1) 本發明之第一實施例係關於呈結晶形式1之化合物1，其中X射線粉末繞射圖案在以下折射角2q處具有峰：11.9°、13.4°及20.3°，其中該X射線粉末繞射圖案使用Cu Ka (1.5418 Å)源來量測。 2) 本發明之另一實施例係關於呈結晶形式1之化合物1，其中X射線粉末繞射圖案在以下折射角2q處具有峰：6.7°、11.9°、13.4°、19.0°及20.3°，其中該X射線粉末繞射圖案使用Cu Ka (1.5418 Å)源來量測。 3) 本發明之另一實施例係關於呈結晶形式1之化合物1，其中X射線粉末繞射圖案在以下折射角2q處具有峰：6.7°、7.5°、11.9°、13.4°、15.1°、15.4°、18.1°、19.0°、20.3°及24.5°，其中該X射線粉末繞射圖案使用Cu Ka (1.5418 Å)源來量測。 4) 本發明之另一實施例係關於呈結晶形式1之化合物1，其基本上展示如圖1中所描繪之X射線粉末繞射圖案。 5) 本發明之另一實施例係關於呈結晶形式1之化合物1，其可藉由如實例1中所描述之方法獲得。 6) 本發明之另一實施例係關於如實施例5)之呈結晶形式1之化合物1，其中X射線粉末繞射圖案在以下折射角2q處具有峰：11.9°、13.4°及20.3°，其中該X射線粉末繞射圖案使用Cu Ka (1.5418 Å)源來量測。 7) 本發明之另一實施例係關於如實施例5)之呈結晶形式1之化合物1，其中X射線粉末繞射圖案在以下折射角2q處具有峰：6.7°、11.9°、13.4°、19.0°及20.3°，其中該X射線粉末繞射圖案使用Cu Ka (1.5418 Å)源來量測。 8) 本發明之另一實施例係關於如實施例5)之呈結晶形式1之化合物1，其中X射線粉末繞射圖案在以下折射角2q處具有峰：6.7°、7.5°、11.9°、13.4°、15.1°、15.4°、18.1°、19.0°、20.3°及24.5°，其中該X射線粉末繞射圖案使用Cu Ka (1.5418 Å)源來量測。 9) 本發明之另一實施例係關於一種包含如實施例1)至8)中任一項之呈結晶形式1之化合物1的組合物，其進一步包含至少一種醫藥學上可接受之賦形劑。 10) 本發明之另一實施例係關於如實施例1)至8)中任一項之呈結晶形式1之化合物1或如實施例9)之組合物，其適用作藥物。 11) 本發明之另一實施例係關於如實施例1)至8)中任一項之呈結晶形式1之化合物1或如實施例9)之組合物，其用於治療或預防，較佳治療細菌性疾病症。 12) 本發明之另一實施例係關於如實施例1)至8)中任一項之呈結晶形式1之化合物1或如實施例9)之組合物，其用於治療或預防，較佳治療由革蘭氏陰性菌介導的細菌性疾病。 13) 本發明之另一實施例係關於如實施例1)至8)中任一項之呈結晶形式1之化合物1或如實施例9)之組合物，其用於治療或預防，較佳治療由選自肺炎克雷伯氏桿菌(Klebsiella pneumoniae
)、綠膿桿菌(Pseudomonas aeruginosa
)及大腸桿菌(Escherichia coli
)之革蘭氏陰性菌介導的細菌性疾病。 14) 本發明之另一實施例係關於呈結晶形式2之化合物1，其中X射線粉末繞射圖案在以下折射角2q處具有峰：7.4°、13.9°及16.5°，其中該X射線粉末繞射圖案使用Cu Ka (1.5418 Å)源來量測。 15) 本發明之另一實施例係關於呈結晶形式2之化合物1，其中X射線粉末繞射圖案在以下折射角2q處具有峰：6.8°、7.4°、13.9°、16.5°及21.5°，其中該X射線粉末繞射圖案使用Cu Ka (1.5418 Å)源來量測。 16) 本發明之另一實施例係關於呈結晶形式2之化合物1，其中X射線粉末繞射圖案在以下折射角2q處具有峰：6.8°、7.4°、12.1°、13.1°、13.9°、16.5°、18.1°、19.2°、21.5°及24.4°，其中該X射線粉末繞射圖案使用Cu Ka (1.5418 Å)源來量測。 17) 本發明之另一實施例係關於呈結晶形式2之化合物1，其基本上展示如圖2中所描繪之X射線粉末繞射圖案。 18) 本發明之另一實施例係關於呈結晶形式2之化合物1，其可藉由如實例2中所描述之方法獲得。 19) 本發明之另一實施例係關於如實施例18)之呈結晶形式2之化合物1，其中X射線粉末繞射圖案在以下折射角2q處具有峰：7.4°、13.9°及16.5°，其中該X射線粉末繞射圖案使用Cu Ka (1.5418 Å)源來量測。 20) 本發明之另一實施例係關於如實施例18)之呈結晶形式2之化合物1，其中X射線粉末繞射圖案在以下折射角2q處具有峰：6.8°、7.4°、13.9°、16.5°及21.5°，其中該X射線粉末繞射圖案使用Cu Ka (1.5418 Å)源來量測。 21) 本發明之另一實施例係關於如實施例18)之呈結晶形式2之化合物1，其中X射線粉末繞射圖案在以下折射角2q處具有峰：6.8°、7.4°、12.1°、13.1°、13.9°、16.5°、18.1°、19.2°、21.5°及24.4°，其中該X射線粉末繞射圖案使用Cu Ka (1.5418 Å)源來量測。 22) 本發明之另一實施例係關於包含如實施例14)至21)中任一項之呈結晶形式2之化合物1的組合物，其進一步包含至少一種醫藥學上可接受之賦形劑。 23) 本發明之另一實施例係關於如實施例14)至21)中任一項之呈結晶形式2之化合物1或如實施例22)之組合物，其適用作藥物。 24) 本發明之另一實施例係關於如實施例14)至21)中任一項之呈結晶形式2之化合物1或如實施例22) 之組合物，其用於治療或預防，較佳治療細菌性疾病。 25) 本發明之另一實施例係關於如實施例14)至21)中任一項之呈結晶形式2之化合物1或如實施例22)之組合物，其用於治療或預防，較佳治療由革蘭氏陰性菌介導的細菌性疾病。 26) 本發明之另一實施例係關於如實施例14)至21)中任一項之呈結晶形式2之化合物1或如實施例22)之組合物，其用於治療或預防，較佳治療由選自肺炎克雷伯氏桿菌、綠膿桿菌及大腸桿菌之革蘭氏陰性菌介導的細菌性疾病。 27) 本發明之另一實施例係關於呈結晶形式3之化合物1，其中X射線粉末繞射圖案在以下折射角2q處具有峰：6.9°、11.9°及23.9°，其中該X射線粉末繞射圖案使用Cu Ka (1.5418 Å)源來量測。 28) 本發明之另一實施例係關於呈結晶形式3之化合物1，其中X射線粉末繞射圖案在以下折射角2q處具有峰：6.9°、11.9°、23.9°、24.2°及25.0°，其中該X射線粉末繞射圖案使用Cu Ka (1.5418 Å)源來量測。 29) 本發明之另一實施例係關於呈結晶形式3之化合物1，其中X射線粉末繞射圖案在以下折射角2q處具有峰：6.9°、11.9°、13.9°、15.1°、18.2°、19.3、23.9°、24.2°、25.0°及27.9°，其中該X射線粉末繞射圖案使用Cu Ka (1.5418 Å)源來量測。 30) 本發明之另一實施例係關於呈結晶形式3之化合物1，其基本上展示如圖3中所描繪之X射線粉末繞射圖案。 31) 本發明之另一實施例係關於呈結晶形式3之化合物1，其可藉由如實例3中所描述之方法獲得。 32) 本發明之另一實施例係關於如實施例31)之呈結晶形式3之化合物1，其中X射線粉末繞射圖案在以下折射角2q處具有峰：6.9°、11.9°及23.9°，其中該X射線粉末繞射圖案使用Cu Ka (1.5418 Å)源來量測。 33) 本發明之另一實施例係關於如實施例31)之呈結晶形式3之化合物1，其中X射線粉末繞射圖案在以下折射角2q處具有峰：6.9°、11.9°、23.9°、24.2°及25.0°，其中該X射線粉末繞射圖案使用Cu Ka (1.5418 Å)源來量測。 34) 本發明之另一實施例係關於如實施例31)之呈結晶形式3之化合物1，其中X射線粉末繞射圖案在以下折射角2q處具有峰：6.9°、11.9°、13.9°、15.1°、18.2°、19.3、23.9°、24.2°、25.0°及27.9°，其中該X射線粉末繞射圖案使用Cu Ka (1.5418 Å)源來量測。 35) 本發明之另一實施例係關於包含如實施例27)至34)中任一項之呈結晶形式3之化合物1的組合物，其進一步包含至少一種醫藥學上可接受之賦形劑。 36) 本發明之另一實施例係關於如實施例27)至34)中任一項之呈結晶形式3之化合物1或如實施例35) 之組合物，其適用作藥物。 37) 本發明之另一實施例係關於如實施例27)至34)中任一項之呈結晶形式3之化合物1或如實施例35)之組合物，其用於治療或預防，較佳治療細菌性疾病。 38) 本發明之另一實施例係關於如實施例27)至34)中任一項之呈結晶形式3之化合物1或如實施例35)之組合物，其用於治療或預防，較佳治療由革蘭氏陰性菌介導的細菌性疾病。 39) 本發明之另一實施例係關於如實施例27)至34)中任一項之呈結晶形式3之化合物1或如實施例35)之組合物，其用於治療或預防，較佳治療由選自肺炎克雷伯氏桿菌、綠膿桿菌及大腸桿菌之革蘭氏陰性菌介導的細菌性疾病。 40) 本發明之另一實施例係關於呈非晶形式之化合物1。 41) 本發明之另一實施例係關於可藉由如實例4中所描述之過程獲得之呈非晶形式的化合物1。 42) 本發明之另一實施例係關於包含如實施例40)及41)中任一項之呈非晶形式之化合物1的組合物，其進一步包含至少一種醫藥學上可接受之賦形劑。 43) 本發明之另一實施例係關於如實施例40)及41)中任一項之化合物1或實施例42)之組合物，其適用作藥物。 44) 本發明之另一實施例係關於如實施例40)及41)中任一項之化合物或實施例42)之組合物，其用於治療或預防，較佳治療細菌性疾病。 45) 本發明之另一實施例係關於如實施例40)及41)中任一項之化合物或實施例42)之組合物，其用於治療或預防，較佳治療由革蘭氏陰性菌介導的細菌性疾病。 46) 本發明之另一實施例係關於如實施例40)及41)中任一項之化合物，或實施例42)之組合物，其用於治療或預防，較佳治療由選自肺炎克雷伯氏桿菌、綠膿桿菌及大腸桿菌之革蘭氏陰性菌介導的細菌性疾病。 基於如上文中所揭示之不同實施例1)至46)之相依性，以下實施例因此為可能的及期望的，且在此以個別化形式具體地揭示： 6+5、7+5、8+5、9+1、9+2、9+3、9+4、9+5、9+6+5、9+7+5、9+8+5、10+1、10+2、10+3、10+4、10+5、10+6+5、10+7+5、10+8+5、10+9+1、10+9+2、10+9+3、10+9+4、10+9+5、10+9+6+5、10+9+7+5、10+9+8+5、11+1、11+2、11+3、11+4、11+5、11+6+5、11+7+5、11+8+5、11+9+1、11+9+2、11+9+3、11+9+4、11+9+5、11+9+6+5、11+9+7+5、11+9+8+5、12+1、12+2、12+3、12+4、12+5、12+6+5、12+7+5、12+8+5、12+9+1、12+9+2、12+9+3、12+9+4、12+9+5、12+9+6+5、12+9+7+5、12+9+8+5、13+1、13+2、13+3、13+4、13+5、13+6+5、13+7+5、13+8+5、13+9+1、13+9+2、13+9+3、13+9+4、13+9+5、13+9+6+5、13+9+7+5、13+9+8+5、19+18、20+18、21+18、22+14、22+15、22+16、22+17、22+18、22+19+18、22+20+18、22+21+18、23+14、23+15、23+16、23+17、23+18、23+19+18、23+20+18、23+21+18、23+22+14、23+22+15、23+22+16、23+22+17、23+22+18、23+22+19+18、23+22+20+18、23+22+21+18、24+14、24+15、24+16、24+17、24+18、24+19+18、24+20+18、24+21+18、24+22+14、24+22+15、24+22+16、24+22+17、24+22+18、24+22+19+18、24+22+20+18、24+22+21+18、25+14、25+15、25+16、25+17、25+18、25+19+18、25+20+18、25+21+18、25+22+14、25+22+15、25+22+16、25+22+17、25+22+18、25+22+19+18、25+22+20+18、25+22+21+18、26+14、26+15、26+16、26+17、