TW201726630A - Antimicrobial compounds and methods of making and using the same - Google Patents
Antimicrobial compounds and methods of making and using the same Download PDFInfo
- Publication number
- TW201726630A TW201726630A TW106101234A TW106101234A TW201726630A TW 201726630 A TW201726630 A TW 201726630A TW 106101234 A TW106101234 A TW 106101234A TW 106101234 A TW106101234 A TW 106101234A TW 201726630 A TW201726630 A TW 201726630A
- Authority
- TW
- Taiwan
- Prior art keywords
- group
- unsaturated
- alkyl
- saturated
- pharmaceutically acceptable
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pathology (AREA)
- Molecular Biology (AREA)
- Physics & Mathematics (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Medical Informatics (AREA)
- Biophysics (AREA)
- Surgery (AREA)
- Ophthalmology & Optometry (AREA)
- Otolaryngology (AREA)
- Vascular Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Materials For Medical Uses (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
本申請案主張在2009年10月16日提出申請之美國臨時申請案第61/252,478號、在2010年3月16日提出申請之美國臨時申請案第61/314,287號及在2010年6月24日提出申請之美國臨時申請案第61/358,201號之利益。將前述申請案的內容以其全文併入本文以供參考。 This application claims U.S. Provisional Application No. 61/252,478, filed on October 16, 2009, and U.S. Provisional Application No. 61/314,287, filed on March 16, 2010, and on June 24, 2010 The interest of US Provisional Application No. 61/358,201 filed by Japan. The contents of the aforementioned application are incorporated herein by reference in their entirety.
本發明大體上關於抗微生物性化合物領域及其製造與使用方法。該等化合物有用於治療、預防人類和動物的微生物感染及減低其風險。 The present invention relates generally to the field of antimicrobial compounds and methods of making and using same. These compounds are useful for treating, preventing, and reducing the risk of microbial infections in humans and animals.
自從在1920年代發現青黴素及在1940年代發現鏈黴素以來,已發現或尤其設計用作為抗生素的許多新型化合物。曾經認為使用該等治療劑可使感染性疾病完全受到控制或根除。然而,此看法受到挑戰,因為對抗目前有效的治療劑之細胞株或微生物持續進化。幾乎每一種經開發出 臨床用途的抗生素最終遭遇抗藥性細菌出現的問題。例如,已發展出抗藥性革蘭氏(Gram)陽性菌株,諸如二甲苯青黴素(methicillin)抗藥性葡萄球菌、青黴素抗藥性鏈球菌及萬古黴素抗藥性腸球菌。抗藥性細菌可使感染之病患引起嚴重且甚至致命的結果。參見Lowry,F.D.“Antimicrobial Resistance:The Example of Staphylococcus aureus”,J.Clin.Invest.,vol.111,no.9,pp.1265-1273(2003);及Gold,H.S.and Moellering,R.C.,Jr.,“Antimicrobial-Drug Resistance”,N.Engl.J.Med.,vol.335,pp.1445-53(1996)。 Since the discovery of penicillin in the 1920s and the discovery of streptomycin in the 1940s, many novel compounds have been discovered or especially designed for use as antibiotics. It has been thought that the use of such therapeutic agents can completely control or eradicate infectious diseases. However, this view is challenged because cell lines or microorganisms that fight the currently effective therapeutic agents continue to evolve. Almost every one developed Antibiotics for clinical use eventually encounter problems with drug-resistant bacteria. For example, drug-resistant Gram-positive strains such as methicillin-resistant staphylococci, penicillin-resistant streptococcus, and vancomycin-resistant enterococci have been developed. Drug-resistant bacteria can cause serious and even fatal results in infected patients. See Lowry, FD "Antimicrobial Resistance: The Example of Staphylococcus aureus", J. Clin. Invest., vol. 111, no. 9, pp. 1265-1273 (2003); and Gold, HS and Moellering, RC, Jr. , "Antimicrobial-Drug Resistance", N. Engl. J. Med., vol. 335, pp. 1445-53 (1996).
新型抗細菌劑的發現及開發已為許多醫藥公司數十年來的主要重點。但是,在最近幾年已有醫藥公司從此研究及藥物開發領域退出。此退出的結果使得非常少的新型抗生素進入市場。此新型抗生素的缺乏特別感到不安,尤其是在對目前醫療法的細菌抗藥性正於醫院及社區兩者環境中增加。 The discovery and development of new antibacterial agents has been a major focus for many pharmaceutical companies for decades. However, in recent years, pharmaceutical companies have withdrawn from this research and drug development field. The result of this withdrawal made very few new antibiotics enter the market. The lack of this new type of antibiotic is particularly disturbing, especially as the bacterial resistance to current medical practices is increasing in both hospital and community settings.
在新型抗生素的探索中,研究員嘗試組合或連結各種部分的抗生素分子,以創造多功能或混成化合物。其他的研究員嘗試製造已知的抗生素類別之衍生物,例如以商標Ketek®銷售之泰利黴素(telithromycin)為紅黴素之衍生物。然而,該等方法取得有限的成功。 In the exploration of new antibiotics, researchers have attempted to combine or link various parts of antibiotic molecules to create multifunctional or mixed compounds. Other researchers have attempted to make derivatives of known antibiotic classes, such as telithromycin, marketed under the trademark Ketek®, as a derivative of erythromycin. However, these methods have had limited success.
開發新型抗微生物性化合物之方法為設計細菌核糖體功能之調節劑,例如抑制劑。此等抗微生物性化合物可藉由調節或抑制細菌核糖體功能而干擾基本過程,諸如 RNA轉譯及蛋白質合成,藉此提供抗微生物效果。事實上,已知一些抗生素化合物與核糖體結合,諸如紅黴素、克林達黴素(clindamycin)及利奈唑德(linezolid)。 A method of developing novel antimicrobial compounds is to design modulators of bacterial ribosome functions, such as inhibitors. Such antimicrobial compounds can interfere with basic processes by modulating or inhibiting bacterial ribosome functions, such as RNA translation and protein synthesis, thereby providing an antimicrobial effect. In fact, some antibiotic compounds are known to bind to ribosomes, such as erythromycin, clindamycin, and linezolid.
本發明利用以結構為基準之藥物設計方法來發現及開發新型抗微生物劑。此方法係以核糖體的高解析X-射線晶體開始,以設計具有特殊的化學結構、核糖體結合特徵及抗微生物活性之抗微生物性化合物的新分類。此以結構為基準之藥物發現方法說明於以下發表中:Franceschi,F.and Duffy,E.M.,“Structure-based drug design meets the ribosome”,Biochemical Pharmacology,vol.71,pp.1016-1025(2006)。 The present invention utilizes a structure-based drug design method to discover and develop new antimicrobial agents. This method begins with a high-resolution X-ray crystal of ribosomes to design a new classification of antimicrobial compounds with specific chemical structures, ribosome binding characteristics, and antimicrobial activity. This structure-based drug discovery method is described in the following publication: Franceschi, F. and Duffy, EM, "Structure-based drug design meets the ribosome", Biochemical Pharmacology, vol. 71, pp. 1016-1025 (2006) .
基於此以結構為基準之藥物設計方法,本發明說明有用於治療人類和動物的細菌感染之抗微生物性化合物的新化學分類。不受理論的限制,咸信該等化合物係藉由與核糖體結合來抑制細菌核糖體功能。本發明的抗微生物性化合物可利用該等核糖體結合位置來提供比目前的抗生素化合物更好的活性,尤其對抗抗藥性細菌株。 Based on this structure-based drug design method, the present invention describes a new chemical classification of antimicrobial compounds for the treatment of bacterial infections in humans and animals. Without being bound by theory, it is believed that these compounds inhibit bacterial ribosome function by binding to ribosomes. The antimicrobial compounds of the present invention can utilize these ribosome binding sites to provide better activity than current antibiotic compounds, particularly against drug resistant bacterial strains.
本發明利用以結構為基準之藥物設計方法來發現及開發新型抗微生物劑。此方法係以核糖體的高解析X-射線晶體開始,以設計具有特殊的化學結構、核糖體結合特徵及所欲抗微生物活性之抗微生物性化合物的新分類。此以結構為基準之藥物發現方法說明於以下發表中:Franceschi,F.and Duffy,E.M.,“Structure-based drug design meets the ribosome”,Biochemical Pharmacology, vol.71,pp.1016-1025(2006)。 The present invention utilizes a structure-based drug design method to discover and develop new antimicrobial agents. This method begins with a high resolution X-ray crystal of ribosomes to design a new classification of antimicrobial compounds with specific chemical structures, ribosome binding characteristics, and desired antimicrobial activity. This structure-based drug discovery method is described in the following publication: Franceschi, F. and Duffy, E.M., "Structure-based drug design meets the ribosome", Biochemical Pharmacology, Vol. 71, pp. 1016-1025 (2006).
本發明因此滿足了提供新型抗微生物劑之重要的持續需求,特別為具有對抗抗藥性病原細菌有機體的活性之抗微生物劑。 The present invention thus satisfies an important continuing need to provide novel antimicrobial agents, particularly antimicrobial agents having activity against drug-resistant pathogenic bacterial organisms.
