temozolomide);亞石肖基脲如卡氣芥（carmustine)、環己 亞石肖腺（lomustine)及鏈左星（streptozocin);以及無機金 屬錯合物劑（如’鉑、鈀或釕之金屬錯合物）如順鉑 (cisplatin)、卡銘（carboplatin)及奥沙利翻 (oxaliplatin)。此等烷基化劑係非常強之化療劑，用以治 療大多數類型之癌症，包括血液腫瘤及實性癌。與大多數 類型之化療劑不同，亞硝基脲能跨越血腦障壁，並因此可 特別有用於治療腦癌。 植物生物鹼 植物生物鹼係一類自各種植物單離之化療劑。紫杉烧 (源自某些杉樹之樹皮）及長春花生物齡·（源自長春花植物） 係抗微管劑（antimicrotubule agent)。喜樹驗 (camptothecan)類似物（源自喜樹）及鬼臼毒素（源自鬼白 植物）係拓撲異構酶（topiosomerase)抑制劑。該等植物生 物鹼係細胞循環特異性者且於細胞***之各種階段中攻擊 94999 14 201121965 細胞。於化學療法中使用之植物生物鹼係包括，但不限於， ' 抗微管劑如紫杉烧（舉例而言，歐洲紫杉醇（docetaxel)及 太平洋紫杉醇（paclitaxel))及長春花生物驗（舉例而言， 長春驗、長春新驗及長春瑞濱（vinorelbine));拓撲異構 酶抑制劑如喜樹驗類似物（舉例而言，伊立替康 (irinotecan)及脫泊替康（topotecan))及鬼臼毒素（表鬼 臼毒素吡喃葡糖苷（etoposide)及表鬼臼毒素噻吩糖苷 (tenisopide)) ° 抗腫瘤抗生素 抗腫瘤抗生素係一類藉由各種鏈黴菌屬生產之化療 劑。抗腫瘤抗生素之作用機制係包括抑制拓撲異構酶及/ 或生成氧自由基，其導致DNA鏈之斷裂並抑制DNA之合成。 用於化學療法之抗腫瘤抗生素係包括，但不限於，蒽環黴 素（anthracyclines)如柔紅黴素（daunorubicin)、阿黴素 (doxorubicin)、表阿黴素（epirubicin)、去曱氧基柔紅黴 素（idarubicin)及米托蒽醌（mitoxantrone);色黴素 (cromomycin)如更生黴素（dactinomycin)及光輝黴素 (plicamycin);以及其他抗腫瘤抗生素如爭光黴素 (bleomycin)及絲裂黴素。 抗代謝物 抗代謝物係細胞代謝中相關之分子的抑制劑（拮技^ 劑）。抗代謝物通常係細胞循環特異性者且根據他們干擾之 物質進行分類。於化學療法中使用之抗代謝物係包括，但 不限於，葉酸拮抗劑如曱氨喋呤（methotrexate);喷咬;枯 94999 15 201121965 抗劑如卡培他濱（Capecitabine)、阿糖胞苷（cytarabine)、 5氣尿吨定（5 FU)、氟尿苦（f〇xuridine)及吉西他濱 (gemcitabine);嘌呤拮抗劑如6_酼基嘌呤基6_硫代鳥嘌 吟；腺皆去胺酶抑制劑如克拉屈濱（cladribine)、氟達拉 /負（fludarabine)、奈拉濱（neiarabine)及喷司他丁 (pentostatin);以及核糖核苷酸還原酶抑制劑如羥基脲。 拓撲異構酶抑制劑 拓撲異構酶抑制劑係一類分子其干擾拓撲異構酶類 之拓撲異構酶I及拓撲異構酶II之作用，並抑制DNA複 製。用於化學療法之拓撲異構酶抑制劑係包括，但不限於， 拓撲異構酶I抑制劑如伊立替康及脫泊替康；以及拓撲異 構酶π抑制劑如安吖唆（amsacrine)、表鬼臼毒素β比喃葡 糖苷、磷酸表鬼臼毒素吡喃葡糖苷及表鬼臼毒素噻吩糖苷。 