26+18、26+19+18、26+20+18、26+21+18、26+22+14、26+22+15、26+22+16、26+22+17、26+22+18、26+22+19+18、26+22+20+18、26+22+21+18、32+31、33+31、34+31、35+27、35+28、35+29、35+30、35+31、35+32+31、35+33+31、35+34+31、36+27、36+28、36+29、36+30、36+31、36+32+31、36+33+31、36+34+31、36+35+27、36+35+28、36+35+29、36+35+30、36+35+31、36+35+32+31、36+35+33+31、36+35+34+31、37+27、37+28、37+29、37+30、37+31、37+32+31、37+33+31、37+34+31、37+35+27、37+35+28、37+35+29、37+35+30、37+35+31、37+35+32+31、37+35+33+31、37+35+34+31、38+27、38+28、38+29、38+30、38+31、38+32+31、38+33+31、38+34+31、38+35+27、38+35+28、38+35+29、38+35+30、38+35+31、38+35+32+31、38+35+33+31、38+35+34+31、39+27、39+28、39+29、39+30、39+31、39+32+31、39+33+31、39+34+31、39+35+27、39+35+28、39+35+29、39+35+30、39+35+31、39+35+32+31、39+35+33+31、39+35+34+31、42+40、42+41、43+40、43+41、43+42+40、43+42+41、44+40、44+41、44+42+40、44+42+41、45+40、45+41、45+42+40、45+42+41、46+40、46+41、46+42+40、46+42+41 在以上清單中，數字係指根據上文中所提供之其編號的實施例，而「+」指示與另一實施例之相依性。不同個別化實施例藉由逗號分離。換言之，「11+9+1」例如係指實施例11)依附於實施例9)、依附於實施例1)，亦即實施例「11+9+1」對應於實施例1)進一步由實施例9)及11)之特徵表徵。 本文中所提供之定義意欲一律應用於如實施例1)至46)中之任一項中所定義之主題，且在細節上做必要之修改後，貫穿說明書及申請專利範圍，除非另外明確地陳述的定義提供更寬或更窄的定義。將較佳理解，獨立於如本文中所定義之任何或所有其他術語或表述之任何定義或較佳定義(且與其組合)，術語或表述之定義或較佳定義定義且可替換各別術語或表述。 化合物1之結晶形式1、2及3或其非晶形式可尤其以基本上純淨之形式存在。表述「以基本上純淨之形式」理解為尤其意謂化合物1之至少90重量%，較佳地至少95重量%，且最佳地至少99重量%以本發明之單一形式存在。 關於疾病所使用之術語「預防(prevent/prevention/ preventing)」意謂該疾病不出現於患者或動物中，或即使動物或患者受疾病影響，該疾病之部分或所有症狀減少或不存在。 關於疾病所使用之術語「治療(treat/treatment/ treating)」意謂該疾病在患者或動物中治癒，或即使動物或患者仍受疾病影響，但該疾病之部分或所有症狀減少或消除。 當在例如X射線粉末繞射圖式中定義峰之存在時，一種常見方法為按照S/N比(S=訊號，N=雜訊)來進行此定義。根據此定義，當陳述峰必須存在於X射線粉末繞射圖中時，應理解X射線粉末繞射圖中之峰藉由大於x (x數值大於1)，通常大於2，尤其大於3之S/N比(S=訊號，N=雜訊)定義。 在其中陳述結晶形式基本上分別展示如圖1至圖3中所描繪之X射線粉末繞射(XRPD)圖案之上下文中，術語「基本上」意謂相較於圖式中之最強峰，至少該等圖中描繪之圖式之主峰(亦即具有大於20%，尤其大於10%之相對強度的彼等峰)必須存在。然而，熟習X射線粉末繞射之技術者將認識到，X射線粉末繞射圖中之相對強度因較佳定向效應可經歷較強強度變化。除非關於溫度使用，否則置放於數值「X」之前的術語「約」在本申請案中係指自X減10% X延伸至X加10% X之區間，且較佳地係指自X減5% X延伸至X加5% X之區間。在溫度之特定情況下，置放於溫度「Y」之前的術語「約」在本申請案中係指自溫度Y減5℃延伸至Y加5℃之區間，且較佳地係指自Y減3℃延伸至Y加3℃之區間。室溫意謂約23℃之溫度。 當在本申請案中針對峰指定繞射角2q (2theta)時，應理解，所給定值將理解為自該值減0.2°至該值加0.2°，且較佳地自該值減0.1°至該值加0.1°之區間。 化合物1之結晶形式1、2及3中之每一者或其非晶形式(作為單一組分(較佳)或連同化合物1之其他結晶形式及/或非晶形式)可用作例如呈用於在人體中非經腸及/或經腸投與，尤其非經腸投與之醫藥組合物之形式的藥物，且適用於預防或治療細菌性疾病，尤其由諸如肺炎克雷伯氏桿菌、綠膿桿菌及大腸桿菌的革蘭氏陰性菌所導致之細菌性疾病。藉由將化合物1之結晶形式1、2及3中之每一者(作為單一組分或連同化合物1之其他結晶形式及/或非晶形式)視需要與其他治療有價值之物質組合，連同合適、無毒、惰性、醫藥學上可接受之固體或液體載劑材料及(視需要)常見醫藥佐劑引入至蓋倫投藥劑型中，醫藥組合物之生產可以將對任何熟習此項技術者熟悉之方式實現(參見例如Remington, The Science and Practice of Pharmacy, 第21版(2005), 部分5, 「Pharmaceutical Manufacturing」[由Lippincott Williams及Wilkins出版])。醫藥組合物亦可進一步含有額外已知抗生素。 化合物1之結晶形式1、2、3中之每一者或其非晶形式對細菌為活性的。因此，其可特別適用於治療哺乳動物，尤其人體中之細菌感染，以用於防治及化療由醱酵性或非醱酵性革蘭氏陰性菌所導致之局部及全身感染，尤其由易感及多抗藥性革蘭氏陰性菌所導致之彼等感染。此類革蘭氏陰性菌之實例包括不動桿菌屬(Acinetobacter spp
)，諸如鮑氏不動桿菌(Acinetobacter baumannii
)或溶血不動桿菌(Acinetobacter haemolyticus
)；放線共生放線桿菌(Actinobacillus actinomycetemcomitans
)；無色桿菌屬(Achromobacter spp.
)，諸如氧化木糖氧化無色桿菌(Achromobacter xylosoxidans
)或腸球菌無色桿菌(Achromobacter faecalis
)；氣單胞菌屬(Aeromonas spp.
)，諸如嗜水氣單胞菌(Aeromonas hydrophila
)；擬桿菌屬(Bacteroides spp.
)，諸如脆弱擬桿菌(Bacteroides fragilis
)、多形類擬桿菌(Bacteroides theataioatamicron
)、狄氏擬桿菌(Bacteroides distasonis
)、卵形擬桿菌(Bacteroides ovatus
)或普通擬桿菌(Bacteroides vulgatus
)；巴東氏菌(Bartonella hensenae
)；博特氏菌屬(Bordetella spp.
)，諸如百日咳博特氏菌(Bordetella pertussis
)；螺旋體屬(Borrelia spp.
)，諸如博氏疏螺旋體(Borrelia Burgdorferi
)；布魯桿菌屬(Brucella spp.
)，諸如羊布魯氏桿菌(Brucella melitensis
)；伯克霍爾德氏菌屬(Burkholderia spp
)，諸如洋蔥伯克霍爾德氏菌(Burkholderia cepacia
)、類鼻疽伯克霍爾德氏菌(Burkholderia pseudomallei
)或鼻疽伯克霍爾德氏菌(Burkholderia mallei
)；彎曲桿菌屬(Campylobacter spp.
)，諸如空腸彎曲桿菌(Campylobacter jejuni
)、胚胎彎曲桿菌(Campylobacter fetus
)或大腸彎曲桿菌(Campylobacter coli
)；西地西菌屬(Cedecea
)；披衣菌屬(Chlamydia spp.
)，
諸如肺炎披衣菌(Chlamydia pneumoniae
)、沙眼披衣菌(Chlamydia trachomatis
)；檸檬酸桿菌屬(Citrobacter spp.
)，諸如差異(克氏)檸檬酸桿菌(Citrobacter diversus (koseri)
)或弗氏檸檬酸桿菌(Citrobacter freundii
)；貝氏考克斯菌(Coxiella burnetii
)；愛德華氏菌屬(Edwardsiella spp.
)，諸如遲發性愛德華氏菌(Edwarsiella tarda
)；查菲斯艾利希體屬( Ehrlichia chafeensis )
；嚙蝕艾肯菌(Eikenella corrodens
)；腸桿菌屬(Enterobacter spp.
)，諸如陰溝腸桿菌(Enterobacter cloacae
)、產氣腸桿菌(Enterobacter aerogenes
)、成團腸桿菌(Enterobacter agglomerans
)、大腸桿菌；土拉熱弗朗西絲菌(Francisella tularensis
)；梭桿菌屬(Fusobacterium spp.
)；嗜血桿菌屬(Haemophilus spp.
)，
諸如流感嗜血桿菌(Haemophilus influenzae
) (β-內醯胺酶陽性及陰性)或杜氏嗜血桿菌(Haemophilus ducreyi
)；幽門螺旋桿菌(Helicobacter pylori
)；金格桿菌(Kingella kingae
)；克雷伯氏菌屬(Klebsiella spp.
)，諸如產酸克雷伯氏菌(Klebsiella oxytoca
)、肺炎克雷伯氏桿菌(包括編碼延伸頻譜β-內醯胺酶(下文中「ESBL」)、碳青黴烯酶(KPC)、頭孢噻肟酶-慕尼黑(cefotaximase-Munich) (CTX-M)、金屬-β-內醯胺酶以及對當前可用之頭胞菌素、頭黴素、碳青黴烯、β-內醯胺及β-內醯胺/β-內醯胺酶抑制劑組合賦予抗性之AmpC型β-內醯胺酶之彼等)；鼻硬結病克雷伯氏菌(Klebsiella rhinoscleromatis
)或惡臭埃希氏克雷伯氏菌(Klebsiella ozaenae
)；嗜肺性退伍軍人桿菌(Legionella pneumophila
)；溶血性曼氏桿菌屬(Mannheimia haemolyticus
)、黏膜炎莫拉氏菌(Moraxella catarrhalis
) (β-內醯胺酶陽性及陰性)；摩氏摩根屬(Morganella morganii
)；奈瑟氏菌屬(Neisseria spp.
)，諸如淋病奈瑟氏菌(Neisseria gonorrhoeae
)或腦膜炎奈瑟氏菌(Neisseria meningitidis
)；巴氏桿菌屬(Pasteurella spp.
)，諸如多殺性巴氏桿菌(Pasteurella multocida
)；類志賀氏鄰單胞菌(Plesiomonas shigelloides
)；卟啉單胞菌屬(Porphyromonas spp.
)，諸如不解糖卟啉單胞菌(Porphyromonas asaccharolytica
)；普雷沃氏菌屬(Prevotella spp.
)，諸如體虱普雷沃氏菌(Prevotella corporis
)、中間普雷沃氏菌(Prevotella intermedia
)或牙髓普雷沃氏菌(Prevotella endodontalis
)；變形桿菌屬(Proteus spp.
)，諸如奇異變形桿菌(Proteus mirabilis
)、普通變形桿菌(Proteus vulgaris
)、彭內里變形桿菌(Proteus penneri
)或產黏變形桿菌(Proteus myxofaciens
)；不解糖卟啉單胞菌；類志賀氏鄰單胞菌；普羅威登斯菌屬(Providencia spp.
)，諸如斯氏普羅威登斯菌(Providencia stuartii
)、雷氏普羅威登斯菌(Providencia rettgeri
)或產鹼普羅威登斯菌(Providencia alcalifaciens
)；假單胞菌屬(Pseudomonas spp.