本發明概括關於抗微生物性化合物領域及其製造與使用方法。該等化合物有用於治療、預防人類和動物的微生物感染及減低其風險。本發明亦提供該等化合物在醫藥上可接受之鹽、酯、N-氧化物及前藥。 The invention summarizes the field of antimicrobial compounds and methods of making and using same. These compounds are useful for treating, preventing, and reducing the risk of microbial infections in humans and animals. The invention also provides pharmaceutically acceptable salts, esters, N-oxides and prodrugs of such compounds.
本發明提供具有以下結構之化合物:
其中為選自下式之化學部分:
另外,本發明提供合成前述化合物之方法。在合成之後,可將化合物中之一或多者以治療有效量與醫藥上可接受之載劑調配,用作為抗微生物劑,特別為抗細菌劑投於人類或動物。在特定的具體例中,本發明化合物有用治療、預防微生物感染或減低其風險或用於製造供治療、預防微生物感染或減低其風險之藥劑。據此,化合物或調配物例如可經口、非經腸、耳、眼、鼻或局部投予,以提供有效量化合物予人類或動物。 Additionally, the invention provides methods of synthesizing the foregoing compounds. After synthesis, one or more of the compounds can be formulated in a therapeutically effective amount with a pharmaceutically acceptable carrier for administration to humans or animals as an antimicrobial agent, particularly an antibacterial agent. In a particular embodiment, the compounds of the invention are useful for treating, preventing or reducing the risk of microbial infection or for the manufacture of a medicament for the treatment, prevention or reduction of the risk of microbial infection. Accordingly, the compound or formulation can be administered, for example, orally, parenterally, ear, eye, nose or topically to provide an effective amount of the compound to a human or animal.
本發明的前述及其他觀點及具體例可藉由參考以下的詳細說明和申請專利範圍更完整了解。 The above and other aspects and specific examples of the invention are more fully understood from the following detailed description and claims.
本發明提供可用作為抗微生物劑,更特別用作為抗細菌劑之化合物家族。 The present invention provides a family of compounds that can be used as antimicrobial agents, more particularly as antibacterial agents.
本發明包括本文所述化合物在醫藥上可接受之鹽、酯、互變異構物、N-氧化物及前藥。 The invention includes pharmaceutically acceptable salts, esters, tautomers, N-oxides and prodrugs of the compounds described herein.
本文所述化合物可具有不對稱中心。含有不對稱取代原子之本發明化合物可以光學活性或外消旋形式分離。在本技藝中熟知如何製備光學活性形式,諸如藉由分解外消旋形式或藉由從光學活性起始材料合成。烯烴、C=N雙鍵及類似物的許多幾何異構物亦可存在於本文所述化合物中,且將所有此等穩定的異構物涵蓋於本發明中。本發明化合物的順式和反式幾何異構物係經說明且可分離成異構物混合物或單獨的異構物形式。意欲涵蓋結構的所有手性、非鏡像、外消旋及幾何異構物形式,除非特定標示特殊的立體化學或異構物形式。用於製備本發明化合物的所有方法及其中所製備之中間物被認為是本發明的一部分。所顯示或所述之化合物的所有互變異構物亦被認為是本發明的一部分。此外,本發明亦包括本文所述化合物的代謝物。 The compounds described herein can have asymmetric centers. Compounds of the invention containing asymmetrically substituted atoms can be separated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by decomposition of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are encompassed by the present invention. The cis and trans geometric isomers of the compounds of the invention are illustrated and can be separated into a mixture of isomers or as individual isomers. It is intended to cover all chiral, non-mirrored, racemic, and geometric isomer forms of the structure, unless a particular stereochemistry or isomer form is specifically indicated. All methods for preparing the compounds of the invention and intermediates prepared therein are considered to be part of the invention. All tautomers of the compounds shown or described are also considered to be part of the invention. In addition, the invention also includes metabolites of the compounds described herein.
本發明意欲包括出現在本發明化合物中之原子的所有同位素。同位素包括那些具有相同的原子數,但是不同的質量數之原子。以一般的實例方式而非限制的氫同位素包括氚及氘。碳同位素包括C-13及C-14。 The invention is intended to include all isotopes of atoms occurring in the compounds of the invention. Isotopes include those atoms that have the same number of atoms but different mass numbers. Hydrogen isotopes, which are by way of general example and not limitation, include hydrazine and hydrazine. Carbon isotopes include C-13 and C-14.
當任何變體(例如,R6)在化合物的任何構造或化學式中出現一次以上時,則其在各出現場合的定義與其在每次其他出現場合的定義無關。因此,例如若基團經顯示被一或多個R6部分取代時,則R6在各出現場合係獨立選自R6 之定義。取代基及/或變體的組合亦受到許可,但僅在若此等組合導致在特許之原子正常價數內的穩定化合物時。 When any variation thereof (e.g., R 6) occurs more than once in any structure or chemical formula for a compound, its definition on each occurrence is independent of its definition of where each occurrence of other occasions. Thus, for example, if a group was shown to be substituted with one or more R 6 portions 6 in the case where the system is defined independently selected from R 6 each occurrence of R. Combinations of substituents and/or variants are also permitted, but only if such combinations result in stable compounds within the normal valence of the licensed atom.
以點線圖像顯示化學鍵的化學結構標示鍵可隨意地存在。例如,緊鄰實線單鍵所繪製之點線標示該鍵可為單鍵或雙鍵。 The chemical structure designation key showing the chemical bond in a dotted line image can be arbitrarily present. For example, a dotted line drawn next to a solid single button indicates that the key can be a single or double key.
當至取代基的鍵經顯示與連接環中的兩個原子之鍵交叉時,則此取代基可與環上的任何原子鍵結。當取代基經陳列而未標示此取代基係經由何原子與既定化學式之化合物的其餘部分鍵結時,則此取代基可經由此式中任何原子鍵結。取代基及/或變體的組合受到許可,但僅在若此等組合導致穩定的化合物時。 When the bond to the substituent is shown to cross the bond of two atoms in the linker, then the substituent can be bonded to any atom on the ring. When a substituent is shown to indicate that the substituent is bonded via the atom to the remainder of the compound of the formula, then the substituent may be bonded via any atom of the formula. Combinations of substituents and/or variants are permissible, but only if such combinations result in stable compounds.
在其中本發明化合物有氮原子的情況中,若適當時,該等氮原子可藉由以氧化劑(例如,MCPBA及/或過氧化氫)處理而轉化成N-氧化物。因此,若適當時,所顯示且主張之氮原子被認為包括所顯示之氮及其N-氧化物(N→O)衍生物二者。 In the case where the compound of the present invention has a nitrogen atom, if appropriate, the nitrogen atom can be converted to an N-oxide by treatment with an oxidizing agent (for example, MCPBA and/or hydrogen peroxide). Thus, if appropriate, the nitrogen atoms shown and claimed are considered to include both the nitrogen shown and its N-oxide (N→O) derivatives.
一種開發出改進之抗增殖劑及抗感染劑之方法係提供核糖體功能調節劑(例如,抑制劑)。 One method of developing improved anti-proliferative and anti-infective agents provides ribosome functioning modulators (e.g., inhibitors).
核糖體為存在於原核生物及真核生物二者中的核糖核蛋白。核糖體為負責蛋白質合成之細胞器。在基因表現期間,核糖體轉錄在信使RNA中編碼之遺傳訊息至蛋白質中(Garrett等人之(2000)”The Ribosome:Structure,Function,Antibiotics and Cellular Interactions”,American Society for Microbiology,Washington,D.C.)。 Ribosomes are ribonucleoproteins found in both prokaryotes and eukaryotes. Ribosomes are organelles responsible for protein synthesis. During gene expression, ribosomes transcribe genetic messages encoded in messenger RNA into proteins (Garrett et al. (2000) "The Ribosome: Structure, Function, Antibiotics and Cellular Interactions", American Society for Microbiology, Washington, DC) .
核糖體包含非對等核糖核蛋白次單元。較大的次單元(亦稱為"大核糖體次單元")具有約2倍較小的次單元(亦稱為"小核糖體次單元")尺寸。小核糖體次單元結合信使RNA(mRNA)且介導在mRNA與轉送RNA(tRNA)反密碼子之間的交互作用,轉錄保真性係取決於此交互作用。大核糖體次單元催化肽鍵形成,亦即蛋白質合成的肽基轉移酶反應,且包括至少三個不同的tRNA結合位置,已知為胺醯基、肽基及出口位置。胺醯基或A-位置容納進來的胺醯基-tRNA,有助於其胺基酸至生長肽鏈。A-位置的A空間亦重要。肽基位置或P-位置容納肽基-tRNA複合物,亦即具有其胺基酸的tRNA,其為生長肽鏈的一部分。出口或E-位置係在給予其胺基酸至生長聚肽鏈之後容納去醯化tRNA。 Ribosomes contain non-peer ribonucleoprotein subunits. Larger subunits (also known as "large ribosome subunits") have about 2 times smaller secondary units (also known as "small ribosome subunits") sizes. The small ribosome subunit binds to messenger RNA (mRNA) and mediates the interaction between the mRNA and the transfer RNA (tRNA) anticodon, which depends on this interaction. The large ribosome subunit catalyzes peptide bond formation, that is, a peptidyl transferase reaction for protein synthesis, and includes at least three different tRNA binding sites, known as amine sulfhydryl groups, peptidyl groups, and export sites. The amine thiol-tRNA contained in the amine sulfhydryl or A-position facilitates its amino acid to the growing peptide chain. The A space of the A-position is also important. The peptidyl position or P-position accommodates a peptidyl-tRNA complex, i.e., a tRNA having its amino acid, which is part of the growing peptide chain. The export or E-position accommodates the deuterated tRNA after administration of its amino acid to the growing polypeptide chain.