綜合化療劑 用於化學療法之額外類型之化合物係包括，但不限 於，抗腎上腺素劑（andren〇iytic agent)如腎上腺皮質類 固醇抑制劑米托坦（mitotane);酶如天冬醯胺酸酶及聚乙 二醇天冬醯胺酸酶（pegaspargase);類視色素如貝沙羅汀 (bexarotene)、異維甲酸（isotretinoin)及維曱酸 (tretinoin)(全反式視網酸）。 接受化學療法或放射療法之哺乳動物通常顯示中等 或嚴重之嗜中性白血球減少症。本發明提供預防、抑制、 緩解或治療嗜中性白血球減少症的方法，特別是加速恢復 嗜中性白血球，以及降低嗜中性白血球減少症之程度及持 94999 16 201121965 續期的方法’包含對哺乳動物給藥治療有效量之式⑴化合 '物。對於此等方法，式⑴化合物可根據用於刺激G-CSF /之產生的相同方法及時間間隔予以給藥。當將吉米沙星作 為代表性式⑴化合物對錢受化學療法或放射療法後具 有降低之絕對嗜中性白血球計數（ANC)的患者給藥時;，將嗜 中性白血球之數目恢復至正常濃度所需之時間以及嗜中性 白血球之持續期與彼等以治療有效量之G_CSF治療者一 致。此外，本發明包括下述方法，該方法包含於接受化學 療法或放射療法之患者出現發熱之前，對該患者給藥治療 有效量之式（1)化合物。' 根據本發明’式（1)化合物係作為治療嗜中性白血球 的藥物；其可有利地用於下列者： (1) 治療於接受骨髓抑制性化學療法之癌症患者所 誘發的發熱性嗜中性白金球減少症； (2) 治療於接受放射療法之癌症患者所誘發的嗜中 性白血球減少症； (3) 治療接受化學療法之成年急性骨髓性白血病患 者； (4) 治療於接受非骨髓壓抑性化學療法如更昔洛韋 (ganciclivir)、阿昔洛韋（aciclovir)、芬昔洛 韋（famciclovir)、阿糖腺苷（vidarabine)、阿 糖胞苷（cytarabine)、蛾苷（idoxuridine)、三 氟尿苷（trifluridine)、依度尿苷（edoxudine)、 溴夫定（brivudine)、AZT等之癌症患者所誘發的 17 94999 201121965 嗜中性白血球減少症； (5 )/〇療由於感染所造成之嗜中性白血球減少症； (6)治療嚴重之慢性嗜中性白血球減少症，包括内因 性、先天性、或週期性之嗜中性白血球減少症。 於本發明中，嗜中性白血球減少症之治療包括嗜中性 白血球減少症之預防、抑制、緩解及治療。此外，式（D 化合物促進G〜CSF之產生，從而增加嗜中性白血球之數目 並治療嗜中性白血球減少症。然而，葡萄糖濃度之增加與 此製程無關。 此外’式（1)化合物可用於由於化學療法及/或放射療 法造成之，血損害的患者的免疫細胞的早期恢復。舉例而 言’與彼等曝露於致死轄射之存活實驗中之對照群組相 比，經吉米沙星治療之群組的存活率非常高（第1〇圖）。 根據本發明，式⑴化合物係用作免疫細胞早期恢復 的藥物，其可有利地用於下列者： (1) 接受化學清贿法及/或放射㈣療法之自源性 或外源性骨鑛移植患者之免疫細胞的早期恢 復；以及 (2) 接受外科手術或化學療法並藉此防止殘餘癌擴 散之患有轉移癌之患者的免疫系統提升。 式（1)化合物亦可用以 (1) 使付骨髓移植授體之造血幹細胞自骨髓移動至 末梢血液，並藉此收集他們； (2) 誘發收集用之末梢無液先驅細胞之增殖；以及 94999 18 201121965 (3)治療原發性骨髓衰竭。 - 最後，式（1)化合物可作為用於哺乳動物宿主之瞬時 ， 造血重建的藥物，對於此目的，可使用下列（a)或（b)之方 法： (a) 方法係包含：將式（1)化合物加入含有細胞介素 及生長因子之混合物的中，用於培養包括造血幹 細胞之細胞群組，從而增加該細胞群組中的骨髓 性先驅細胞，以及 (b) 方法係包含：將式（1)化合物加入適用於對哺乳 動物宿主給藥之醫藥可接受的介質中，並再懸浮 骨髓性先驅細胞。 根據本發明之式（1)化合物可作為游離化合物之形式 使用，或作為醫藥可接受之鹽、包括水合物之溶劑合物、 酯、異構物或前藥之形式使用。術語“醫藥可接受之鹽” 係意指不對將其給藥之有機體造成顯著之刺激，且不廢止 該化合物之生物活性及性能。此等醫藥可接受之鹽係包括 藉由具有用以形成非毒性酸加成鹽之醫藥可接受之陰離子 的酸形成的酸加成鹽，該等酸係包括，舉例而言，無機酸 如鹽酸、硫酸、硝酸、磷酸、氫溴酸、氫碘酸等；有機酸 如酒石酸、甲酸、擰檬酸、乙酸、三氣乙酸、三氟乙酸、 葡萄糖酸、苯曱酸、乳酸、富馬酸、馬來酸、柳酸等；續 酸如曱统確酸、乙烧石黃酸、苯石黃酸、對曱苯石黃酸等。此外， 該醫藥可接受之鹽係包括與鹼金屬或鹼土金屬如鋰、鈉、 鉀、鈣及鎂等形成之鹽；與胺基酸如離胺酸、精胺酸及胍 19 94999 201121965 等形成之鹽；以及與有機驗如二環已基胺、N-甲基-D-葡萄 糖胺、參（經甲基）甲基銨、二乙醇胺、膽驗及三乙胺形成 之鹽。該式⑴化合物可藉由該技藝中已知之常規方法轉化 為其鹽^ 。亥式（1)化合物之水合物係較佳者，蓋因他們於製藥 相關之乾燥製程中非常安定，且於寬範圍之相對濕度内難 =潤，且不顯示滞後現象。舉例而言’吉米沙星較佳係以 八倍+水合物或三水合物形式使用。吉米沙星之該等水人 :係具體揭示於W0 98/麵中，該申請之内容係藉由整 體引用而併入本文。 ^據本發明之該等水合物係包括式⑴化合物之醫藥 11接又之鹽以及式⑴化合物之驗形式。 ^ X式（1)化合物係具有各種先前述及之藥理 其可配製為便利給藥之藥物& 、 枯淋;蓺士 樂。可根據常規配製 f打及該技藝中已知之方法與抗録法之其他佐劑一起! 成配方。因此，本發明包括包含式⑴化: 之載劑或_劑之醫藥組成物。 及醫樂了接受 包含該式（1)化合物作為活性成份之醫藥 製為藉由各種適當之途徑，如σ服、非經σ或成β配 行給藥。該等組成物可為片劑、膠囊顆::進 液或懸浮液。用於口服”容 劑量形式，且可含有如黏 Γ配製為早兀 基纖維素、經丙基纖維素、***膠糖聚:二= 94999 20 201121965 醇、黃耆膠或聚乙烯基σ比咯烷酮；填料如微晶纖維素、乳 糖、糖、玉米澱粉、磷酸鈣、山梨糖醇或甘胺酸；壓片潤 - 滑劑如硬脂酸鎂、滑石、聚乙二醇或二氧化矽；崩解劑如 羥乙酸澱粉鈉、交聯聚乙烯基吡咯烷酮或馬鈐薯澱粉；或 可接受之潤濕劑如月桂基硫酸鈉。該等片劑可根據正常醫 藥實踐中習知之方法包覆之。舉例而言，口服液體製劑可 係水性或油性之懸浮液、溶液、乳液、糖漿或酏劑之形式， 或可作為於使用之前以水或其他適當之載劑重構之乾燥產 物而存在。此等液體製劑可含有常規添加劑，如懸浮劑如 山梨糖醇、曱基纖維素、葡萄糖漿、明膠、羥乙基纖維素、 羧曱基纖維素、硬脂酸鋁凝膠或氫化食用油脂；乳化劑如 卵磷脂、去水山梨醇單硬脂酸酯或***膠；非水性載劑 (其可包括食用油）如杏仁油、油性s旨、甘油、丙二醇或乙 醇；防腐劑如對羥基苯曱酸曱酯或對羥基苯曱酸丙酯或山 梨酸；以及，若需要，常規芳香基或染色劑。 