)，諸如綠膿桿菌(包括抗頭孢他啶綠膿桿菌(P. aeruginosa
)、抗頭孢匹羅綠膿桿菌及抗頭孢吡肟綠膿桿菌、抗卡巴盤尼姆綠膿桿菌或抗喹諾酮綠膿桿菌)或螢光假單胞菌(Pseudomonas fluorescens
)；普氏立克次體(Ricketsia prowazekii
)；沙門氏菌屬(Salmonella spp.
)，諸如傷寒沙門氏菌(Salmonella typhi
)或副傷寒沙門氏菌(Salmonella paratyphi
)；黏質沙雷氏菌(Serratia marcescens
)；志賀氏菌屬(Shigella spp.
)，諸如弗氏志賀氏菌(Shigella flexneri
)、鮑氏志賀氏菌(Shigella boydii
)、索氏志賀氏菌(Shigella sonnei
)或痢疾志賀氏菌(Shigella dysenteriae
)；念珠狀鏈桿菌(Streptobacillus moniliformis
)；嗜麥芽窄食單胞菌(Stenotrophomonas maltophilia
)；螺旋體屬(Treponema spp.
)；弧菌屬(Vibrio spp.
)，諸如霍亂弧菌(Vibrio cholerae
)、副溶血性弧菌(Vibrio parahaemolyticus
)、創傷弧菌(Vibrio vulnificus
)、溶藻弧菌(Vibrio alginolyticus
)；耶爾森氏菌屬(Yersinia spp.
)，諸如小腸結腸炎耶爾森氏菌(Yersinia enterocolitica
)、鼠疫耶爾森氏菌(Yersinia pestis
)或假結核耶爾森氏菌(Yersinia pseudotuberculosis
)。 化合物1之結晶形式1、2、3中之每一者或其非晶形式可用於製備藥物。 化合物1之結晶形式1、2、3中之每一者或其非晶形式適用於預防或治療(且尤其治療)由如美國疾病控制中心(US Center for Disease Control) (www.selectagents.gov/Select AgentsandToxinsList.html)所列的生物威脅革蘭氏陰性細菌病原體，且尤其由選自由以下各者組成之群組的革蘭氏陰性病原體所導致之感染：鼠疫耶爾森氏菌、土拉熱弗朗西絲菌(土拉菌病)、類鼻疽伯克霍爾德氏菌及鼻疽伯克霍爾德氏菌。 病原體之前述清單僅解釋為實例且絕不為限制性的。 化合物1之結晶形式1、2、3中之每一者或其非晶形式可用於獸醫學應用，諸如治療家畜及伴侶動物之感染。可治療諸如豬、反芻動物、馬、狗、貓及家禽之動物。 該等形式可另外用於保護無機及有機材料，特定而言例如聚合物、潤滑劑、塗料、纖維、皮革、紙張及木材之所有類型之有機材料；出於清潔目的，例如以用於自手術器械、導管及人工植入物去除病原性微生物及細菌或用於表面滅菌。出於此等目的，該等形式可含於溶液、懸浮液、噴霧劑或固體調配物中。 化合物1之結晶形式1、2、3中之每一者或其非晶形式可另外用於製備用於預防或治療，尤其治療本文中所提及疾病的藥物。 化合物1之結晶形式1、2、3中之每一者或其非晶形式可因此尤其適用於製備藥物，且適用於預防或治療選自以下各者之細菌感染：泌尿道感染、全身感染(諸如菌血症及敗血症)、皮膚及軟組織感染(包括灼傷患者)、手術感染、腹內感染及肺感染(包括患有囊腫性纖維化之患者中之彼等)，且特定而言用於預防或治療選自泌尿道感染及腹內感染之細菌感染。 本發明亦涉及一種用於預防或治療，尤其治療本文中所提及之疾病的方法，該方法包含向對其有需要之個體(尤其人類個體)投與醫藥活性量之化合物1之結晶形式1、2、3或其非晶形式。 化合物1之結晶形式1、2、3中之每一者及其非晶形式呈現固有抗菌特性，且具有改良革蘭氏陰性菌之外膜對其他抗細劑之滲透性的能力。其與另一種抗菌劑組合使用可提供一些其他優勢，諸如由於所使用劑量較低或治療時間較短而降低藥物副作用，更快的治癒感染，從而縮短住院時間，增加所控制之病原體範圍及降低對抗生素之抗性發展的發生率。與根據本發明之化合物1組合使用之抗菌劑將選自由以下組成之群組：青黴素抗生素(諸如安比西林(ampicillin)、哌拉西林(piperacillin)、青黴素G、阿莫西林(amoxicillin)或替卡西林(ticarcillin))、頭孢菌素抗生素(諸如頭孢曲松(ceftriaxone)、頭孢他啶、頭孢吡肟、頭孢噻肟(cefotaxime))、卡巴盤尼姆抗生素(諸如亞胺培南(imipenem)或美羅培南(meropenem))、單醯胺菌素抗生素(諸如安曲南(aztreonam)或卡蘆莫南(carumonam))、氟喹諾酮抗生素(諸如環丙沙星(ciprofloxacin)、莫西沙星(moxifloxacin)或左氧氟沙星(levofloxacin))、巨環內酯抗生素(諸如紅黴素(erythromycin)或阿奇黴素(azithromycin))、胺基醣苷抗生素(諸如胺丁卡黴素(amikacin)、健大黴素(gentamycin)或托普黴素(tobramycin))、醣肽抗生素(諸如萬古黴素(vancomycin)或替考拉寧(teicoplanin))、四環素抗生素(諸如四環素、土黴素(oxytetracycline)、多西環素(doxycycline)、二甲胺四環素或泰格環黴素(tigecycline))及利奈唑胺(linezolid)、克林達黴素(clindamycin)、特拉萬星(telavancin)、達托黴素(daptomycin)、新生黴素(novobiocin)、立複黴素(rifampicin)及多黏菌素(polymyxin)。較佳地，與根據本發明之化合物1組合使用之抗菌劑將選自由萬古黴素、泰格環黴素及立複黴素組成之群組。實驗部分
如本文中所使用之縮寫：AcOH 乙酸 aq. 水溶液 CC 經由矽膠之管柱層析 DAD 二極體陣列偵測 DCM 二氯甲烷 DMSO 二甲亞碸 EA 乙酸乙酯 ELSD 蒸發光散射偵測器 ESI 電灑離子化 Et2
O *** EtOH 乙醇 Fig. 圖 h 小時1
H-NMR 質子核磁共振 Hept 庚烷 HPLC 高壓液相層析 IT 內部溫度 LC 液相層析 LC-MS 液相層析質譜 MeCN 乙腈 MeOH 甲醇 min 分鐘 MS 質譜 NBSN - 溴代丁二醯亞胺
org. 有機 prep-HPLC 製備型HPLC rpm 每分鐘旋轉 rt 室溫 sat. 飽和 sec 秒 TBAF 氟化四正丁基銨 TBME 第三丁基甲基醚 TFA 三氟乙酸 TLC 薄層層析 tR
滯留時間 XRPD X射線粉末繞射所使用之方法 分析型 TLC
表徵用0.2 mm培養盤：Merck，矽膠60 F254
來執行。用EA、Hept、DCM、MeOH或其混合物執行溶離。用UV光或用KMnO4
(3 g)、K2
CO3
(20 g)、5% NaOH (3 mL)及H2
O (300 mL)之溶液，隨後加熱來進行偵測。管柱層析
(CC)使用Brunschwig 60A矽膠(0.032 mm至0.63 mm)或使用ISCO CombiFlash系統及預填充SiO2
盒來執行，溶離用具有適當梯度之Hept-EA或DCM-MeOH混合物來進行。當化合物含有酸官能基時，向溶離劑添加1% AcOH。當化合物含有鹼官能基時，向溶離劑添加1% NH4
OH (25%水溶液)。在溶離結束時，含有所需化合物之溶離份經組合且在減壓下濃縮至乾燥。 1 H-NMR
(400 MHz，Bruker Avance 400或500 MHz，Bruker Avance 500 Cryoprobe)係用於表徵。化學位移δ以相對於所使用溶劑之ppm給定；多峰性：s=單峰，d=雙重峰，t=三重峰，q=四重峰，p=五重峰，hex=六重峰，hep=七重峰，m=多重峰，br.=寬峰；偶合常數J以Hz給出。LC-MS
(具有帶DAD及ELSD之Agilent 1100 Binary Pump之Sciex API 2000或具有帶DAD及ELSD之Agilent 1200 Binary Pump之Agilent四極MS 6140)係用於在某些情況中表徵。分析型LC-MS資料已使用以下各別條件獲得： o 管柱：Zorbax SB-Aq，30.5 mm，4.6×50 mm； o 注射體積：1 µL； o 管柱烘箱溫度：40℃； o 偵測：UV 210 nm，ELSD及MS； o MS電離模式：ESI+； o 溶離劑：A：H2
O+0.04% TFA；及B：MeCN； o 流速：40.5 mL/min； o 梯度：5% B至95% B (0.0 min至1.0 min)，95% B (1.0 min至1.45 min)。 針對各經測試化合物之相應[M+H+
]峰以及滯留時間(tR
) 給定之十進位數取決於實際上使用之LC-MS裝置之準確度。製備型 HPLC
分離係使用以下條件在配備有Gilson 215自動取樣器、Gilson 333/334泵、Dionex MSQ Plus偵測器系統以及Dionex UVD340U (或Dionex DAD-3000) UV偵測器之Gilson HPLC系統上執行： o 管柱：Waters XBridge C18，10 µm，30×75 mm； o 流速：75 mL/min； o 溶離劑：A：H2
O+0.5% NH4
OH溶液(25%)；B：MeCN； o 梯度：90% A至5% A (0.0 min至4.0 min)，5% A (4.0 min至6.0 min)。 在溶離結束時，含有所需化合物之溶離份經組合且在減壓下濃縮至乾燥。X 射線粉末繞射
圖案在配備有在反射模式中用CuKa-輻射操作之Lynxeye偵測器的Bruker D8 X射線繞射儀上經收集。典型地，在40 kV/40 mA下操作X射線管。在2θ中之2.5-50°之掃描範圍內應用0.02° (2θ)步長大小及37秒之步長時間。將粉末略微壓製入深度0.1 mm之矽單晶試樣夾中，且在量測期間使樣本在其自身平面中旋轉。使用Cu Ka (l=1.5418 Å)報導繞射資料。如本文中所提供之2θ值之準確度在+/- 0.1-0.2°範圍內，其一般為習知記錄之X射線粉末繞射圖案之情況。為避免任何疑慮，不論何時上文實施例中之一者指「X射線粉末繞射圖中之峰在以下折射角2q處」，該X射線粉末繞射圖均藉由使用Cu Ka射線(l=1.5418 Å)獲得；且應理解，本文中所提供之2q值之準確度在+/-0.1-0.2°之範圍內。值得注意，當在本發明實施例及申請專利範圍中指定峰之折射角2θ(2theta)時，所給定2θ值理解為該值減0.2°至該值加0.2°之區間(2θ +/-0.2°)；且較佳地該值減0.1°至該值加0.1°之區間(2θ +/- 0.1°)。最小抑制濃度
(MIC；mg/L)在經陽離子調節之Mueller-Hinton培養液中藉由微稀釋法，按照「Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically
」，批准標準，第7版，臨床及實驗室標準委員會(Clinical and Laboratory Standards Institute；CLSI)文獻M7-A7, Wayne, PA, USA (2006)中所給出之說明來測定。化合物 1 之製備
所有溫度係以℃陳述。除非另外指示，否則反應在rt下發生。除非另外規定，否則將產生於水性層之處理的經合併有機層用最小體積之鹽水洗滌，經MgSO4
乾燥，過濾且蒸發至乾燥以提供所謂的蒸發殘留物。製備 A ： 3-( 溴乙炔基 )-1-(2-(( 第三丁基二甲基矽烷基 ) 氧基 ) 乙基 ) 氮雜環丁烷 A.i. 3-( 溴乙炔基 ) 氮雜環丁烷 -1- 羧酸 第三丁 酯：
向3-乙炔基氮雜環丁烷-1-羧酸第三丁酯(9.89 g；54.6 mmol；如WO 2015/13228中所描述來製備)及NBS (11.69 g；65.7 mmol)於丙酮(220 mL)中之攪拌溶液添加AgNO3
(989 mg；5.82 mmol)。在rt下攪拌反應混合物2 h且經由矽藻土過濾。濃縮過濾物至乾燥且藉由CC (Hex-TBME)純化殘留物以得到呈無色油狀之標題化合物(14.15 g，100%產率)。1
H NMR (d6
-DMSO) δ: 4.10-4.03 (m, 2H); 3.78-3.71 (m, 2H); 3.50-3.43 (m, 1H); 1.38 (s, 9H)。A.ii. 3-( 溴乙炔基 ) 氮雜環丁烷氫氯化物
：在rt下攪拌含中間產物A.i (14.15 g；54.4 mmol)之4M
HCl溶液於二噁烷(141 mL)中之溶液30 min。將反應混合物濃縮至乾燥且在Et2
O (60 mL)中濕磨殘留物。固體經收集且乾燥以得到呈灰白色固體(9.76 g；91%產率)之標題化合物。1
H NMR (d6
-DMSO) δ: 9.26 (br. s, 2H); 4.13-4.07 (m, 2H); 3.94-3.88 (m, 2H); 3.78-3.70 (m, 1H)。A.iii 3-( 溴乙炔基 )-1-(2-(( 第三丁基二甲基矽烷基 ) 氧基 ) 乙基 ) 氮雜環丁烷 ：
向中間產物A ii (9.76 g；49.7 mmol)於DCM (300 mL)中之溶液中添加(第三丁基二甲基矽烷氧基)乙醛(11.6 mL；54.6 mmol)及NaBH(OAc)3
(14.81g，69.9 mmol)。在rt下攪拌反應混合物2 h。添加MeOH (34 mL)、飽和NaHCO3
水溶液(400 mL)及DCM (300 mL)。分離兩個層，用DCM (2×300 mL)萃取水層，且用鹽水洗滌經合併有機層。藉由CC (Hept-EA)純化蒸發殘留物以得到呈橙色油狀之標題化合物(12.85 g；81%產率)。1
H NMR (d6
-DMSO) δ: 3.52 (t, J = 5.7 Hz, 2H); 3.49-3.45 (m, 2H); 3.20 (p, J = 7.4 Hz, 1H); 3.02-2.96 (m, 2H); 2.45 (t, J = 5.7 Hz, 2H); 0.86 (s, 9H); 0.03 (s, 6H)。C13
H24
NOBrSi之MS (ESI, m/z)：318.01及320.00 [兩種主要同位素之M+H+
]；tR
= 0.70 min。製備 B ： (2R
)-4-(6-((1-(2- 羥基乙基 ) 氮雜環丁烷 -3- 基 ) 丁 -1,3- 二炔 -1- 基 ) -3- 氧基 -1H
- 吡咯并 [1,2-c
] 咪唑 -2(3H
)- 基 )-2- 甲基 -2-( 甲磺醯基 )-N-
((2RS
)-( 四氫 -2H
- 哌喃 -2- 基 ) 氧基 ) 丁醯胺 B.i (2R)-4-(6-((1-(2-(( 第三丁基二甲基矽烷基 ) 氧基 ) 乙基 ) 氮雜環丁烷 -3- 基 ) 丁 -1,3- 二炔 -1- 基 ) -3- 氧基 -1H- 吡咯并 [1,2-c] 咪唑 -2(3H)- 基 )-2- 甲基 -2-( 甲磺醯基 )-N-((2RS)-( 四氫 -2H- 哌喃 -2- 基 ) 氧基 ) 丁醯胺
在rt下向正丁胺(6.5 mL)於水(16.5 mL)中之溶液中添加CuCl (257 mg，2.60 mmol)。向所得藍色溶液添加NH2
OH.HCl (1.82 g，26.1 mmol)，在rt下另外攪拌所得無色反應混合物15 min，且接著用(2R
)-4-(6-乙炔基-3-氧基-1H
-吡咯并[1,2-c
]咪唑-2(3H
)-基)-2-甲基-2-(甲磺醯基)-N-
(((2RS
)-四氫-2H
-哌喃-2-基)氧基)丁醯胺(5.50 g；13.0 mmol；如WO 2015/13228中所描述來製備)處理。在rt下攪拌反應混合物15 min且冷卻至0℃。 歷經40 min逐滴添加製備A之化合物(5.17 g；16.2 mmol)於正丁胺(6.5 mL)中之溶液，同時保持IT低於6℃。在添加結束時，在0℃下攪拌反應混合物10分鐘且接著在rt下攪拌1 h。將反應混合物冷卻低至0℃且逐滴添加製備A之化合物(727 mg；0.18 mmol)於正丁胺 (1.0 mL)中之溶液，同時保持IT低於6℃。在添加結束時，在0℃下攪拌反應混合物10分鐘，且接著在rt下攪拌2 h。添加水(200 mL)及EA (300 mL)且分離兩個層。用EA (2×200 mL)萃取水層並用鹽水洗滌經合併有機層。蒸發殘留物接著藉由CC (Hept-EA，接著EA-MeOH 9:1)來純化以得到呈黃色發泡體狀之標題化合物(6.21 g；72%)。1
H NMR (d6
-DMSO) (立體異構體之混合物): δ: 11.37 (br. s, 0.5H); 11.35 (br. s, 0.5H); 7.56 (d, J = 0.7 Hz, 0.5H); 7.55 (d, J = 0.7 Hz, 0.5H); 6.27-6.24 (m, 1H); 4.88-4.84 (m, 0.5H); 4.50-4.47 (m, 0.5H); 4.46-4.37 (m, 2H); 4.06-3.99 (m, 0.5H); 3.98-3.92 (m, 0.5H); 3.56-3.50 (m, 4H); 3.50-3.35 (m, 4H); 3.08-3.02 (重疊m, 2H); 3.06 (s, 1.5H); 3.03 (s, 1.5H); 2.70-2.56 (m, 1H); 2.47 (t, J = 5.6 Hz, 2H); 2.02-1.93 (m, 1H); 1.70-1.61 (m, 2H); 1.58-1.45 (重疊m, 4H); 1.56 (s, 1.5H); 1.54 (s, 1.5H); 0.87 (s, 9H); 0.04 (s, 6H)。C32
H48
N4
O7
Ssi之MS (ESI，m/z)：661.24 [M+H+
]；tR
= 0.82 min。B.ii (2R)-4-(6-((1-(2- 羥基乙基 ) 氮雜環丁烷 -3- 基 ) 丁 -1,3- 二炔 -1- 基 )-3- 氧基 -1H- 吡咯并 [1,2-c] 咪唑 -2(3H)- 基 )-2- 甲基 -2-( 甲磺醯基 )-N-((2RS)-( 四氫 -2H- 哌喃 -2- 基 ) 氧基 ) 丁醯胺
向中間產物B.i (6.21 g；9.4 mmol)之溶液於THF (16 mL)中之溶液中添加TBAF於THF (20 mL)中之1M
溶液。攪拌所得溶液4 h。在減壓下濃縮反應混合物且使殘留物溶於EA (250 mL)中。添加水(150 mL)且分離兩個層。用EA (2×150 mL)萃取水層且用NH4
Cl及鹽水洗滌經合併有機層。藉由CC (DCM-MeOH)純化蒸發殘留物以獲得呈米色發泡體之標題化合物(4.25 g；83%產率)。1
H NMR (d6
-DMSO) (立體異構體混合物) δ: 11.37-11.34 (m, 1H); 7.56 (d, J = 0.7 Hz, 0.5H); 7.55 (d, J = 0.7 Hz, 0.5H); 6.27-6.24 (m, 1H); 4.88-4.84 (m, 0.5H); 4.50-4.47 (m, 0.5H); 4.46-4.37 (m, 3H); 4.05-3.99 (m, 0.5H); 3.98-3.91 (m, 0.5H); 3.56-3.46 (m, 4H); 3.45-3.38 (m, 2H); 3.37-3.30 (m, 2H); 3.07 (s, 1.5H); 3.05-3.00 (重疊m, 2H); 3.04 (s, 1.5H); 2.70-2.55 (m, 1H); 2.43 (t, J = 6.0 Hz, 2H); 2.02-1.93 (m, 1H); 1.70-1.60 (m, 2H); 1.60-1.44 (重疊m, 4H); 1.55 (s, 1.5H); 1.53 (s, 1.5H)。C26
H34
N4
O7
S之MS (ESI，m/z)：547.10 [M+H+
]；tR