"異構現象"意謂具有相同的分子式,但是彼等原子的鍵結順序或彼等原子在空間中排列不同的化合物。彼等原子在空間中排列不同的異構物被稱為"立體異構物"。彼此不為鏡像的立體異構物被稱為"非鏡像異構物",而彼此鏡像不可重疊的立體異構物被稱為"鏡像異構物"或有時被稱為光學異構物。與四個不相同的取代基鍵結之碳原子被稱為"手性中心"。 "Isomerism" means having the same molecular formula, but the order of bonding of the atoms or the compounds in which the atoms are arranged differently in space. The isomers in which atoms are arranged in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are referred to as "non-mirror isomers", while stereoisomers that are non-superimposable mirror images of one another are termed "mirromeric isomers" or are sometimes referred to as optical isomers. A carbon atom bonded to four different substituents is referred to as a "chiral center."
"手性異構物"意謂具有至少一個手性中心的化合物。其具有兩個對立手性的鏡像異構物形式且可以單獨的鏡像 異構物或以鏡像異構物之混合物存在。含有等量的對立手性之個別鏡像異構物形式的混合物被稱為"外消旋性混合物"。具有超過一個手性中心的化合物具有2n-1個鏡像異構物對,其中n為手性中心數量。具有超過一個手性中心的化合物可以個別的非鏡像異構物或以稱為"非鏡像異構物混合物"的非鏡像異構物之混合物存在。當有一個手性中心存在時,則立體異構物可以該手性中心的絕對組態(R或S)特徵化。絕對組態係指與手性中心連接的取代基之空間排列。與手性中心連接的取代基之考量係依照Sequence Rule of Cahn,Ingold and Prelog.(Cahn等人之Angew.Chem.Inter.Edit.1966,5,385;errata 511;Cahn等人之Angew.Chem.1966,78,413;Cahn and Ingold,J Chem.Soc.1951(London),612;Cahn等人之Experientia 1956,12,81;Cahn,J Chem.Educ.1964,41,116)分等級。 "Chiral isomer" means a compound having at least one chiral center. It has two opposite chiral mirror image isomer forms and may be present as a single mirror image isomer or as a mixture of mirror image isomers. A mixture of individual mirror image isomer forms containing equal amounts of opposite chirality is referred to as a "racemic mixture." Compounds with more than one chiral center have 2 n-1 mirror image isomer pairs, where n is the number of chiral centers. Compounds having more than one chiral center may be present as individual non-image isomers or as a mixture of non-image isomers known as "non-mirromeric mixtures". When a chiral center is present, the stereoisomer can be characterized by the absolute configuration (R or S) of the chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to a chiral center. The substituents attached to the chiral center are considered in accordance with Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. , 78, 413; Cahn and Ingold, J Chem. Soc. 1951 (London), 612; Experientia 1956, 12, 81 by Cahn et al; Cahn, J Chem. Educ. 1964, 41, 116).
"幾何異構物"意謂彼等的存在歸因於雙鍵周圍旋轉受阻的非鏡像異構物。該等組態係根據Cahn-Ingold-Prelog規則在名字上以字首順式和反式,或Z和E區別,其標示基團係在分子雙鍵的相同面或對立面上。 "Geometric isomers" means that their existence is due to a non-image isomer that is blocked by rotation around the double bond. These configurations are distinguished by the word cis and trans, or Z and E, according to the Cahn-Ingold-Prelog rule, which indicates that the group is on the same or opposite side of the molecular double bond.
再者,在本申請案中所討論的結構及其他化合物包括所有的其限制構形異構物。"限制構形異構物"為其中兩種異構物的原子在空間排列不同的立體異構物類型。限制構形異構物的存在歸因於大基團在中心鍵周圍旋轉受阻所引起的限制旋轉。此等限制構形異構物典型地以混合物存在,然而,由於層析技術的新近進展,已有可能在選擇性 情況下分離兩種限制構形異構物之混合物。 Moreover, the structures and other compounds discussed in this application include all of their restricted conformational isomers. The "restricted conformational isomer" is a type of stereoisomer in which the atoms of the two isomers are arranged differently in space. The presence of a restricted conformational isomer is attributed to the limited rotation caused by the large group being blocked by rotation around the central bond. Such restricted conformational isomers are typically present as a mixture, however, due to recent advances in chromatography techniques, it is possible to be selective In the case, a mixture of two restricted conformation isomers is separated.
"互變異構物"係指其結構的原子排列顯著不同,但是其輕易且炔速平衡存在的化合物。應了解可將式I化合物描述為不同的互變異構物。亦應了解當化合物具有互變異構物形式時,意欲以所有的互變異構物形式在本發明的範疇內,且化合物的命名不排除任何互變異構物形式。 "Tautomer" means a compound whose structure has a substantially different atomic arrangement, but which is readily and equilibrated at equilibrium. It will be appreciated that the compounds of formula I can be described as different tautomers. It will also be understood that when a compound has the tautomeric form, it is intended to be within the scope of the invention in all tautomeric forms, and the nomenclature of the compound does not exclude any tautomeric form.
本發明的一些化合物可以互變異構物形式存在,亦意欲將其包含在本發明的範疇內。 Some of the compounds of the invention may exist in tautomeric forms and are intended to be included within the scope of the invention.
本發明的化合物、鹽及前藥可以數種互變異構物形式存在,包括烯醇及亞胺形式及酮基及烯胺形式,與其幾何異構物及混合物。所有的此等互變異構物形式包括在本發明的範疇內。互變異構物係以互變異構物組於溶液中的混合物存在。在固體形式中,經常以一種互變異構物佔優勢。雖然可以一種互變異構物說明,但是本發明包括本發明化合物的所有互變異構物。 The compounds, salts and prodrugs of the present invention can exist in several tautomeric forms, including the enol and imine forms as well as the keto and enamine forms, as well as geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the invention. Tautomers are present as a mixture of tautomeric groups in solution. In solid form, it is often dominated by one tautomer. While a tautomer can be illustrated, the invention includes all tautomers of the compounds of the invention.
互變異構物為平衡存在且可輕易地從一種異構物形式轉化成另一種形式的二或多種結構異構物中之一。此反應導致伴隨有相鄰的共軛雙鍵轉換的氫原子正式遷移。在其中可能有互變異構化作用的溶液中,可達成互變異構物的化學平衡。互變異構物的真實比率係取決於許多因素而定,包括溫度、溶劑及pH。以互變異構化作用可互相轉化的互變異構物之概念被稱為互變異構現象。 A tautomer is one of two or more structural isomers that exist in equilibrium and can be readily converted from one isomeric form to another. This reaction results in a formal migration of a hydrogen atom accompanied by an adjacent conjugated double bond transition. In solutions in which there may be tautomerization, the chemical equilibrium of the tautomers can be achieved. The true ratio of tautomers depends on many factors including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism.
在有可能的互變異構現象的各種類型之中,常觀察到兩種類型。在酮基-烯醇互變異構現象中發生電子及氫原 子的同步位移。環-鏈互變異構現象係以葡萄糖展現。其係由於糖鏈分子中的醛基(-CHO)與相同分子中的羥基(-OH)中之一反應而出現,得到環(成環狀)形式的葡萄糖。 Of the various types of possible tautomerism, two types are often observed. Electrons and hydrogenogens occur in keto-enol tautomerism The synchronous displacement of the child. The cyclo-chain tautomerism is exhibited by glucose. This occurs because the aldehyde group (-CHO) in the sugar chain molecule reacts with one of the hydroxyl groups (-OH) in the same molecule to obtain a ring (ring-forming) form of glucose.
互變異構化作用可藉由鹼:1.去質子化;2.形成非定域陰離子(例如,烯醇鹽);3.在陰離子的不同位置上質子化;酸:1.質子化;2.形成非定域陽離子;3.在與陽離子相鄰的不同位置上去質子化而催化。 The tautomerization can be carried out by a base: 1. deprotonation; 2. formation of a delocalized anion (for example, an enolate); 3. protonation at different positions of the anion; acid: 1. protonation; Forming a non-localized cation; 3. catalyzing by deprotonation at different positions adjacent to the cation.