對於非經口給藥，係使用該化合物及無菌載劑，較佳 係水，製備流體單元劑型形式，且他們經諸如IV或IV輸 液給藥。依據所使用之載劑及濃度，式（1)化合物可懸浮於 或溶解於該載劑中。於溶劑之裝備後，可將該活性化合物 溶解於注射用水中，並於填裝入適當之小瓶或安瓿中並密 封之前進行無菌過濾。有利地，可將試劑如局部麻醉劑、 防腐劑及緩衝劑溶解於該載劑中。為了提升安定性，可將 該組成物凍乾，並將乾燥之凍乾粉封閉於小瓶中，並提供 注射用水之輔助小瓶以於使用之前重構該粉末。除了係將 21 94999 201121965 該式（1)化合物懸浮於該栽 菌化無法藉由猶完叙外㈣溶解於該_中，且無 同之方式製備之。可藉由將經口懸浮液係以本質上相 劑中之前，將該化合物曝露Χ )化合物於懸浮於該無菌载 利地，該組成物中係包括衣而氧乙烷令予以無菌化。有 (1)化合物之均勻分佈。1 '舌性劑或潤濕劑以促進該式 製為獸醫用之***内組成物。 篁/0杈佳10重量％至99 5重量％，更 重量％至".5重量％之，_量呈游祕之活性成份。當該等 組成物係包含若干劑量單^時，每―單讀佳應含有5〇 至1500毫克（mg)之經測量呈游離鹼之活性成份。用於成年 人類治療之劑量，依據給藥之途徑及頻率，成年患者（體重 70千克（kg))平均每人每天160至800lng之範圍，較佳每 天200至600mg，更佳每天300至500mg，最佳每天32〇mg。 曰劑：E可藉由在24小時期間内一次或多次給藥該活性成 份而適合地給予，如，可一天一次給藥高達4〇〇mg。實際 上，個體患者最適用之給藥之劑量及頻率將隨著患者之年 齡、體重及響應而變化，視情況醫師可選擇更高或更低之 給藥劑量及不同之給藥頻率。此等劑量之方案係位於本發 明範疇之内。 於抗癌療法中作為佐劑之常規使用之G-CSF具有非常 不安定的缺點’因此’其可於身體内保持非常短的時間。 為了克服這些問題’通常建議包含將生物相容性大分子妹 94999 22 201121965 合至g—csf之方法。根據本發明，式（！）之啥琳_抗生 合物於身體内促進G-CSF之安定產生，因此，其古素化 ^ ^致地用 於可使用G-CSF治療或緩解之全部疾病或不適。 此外，G-CSF係自細胞培養獲得之昂貴的生物藥 且其製造成本高。以低成本之合成藥劑替代G-csp 物 非常有 意義’蓋因其提供低成本及良好治療品質之益處 藉由下列實施例更詳細揭示本發明，但本發明之々 並不藉此以任何方式予以限制。 已可 實施本發明之最佳模式 實驗動物 自Orient Bio公司購買6至8週齡之雄性及雄性 C57BL/6小鼠（體重20至27公克（g))並用於實驗中。 部小鼠保持於標準培育環境中，其中，溫度係控制於7王 °C ’濕度為55%至60% ’以及照光與黑暗係分別維持12 ±2 時。自由地提供固體飼料及水。分別對小鼠腹腔注射（i PBS或兩種不同劑量（50 mg/kg及1〇〇 mg/kg)吉米沙星* 日’於第5日將免疫細胞染色並研究血清細胞介素。 流動式細胞測量術 實施下列實驗對含有大量小鼠造血幹細胞之LSK (譜 系-、Sca-1+、c-Kit+)細胞進行分段研究。為了獲得骨髓 細胞’以3%鹵神麻醉鼠至安樂死，使頸椎脫節。使用針筒 清洗來自經無菌萃取之脛骨、股骨及坐骨之骨髓而單離骨 髓細胞。對於經單離之骨髓細胞，實施對應於譜系細胞之 CD4、CD8、B220、Gr-1 (Ly-6G)、Mac-1 (CDllb)及 Ter-119 23 94999 201121965 經標記之抗原及Sea-卜c-Kit抗原抗體染色，隨後研究該 LSK細胞。 