= 0.58 min。實例 1 ： 製備化合物 1 之結晶形式 1
在0℃下向製備B之化合物(1.88 g；3.44 mmol)於MeOH (30 mL)及水(10 mL)中之溶液中添加2M
HCl水溶液(14 mL；28 mmol)。在0℃下攪拌反應混合物1 h，且接著在rt下攪拌1 h。在用25% NH4
OH水溶液中和且在減壓下移除MeOH之後，反應混合物藉由製備型HPLC，隨後藉由CC (DCM-MeOH+1% NH4
OH)純化。使殘留物溶解於MeCN (4 mL)中，在rt下攪拌所得懸浮液30 min，經過濾且收集固體並乾燥，以得到白色的化合物 1 之結晶形式 1
(110 mg，7%產率)。1
H NMR (d6
-DMSO) δ: 10.94 (br. s, 1H); 9.20 (br. s, 1H); 7.57 (d, J = 1.0 Hz, 1H); 6.27-6.25 (m, 1H); 4.43 (s, 2H); 4.42 (t, J = 5.5 Hz, 1H); 3.51 (t, J = 6.9 Hz, 2H); 3.54-3.45 (重疊m, 1H); 3.43-3.30 (重疊m, 4H); 3.06 (s, 3H); 3.03 (t, J = 6.9 Hz, 2H); 2.63-2.56 (m, 1H); 2.43 (t, J = 6.0 Hz, 2H); 2.00-1.93 (m, 1H); 1.53 (s, 3H)。C21
H26
N4
O6
S之MS (ESI，m/z)：463.03 [M+H+
]；tR
= 0.49 min。實例 2 ： 製備化合物 1 之結晶形式 2
在0℃下向製備B之化合物(4.55 g；8.32 mmol)於MeOH (25 mL)及水(10 mL)中之溶液中添加2M
HCl水溶液(15 mL；30 mmol)。在0℃下攪拌反應混合物10分鐘且接著在rt下攪拌1小時。使反應混合物冷卻低至0℃，添加25% NH4
OH水溶液(2.5 mL)且在rt下攪拌懸浮液15 min。沈澱物經收集，經乾燥且另外溶解於0.5% NH4
OH水溶液(30 mL)中並在rt下攪拌30 min。過濾懸浮液且收集固體並乾燥，以得到白色的化合物 1 之結晶形式 2
(2.42 g；63%產率)。1
H NMR (d6
-DMSO) δ: 10.94 (br. s, 1H); 9.20 (br. s, 1H); 7.57 (d, J = 1.0 Hz, 1H); 6.27-6.25 (m, 1H); 4.43 (s, 2H); 4.42 (t, J = 5.5 Hz, 1H); 3.51 (t, J = 6.9 Hz, 2H); 3.54-3.45 (重疊m, 1H); 3.43-3.30 (重疊m, 4H); 3.06 (s, 3H); 3.03 (t, J = 6.9 Hz, 2H); 2.63-2.56 (m, 1H); 2.43 (t, J = 6.0 Hz, 2H); 2.00-1.93 (m, 1H); 1.53 (s, 3H)。C21
H26
N4
O6
S之MS (ESI，m/z)：463.03 [M+H+
]；tR
= 0.49 min。實例 3 ： 製備化合物 1 之結晶形式 3
將0.1 g呈形式1之化合物1溶解於含1 mL DMSO之新的4 mL玻璃瓶中。在完成溶解之後，在以300 rpm震盪且在40℃及0.035 mbar下操作之來自Hettich AG (Bäch，Switzerland)之Combidancer裝置中蒸發溶劑80 min。其後立即向瓶添加0.5 mL MeCN且在室溫下使該瓶靜置封閉1天。固體殘留物為根據以MeCN濕潤狀態所量測之XRPD的化合物 1 之結晶形式 3
。實例 4 ：製備化合物 1 之非晶形式
將0.1 g呈形式1之化合物1溶解於含1 mL DMSO之新的4 mL玻璃瓶中。在完成溶解之後，在以300 rpm震盪且在40℃及0.035 mbar下操作之來自Hettich AG (Bäch，Switzerland)之Combidancer裝置中蒸發溶劑80 min。殘留物為呈非晶形式之化合物 1
。化合物 1 之藥理學特性
藉助於如上文所描述之活體外分析，針對若干革蘭氏陰性細菌(亦即肺炎克雷伯氏桿菌A-651 (多抗性菌株；特定而言抗喹諾酮)及兩個喹諾酮敏感性菌株(大腸桿菌ATCC 25922及綠膿桿菌ATCC 27853)來測試化合物1。化合物1對所有經測試菌株呈現0.5 mg/L之細菌生長最小抑制濃度(MIC)。1) A first embodiment of the invention relates to compound 1 in crystalline form 1, wherein the X-ray powder diffraction pattern has peaks at the following refraction angle 2q: 11.9°, 13.4° and 20.3°, wherein the X-ray powder is wound The shot pattern was measured using a Cu Ka (1.5418 Å) source. 2) Another embodiment of the invention relates to compound 1 in crystalline form 1, wherein the X-ray powder diffraction pattern has peaks at the following refraction angle 2q: 6.7°, 11.9°, 13.4°, 19.0°, and 20.3°, Wherein the X-ray powder diffraction pattern was measured using a Cu Ka (1.5418 Å) source. 3) Another embodiment of the invention relates to compound 1 in crystalline form 1, wherein the X-ray powder diffraction pattern has peaks at the following refraction angle 2q: 6.7°, 7.5°, 11.9°, 13.4°, 15.1°, 15.4°, 18.1°, 19.0°, 20.3°, and 24.5°, wherein the X-ray powder diffraction pattern was measured using a Cu Ka (1.5418 Å) source. 4) Another embodiment of the invention pertains to Compound 1 in crystalline Form 1, which substantially exhibits an X-ray powder diffraction pattern as depicted in FIG. 5) Another embodiment of the invention pertains to compound 1 in crystalline form 1, which is obtainable by the method as described in Example 1. 6) Another embodiment of the invention relates to compound 1 in crystalline form 1 as in Example 5), wherein the X-ray powder diffraction pattern has peaks at the following refraction angle 2q: 11.9°, 13.4° and 20.3°, Wherein the X-ray powder diffraction pattern was measured using a Cu Ka (1.5418 Å) source. 7) Another embodiment of the invention relates to compound 1 in crystalline form 1 as in Example 5), wherein the X-ray powder diffraction pattern has peaks at the following refraction angle 2q: 6.7°, 11.9°, 13.4°, 19.0° and 20.3°, wherein the X-ray powder diffraction pattern was measured using a Cu Ka (1.5418 Å) source. 8) Another embodiment of the invention relates to compound 1 in crystalline form 1 as in Example 5), wherein the X-ray powder diffraction pattern has peaks at the following refraction angle 2q: 6.7°, 7.5°, 11.9°, 13.4°, 15.1°, 15.4°, 18.1°, 19.0°, 20.3°, and 24.5°, wherein the X-ray powder diffraction pattern was measured using a Cu Ka (1.5418 Å) source. 9) A further embodiment of the invention relates to a composition comprising Compound 1 in crystalline form 1 according to any one of embodiments 1) to 8), which further comprises at least one pharmaceutically acceptable form Agent. 10) Another embodiment of the invention relates to the compound 1 of crystalline form 1 or the composition of Example 9) according to any one of embodiments 1) to 8), which is suitable for use as a medicament. 11) Another embodiment of the present invention relates to the compound 1 of the crystalline form 1 or the composition of the embodiment 9) according to any one of the embodiments 1) to 8) for use in therapy or prevention, preferably Treat bacterial diseases. 12) Another embodiment of the present invention relates to the compound 1 in crystalline form 1 or the composition as in Example 9) according to any one of embodiments 1) to 8) for use in therapy or prevention, preferably Treatment of bacterial diseases mediated by Gram-negative bacteria. 13) Another embodiment of the present invention relates to the compound 1 in crystalline form 1 or the composition as in Example 9) according to any one of embodiments 1) to 8) for use in therapy or prevention, preferably Treatment consists of Klebsiella pneumoniae (Klebsiella pneumoniae
), Pseudomonas aeruginosaPseudomonas aeruginosa
) and E. coliEscherichia coli
Gram-negative bacteria mediated bacterial disease. 14) Another embodiment of the invention relates to compound 1 in crystalline form 2, wherein the X-ray powder diffraction pattern has peaks at the following refraction angle 2q: 7.4°, 13.9° and 16.5°, wherein the X-ray powder is wound The shot pattern was measured using a Cu Ka (1.5418 Å) source. 15) Another embodiment of the invention relates to compound 1 in crystalline form 2, wherein the X-ray powder diffraction pattern has peaks at the following refraction angle 2q: 6.8°, 7.4°, 13.9°, 16.5° and 21.5°, Wherein the X-ray powder diffraction pattern was measured using a Cu Ka (1.5418 Å) source. 16) Another embodiment of the invention relates to compound 1 in crystalline form 2, wherein the X-ray powder diffraction pattern has peaks at the following refraction angle 2q: 6.8°, 7.4°, 12.1°, 13.1°, 13.9°, 16.5°, 18.1°, 19.2°, 21.5°, and 24.4°, wherein the X-ray powder diffraction pattern was measured using a Cu Ka (1.5418 Å) source. 17) Another embodiment of the invention pertains to Compound 1 in crystalline Form 2, which substantially exhibits an X-ray powder diffraction pattern as depicted in Figure 2. 18) Another embodiment of the invention pertains to Compound 1 in crystalline Form 2, which is obtainable by the method as described in Example 2. 19) Another embodiment of the invention relates to compound 1 in crystalline form 2 as in Example 18), wherein the X-ray powder diffraction pattern has peaks at the following refraction angle 2q: 7.4°, 13.9° and 16.5°, Wherein the X-ray powder diffraction pattern was measured using a Cu Ka (1.5418 Å) source. 20) Another embodiment of the invention relates to compound 1 in crystalline form 2 as in Example 18), wherein the X-ray powder diffraction pattern has peaks at the following refraction angle 2q: 6.8°, 7.4°, 13.9°, 16.5° and 21.5°, wherein the X-ray powder diffraction pattern was measured using a Cu Ka (1.5418 Å) source. 21) Another embodiment of the invention relates to compound 1 in crystalline form 2 as in Example 18), wherein the X-ray powder diffraction pattern has peaks at the following refraction angle 2q: 6.8°, 7.4°, 12.1°, 13.1°, 13.9°, 16.5°, 18.1°, 19.2°, 21.5°, and 24.4°, wherein the X-ray powder diffraction pattern was measured using a Cu Ka (1.5418 Å) source. Another embodiment of the present invention relates to a composition comprising Compound 1 in crystalline form 2 according to any one of embodiments 14) to 21), which further comprises at least one pharmaceutically acceptable excipient . 23) Another embodiment of the invention relates to the compound 1 of crystalline form 2 or the composition of Example 22) according to any one of embodiments 14) to 21), which is suitable for use as a medicament. 