常見的互變異構物對為:酮-烯醇、醯胺-腈、內醯胺-內醯亞胺、在雜環系環中的醯胺-醯亞胺酸互變異構現象(例如,在核鹼基中的鳥嘌呤、胸腺嘧啶及胞嘧啶)、胺-烯胺及烯胺-烯胺。以例證為目的包括以下實例,且本發明不限於此實例:
術語"晶體多形物"或"多形物"或"晶體形式"意謂其中化合物(或其鹽或溶劑合物)可以不同的晶體堆積排列而結晶的晶體結構,所有的結構皆具有相同的元素組成。不同的晶體形式經常具有不同的X-射線繞射圖案、紅外線光譜、熔點、密度硬度、晶體形狀、光學和電性質、穩定性及溶解度。再結晶溶劑、結晶速度、貯存溫度及其他因素可引起一種晶體形式成為優勢。化合物的晶體多形物可藉由在不同的條件下結晶而製備。 The term "crystal polymorph" or "polymorph" or "crystal form" means a crystal structure in which a compound (or a salt or a solvate thereof) can be crystallized by different crystal packing arrangements, all of which have the same structure. Elemental composition. Different crystal forms often have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. The recrystallization solvent, crystallization rate, storage temperature, and other factors can cause a crystal form to become advantageous. Crystalline polymorphs of compounds can be prepared by crystallization under different conditions.
如本文所使用之術語"經取代之"意謂在特許原子上(經常為碳、氧或氮原子)的任何一或多個氫被選自指定的基團替換,其先決條件係不超過特許原子的正常價數,且取代導致穩定的化合物。當取代基為酮基(亦即=O)時,則替換在原子上的2個氫原子。如本文所使用之環雙鍵為在兩個相鄰的環原子之間形成的雙鍵(例如,C=C、C=N或N=N)。 The term "substituted" as used herein means that any one or more hydrogens on a licensed atom (often a carbon, oxygen or nitrogen atom) are replaced by a selected group, the prerequisites of which do not exceed the license. The normal valence of an atom, and the substitution results in a stable compound. When the substituent is a keto group (ie, =0), then two hydrogen atoms on the atom are replaced. A ring double bond as used herein is a double bond formed between two adjacent ring atoms (eg, C=C, C=N, or N=N).
如本文所使用之術語"變旋異構碳"意謂醣苷之縮醛碳。 The term "cyclonic isomeric carbon" as used herein means acetal carbon of a glycoside.
如本文所使用之術語"醣苷"為環系縮醛。 The term "glycoside" as used herein is a cyclic acetal.
如本文所使用之"烷基"意欲包括具有指定的碳原子數之直鏈或支鏈飽和脂族烴基二者。例如,C1-6烷基意欲包括C1、C2、C3、C4、C5及C6烷基。烷基的一些實例包括(但不限於此)甲基、乙基、正丙基、異丙基、正丁基、第二丁基、第三丁基、正戊基、第二戊基、正己基、正庚基及正辛基。 "Alkyl" as used herein is intended to include both straight-chain or branched saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, a C 1-6 alkyl group is intended to include C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkyl groups. Some examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, t-butyl, n-pentyl, second pentyl, hexyl Base, n-heptyl and n-octyl.
如本文所使用之"烯基"意欲包括直鏈或支鏈組態及可出現在沿著鏈的任何穩定點的一或多個不飽和碳-碳鍵之烴鏈,諸如乙烯基及丙烯基。例如,C2-6烯基意欲包括C2、C3、C4、C5及C6烯基。 "Alkenyl" as used herein is intended to include both straight-chain or branched-chain configurations and hydrocarbon chains which may occur at one or more unsaturated carbon-carbon bonds along any stable point of the chain, such as vinyl and propenyl. . For example, C 2-6 alkenyl is intended to include C 2 , C 3 , C 4 , C 5 and C 6 alkenyl groups.
如本文所使用之"炔基"意欲包括直鏈或支鏈組態及可出現在沿著鏈的任何穩定點的一或多個碳-碳參鍵之烴鏈,諸如乙炔基及丙炔基。例如,C2-6炔基意欲包括C2、C3、C4、C5及C6炔基。 "Alkynyl" as used herein is intended to include both straight-chain or branched-chain configurations and hydrocarbon chains which may occur at one or more carbon-carbon bonds along any stable point of the chain, such as ethynyl and propynyl. . For example, C 2-6 alkynyl is intended to include C 2 , C 3 , C 4 , C 5 and C 6 alkynyl groups.
此外,"烷基"、"烯基"及"炔基"意欲包括為二基團的部分,亦即具有兩個連接點,在本發明的實例為D係選自該等化學基團時。此烷基部分為二基團的非限制性實例為-CH2CH2-,亦即經由各末端碳原子與分子其餘部分共價鍵結的C2烷基。烷二基亦被稱為"伸烷基(alkylenyl)"。烯二基亦被稱為"伸烯基(alkenylenyl)"。炔二基亦被稱為"伸炔基(alkynylenyl)"。 Furthermore, "alkyl", "alkenyl" and "alkynyl" are intended to be included as part of a di-group, that is, having two points of attachment, in the case of the present invention where D is selected from such chemical groups. The alkyl moiety is non-limiting examples two groups are -CH 2 CH 2 -, i.e. via each terminal carbon atom with the remainder of the molecule is covalently bonded to C 2 alkyl. Alkanediyl is also known as "alkylenyl". The enediyl group is also known as "alkenylenyl". The alkynediyl group is also known as "alkynylenyl".
如本文所使用之"環烷基"意欲包括飽和環基團,諸如環丙基、環丁基或環戊基。C3-8環烷基意欲包括C3、C4、C5、C6、C7及C8環烷基。 "Cycloalkyl" as used herein is intended to include saturated ring groups such as cyclopropyl, cyclobutyl or cyclopentyl. The C 3-8 cycloalkyl group is intended to include C 3 , C 4 , C 5 , C 6 , C 7 and C 8 cycloalkyl groups.
如本文所使用之"相對離子"係用於意謂與相反電荷之離子共同存在的正或負荷電物種。相對離子的非限制性實例為抗衡有機化合物上的電荷或電荷類而存在的離子或離子類。相對離子的非限制性實例包括氯化物、溴化物、氫氧化物、乙酸鹽、硫酸鹽及銨。 As used herein, "relative ion" is used to mean a positive or load electrical species that coexists with oppositely charged ions. Non-limiting examples of relative ions are ions or ions that are present in counteracting the charge or charge on the organic compound. Non-limiting examples of relative ions include chlorides, bromides, hydroxides, acetates, sulfates, and ammonium.
如本文所使用之"鹵基"或"鹵素"係指氟基、氯基、溴基及碘基取代基。 As used herein, "halo" or "halogen" refers to a fluoro, chloro, bromo and iodo substituent.
如本文所使用之"鹵烷基"意欲包括以1或多個鹵素取代之具有標示的碳原子數之直鏈及支鏈飽和脂族烴基二者(例如,-CvFw,其中v=1至3及w=1至(2v+1))。鹵烷基的實例包括(但不限於此)三氟甲基、三氯甲基、五氟乙基及五氯乙基。 "Haloalkyl" as used herein is intended to include both straight-chain and branched saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms substituted with one or more halogens (eg, -C v F w , where v = 1 to 3 and w=1 to (2v+1)). Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
如本文所使用之"烷氧基"係指經由氧橋連接之具有標示的碳原子數量的如上述定義之烷基。C1-6烷氧基意欲包 括C1、C2、C3、C4、C5及C6烷氧基。C1-6烷氧基意欲包括C1、C2、C3、C4、C5、C6、C7及C8烷氧基。烷氧基的實例包括(但不限於此)甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、第二丁氧基、第三丁氧基、正戊氧基、第二戊氧基、正庚氧基及正辛氧基。 "Alkoxy" as used herein refers to an alkyl group, as defined above, having the indicated number of carbon atoms attached via an oxygen bridge. The C 1-6 alkoxy group is intended to include C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy groups. The C 1-6 alkoxy group is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 and C 8 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, second butoxy, tert-butoxy, n-pentyloxy Base, second pentyloxy, n-heptyloxy and n-octyloxy.
如本文所使用之"烷硫基"係指經由硫橋連接之具有標示的碳原子數量的如上述定義之烷基。C1-6烷硫基意欲包括C1、C2、C3、C4、C5及C6烷硫基。C1-6烷硫基意欲包括C1、C2、C3、C4、C5、C6、C7及C8烷硫基。 As used herein, "alkylthio" refers to an alkyl group as defined above having the indicated number of carbon atoms attached via a sulfur bridge. The C 1-6 alkylthio group is intended to include C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkylthio groups. The C 1-6 alkylthio group is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 and C 8 alkylthio groups.