為了以流動式細胞測量術研究來自小鼠之骨髓、脾臟 及末梢血液的粒細胞’以對應小鼠Gr-l(Ly-6G)及Mac_l (CDllb)標記之抗原的抗體將來自各別器官之經分離細胞 染色。 藉由使用FACSCalibur系統收集及使用Fi〇wj〇分析， 經由經標記之抗原實施細胞如顆粒細胞、淋巴球等的分段 研究。藉由動物血液計數器計數淋巴球、粒細胞、血紅細 胞及血小板之總數目。 實施例1 根據EP688772之實施例180中揭示之方法製備吉米 沙星。 經由i. ρ·用50 mg/kg或100 mg/kg之吉米沙星治療 小鼠4日之後，將該鼠之末梢血液或脾臟細胞中淋巴球 (CD4+、CD8+、B220+)及嗜中性白血球（Gr-1+、CDllb+)之 數目與陰性對照小鼠（經pBS治療之小鼠）之彼等相比較。 藉由流動式細胞測量術測量淋巴球及粒細胞之計數於吉米 沙星治療之後的改變，結果係顯示於第1圖及第2圖中。 於經吉米沙星治療之群組中，嗜中性白血球（Gr_ 1 +、CD 11 b+) 之數目為劑量依賴性地增加，使用流動式細胞測量術予以 證實（第3圖）。結果證明，於正常鼠中使用吉米沙星治療 增加末梢血液或脾臟中嗜中性白血球的數目。 實施例2 24 94999 201121965 對於實施例1中之小鼠群組，使用蛋白質分析試劑盒 : (Pr〇tein array kit)研究血液中細胞介素的改變。如第4 圖中所顯示者，結果顯示，使用吉米沙星之治療誘發 G-CSF、MCP-6(單核細胞趨化性因子）及TREM_i (其係與骨 髓細胞之活性相關）之增加’以及沾卜丨（與造血幹細胞自 骨髓移動至末梢血液相關之因子）之降低。結果顯示，吉米 沙星增加活體内G-CSF之數目，並藉此於恢復造血及增加 嗜中性白血球中扮演角色。 實施例3The 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

為了證明吉米沙星增加活體内之G_CSF並藉此促進造 血幹細胞之自我複製，進行下列實施例，對含有大量小鼠 造血幹細胞之LSK(譜系-、Sca__1+、c_Kit+)細胞進行分段 研究。為了獲得骨髓細胞’卩神麻醉鼠至安樂死，使 頸椎脫節。使用針筒清洗來自經無菌萃取之脛骨、股骨及 坐骨之骨髓而單離骨髓細胞。對於經單離之骨趙細胞月實 施對應於譜系細胞之CD4、⑽、B22G、Gr_lay_6(J)U (CDllb)及Ter-119標記之抗原及㈣、c，t抗原抗體 染色。藉由流動式細胞測量術研究表示對於&3_卜c K.t 陽性之細胞及麟譜緣性之細胞。如第5圖所示^ 性對照群組（經PBS治療之小鼠）相比，經吉来沙星治療: 群組之總造血幹細胞的頻率増加了約2倍（自〇 3眯至“ 〇. 62%或0. 63%)。第6圖中顯示之結果進—步支持這— 實，第6圖顯示通過臓（蘇木精及曙紅）組織染f 吉米沙星治療誘發之脾臟（a)及骨内骨_胞^ 94999 25 201121965 殖。 實施例4-1 將吉米沙星對於末梢血液中骨髓細胞增殖之治療效 果與陽性對照藥劑環丙沙星（ciprof 1 oxacin)之治療效果 相比較。藉由流動式細胞測量術分析該等骨髓細胞。經由 i. P.對小鼠給藥150 mg/kg之抗癌藥劑5-FU，24小時之 後，以實施例1揭示之方法給藥吉米沙星或PBS。經由i. p. 以25 mg/kg之劑量每天給藥2次。如第7圖所示，陰性對 照群組（經PBS治療之小鼠）之末梢血液中，由Ly-6G (Gr-1 + )及CDllb+表示之嗜中性白血球未增加。