24) A further embodiment of the invention, wherein the compound of crystalline form 2, or the composition of Example 22), according to any one of embodiments 14) to 21), is for use in therapy or prevention, preferably Treat bacterial diseases. Another embodiment of the present invention relates to the compound 1 of the crystalline form 2 or the composition of the example 22) according to any one of the embodiments 14) to 21) for use in therapy or prevention, preferably Treatment of bacterial diseases mediated by Gram-negative bacteria. Another embodiment of the present invention relates to the compound 1 of the crystalline form 2 or the composition of the embodiment 22) according to any one of the embodiments 14) to 21) for use in therapy or prevention, preferably Treatment of bacterial diseases mediated by Gram-negative bacteria selected from Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli. 27) Another embodiment of the invention relates to compound 1 in crystalline form 3, wherein the X-ray powder diffraction pattern has peaks at the following refraction angle 2q: 6.9°, 11.9° and 23.9°, wherein the X-ray powder is wound The shot pattern was measured using a Cu Ka (1.5418 Å) source. 28) Another embodiment of the invention relates to compound 1 in crystalline form 3, wherein the X-ray powder diffraction pattern has peaks at the following refraction angle 2q: 6.9°, 11.9°, 23.9°, 24.2°, and 25.0°, Wherein the X-ray powder diffraction pattern was measured using a Cu Ka (1.5418 Å) source. 29) Another embodiment of the invention relates to compound 1 in crystalline form 3, wherein the X-ray powder diffraction pattern has peaks at the following refraction angle 2q: 6.9°, 11.9°, 13.9°, 15.1°, 18.2°, 19.3, 23.9°, 24.2°, 25.0°, and 27.9°, wherein the X-ray powder diffraction pattern was measured using a Cu Ka (1.5418 Å) source. 30) Another embodiment of the invention pertains to Compound 1 in crystalline Form 3, which substantially exhibits an X-ray powder diffraction pattern as depicted in Figure 3. 31) Another embodiment of the invention pertains to Compound 1 in crystalline Form 3, which is obtainable by the method as described in Example 3. 32) Another embodiment of the invention relates to compound 1 in crystalline form 3 as in Example 31), wherein the X-ray powder diffraction pattern has peaks at the following refraction angle 2q: 6.9°, 11.9° and 23.9°, Wherein the X-ray powder diffraction pattern was measured using a Cu Ka (1.5418 Å) source. 33) Another embodiment of the invention relates to compound 1 in crystalline form 3 as in Example 31), wherein the X-ray powder diffraction pattern has peaks at the following refraction angle 2q: 6.9°, 11.9°, 23.9°, 24.2° and 25.0°, wherein the X-ray powder diffraction pattern was measured using a Cu Ka (1.5418 Å) source. 34) Another embodiment of the invention relates to compound 1 in crystalline form 3 as in Example 31), wherein the X-ray powder diffraction pattern has peaks at the following refraction angle 2q: 6.9°, 11.9°, 13.9°, 15.1°, 18.2°, 19.3, 23.9°, 24.2°, 25.0°, and 27.9°, wherein the X-ray powder diffraction pattern was measured using a Cu Ka (1.5418 Å) source. 35) Another embodiment of the present invention relates to a composition comprising Compound 1 in crystalline Form 3 according to any one of embodiments 27) to 34), further comprising at least one pharmaceutically acceptable excipient . 36) A further embodiment of the invention relates to the compound 1 of crystalline form 3 or the composition of example 35) according to any one of embodiments 27) to 34), which is suitable for use as a medicament. 37) A further embodiment of the invention, wherein the compound of crystalline form 3, or the composition of Example 35), according to any one of embodiments 27) to 34), for use in therapy or prevention, preferably Treat bacterial diseases. 38) A further embodiment of the invention, wherein the compound of crystalline form 3, or the composition of Example 35), according to any one of embodiments 27) to 34), for use in therapy or prevention, preferably Treatment of bacterial diseases mediated by Gram-negative bacteria. 39) A further embodiment of the invention, wherein the compound of crystalline form 3, or the composition of Example 35), according to any one of embodiments 27) to 34), is for use in therapy or prevention, preferably Treatment of bacterial diseases mediated by Gram-negative bacteria selected from Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli. 40) Another embodiment of the invention relates to Compound 1 in amorphous form. 41) Another embodiment of the invention pertains to Compound 1 in amorphous form which is obtainable by the procedure as described in Example 4. 42) A further embodiment of the invention relates to a composition comprising Compound 1 in amorphous form according to any one of embodiments 40) and 41), further comprising at least one pharmaceutically acceptable excipient . 43) A further embodiment of the invention relates to a composition of compound 1 or embodiment 42) according to any one of embodiments 40) and 41) which is suitable for use as a medicament. 44) A further embodiment of the invention, wherein the compound of any one of embodiments 40) and 41) or the composition of embodiment 42) is for use in the treatment or prevention, preferably in the treatment of a bacterial disease. 45) A further embodiment of the invention, wherein the compound of any one of embodiments 40) and 41) or the composition of embodiment 42) is for use in therapy or prevention, preferably by Gram-negative bacteria A mediated bacterial disease. 46) A further embodiment of the invention, wherein the compound of any one of embodiments 40) and 41), or the composition of embodiment 42), for use in therapy or prevention, preferably treated by a pneumonia A bacterial disease mediated by Gram-negative bacteria of U. aureus, Pseudomonas aeruginosa and Escherichia coli. Based on the dependencies of the different embodiments 1) to 46) as disclosed above, the following embodiments are therefore possible and desirable, and are specifically disclosed herein in individualized form: 6+5, 7+5, 8+ 5, 9+1, 9+2, 9+3, 9+4, 9+5, 9+6+5, 9+7+5, 9+8+5, 10+1, 10+2, 10+ 3, 10+4, 10+5, 10+6+5, 10+7+5, 10+8+5, 10+9+1, 10+9+2, 10+9+3, 10+9+ 4, 10+9+5, 10+9+6+5, 10+9+7+5, 10+9+8+5, 11+1, 11+2, 11+3, 11+4, 11+ 5, 11+6+5, 11+7+5, 11+8+5, 11+9+1, 11+9+2, 11+9+3, 11+9+4, 11+9+5, 11+9+6+5, 11+9+7+5, 11+9+8+5, 12+1, 12+2, 12+3, 12+4, 12+5, 12+6+5, 12+7+5, 12+8+5, 12+9+1, 12+9+2, 12+9+3, 12+9+4, 12+9+5, 12+9+6+5, 12+9+7+5, 12+9+8+5, 13+1, 13+2, 13+3, 13+4, 13+5, 13+6+5, 13+7+5, 13+ 8+5, 13+9+1, 13+9+2, 13+9+3, 13+9+4, 13+9+5, 13+9+6+5, 13+9+7+5, 13+9+8+5, 19+18, 20+18, 21+18, 22+14, 22+15, 22+16, 22+17, 22+18, 22+19+18, 22+20+ 18, 22+21+18, 23+14, 23+15, 23+16, 23+17, 23+18, 23+19+18, 23+20+18, 23+21+18, 23+22+ 14, 23+22+15, 23+22+16, 23+ 22+17, 23+22+18, 23+22+19+18, 23+22+20+18, 23+22+21+18, 24+14, 24+15, 24+16, 24+17, 24+18, 24+19+18, 24+20+18, 24+21+18, 24+22+14, 24+22+15, 24+22+16, 24+22+17, 24+22+ 18, 24+22+19+18, 24+22+20+18, 24+22+21+18, 25+14, 25+15, 25+16, 25+17, 25+18, 25+19+ 18, 25+20+18, 25+21+18, 25+22+14, 25+22+15, 25+22+16, 25+22+17, 25+22+18, 25+22+19+ 18, 25+22+20+18, 25+22+21+18, 26+14, 26+15, 26+16, 26+17, 26+18, 26+19+18, 26+20+18, 26+21+18, 26+22+14, 26+22+15, 26+22+16, 26+22+17, 26+22+18, 26+22+19+18, 26+22+20+ 18, 26+22+21+18, 32+31, 33+31, 34+31, 35+27, 35+28, 35+29, 35+30, 35+31, 35+32+31, 35+ 33+31, 35+34+31, 36+27, 36+28, 36+29, 36+30, 36+31, 36+32+31, 36+33+31, 36+34+31, 36+ 35+27, 36+35+28, 36+35+29, 36+35+30, 36+35+31, 36+35+32+31, 36+35+33+31, 36+35+34+ 31, 37+27, 37+28, 37+29, 37+30, 37+31, 37+32+31, 37+33+31, 37+34+31, 37+35+27, 37+35+ 28, 37+35+29, 37+35+30, 37+35+31, 37+35+32+31, 37+35+33+31, 37+35+ 34+31, 38+27, 38+28, 38+29, 38+30, 38+31, 38+32+31, 38+33+31, 38+34+31, 38+35+27, 38+ 35+28, 38+35+29, 38+35+30, 38+35+31, 38+35+32+31, 38+35+33+31, 38+35+34+31, 39+27, 39+28, 39+29, 39+30, 39+31, 39+32+31, 39+33+31, 39+34+31, 39+35+27, 39+35+28, 39+35+ 29, 39+35+30, 39+35+31, 39+35+32+31, 39+35+33+31, 39+35+34+31, 42+40, 42+41, 43+40, 43+41, 43+42+40, 43+42+41, 44+40, 44+41, 44+42+40, 44+42+41, 45+40, 45+41, 45+42+40, 45+42+41, 46+40, 46+41, 46+42+40, 46+42+41 In the above list, the numbers refer to the embodiments according to the numbers provided above, and the “+” indication Dependence with another embodiment. Different individualized embodiments are separated by commas. In other words, "11+9+1" means, for example, that the embodiment 11) is attached to the embodiment 9) and is attached to the embodiment 1), that is, the embodiment "11+9+1" corresponds to the embodiment 1) and is further implemented. Characterization of Examples 9) and 11). The definitions provided herein are