如本文所使用之"碳環"或"碳環系環"意欲意謂(除非另有其他指定)任何穩定的3、4、5、6、7、8、9、10、11或12-員單環、雙環或三環系環,任何該等環可為飽和、不飽和(包括部分及完全不飽和)或芳族。此等碳環的實例包括(但不限於此)環丙基、環丁基、環丁烯基、環戊基、環戊烯基、環己基、環己烯基、環庚基、環庚烯基、金剛烷基、環辛基、環辛烯基、環辛二烯基、[3.3.0]雙環辛烷、[4.3.0]雙環壬烷、[4.4.0]雙環癸烷、[2.2.2]雙環辛烷、茀基、苯基、萘基、二氫茚基、金剛烷基及四氫萘基。如上所示,橋連環亦包括在碳環的定義中(例如,[2.2.2]雙環辛烷)。當一或多個碳原子連結兩個不相鄰的碳原子時,則發生橋連環。較佳的橋具有1或2個碳原子。應注意橋總是將單環系環轉化成三環系環。當環被橋連時,以環引述之取代基亦可出現在橋上。亦包括稠合環(例如,萘基及四氫萘基)及螺旋環。 As used herein, "carbocyclic" or "carbocyclic ring" is intended to mean (unless otherwise specified) any stable 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12-member. Monocyclic, bicyclic or tricyclic ring, any of which may be saturated, unsaturated (including partially and fully unsaturated) or aromatic. Examples of such carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptene Alkyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclononane, [2.2 .2] bicyclooctane, indenyl, phenyl, naphthyl, indanyl, adamantyl and tetrahydronaphthyl. As indicated above, the bridging ring is also included in the definition of carbocycle (for example, [2.2.2] bicyclooctane). A bridging ring occurs when one or more carbon atoms join two non-adjacent carbon atoms. Preferred bridges have 1 or 2 carbon atoms. It should be noted that the bridge always converts a single ring to a tricyclic ring. When the ring is bridged, the substituents quoted by the ring may also be present on the bridge. Also included are fused rings (eg, naphthyl and tetrahydronaphthyl) and helical rings.
如本文所使用之術語"雜環"意謂(除非另有其他陳述)穩定的3、4、5、6、7、8、9、10、11或12-員單環、雙環或三環系環,其為飽和、不飽和(包括部分及完全不飽和)或芳族,且由碳原子及一或多個環雜原子所組成,例如1或1-2或1-3或1-4或1-5或1-6個獨立選自氮、氧及硫的雜原子,且包括任何雙環或三環基團,其中將上述定義之雜環系環中任一者稠合或與第二個環(例如,苯環)連接。氮及硫雜原子可隨意地被氧化(亦即N→O及S(O)p,其中p=1或2)。當氮原子包括在環中時,其為N或NH,其係取決是否其與環中的雙鍵連接(亦即若有必要維持氮原子的三價數時,則有氫原子的存在)。氮原子可被取代或未被取代(亦即N或NR,其中R為H或如定義之另一取代基)。可將雜環系環在任何雜原子或碳原子上與其側基團連接,其導致穩定的結構。本文所述之雜環系環可在碳上或在氮原子上被取代,假設所得化合物是穩定的。在雜環中的氮可隨意地四級化。橋連環亦包括在雜環的定義中。當一或多個原子(亦即C、O、N或S)連結兩個不相鄰的碳或氮原子時,則發生橋連環。較佳的橋包括(但不限於此)1個碳原子,2個碳原子,1個氮原子,2個氮原子及碳-氮基團。當環被橋連時,以環引述之取代基亦可出現在橋上。亦包括螺旋環及稠合環。 The term "heterocycle" as used herein means (unless otherwise stated) a stable 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12-membered monocyclic, bicyclic or tricyclic system. a ring which is saturated, unsaturated (including partial and fully unsaturated) or aromatic, and consists of a carbon atom and one or more ring heteroatoms, such as 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur, and including any bicyclic or tricyclic group, wherein any of the heterocyclic ring defined above is fused or second Rings (eg, benzene rings) are attached. Nitrogen and sulfur heteroatoms can be arbitrarily oxidized (i.e., N→O and S(O) p , where p=1 or 2). When a nitrogen atom is included in the ring, it is N or NH depending on whether it is attached to a double bond in the ring (i.e., if it is necessary to maintain the trivalent number of the nitrogen atom, there is a hydrogen atom). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, wherein R is H or another substituent as defined). The heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom, which results in a stable structure. The heterocyclic ring described herein can be substituted on carbon or on a nitrogen atom, assuming that the resulting compound is stable. The nitrogen in the heterocycle can be optionally quaternized. Bridged rings are also included in the definition of heterocycles. A bridging ring occurs when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms. Preferred bridges include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. When the ring is bridged, the substituents quoted by the ring may also be present on the bridge. Also included are spiral rings and fused rings.
如本文所使用之術語"芳族雜環"或"雜芳基"意欲意謂穩定的5、6、7、8、9、10、11或12-員單環或雙環芳族環,其係由碳原子及一或多個雜原子所組成,例如1或1- 2或1-3或1-4或1-5或1-6個獨立選自氮、氧及硫的雜原子。在雙環雜環芳族環的情況中,兩個環之中僅一個必須為芳族(例如,2,3-二氫吲哚),雖然兩個皆可為芳族(例如,喹啉)。可將第二個環稠合或橋連,如上述就雜環所定義。氮原子可被取代或被經取代(亦即N或NR,其中R為H或如定義之其他取代基)。氮及硫雜原子可隨意地被氧化(亦即N→O及S(O)p,其中p=1或2)。在特定的具體例中,S與O原子在芳族雜環中的總數不超過1個以上。 The term "aromatic heterocyclic ring" or "heteroaryl" as used herein is intended to mean a stable 5, 6, 7, 8, 9, 10, 11 or 12-membered monocyclic or bicyclic aromatic ring, the It consists of a carbon atom and one or more heteroatoms, for example 1 or 1 or 2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur. In the case of a bicyclic heterocyclic aromatic ring, only one of the two rings must be aromatic (e.g., 2,3-dihydroanthracene), although both may be aromatic (e.g., quinoline). The second ring may be fused or bridged as defined above for the heterocyclic ring. The nitrogen atom may be substituted or substituted (i.e., N or NR, wherein R is H or other substituent as defined). Nitrogen and sulfur heteroatoms can be arbitrarily oxidized (i.e., N→O and S(O) p , where p=1 or 2). In a specific specific example, the total number of S and O atoms in the aromatic heterocyclic ring is not more than one.
雜環的實例包括(但不限於此)吖啶基、氮雜雙環辛醯基、四氫吖唉基、氮雜環辛四烯基(azocinyl)、苯並咪唑基、苯並呋喃基、苯並硫代呋喃基、苯並噻吩基、苯並噁唑基、苯並噁唑啉基、苯並噻唑基、苯並***基、苯並四唑基、苯並異噁唑基、苯並異噻唑基、苯並咪唑啉基、苯並二噁唑基、苯並噁二唑基、咔唑基、4aH-咔唑基、咔啉基、色滿基、色烯基、噌啉基、環庚基、十氫喹啉基、二氫苯並二噁基、2H,6H-1,5,2-二噻基、二氫呋並[2,3-b]四氫呋喃、呋喃基、呋咕基、咪唑啶基、咪唑啶基亞胺、咪唑啉基、咪唑基、咪唑酮基、1H-吲唑基、吲哚烯基(indolenyl)、吲哚啉基、吲哚基、吲哚基、3H-吲哚基、靛紅醯基(isatinoyl)、異苯並呋喃基、異色滿基、異吲唑基、異吲哚啉基、異吲哚基、異喹啉基、異噻唑基、異噁唑基、甲二氧基苯基、甲基苯並***基、甲基呋喃基、甲基咪唑基、甲基噻唑基、嗎啉基、萘啶基、八氫異喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、 1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑啶基、噁唑啶酮基、噁唑基、羥吲哚基、啡啶基、啡啉基、啡基、啡噻基、啡噁噻基、啡噁基、酞基、哌基、哌酮基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡基、吡唑啶基、吡唑啉基、吡唑基、嗒基、吡啶並噁唑基、吡啶並咪唑基、吡啶並噻唑基、吡啶基(pyridinyl)、吡啶酮基、吡啶基(pyridyl)、嘧啶基、吡咯酮基、吡咯啶基、吡咯啶酮基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹啉基、喹噁啉基、奎寧環基、四氫呋喃基、四氫異喹啉基、四氫喹啉基、四唑基、6H-1,2,5-噻二基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻噁基、噻唑基、噻吩基、噻吩並噻唑基、噻吩並噁唑基、噻吩並咪唑基、噻吩基、硫代嗎啉基二噁啶基、三基、***並嘧啶基、1,2,3-***基、1,2,4-***基、1,2,5-***基、1,3,4-***基及二苯並哌喃基。 Examples of heterocyclic rings include, but are not limited to, acridinyl, azabicyclooctyl, tetrahydroindenyl, azacinyl, benzimidazolyl, benzofuranyl, benzosulfonyl Dehydrofuranyl, benzothienyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazole Benzomidazolinyl, benzobisoxazolyl, benzooxadiazolyl, oxazolyl, 4aH-carbazolyl, porphyrinyl, chromanyl, chromenyl, porphyrinyl, cycloheptane Base, decahydroquinolinyl, dihydrobenzodioxin Base, 2H, 6H-1, 5, 2-dithiazide , dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolidinyl imine, imidazolinyl, imidazolyl, imidazolidinyl, 1H-carbazolyl, anthracene Indolenyl, porphyrinyl, anthracene Base, fluorenyl, 3H-fluorenyl, isatinoyl, isobenzofuranyl, isochroman, isoxazolyl, isoindolyl, isodecyl, isoquinolyl , isothiazolyl, isoxazolyl, methylenedioxyphenyl, methylbenzotriazolyl, methylfuranyl, methylimidazolyl, methylthiazolyl, morpholinyl, naphthyridinyl, octahydrogen Isoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxa Diazolyl, oxazolidinyl, oxazolidinone, oxazolyl, hydroxydecyl, phenanthryl, morpholinyl, brown Thiophene Glycosylthiophene Base Base Base Keto, piperidinyl, piperidinone, 4-piperidinone, piperonyl, pteridinyl, fluorenyl, pyranyl, pyridyl Base, pyrazolidine, pyrazolinyl, pyrazolyl, anthracene , pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyridone, pyridyl, pyrimidinyl, pyrrolidone, pyrrolidinyl, pyrrolidinyl, Pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinoline , quinoxaline, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, tetrazolyl, 6H-1,2,5-thiadi 1,1,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thioxyl, Thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, thiomorpholinyldioxaridinyl, three , triazolopyrimidinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and diphenyl And piperidyl.