與陰性對 照群組相比，經吉米沙星治療之群組之嗜中性白血球增加 了超過4倍（3. 04%對（vs. ) 13. 90%)，而經環丙沙星治療者 之嗜中性白血球未增加。第8圖中顯示之嗜中性白血球之 實際數目進一步支持由流動式細胞測量術獲得之此結果。 實施例4-2 對於下述結構之化合物（後文中指稱為化合物A)，將 其對末梢血液中骨髓細胞增殖之效果與陽性對照藥劑 G-CSF相比較。 根據EP688772之實施例180中揭示之方法製備化合 物A，除了係使用7-氯-6-氟-1-曱基-4-側氧基-1,4-二氩 -[1，8]萘啶-3-羧酸代替1-環丙基-7-氯-6-氟-4-侧氧基 -1,4-二氫-[1，8]萘啶-3-羧酸作為中間體。使用曱胺代替 環丙胺根據EP 1678174A1中揭露之方法獲得7-氯-6-氟 -1-曱基-4-侧氧基-1,4-二氫-[1，8]萘啶-3-羧酸。 26 94999 201121965 ο οIn 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 Ν 分別將化合物Α(50 mg/kg)、PBS及G-CSFC125微克 (#g)/kg)對小鼠給藥，24小時之後，藉由流動式細胞測 量術分析末梢血液中之該等骨髓細胞。如第9圖所示，經 化合物A治療之群組之嗜中性白血球之增加與G-CSF治療 群組中之彼等相似。 實施例5 為了研究吉来沙星對於致死輻射劑量造成之輻射危 害的保護效果’將小鼠分為僅輻射群組（6隻鼠）及輻射後 --------------- d 4 之輻射速率以10 Gy之單一輻射劑量於背側進行 吉米沙星溶解於生理鹽水溶液中，輻射24小時田射 .2毫升（mL)5亥溶液經由丨· 以mg/kg之劑灸 藥7曰。自僅轾紅挪…， 經吉米沙星治療之群組〇隻鼠）。將該等鼠放入輻射裴置 中，使用6 MV線性加速器（Siemens，pA，USA) 之輕私：n、，. Λ 3 Gy/min 5將 將 鼠給 藥7日。自僅+ 巧里鮮，J、 4二星/α療之群組給藥吉米沙星，研究兩群t止輩 麥爾存活率分析計算以致死輻射 存'居率 ln 未々、星治療之群組的致死率，％ 堇 I弟10圖中。社里 _ 果係屋§ - 。果顯不吉米沙星治療保護身體π^硕不 射誘發之輻射危宏艰不受敎 曰彳歪軲射群組中第一隻鼠死後次日 吉米沙星治療之败/‘一……一、停止斟羥 二僅 、 _ 顯f 射誘發之輻射危害，如二 月趟抑制等。 27 ^4999 201121965 咸信此效果係歸因於吉米沙星之作用，吉米沙星經由增加 嗜中性白血球及造血幹細胞而誘發造血細胞之早期恢復， 並藉此預防可能之感染等。 【圖式簡單說明】 第1圖係顯示使用吉米沙星治療之小鼠末梢血液細胞 的數目改變； 第2圖係顯示使用吉米沙星治療之小鼠脾臟細胞的數 目改變； 第3圖係顯示使用流動式細胞測量術分析之使用吉米 沙星治療之小鼠末梢血液細胞内骨艟性細胞的增殖； 第4圖係顯示使用吉米沙星治療之小鼠血清中各種細 胞介素的改變； 第5圖係顯示使用流動式細胞測量術分析之使用吉米 沙星治療之小鼠骨髓造血幹細胞之頻率的改變； 第6圖係表示顯示使用吉米沙星治療之小鼠脾臟紅趟 區域中細胞增殖之組織化學分析的照片（a)，以及顯示使用 吉米沙星治療之小鼠骨髓中骨髓性細胞之增殖之組織化學 分析的照片（b); 第7圖係顯示使用流動式細胞測量術分析之吉米沙星 用於藉由抗癌劑5-FU造成之嗜中性白血球減少症的療效； 第8圖係顯示藉由骨髓性細胞之目標改變表示之吉米 沙星用於藉由抗癌劑5-FU造成之嗜中性白血球減少症的 療效； 第9圖係顯示以嗜中性白血球的數目改變所表示之化 28 94999 201121965 合物A於末梢血液中對於骨髓性細胞的效果；以及 - 第10圖係顯示藉由卡本-麥爾存活率分析 (Kaplan-Meier survival analysis)計算之於致死輕射劑 ' 量之僅輻射群組及經吉米沙星治療之群組的致死率。 