intended to apply uniformly to the subject matter as defined in any one of the embodiments 1) to 46), and the necessary modifications are made in the details, unless the The definition of a statement provides a broader or narrower definition. It will be better understood that any definition or preferred definition of any or all other terms or expressions as defined herein (and combinations thereof), definitions or preferred definitions of terms or expressions are defined and may be substituted for individual terms or Expression. The crystalline forms 1, 2 and 3 of Compound 1, or amorphous forms thereof, may especially exist in substantially pure form. The expression "in a substantially pure form" is understood to mean in particular that at least 90% by weight, preferably at least 95% by weight, and optimally at least 99% by weight of the compound 1 are present in the single form of the invention. The term "prevent/prevention/promoting" as used in relation to a disease means that the disease does not occur in a patient or animal, or that even if the animal or patient is affected by the disease, some or all of the symptoms of the disease are reduced or absent. The term "treat/treatment/treatment" as used in relation to a disease means that the disease is cured in a patient or animal, or even if the animal or patient is still affected by the disease, some or all of the symptoms of the disease are reduced or eliminated. When defining the presence of a peak in, for example, an X-ray powder diffraction pattern, a common method is to make this definition in terms of the S/N ratio (S = signal, N = noise). According to this definition, when the stated peak must be present in the X-ray powder diffraction pattern, it should be understood that the peak in the X-ray powder diffraction pattern is greater than x (x value greater than 1), usually greater than 2, especially greater than 3 /N ratio (S = signal, N = noise) is defined. In the context in which it is stated that the crystalline form substantially exhibits an X-ray powder diffraction (XRPD) pattern as depicted in Figures 1-3, respectively, the term "substantially" means compared to the strongest peak in the figure, at least The main peaks of the patterns depicted in the figures (i.e., those having a relative intensity greater than 20%, especially greater than 10%) must be present. However, those skilled in the art of X-ray powder diffraction will recognize that the relative intensity in the X-ray powder diffraction pattern can undergo a strong intensity change due to better orientation effects. Unless otherwise stated with respect to temperature, the term "about" placed before the value "X" in this application refers to the interval from X minus 10% X to X plus 10% X, and preferably refers to X. Decrease 5% X to extend to X plus 5% X. In the specific case of temperature, the term "about" placed before temperature "Y" means in the present application a range extending from temperature Y by 5 ° C to Y plus 5 ° C, and preferably from Y Decrease by 3 ° C to extend to the range of Y plus 3 ° C. Room temperature means a temperature of about 23 °C. When the diffraction angle 2q (2theta) is specified for the peak in the present application, it will be understood that the given value will be understood to be from the value by 0.2° to the value plus 0.2°, and preferably from the value by 0.1. ° to the value plus 0.1 ° interval. Each of the crystalline forms 1, 2 and 3 of the compound 1, or an amorphous form thereof (as a single component (preferably) or together with other crystalline forms and/or amorphous forms of the compound 1) can be used, for example, as a presentation a medicament for parenteral and/or enteral administration in humans, especially in the form of a pharmaceutical composition for parenteral administration, and for the prevention or treatment of bacterial diseases, in particular, such as Klebsiella pneumoniae, Bacterial disease caused by Pseudomonas aeruginosa and Gram-negative bacteria of Escherichia coli. By combining each of the crystalline forms 1, 2 and 3 of Compound 1 (as a single component or together with other crystalline forms and/or amorphous forms of Compound 1), as desired, in combination with other therapeutically valuable substances, Suitable, non-toxic, inert, pharmaceutically acceptable solid or liquid carrier materials and, if desired, common pharmaceutical adjuvants are introduced into the Galen dosage form, and the pharmaceutical composition can be produced by anyone skilled in the art. Achieved in a familiar manner (see, for example, Remington, The Science and Practice of Pharmacy, 21st Ed. (2005), Section 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams and Wilkins]). The pharmaceutical composition may further contain additional known antibiotics. Each of the crystalline forms 1, 2, 3 of Compound 1, or an amorphous form thereof, is active against bacteria. Therefore, it is particularly suitable for the treatment of bacterial infections in mammals, especially humans, for the prevention and treatment of local and systemic infections caused by lytic or non-fermentative Gram-negative bacteria, especially by susceptibility And infection caused by multi-drug resistant Gram-negative bacteria. Examples of such Gram-negative bacteria include the genus Acinetobacter (Acinetobacter spp
), such as Acinetobacter baumannii (Acinetobacter baumannii
) or Acinetobacter hemolyticus (Acinetobacter haemolyticus
ActinomycetesActinobacillus actinomycetemcomitans
); Achromobacter (Achromobacter spp.
), such as oxidation of xylose-oxidized Achromobacter (Achromobacter xylosoxidans
) or Enterococcus aureus (Achromobacter faecalis
); Aeromonas (Aeromonas spp.
), such as Aeromonas hydrophila (Aeromonas hydrophila
);Bacteroides spp.
), such as Bacteroides fragilisBacteroides fragilis
BacteroidesBacteroides theataioatamicron
BacteroidesBacteroides distasonis
BacteroidesBacteroides ovatus
Or common bacillusBacteroides vulgatus
); Paterella (Bartonella hensenae
); B. genusBordetella spp.
), such as Bordetella pertussis (Bordetella pertussis
);Borrelia spp.
), such as Borrelia burgdorferi (Borrelia Burgdorferi
); Brucella (Brucella spp.
), such as BrucellaBrucella melitensis
); BurkholderiaBurkholderia spp
), such as Burkholderia cepacia (Burkholderia cepacia
), Burkholderia pseudomallei (Burkholderia pseudomallei
) or B. bursii (Burkholderia mallei
); CampylobacterCampylobacter spp.
), such as Campylobacter jejuni (Campylobacter jejuni
), Campylobacter embryos (Campylobacter fetus
) or Campylobacter coliCampylobacter coli
); West genusCedecea
); ChlamydiaChlamydia spp.
),
Such as pneumonia pneumoniae (Chlamydia pneumoniae
), trachoma chlamydia (Chlamydia trachomatis
); CitrobacterCitrobacter spp.
), such as the difference (Krebs) CitrobacterCitrobacter diversus (koseri)
) or Citrobacter freundii (Citrobacter freundii
); Cochlear betaCoxiella burnetii
); Edwards (Edwardsiella spp.
), such as late-onset Edwards (Edwarsiella tarda
); Chaffes Ehrlich( Ehrlichia chafeensis )
Causing EckenellaEikenella corrodens
); Enterobacter (Enterobacter spp.
), such as Enterobacter cloacae (Enterobacter cloacae
), Enterobacter aerogenesEnterobacter aerogenes
EnterobacteriaceaeEnterobacter agglomerans
), Escherichia coli;Francisella tularensis
); Clostridium (Fusobacterium spp.
); HaemophilusHaemophilus spp.
),
Haemophilus influenzae (such asHaemophilus influenzae
(β-endoprolase positive and negative) or Haemophilus Duchenne (Haemophilus ducreyi
); Helicobacter pylori (Helicobacter pylori
); G. gingivalisKingella kingae
); Klebsiella (Klebsiella spp.
), such as acid-producing Klebsiella (Klebsiella oxytoca
Klebsiella pneumoniae (including encoding extended spectrum β-endosaminolase (hereinafter "ESBL"), carbapenemase (KPC), cefotaximease-munich (cefotaximase-Munich) (CTX-M ), metal-β-endoaminase and the combination of currently available cephalosporin, cephamycin, carbapenem, β-indoleamine and β-indoleamine/β-inactamase inhibitor Resistance to AmpC-type β-endoprostanase (their); nasal induration Klebsiella (Klebsiella rhinoscleromatis
) or stinking Escherichia coli (Klebsiella ozaenae
); Lungophilic Legionella vulgaris (Legionella pneumophila
); hemolytic genusMannheimia haemolyticus
), M. catarrhalis (Moraxella catarrhalis
(β-endoprolase positive and negative); Mohs Morgan (Morganella morganii
); NeisseriaNeisseria spp.
), such as Neisseria gonorrhoeae (Neisseria gonorrhoeae
) or Neisseria meningitidis (Neisseria meningitidis
); PasteurellaPasteurella spp.