如本文所使用之慣用語"醫藥上可接受"係指在健全的醫學判斷範圍內適合與人類和動物組織接觸使用而沒有過度毒性、刺激性、過敏反應或其他問題或併發症,具有相稱合理的利益/風險比的該等化合物、材料、組成物、載劑及/或劑型。 As used herein, the phrase "pharmaceutically acceptable" means that it is suitable for use in contact with human and animal tissues within a sound medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications, and is reasonably reasonable. The compounds, materials, compositions, carriers and/or dosage forms of the benefit/risk ratio.
如本文所使用之"醫藥上可接受之鹽"係指所揭示之化合物的衍生物,其中親體化合物係藉由製成其酸或鹼鹽而予以修改。醫藥上可接受之鹽的實例包括(但不限於此)鹼 性殘基(諸如胺)之無機或有機酸鹽;酸性殘基之鹼或有機鹽(諸如羧酸);及類似物。醫藥上可接受之鹽包括例如從無毒性無機或有機酸所形成之親體化合物的習知之無毒性鹽或四級銨鹽。例如,此等習知的無毒性鹽包括(但不限於此)該等從選自下列的無機和有機酸所衍生者:2-乙醯氧基苯甲酸、2-羥基乙烷磺酸、乙酸、抗壞血酸、苯磺酸、苯甲酸、雙碳酸、碳酸、檸檬酸、乙二胺四乙酸、乙烷二磺酸、乙烷磺酸、反丁烯二酸、葡萄庚酸、葡萄糖酸、麩胺酸、乙醇酸、乙二醇對胺苯胂酸、己基間苯二酚酸、哈胺酸(hydrabamic)、氫溴酸、氫氯酸、氫碘酸、羥基順丁烯二酸、羥萘酸、羥乙磺酸、乳酸、乳糖醛酸、月桂基磺酸、順丁烯二酸、蘋果酸、杏仁酸、甲烷磺酸、萘磺酸(napsylic)、硝酸、草酸、雙羥萘酸、泛酸、苯基乙酸、磷酸、聚半乳糖酸、丙酸、水楊酸、硬脂酸、鹽基性酢酸(subacetic)、琥珀酸、胺磺酸、磺胺酸、硫酸、單寧酸、酒石酸及甲苯磺酸。 "Pharmaceutically acceptable salt" as used herein refers to a derivative of the disclosed compound wherein the parent compound is modified by making an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, bases An inorganic or organic acid salt of a sexual residue such as an amine; a base or an organic salt of an acidic residue such as a carboxylic acid; and the like. Pharmaceutically acceptable salts include, for example, the conventional non-toxic salts or quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of 2-ethyloxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid. , ascorbic acid, benzenesulfonic acid, benzoic acid, dicarbonic acid, carbonic acid, citric acid, ethylenediaminetetraacetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucohelic acid, gluconic acid, glutamine Acid, glycolic acid, ethylene glycol to aminobenzoic acid, hexyl resorcinol acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxy maleic acid, hydroxynaphthoic acid , isethionethane, lactic acid, lactaldehyde, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic, nitric acid, oxalic acid, pamoic acid, pantothenic acid , phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, amine sulfonic acid, sulfamic acid, sulfuric acid, tannic acid, tartaric acid and toluene Sulfonic acid.
本發明的醫藥上可接受之鹽可從含有鹼性或酸性部分之親體化合物藉由習知的化學方法合成。此等鹽通常係藉由該等化合物的游離酸或鹼形式與化學劑量之適當的鹼或酸在水或有機溶劑中或在兩種之混合物中反應而製備;通常以非水性介質較佳,如醚、乙酸乙酯、乙醇、異丙醇或乙腈。適合的鹽名單於Remington’s Pharmaceutical Sciences,18th ed.,Mack Publishing Company,Easton,PA,USA,p.1445(1990)中發現。 The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing a basic or acidic moiety by a conventional chemical method. Such salts are usually prepared by reacting the free acid or base form of the compound with a suitable amount of a suitable base or acid in water or an organic solvent or a mixture of the two; usually a non-aqueous medium, Such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. A list of suitable salts is found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, USA, p. 1445 (1990).
因為已知前藥會增強藥劑的許多所欲品質(例如,溶解度、生物利用率、製造等),所以本發明化合物可以前藥形式輸送。因此,本發明意欲涵蓋目前主張之化合物的前藥、輸送前藥之方法及含有前藥之組成物。"前藥"意欲包括任何共價鍵結之載劑,在此等前藥投予哺乳動物對象時於活體內釋出本發明的活性親體藥物。本發明的前藥係藉由修改在化合物中存在的官能基而製備,以此方式使修改物按慣例操作或於活體內裂解成親體化合物。前藥包括其中羥基、胺基或氫硫基與任何基團鍵結的本發明化合物,當本發明前藥投予哺乳動物對象時,該前藥裂解,分別形成游離羥基、游離胺基或游離氫硫基。前藥的實例包括(但不限於此)在本發明化合物中的醇及胺官能基之乙酸酯、甲酸酯和苯甲酸酯衍生物。 Because prodrugs are known to enhance many of the desired qualities of the agent (e.g., solubility, bioavailability, manufacturing, etc.), the compounds of the invention can be delivered in prodrug form. Accordingly, the present invention is intended to cover prodrugs of currently claimed compounds, methods of delivering prodrugs, and compositions containing prodrugs. "Prodrug" is intended to include any covalently bonded carrier which releases the active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. The prodrugs of the present invention are prepared by modifying the functional groups present in the compound in such a manner that the modifications are routinely manipulated or cleaved in vivo into the parent compound. Prodrugs include compounds of the invention wherein a hydroxy, amine or thiol group is bonded to any group, and when a prodrug of the invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group, a free amine group, or a free Hydrogenthio group. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention.
如本文所使用之"穩定的化合物"及"穩定的結構"意謂具有足夠的強度從反應混合物得以分離為有用的純度且調配成有效力的治療劑之化合物。 As used herein, "stable compound" and "stable structure" mean a compound that has sufficient strength to be separated from the reaction mixture into a useful purity and formulated into an effective therapeutic agent.
如本文所使用之術語"病患"意謂可能承受外科或侵入性醫學程序之人類或動物(在動物的情況中,更典型為哺乳動物)對象。由於外科程序或侵入性醫學程序而可能認為此等病患或對象有需要減低感染風險或預防感染之方法。此等病患或對象亦可被認為有需要手術期間的預防。 The term "patient" as used herein means a human or animal (in the case of an animal, more typically a mammal) subject that may be subjected to a surgical or invasive medical procedure. Due to surgical procedures or invasive medical procedures, it may be considered that such patients or subjects have a need to reduce the risk of infection or to prevent infection. Such patients or subjects may also be considered to be in need of prevention during surgery.
如本文所使用之術語"治療"意謂提供治療干預,使感染痊癒或改善。 The term "treating" as used herein means providing a therapeutic intervention to heal or improve the infection.
如本文所使用之術語"預防"意謂完全或幾乎完全停止 感染發生,例如當病患或對象易受感染或易在接觸感染的風險下時。預防亦可包括抑制,亦即遏阻感染發生。 The term "prevention" as used herein means completely or almost completely stopped. Infection occurs, for example, when the patient or subject is susceptible to infection or is at risk of exposure to infection. Prevention can also include inhibition, which is to prevent infection from occurring.
如本文所使用之術語"減低風險"意謂降低感染發生的可能性或或然性,例如當病患或對象易受感染或易在接觸感染的風險下時。 The term "reducing risk" as used herein means reducing the likelihood or likelihood that an infection will occur, such as when the patient or subject is susceptible to infection or at risk of exposure to infection.
如本文所使用之"不飽和"係指具有至少一種不飽和程度(例如,至少一個多重鍵)之化合物且包括部分及完全不飽和化合物。 As used herein, "unsaturated" refers to a compound having at least one degree of unsaturation (eg, at least one multiple bond) and includes both partially and fully unsaturated compounds.
如本文所使用之術語"有效量"係指當作為抗微生物劑單獨或組合投予時有效的本發明化合物或化合物組合量。例如,有效量係指給予接受病患或對象足以誘出生物活性(例如,抗感染活性,諸如抗微生物活性、抗細菌活性、抗真菌活性、抗病毒活性或抗寄生蟲活性)的組成物中、調配物中或醫學裝置上存在的化合物量。 The term "effective amount" as used herein refers to an amount of a compound or combination of compounds of the invention that is effective when administered as an antimicrobial agent, alone or in combination. For example, an effective amount refers to a composition that is administered to a subject or subject sufficient to elicit biological activity (eg, anti-infective activity, such as antimicrobial activity, antibacterial activity, antifungal activity, antiviral activity, or antiparasitic activity). The amount of compound present in the formulation or on the medical device.