【主要元件符號說明】 無 29 94999F 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)

201121965201121965 、申請專利範圍： 一種用於治療嗜t性白血球減少麵藥物，包含治療有 效量之下式⑴衫之化合物、其f討接受之鹽、包 括水合物之溶劑合物♦異構物或前藥作為活性成份: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) 其中， R係表示氫、甲基或胺基， Q 係表示 C-H、C-F、C-C1、C-OH、C-CH3、C-〇-CH3 或N， 系表示氫、環丙基、曱基或乙基，或經由一個或 多個氟原子取代之苯基， R2係表示下列a)至e)之一者： a) 氫、直鏈或分支鏈Ci-C4烷基、環丙基、環丙基 甲基、CH：6炔基、2-鹵乙基、曱氧基甲基、甲氧基羰 基甲基、苯基或埽丙基， b) 下式之基 其中’ X係表不氮、2-、3_或4-之氟、氣基、石肖基、 曱氧基、Ci-C4烧基或2, 4-二氟， 1 94999 201121965 C)下式之基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) 下式之基 9 e) 下式之基 其中，η指稱0或1 ’ m指稱0、1或2，χ係表示 亞曱基、0或N，以及 R3係表示-CMR5R6，其中，Rs與Re係彼此獨立表示 氫或G-C3烷基，或RS與Re可與其所結合之氮原子一 形成環， 匕係表示氫，或 R3與R4與其所結合之碳原子一起形成結構 R,~NC^< ，該結構係以螺環形成與該吡咯啶環組合，其 中’ R?係表示氫或C1-C4烧基。 如申請專利範圍第1項所述之藥物，其中，該式（1)化 5物係吉米沙星（gemif l〇xacin)。 .如申請專利範圍第1或2項所述之藥物，其中，該嗜中 94999 2 201121965 性白血球減少症係誘發於接受骨髓抑制化學療法之癌 症患者的發熱性嗜中性白血球減少症。 4.如申請專利範圍第1或2項所述之藥物，其中，該嗜中 性白血球減少症係誘發於接受放射之癌症患者。 5·如申請專利範圍第1或2項所述之藥物，其中，該嗜中 性白金球減少症係誘發於接受化學療法之成年急性骨 髓性白血病患者。 6. 如申請專利範圍第1或2項所述之藥物，其中，該嗜中 性白血球減少症係於誘發接受非化學療法之骨髓抑制 療法之癌症患者的。 7. 如申請專利範圍第6項所述之藥物，其+，該非化學療 法之骨髓抑制療法係選自下列所成群組：更昔洛韋、阿 昔洛韋、纈昔洛韋、纈更昔洛韋、喷昔洛韋、芬昔洛韋、 阿糖腺皆、阿糖胞苦、蛾皆、二·氣尿皆、依度尿苦及漠 夫定。 8. 如申請專利範圍第丨或2項所述之藥物，其中，該嗜中 性白血球減少症係由感染所造成。 9. 如申請專利範圍第1或2項所述之藥物，其中，該嗜中 性白血球減少症係嚴重的慢性嗜中性白血球減少症。 10. 如申請專利範圍第9項所述之藥物，其中 ’該嚴重的慢 性嗜中性白血球減少症係内因性、先天性、或週期性嗜 中性白血球減少症。 