), such as Pasteurella multocida (Pasteurella multocida
); Pseudostellaria ssp.Plesiomonas shigelloides
); PorphyromonasPorphyromonas spp.
), such as P. gingivalisPorphyromonas asaccharolytica
); Prevos (Prevotella spp.
), such as P. vivax (Prevotella corporis
), intermediate Prevoella (Prevotella intermedia
) or P. vivax (Prevotella endodontalis
); ProteusProteus spp.
), such as Proteus mirabilis (Proteus mirabilis
), common Proteus (Proteus vulgaris
), Proteus pylonii (Proteus penneri
Or visceraProteus myxofaciens
); Pseudomonas syphilis; Pseudomonas sinensis; Providencia (Providencia spp.
), such as ProvidenceProvidencia stuartii
), Providencia serrata (Providencia rettgeri
) or the production of FertilizationProvidencia alcalifaciens
); Pseudomonas (Pseudomonas spp.
), such as Pseudomonas aeruginosa (including anti-ceftazidime Pseudomonas aeruginosa (P. aeruginosa
), anti-cepizopirin and Pseudomonas aeruginosa, anti-cabbage, Pseudomonas aeruginosa or Pseudomonas aeruginosa or Pseudomonas fluorescens (Pseudomonas fluorescens
); Platts rickettsia (Ricketsia prowazekii
); Salmonella (Salmonella spp.
), such as Salmonella typhimurium (Salmonella typhi
) or Salmonella paratyphi (Salmonella paratyphi
); Serratia marcescens (Serratia marcescens
); Shigella (Shigella spp.
), such as Shigella flexneri (Shigella flexneri
), Shigella baumannii (Shigella boydii
), Shigella sojae (Shigella sonnei
) or Shigella dysenteriae (Shigella dysenteriae
);Streptobacillus moniliformis
); Stenotrophomonas maltophilia (Stenotrophomonas maltophilia
);Treponema spp.
); VibrioVibrio spp.
), such as Vibrio cholerae (Vibrio cholerae
Vibrio parahaemolyticusVibrio parahaemolyticus
), Vibrio vulnificusVibrio vulnificus
), Vibrio alginolyticusVibrio alginolyticus
); YersiniaYersinia spp.
), such as Yersinia enterocolitica (Yersinia enterocolitica
), Yersinia pestis (Yersinia pestis
) or pseudotuberculosis Yersinia (Yersinia pseudotuberculosis
). Each of the crystalline forms 1, 2, 3 of Compound 1, or an amorphous form thereof, can be used to prepare a medicament. Each of the crystalline forms 1, 2, 3 of Compound 1, or an amorphous form thereof, is suitable for use in prevention or treatment (and especially treatment) by, for example, the US Center for Disease Control (www.selectagents.gov/ The Agent listed in Select Agents and ToxinsList.html) is a Gram-negative bacterial pathogen, and in particular an infection caused by a Gram-negative pathogen selected from the group consisting of Yersinia pestis, Tula fever Francis (Tursilia), Burkholderia typhimurium, and Burkholderia typhimurium. The foregoing list of pathogens is to be construed as merely illustrative and not restrictive. Each of the crystalline forms 1, 2, 3 of Compound 1, or an amorphous form thereof, can be used in veterinary applications, such as treatment of infections in livestock and companion animals. It can treat animals such as pigs, ruminants, horses, dogs, cats and poultry. These forms may additionally be used to protect inorganic and organic materials, in particular all types of organic materials such as polymers, lubricants, coatings, fibers, leather, paper and wood; for cleaning purposes, for example for self-surgery Instruments, catheters, and artificial implants remove pathogenic microorganisms and bacteria or are used for surface sterilization. For such purposes, such forms may be included in solution, suspension, spray or solid formulation. Each of the crystalline forms 1, 2, 3 of Compound 1, or an amorphous form thereof, can additionally be used to prepare a medicament for the prevention or treatment, particularly for the treatment of the diseases mentioned herein. Each of the crystalline forms 1, 2, 3 of the compound 1, or an amorphous form thereof, may therefore be particularly suitable for the preparation of a medicament, and is suitable for the prevention or treatment of bacterial infections selected from the group consisting of urinary tract infections, systemic infections ( Such as bacteremia and sepsis), skin and soft tissue infections (including burn patients), surgical infections, intra-abdominal infections, and lung infections (including those in patients with cystic fibrosis), and specifically for prevention Or treating a bacterial infection selected from the group consisting of a urinary tract infection and an intra-abdominal infection. The invention also relates to a method for the prophylaxis or treatment, in particular for the treatment of a disease as referred to herein, which comprises administering to a subject in need thereof, in particular a human subject, a pharmaceutically active amount of Compound 1 in crystalline form 1 , 2, 3 or its amorphous form. Each of the crystalline forms 1, 2, and 3 of Compound 1 and its amorphous form exhibit inherent antibacterial properties and have the ability to improve the permeability of the membrane other than Gram-negative bacteria to other anti-fine agents. Its use in combination with another antibacterial agent offers some other advantages, such as lowering drug side effects due to lower doses or shorter treatment times, faster healing of infections, shortening hospital stays, increasing the range of pathogens controlled and reducing The incidence of resistance to antibiotic development. The antibacterial agent used in combination with the compound 1 according to the present invention will be selected from the group consisting of penicillin antibiotics (such as ampicillin, piperacillin, penicillin G, amoxicillin or tica). Citrus (ticarcillin), cephalosporin antibiotics (such as ceftriaxone, ceftazidime, cefepime, cefotaxime), kappa bromide antibiotics (such as imipenem or meropenem) (meropenem)), monopterin antibiotics (such as aztreonam or carumonam), fluoroquinolone antibiotics (such as ciprofloxacin, moxifloxacin or levofloxacin) (levofloxacin)), macrolide antibiotics (such as erythromycin or azithromycin), aminoglycoside antibiotics (such as amikacin, gentamycin or topaz) Tobramycin, glycopeptide antibiotics (such as vancomycin or teicoplanin), tetracycline antibiotics (such as tetracycline, oxytetracycline, doxycycline (doxycycline) Ine), minocycline or tigcycline) and linezolid, clindamycin, telavancin, daptomycin, Novobiocin, rifampicin and polymyxin. Preferably, the antibacterial agent used in combination with Compound 1 according to the present invention will be selected from the group consisting of vancomycin, tegelcycline and rifamycin.Experimental part
Abbreviations as used herein: AcOH Acetic acid aq. Aqueous solution CC by DAD diode array detection DCM dichloromethane DMSO Dimethyl hydrazine EA Ethyl acetate ELSD Evaporative light scattering detector ESI Sprinkle ionization Et2
O diethyl ether EtOH ethanol Fig. Figure h hour1
H-NMR proton nuclear magnetic resonance Hept heptane HPLC high pressure liquid chromatography IT internal temperature LC liquid chromatography LC-MS liquid chromatography mass spectrometry MeCN acetonitrile MeOH methanol min min MS mass spectrometry NBSN - Bromobutane diimine
Org. Organic prep-HPLC preparative HPLC rpm rotation per minute rt room temperature sat. saturation sec seconds TBAF tetra-n-butylammonium fluoride TBME third butyl methyl ether TFA trifluoroacetic acid TLC thin layer chromatography tR
Residence time XRPD X-ray powder diffractionMethod used Analytical TLC
Characterization with 0.2 mm plate: Merck, silicone 60 F254
To execute. The dissolution is carried out with EA, Hept, DCM, MeOH or a mixture thereof. Use UV light or use KMnO4
(3 g), K2
CO3
(20 g), 5% NaOH (3 mL) and H2
A solution of O (300 mL) was then heated for detection.Column chromatography
(CC) using Brunschwig 60A silicone (0.032 mm to 0.63 mm) or using the ISCO CombiFlash system and pre-filled SiO2
The cartridge was run and the dissolution was carried out with a mixture of Hept-EA or DCM-MeOH with appropriate gradients. When the compound contains an acid functional group, 1% AcOH is added to the leaching agent. Add 1% NH to the eliminator when the compound contains a base functional group4
OH (25% aqueous solution). At the end of the dissolution, the fractions containing the desired compound were combined and concentrated under reduced pressure to dryness. 1 H-NMR
(400 MHz, Bruker Avance 400 or 500 MHz, Bruker Avance 500 Cryoprobe) for characterization. The chemical shift δ is given in ppm relative to the solvent used; multimodality: s = singlet, d = doublet, t = triplet, q = quartet, p = quintuple, hex = hexa , hep = heptagon, m = multiplet, br. = broad peak; coupling constant J is given in Hz.LC-MS
(Sciex API 2000 with Agilent 1100 Binary Pump with DAD and ELSD or Agilent Quadrupole MS 6140 with Agilent 1200 Binary Pump with DAD and ELSD) is used for characterization in some cases. Analytical LC-MS data have been obtained using the following individual conditions: o Column: Zorbax SB-Aq, 30.5 mm, 4.6 x 50 mm; o Injection volume: 1 μL; o Column oven temperature: 40 °C; o Detection : UV 210 nm, ELSD and MS; o MS ionization mode: ESI+; o Dissolving agent: A: H2
O+0.04% TFA; and B:MeCN; o Flow rate: 40.5 mL/min; o Gradient: 5% B to 95% B (0.0 min to 1.0 min), 95% B (1.0 min to 1.45 min). Corresponding to each tested compound [M+H+
Peak and residence time (tR
The given decimal number depends on the accuracy of the LC-MS device actually used.Preparation type HPLC
Separation was performed on a Gilson HPLC system equipped with a Gilson 215 autosampler, a Gilson 333/334 pump, a Dionex MSQ Plus detector system, and a Dionex UVD340U (or Dionex DAD-3000) UV detector using the following conditions: o Tube Column: Waters XBridge C18, 10 μm, 30 x 75 mm; o Flow rate: 75 mL/min; o Dissolving agent: A: H2
O+0.5% NH4
OH solution (25%); B: MeCN; o Gradient: 90% A to 5% A (0.0 min to 4.0 min), 5% A (4.0 min to 6.0 min). At the end of the dissolution, the fractions containing the desired compound were combined and concentrated under reduced pressure to dryness.X Ray powder diffraction