術語"預防有效量"意謂用於預防由於外科程序或侵入性醫學程序之感染或減低其風險而投予之本發明化合物或化合物類的有效量。 The term "prophylactically effective amount" means an effective amount of a compound or compound of the invention administered to prevent infection or reduce the risk of a surgical procedure or an invasive medical procedure.
應進一步了解"氫鍵受體-氫鍵受體-氫鍵施體"及"氫鍵受體-氫鍵受體-氫鍵受體"之表述意謂表明氫鍵受體與施體的相對定位,並不意謂限制此等基團直接連接在一起,預期額外的原子或原子之基團可包括在該等基團之間。 It should be further understood that the expression "hydrogen bond acceptor-hydrogen bond acceptor-hydrogen bond donor" and "hydrogen bond acceptor-hydrogen bond acceptor-hydrogen bond acceptor" means that the hydrogen bond acceptor is opposite to the donor body. Positioning, and is not meant to limit the direct attachment of such groups, it is contemplated that additional atoms or groups of atoms may be included between the groups.
在說明書中,單數形式亦包括複數,除非在上下文中另有其他明確的指定。除非另有其他定義,在本文所使用之所有技術及科學術語皆具有與熟諳屬於本發明技藝者一 般了解的意義。在有抵觸的情況下,將對照本發明說明書。如本文所使用之"哺乳動物"係指人類和非人類病患。 In the description, the singular forms also include the plural, unless otherwise specified in the context. Unless otherwise defined, all technical and scientific terms used herein have the art and skill of the present invention. The meaning of understanding. In case of conflict, the description of the invention will be followed. "Mammal" as used herein refers to both human and non-human patients.
如本文所使用之術語"治療有效量"係指本發明化合物或化合物組合以足以誘出生物活性(例如,抗微生物活性、抗真菌活性、抗病毒活性、抗寄生蟲活性、抗腹瀉活性及/或抗增殖活性)之量存在於接受者中或上。化合物的組合較佳為協乘性組合物。當以組合投予時的化合物效果比以單一試劑單獨投予時更大的化合物加成效果時,則發生協乘性,如由例如Chou and Talalay,Adv.Enzyme Regul.vol.22,pp.27-55(1984)所述。通常在化合物的次優濃度下最明確地證明出協乘效果。協乘性可以較低的細胞毒性或增加的抗增殖效果或與各個組份相比的一些其他有利的組合效應為角度。 The term "therapeutically effective amount" as used herein refers to a compound or combination of compounds of the invention sufficient to induce biological activity (eg, antimicrobial activity, antifungal activity, antiviral activity, antiparasitic activity, antidiarrheal activity, and/or Or the amount of anti-proliferative activity) is present in or on the recipient. The combination of compounds is preferably a synergistic composition. Co-multiplicative occurs when the compound effect when administered in combination is greater than the compound addition effect when administered alone as a single agent, as by, for example, Chou and Talalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984). The synergistic effect is most clearly demonstrated at suboptimal concentrations of the compound. The synergistic effect can be at a lower cytotoxicity or an increased anti-proliferative effect or some other advantageous combined effect compared to each component.
如本文所使用之術語"RNA微螺旋結合位置"係指由式III之RNA微螺旋佔據之大核糖體次單元的核糖功能所在地。RNA微螺旋結合位置限定至少一部分與E-位置的重疊。 The term "RNA microhelical binding position" as used herein refers to the location of the ribose function of the large ribosomal subunit occupied by the RNA microhelix of Formula III. The RNA microhelical binding position defines an overlap of at least a portion of the E-position.
如本文所使用之術語"A-位置"係指在其參與肽鍵形成反應之前立即由胺醯基-tRNA分子佔據之核糖功能所在地。 The term "A-position" as used herein refers to the location of the ribo function occupied by the amine thiol-tRNA molecule immediately prior to its participation in the peptide bond formation reaction.
如本文所使用之術語"E-位置"係指在其參與肽鍵形成反應之後由去醯化tRNA分子佔據之核糖功能所在地。 The term "E-position" as used herein refers to the locus of ribo functions occupied by de-deuterated tRNA molecules after their participation in the peptide bond formation reaction.
如本文所使用之術語"P-位置"係指在其參與肽鍵形成反應的同時由肽基-tRNA佔據之核糖功能所在地。 The term "P-position" as used herein refers to the locus of ribo functions occupied by peptidyl-tRNA while participating in the peptide bond formation reaction.
如本文所使用之術語"A-空間"係指在肽基轉移酶中心內結合胺醯化-tRNA之胺基酸部分的一部分A-位置,或者係指結合利奈唑德之噁唑啶酮環的一部分A-位置。 The term "A-space" as used herein refers to a portion of the A-position of an amino acid moiety that binds to an amine deuteration-tRNA within the peptidyl transferase center, or refers to an oxazolidinone ring that binds to linozide. Part of the A-position.
應了解如本文所使用及關於核糖體或核糖體次單元之術語"一部分"或"立體結構的一部分"意謂藉由核糖體或核糖體次單元的至少3個,更佳為至少3至10個,而最佳為至少10個胺基酸殘基及/或核苷酸殘基所形成之核糖體或核糖體次單元之立體結構的一部分,包括電荷分布及親水性/疏水性特徵。形成此一部分的殘基可為例如(i)以例如核糖體RNA或核糖體蛋白質的第一序列為基準之連續殘基,(ii)形成核糖體或核糖體次單元之立體結構的連續部分之殘基,或(c)其組合。應了解如本文所使用及關於RNA微螺旋之術語"一部分"或"立體結構的一部分"意謂藉由式III之一或多個核心殘基的至少3個,更佳為至少3至10個原子所形成之RNA微螺旋之立體結構的一部分,包括電荷分布及親水性/疏水性特徵。形成此一部分的原子可為例如(i)埋藏在RNA微螺旋核心內之溶劑不可及原子,(ii)RNA微螺旋之溶劑可及原子,或(iii)其組合。 It will be understood that the term "a portion" or "part of a steric structure" as used herein with respect to a ribosome or ribosome subunit means at least 3, more preferably at least 3 to 10, by ribosome or ribosome subunit. And preferably a portion of the steric structure of the ribosome or ribosome subunit formed by at least 10 amino acid residues and/or nucleotide residues, including charge distribution and hydrophilic/hydrophobic characteristics. The residue forming this portion may be, for example, (i) a contiguous residue based on, for example, the first sequence of ribosomal RNA or ribosomal protein, (ii) a contiguous portion of the steric structure forming a ribosome or ribosome subunit. a residue, or (c) a combination thereof. It will be understood that the term "a portion" or "a portion of a stereostructure" as used herein and with respect to an RNA microhelix means at least 3, more preferably at least 3 to 10, of one or more core residues of Formula III. A portion of the three-dimensional structure of the RNA microhelix formed by the atom, including charge distribution and hydrophilic/hydrophobic characteristics. The atom forming this portion may be, for example, (i) a solvent inaccessible atom buried in the core of the RNA microhelix, (ii) a solvent accessible atom of the RNA microhelix, or (iii) a combination thereof.
本文所使用之所有百分比及比值係以重量計,除非另有其他標示。 All percentages and ratios used herein are by weight unless otherwise indicated.
在整個說明中,在以具有、包括或包含特殊的組份說明組成物時,或在以具有、包括或包含特殊的方法步驟說明方法時,預期本發明組成物基本上亦由或由所引述之組份所組成,且本發明方法基本上亦由或由所引述之處理步 驟所組成。再者,應了解步驟的次序或執行特定作用的次序不重要,只要本發明仍維持為可操作。而且,可同時進行二或多個步驟或作用。 Throughout the description, when the composition is described as having, including or comprising a particular component, or when the method is described as having, including or comprising a particular method step, it is contemplated that the composition of the invention is also substantially or by reference. Composition of the components, and the method of the invention is basically also or by the recited processing steps The composition of the steps. Again, it should be understood that the order of the steps or the order in which the particular actions are performed is not critical as long as the invention remains operational. Moreover, two or more steps or actions can be performed simultaneously.
在一個觀點中,本發明關於具有以下結構之化合物:
其中為選自下式之化學部分:
在一些具體例中,本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中進一步包含氫鍵施體部分或額外的氫鍵受體部分。 In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein Further comprising a hydrogen bond donor moiety or an additional hydrogen bond acceptor moiety.
在一些具體例中,本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中為包含至少兩個氫鍵受體部分及至少一個氫鍵施體部分之化學部分。 In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein A chemical moiety comprising at least two hydrogen bond acceptor moieties and at least one hydrogen bond donor moiety.
在一些具體例中,本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中氫鍵受體部 分及氫鍵施體部分係呈氫鍵受體-氫鍵受體-氫鍵施體之定向。如上述所使用之術語"呈定向"不意謂氫鍵施體或受體部分必然直接連接在一起,因為可以有其他干預原子或原子之基團在氫鍵施體或受體部分之間。 In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein the hydrogen bond acceptor moiety The fraction and the hydrogen bond donor moiety are oriented by a hydrogen bond acceptor-hydrogen bond acceptor-hydrogen bond donor. The term "oriented" as used above does not mean that the hydrogen bond donor or acceptor moiety is necessarily directly joined together, as other groups of interfering atoms or atoms may be between the hydrogen bond donor or acceptor moiety.