11. 一種用於免疫細胞之早期恢復的藥物，係包含治療有致 量之申請專利範圍第丨項中所定義之式（1)化合物、其 3 94999 201121965 醫藥可接受之鹽、包括水合物之溶劑合物、酯、異構物 • 或前藥作為活性成份。 • 12.如申請專利範圍第11項所述之藥物，其中，其係用於 早期恢復接受化學清髓療法或放射清髓療法之自源性 或外源性骨髓移植患者之免疫細胞的藥物。 13. 如申請專利範圍第11項所述之藥物，其中，其係用於 提升接受外科手術或化學療法並藉此防止殘餘癌擴散 之患有轉移癌之患者的免疫力。 14. 一種用於將細胞自骨髓向末梢血液移動之藥物，其係包 含治療有效量之申請專利範圍第1項中所定義之式（1) 化合物、其醫藥可接受之鹽、包括水合物之溶劑合物、 酯、異構物或前藥作為活性成份。 15. 如申請專利範圍第14項之藥物，其中，其係用於收集 骨髓移植供體之造血幹細胞。 16. —種用於收集細胞之藥物，係包含治療有效量之申請專 利範圍第1項中所定義之式（1)化合物、其醫藥可接受 之鹽、包括水合物之溶劑合物、酯、異構物或前藥作為 活性成份。 17. 如申請專利範圍第16項所述之藥物，其中，該細胞之 收集係藉由誘發末梢血液先驅細胞之增殖而達成。 18. —種用於治療原發性骨髓衰竭之藥物，係包含治療有效 量之申請專利範圍第1項中所定義之式（1)化合物、其 醫藥可接受之鹽、包括水合物之溶劑合物、醋、異構物 或前藥作為活性成份。 4 94999 201121965 19. 一種用於哺乳動物宿主之瞬時造血重建的藥物，係包含 治療有效量之申請專利範圍第1項中所定義之式（1)化 合物、其醫藥可接受之鹽、包括水合物之溶劑合物、酯、 異構物或前藥作為活性成份。 20. 如申請專利範圍第19項所述之藥物，其中，該造血重 建係根據下述（a)或（b)方法達成： (a)方法係包含：將式（1)化合物加入含有細胞介素及 生長因子之混合物的介質中，用於培養包括造血幹 細胞之細胞群組，從而增加該細胞群組中的骨髓性 先驅細胞，以及 (b )方法係包含：將式（1)化合物加入適用於對哺乳動 物宿主給藥之醫藥可接受的介質中，並再懸浮骨髓 性先驅細胞。 21. 如申請專利範圍第11、14、16、18及19項任一項所述 之藥物，其中，該式（1)化合物係吉米沙星。 22. —種用於治療哺乳動物之嗜中性白血球減少症或達成 哺乳動物之免疫細胞之早期恢復的方法，其係包含對哺 乳動物給藥治療有效量之申請專利範圍第1項中所定 義之式（1)化合物、其醫藥可接受之鹽、包括水合物之 溶劑合物、酯、異構物或前藥。 23. —種用於預防、抑制、緩解或治療藉由化學療法或放射 療法造成之嗜中性白企球減少症的方法，其係包含對接 受該化學療法或放射療法之哺乳動物給藥對預防、抑 制、缓解或治療嗜中性白血球減少症為有效量的申請專 5 94999 •201121965 利I巳圍第1項中所定義之式⑴化合物、其醫藥可接受 · 之鹽、包括水合物之溶劑合物、酯、異構物或前藥。 • 24.如申請專利範圍第22或23項所述之方法，其中，該式 (1)化合物係吉米沙星。 25.—種申請專利範圍第〖項所述之式（1)化合物之用途， 其係用於製造用以治療嗜中性白血球減少症，尤指藉由 化學療法或放射療法所造成之嗜中性白血球減少症，以 及早期恢復免疫細胞之藥物。 94999 6d) 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