The pattern was collected on a Bruker D8 X-ray diffractometer equipped with a Lynxeye detector operating in CuKa-radiation in reflection mode. Typically, the X-ray tube is operated at 40 kV / 40 mA. A 0.02° (2θ) step size and a 37 second step time are applied in the scan range of 2.5-50° in 2θ. The powder was slightly pressed into a single crystal sample holder of depth 0.1 mm and the sample was rotated in its own plane during the measurement. The diffraction data was reported using Cu Ka (l = 1.5418 Å). The accuracy of the 2θ values as provided herein is in the range of +/- 0.1-0.2°, which is generally the case for conventionally recorded X-ray powder diffraction patterns. In order to avoid any doubt, whenever one of the above embodiments refers to "the peak in the X-ray powder diffraction pattern is at the following refraction angle 2q", the X-ray powder diffraction pattern is obtained by using Cu Ka rays (l = 1.5418 Å) Obtained; and it should be understood that the accuracy of the 2q values provided herein is in the range of +/- 0.1-0.2°. It should be noted that when the refraction angle 2θ(2theta) of the peak is specified in the embodiment of the present invention and the patent application, the given 2θ value is understood to be the value minus 0.2° to the value plus 0.2° (2θ +/- 0.2). °); and preferably the value is reduced by 0.1° to the value plus 0.1° interval (2θ +/- 0.1°).Minimum inhibitory concentration
(MIC; mg/L) in a cation-adjusted Mueller-Hinton medium by microdilution method, according to "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically
The approval criteria, 7th edition, Clinical and Laboratory Standards Institute (CLSI) document M7-A7, Wayne, PA, USA (2006) are used to determine.Compound 1 Preparation
All temperatures are stated in °C. The reaction occurs at rt unless otherwise indicated. Unless otherwise specified, the combined organic layers resulting from the treatment of the aqueous layer were washed with a minimum volume of brine over MgSO.4
Dry, filter and evaporate to dryness to provide a so-called evaporation residue.preparation A : 3-( Bromoethynyl )-1-(2-(( Third butyl dimethyl decyl ) Oxyl ) Ethyl ) Azetidine Ai 3-( Bromoethynyl ) Azetidine -1- carboxylic acid Third ester:
To 3-ethynylazetidine-1-carboxylic acid tert-butyl ester (9.89 g; 54.6 mmol; prepared as described in WO 2015/13228) and NBS (11.69 g; 65.7 mmol) in acetone (220) Add AgNO to the stirred solution in mL)3
(989 mg; 5.82 mmol). The reaction mixture was stirred at rt for 2 h and filtered over EtOAc. The filtrate was concentrated to dryness EtOAcqqqqqqm1
H NMR (D6
- DMSO) δ: 4.10-4.03 (m, 2H); 3.78-3.71 (m, 2H); 3.50-3.43 (m, 1H); 1.38 (s, 9H).A.ii. 3-( Bromoethynyl ) Azetidine hydrochloride
: stirring the intermediate product A.i (14.15 g; 54.4 mmol) at rtM
A solution of the HCl solution in dioxane (141 mL) was applied for 30 min. The reaction mixture was concentrated to dryness at Et2
Wet grinding residue in O (60 mL). The solid was collected and dried to give the title compound.1
H NMR (D6
- DMSO) δ: 9.26 (br. s, 2H); 4.13-4.07 (m, 2H); 3.94-3.88 (m, 2H); 3.78-3.70 (m, 1H).A.iii 3-( Bromoethynyl )-1-(2-(( Third butyl dimethyl decyl ) Oxyl ) Ethyl ) Azetidine :
To the solution of the intermediate product A ii (9.76 g; 49.7 mmol) in DCM (300 mL), (t-butyl dimethyl decyloxy) acetaldehyde (11.6 mL; 54.6 mmol) and NaBH (OAc)3
(14.81g, 69.9 mmol). The reaction mixture was stirred at rt for 2 h. Add MeOH (34 mL), saturated NaHCO3
Aqueous solution (400 mL) and DCM (300 mL). The two layers were separated, the aqueous layer was extracted with DCM (2.times.300 mL) and the combined organic layers were washed with brine. The title compound (12.85 g; 81% yield).1
H NMR (D6
-DMSO) δ: 3.52 (t, J = 5.7 Hz, 2H); 3.49-3.45 (m, 2H); 3.20 (p, J = 7.4 Hz, 1H); 3.02-2.96 (m, 2H); 2.45 (t , J = 5.7 Hz, 2H); 0.86 (s, 9H); 0.03 (s, 6H). C13
Htwenty four
MS of MS (ESI, m/z): 318.01 and 320.00 [M+H of two major isotopes+
];tR
= 0.70 min.preparation B : (2 R )-4-(6-((1-(2- Hydroxyethyl ) Azetidine -3- base ) Ding -1,3- Diacetylene -1- base ) -3- Oxyl -1 H - Pyrrole [1,2- c ] Imidazole -2(3 H )- base )-2- methyl -2-( Methanesulfonyl )- N- ((2 RS )-( Tetrahydrogen -2 H - Piper -2- base ) Oxyl ) Butylamine Bi (2R)-4-(6-((1-(2-(( Third butyl dimethyl decyl ) Oxyl ) Ethyl ) Azetidine -3- base ) Ding -1,3- Diacetylene -1- base ) -3- Oxyl -1H- Pyrrole [1,2-c] Imidazole -2(3H)- base )-2- methyl -2-( Methanesulfonyl )-N-((2RS)-( Tetrahydrogen -2H- Piper -2- base ) Oxyl ) Butylamine
CuCl (257 mg, 2.60 mmol) was added to a solution of n-butylamine (6.5 mL) in water (16.5 mL) at rt. Adding NH to the resulting blue solution2
OH.HCl (1.82 g, 26.1 mmol), EtOAc m.R
)-4-(6-ethynyl-3-oxy-1H
-pyrrolo[1,2-c
Imidazole-2 (3H
)-yl)-2-methyl-2-(methylsulfonyl)-N-
(((2RS
)-tetrahydro-2H
- Piperan-2-yl)oxy)butanamine (5.50 g; 13.0 mmol; prepared as described in WO 2015/13228). The reaction mixture was stirred at rt for 15 min and cooled to 0 °C. A solution of the compound of Preparation A (5.17 g; 16.2 mmol) in n-butylamine (6.5 mL) was added dropwise over 40 min while keeping IT below 6 °C. At the end of the addition, the reaction mixture was stirred at 0 °C for 10 min and then at rt for 1 h. The reaction mixture was cooled to 0 ° C and a solution of compound A (727 mg; 0.18 mmol) in n-butylamine (1.0 mL) was added dropwise while keeping IT below 6 °C. At the end of the addition, the reaction mixture was stirred at 0 °C for 10 min and then at rt for 2 h. Water (200 mL) and EA (300 mL) were added and the two layers were separated. The aqueous layer was extracted with EA (2×200 mL) and brine. The residue was purified by EtOAc EtOAcqqqqqqq1
H NMR (D6
- DMSO) (mixture of stereoisomers): δ: 11.37 (br. s, 0.5H); 11.35 (br. s, 0.5H); 7.56 (d, J = 0.7 Hz, 0.5H); 7.55 (d , J = 0.7 Hz, 0.5H); 6.27-6.24 (m, 1H); 4.88-4.84 (m, 0.5H); 4.50-4.47 (m, 0.5H); 4.46-4.37 (m, 2H); 4.06- 3.99 (m, 0.5H); 3.98-3.92 (m, 0.5H); 3.56-3.50 (m, 4H); 3.50-3.35 (m, 4H); 3.08-3.02 (overlap m, 2H); 3.06 (s, 1.5H); 3.03 (s, 1.5H); 2.70-2.56 (m, 1H); 2.47 (t, J = 5.6 Hz, 2H); 2.02-1.93 (m, 1H); 1.70-1.61 (m, 2H) 1.58-1.45 (overlap m, 4H); 1.56 (s, 1.5H); 1.54 (s, 1.5H); 0.87 (s, 9H); 0.04 (s, 6H). C32
H48
N4
O7
MS of Ssi (ESI, m/z): 661.24 [M+H+
];tR
= 0.82 min.B.ii (2R)-4-(6-((1-(2- Hydroxyethyl ) Azetidine -3- base ) Ding -1,3- Diacetylene -1- base )-3- Oxyl -1H- Pyrrole [1,2-c] Imidazole -2(3H)- base )-2- methyl -2-( Methanesulfonyl )-N-((2RS)-( Tetrahydrogen -2H- Piper -2- base ) Oxyl ) Butylamine
Add TBAF to THF (20 mL) to a solution of the intermediate B.i (6.21 g; 9.4 mmol) in THF (16 mL)M
Solution. The resulting solution was stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was evaporatedjjjjjjjj Water (150 mL) was added and the two layers were separated. Extract the aqueous layer with EA (2 x 150 mL) and use NH4
The combined organic layers were washed with Cl and brine. The residue was purified by EtOAc (EtOAc) elute1
H NMR (D6
- DMSO) (stereoisomer mixture) δ: 11.37-11.34 (m, 1H); 7.56 (d, J = 0.7 Hz, 0.5H); 7.55 (d, J = 0.7 Hz, 0.5H); 6.27-6.24 (m, 1H); 4.88-4.84 (m, 0.5H); 4.50-4.47 (m, 0.5H); 4.46-4.37 (m, 3H); 4.05-3.99 (m, 0.5H); 3.98-3.91 (m , 0.5H); 3.56-3.46 (m, 4H); 3.45-3.38 (m, 2H); 3.37-3.30 (m, 2H); 3.07 (s, 1.5H); 3.05-3.00 (overlap m, 2H); 3.04 (s, 1.5H); 2.70-2.55 (m, 1H); 2.43 (t, J = 6.0 Hz, 2H); 2.02-1.93 (m, 1H); 1.70-1.60 (m, 2H); 1.60-1.44 (overlapping m, 4H); 1.55 (s, 1.5H); 1.53 (s, 1.5H). C26
H34
N4
O7
MS of MS (ESI, m/z): 547.10 [M+H+
];tR
= 0.58 min.Instance 1 : Preparation of compounds 1 Crystal form 1
Add 2 to a solution of the compound of Preparation B (1.88 g; 3.44 mmol) in MeOH (30 mL) and water (10 mL)M
Aqueous HCl (14 mL; 28 mmol). The reaction mixture was stirred at 0 ° C for 1 h and then at rt for 1 h. Using 25% NH4
After neutralizing the OH aqueous solution and removing the MeOH under reduced pressure, the reaction mixture was purified by preparative HPLC followed by CC (DCM-MeOH +1% NH4
OH) purification. The residue was dissolved in MeCN (4 mL), and the obtained mixture was stirred at rt for 30 min, filtered and collected and dried to give whiteCompound 1 Crystal form 1
(110 mg, 7% yield).1
H NMR (D6
-DMSO) δ: 10.94 (br. s, 1H); 9.20 (br. s, 1H); 7.57 (d, J = 1.0 Hz, 1H); 6.27-6.25 (m, 1H); 4.43 (s, 2H) ; 4.42 (t, J = 5.5 Hz, 1H); 3.51 (t, J = 6.9 Hz, 2H); 3.54-3.45 (overlap m, 1H); 3.43-3.30 (overlap m, 4H); 3.06 (s, 3H) 3.03 (t, J = 6.9 Hz, 2H); 2.63-2.56 (m, 1H); 2.43 (t, J = 6.0 Hz, 2H); 2.00-1.93 (m, 1H); 1.53 (s, 3H) . Ctwenty one
H26
N4
O6
MS of MS (ESI, m/z): 463.03 [M+H+
];tR
= 0.49 min.Instance 2 : Preparation of compounds 1 Crystal form 2
Add 2 to a solution of the compound of Preparation B (4.55 g; 8.32 mmol) in MeOH (25 mL) and water (10 mL)M
Aqueous HCl (15 mL; 30 mmol). The reaction mixture was stirred at 0 °C for 10 min and then at rt for 1 h. Allow the reaction mixture to cool down to 0 ° C and add 25% NH4
Aqueous OH (2.5 mL) was stirred at rt for 15 min. The precipitate was collected, dried and additionally dissolved in 0.5% NH4
Aqueous OH (30 mL) was stirred at rt for 30 min. Filter the suspension and collect the solids and dry to give a whiteCompound 1 Crystal form 2
(2.42 g; 63% yield).1
H NMR (D6
-DMSO) δ: 10.94 (br. s, 1H); 9.20 (br. s, 1H); 7.57 (d, J = 1.0 Hz, 1H); 6.27-6.25 (m, 1H); 4.43 (s, 2H) ; 4.42 (t, J = 5.5 Hz, 1H); 3.51 (t, J = 6.9 Hz, 2H); 3.54-3.45 (overlap m, 1H); 3.43-3.30 (overlap m, 4H); 3.06 (s, 3H) 3.03 (t, J = 6.9 Hz, 2H); 2.63-2.56 (m, 1H); 2.43 (t, J = 6.0 Hz, 2H); 2.00-1.93 (m, 1H); 1.53 (s, 3H) . Ctwenty one
H26
N4
O6
MS of MS (ESI, m/z): 463.03 [M+H+
];tR
= 0.49 min.Instance 3 : Preparation of compounds 1 Crystal form 3
0.1 g of Compound 1 in Form 1 was dissolved in a new 4 mL glass vial containing 1 mL of DMSO. After the dissolution was completed, the solvent was evaporated in a Combidancer apparatus from Hettich AG (Bäch, Switzerland) oscillated at 300 rpm and operated at 40 ° C and 0.035 mbar for 80 min. Immediately thereafter, 0.5 mL of MeCN was added to the bottle and the bottle was allowed to stand for 1 day at room temperature. The solid residue is based on the XRPD measured in the wet state of MeCN.Compound 1 Crystal form 3
.Instance 4 : Preparation of compounds 1 Amorphous form
0.1 g of Compound 1 in Form 1 was dissolved in a new 4 mL glass vial containing 1 mL of DMSO. After the dissolution was completed, the solvent was evaporated in a Combidancer apparatus from Hettich AG (Bäch, Switzerland) oscillated at 300 rpm and operated at 40 ° C and 0.035 mbar for 80 min. Residue isCompound in amorphous form 1
.Compound 1 Pharmacological properties
By means of an in vitro assay as described above, against several Gram-negative bacteria (ie Klebsiella pneumoniae A-651 (multi-resistant strain; in particular anti-quinolone) and two quinolone-sensitive strains) Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853) were tested for Compound 1. Compound 1 exhibited a minimum inhibitory concentration (MIC) of bacterial growth of 0.5 mg/L for all tested strains.