在一些具體例中,本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中氫鍵受體部分彼此係在5埃之內及氫鍵施體部分係在氫鍵受體部分的5埃之內。 In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein the hydrogen bond acceptor moiety is within 5 angstroms of each other and the hydrogen bond donor moiety It is within 5 angstroms of the hydrogen bond acceptor moiety.
在一些具體例中,本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中氫鍵受體部分彼此係在3埃之內及氫鍵施體部分係在氫鍵受體部分的3埃之內。 In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein the hydrogen bond acceptor moiety is within 3 angstroms of each other and the hydrogen bond donor moiety It is within 3 angstroms of the hydrogen bond acceptor moiety.
在一些具體例中,本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中氫鍵受體部分係包含於環結構內,其中該環結構為單環結構或稠合之多環結構。 In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein the hydrogen bond acceptor moiety is contained within a ring structure, wherein the ring structure is a single Ring structure or fused multi-ring structure.
在一些具體例中,本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中為包含至少三個氫鍵受體部分之化學部分。 In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein Is a chemical moiety comprising at least three hydrogen bond acceptor moieties.
在一些具體例中,本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中氫鍵受體部分係呈氫鍵受體-氫鍵受體-氫鍵受體之定向。如上述所使用之術語"呈定向"不意謂氫鍵施體或受體部分必然直接連接在一起,因為可以有其他干預原子或原子之基團在氫鍵 受體部分之間。 In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein the hydrogen bond acceptor moiety is a hydrogen bond acceptor-hydrogen bond acceptor-hydrogen The orientation of the bond receptor. The term "oriented" as used above does not mean that the hydrogen bond donor or acceptor moiety is necessarily directly joined together because there may be other interfering atoms or atoms in the hydrogen bond. Between the receptor parts.
在一些具體例中,本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中各氫鍵受體部分係在至少一個其他的氫鍵受體部分的約5埃之內。 In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein each hydrogen bond acceptor moiety is attached to at least one other hydrogen bond acceptor moiety Within about 5 angstroms.
在一些具體例中,本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中各氫鍵受體部分係在至少一個其他的氫鍵受體部分的約3埃之內。 In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein each hydrogen bond acceptor moiety is attached to at least one other hydrogen bond acceptor moiety Within about 3 angstroms.
在一些具體例中,本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中氫鍵受體部分中之至少二者係包含於環結構內,其中該環結構為單環結構或稠合之多環結構。 In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein at least two of the hydrogen bond acceptor moieties are contained within a ring structure, wherein The ring structure is a single ring structure or a fused multi-ring structure.
在一些具體例中,本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中該氫鍵受體部分係獨立選自羰基、硫代羰基、亞胺基、經烷基取代之亞胺基、亞碸基、碸基、肟基、經烷基取代之肟基、腙基、經單烷基或二烷基取代之腙基、氧醚(-O-)基、硫化物,亦稱為硫醚基(-S-)、羥基、烷氧基、胺基、經單烷基或二烷基取代之胺基及硝基。 In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein the hydrogen bond acceptor moiety is independently selected from the group consisting of a carbonyl group, a thiocarbonyl group, and an imine Alkyl, alkyl substituted imido, fluorenylene, fluorenyl, fluorenyl, alkyl substituted fluorenyl, fluorenyl, monoalkyl or dialkyl substituted fluorenyl, oxyether (-O) -) a base, a sulfide, also known as a thioether group (-S-), a hydroxyl group, an alkoxy group, an amine group, a monoalkyl or dialkyl substituted amine group and a nitro group.
在一些具體例中,本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中該氫鍵施體部分係選自羥基、硫醇基、胺基及經單取代之胺基。 In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein the hydrogen bond donor moiety is selected from the group consisting of a hydroxyl group, a thiol group, an amine group, and A monosubstituted amine group.
在一些具體例中,本發明係關於一種化合物或其醫藥
上可接受之鹽、酯、互變異構物或前藥,其中包含
下式之結構部分:
在一些具體例中,本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中W為O、NR1、NOR1或S。 In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein W is O, NR 1 , NOR 1 or S.
在一些具體例中,本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中包含下式之結構部分:
其中Z係選自O、NR4或S(O)n;R4係選自H及C1-6烷基,及n為0、1及2。 Wherein Z is selected from O, NR 4 or S(O) n ; R 4 is selected from H and C 1-6 alkyl, and n is 0, 1 and 2.
在一些具體例中,本發明係關於一種化合物或其醫藥
上可接受之鹽、酯、互變異構物或前藥,其中包含
下式之結構部分:
其中R4係選自H及C1-6烷基。 Wherein R 4 is selected from the group consisting of H and C 1-6 alkyl.
在一些具體例中,本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中其中R4為H。 In some embodiments, the present invention is based on a salt of a compound or a pharmaceutically acceptable's, ester, tautomer or prodrug thereof, wherein wherein R 4 is H.
在一些具體例中,本發明係關於一種化合物或其醫藥 上可接受之鹽、酯、互變異構物或前藥,其中包含 胞嘧啶或異胞嘧啶部分或其衍生物。 In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein Contains a cytosine or isocytosine moiety or a derivative thereof.
在一些具體例中,本發明係關於一種化合物或其醫藥
上可接受之鹽、酯、互變異構物或前藥,其中包含
下式之結構部分:
在一些具體例中,本發明係關於一種化合物或其醫藥
上可接受之鹽、酯、互變異構物或前藥,其中包含下
式之結構部分:
其中V係獨立選自-CR4a-或-N-;其中Z係選自O、NR4、S(O)n、NR4CO、CONR4或NR4CONR4,R4係選自H及C1-8烷基,R4a係選自H及C1-8烷基,及n為0、1或2。 Wherein V is independently selected from -CR 4a - or -N-; wherein Z is selected from O, NR 4 , S(O) n , NR 4 CO, CONR 4 or NR 4 CONR 4 , and R 4 is selected from H and C 1-8 alkyl, R 4a is selected from H and C 1-8 alkyl, and n is 0, 1 or 2.
在一些具體例中,本發明係關於一種化合物或其醫藥
上可接受之鹽、酯、互變異構物或前藥,其中包含下
式之結構部分:
在一些具體例中,本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中R4為H。 In some embodiments, the present invention is based on a salt of a compound or a pharmaceutically acceptable's, ester, tautomer or prodrug thereof, wherein R 4 is H.
在一些具體例中,本發明係關於一種具有下式之化合物:
在一些具體例中,本發明係關於一種根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中A係選自:(a)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環,(b)3-14員飽和、不飽和或芳族碳環,及(c)單鍵,其中(a)或(b)隨意地經一或多個R5基團取代。 In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va or a pharmaceutically acceptable salt, ester, tautomer thereof or a prodrug wherein A is selected from the group consisting of: (a) a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (b) 3-14 member saturated And an unsaturated or aromatic carbocyclic ring, and (c) a single bond wherein (a) or (b) is optionally substituted with one or more R 5 groups.
在一些具體例中,本發明係關於一種根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中B係選自(a)-(C1-8烷基)-,(b)-(C2-8烯基)-,(c)-(C2-8炔基)-,及(d)單鍵,其中i)上述(a)-(c)中任一者中的0-4個碳原子隨意地經選自-O-、-S(O)p-、-NR6-、-(C=O)-、 -C(=NR6)-、-S(O)pNR6-及-NR6S(O)pNR6-之部分替換,ii)上述(a)-(c)中任一者隨意地經一或多個R5基團取代,及iii)上述(a)-(c)中任一者隨意地經-(C1-8烷基)-R5基團取代。 In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va or a pharmaceutically acceptable salt, ester, tautomer thereof or a prodrug wherein B is selected from the group consisting of (a)-(C 1-8 alkyl)-, (b)-(C 2-8 alkenyl)-, (c)-(C 2-8 alkynyl)-, And (d) a single bond, wherein i) 0-4 carbon atoms in any of the above (a) to (c) are optionally selected from -O-, -S(O) p -, -NR 6 -, -(C=O)-, -C(=NR 6 )-, -S(O) p NR 6 - and -NR 6 S(O) p NR 6 - partial replacement, ii) above (a) - (c) optionally substituted with one or more R 5 groups, and iii) any of the above (a) - (c) optionally via -(C 1-8 alkyl)-R 5 group substitution.
在一些具體例中,本發明係關於一種根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中C係選自(a)NH2,(b)-NHC(=NH)NH2及(c)氫。 In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va or a pharmaceutically acceptable salt, ester, tautomer thereof or A prodrug wherein C is selected from the group consisting of (a) NH 2 , (b)-NHC (=NH)NH 2 and (c) hydrogen.
在一些具體例中,本發明係關於一種根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中A係選自:(a)含有一或多個選自氮、氧及硫之雜原子的4-7員飽和、不飽和或芳族雜環,(b)4-7員飽和、不飽和或芳族碳環,及(c)單鍵,其中(a)或(b)隨意地經一或多個R5基團取代;或其醫藥上可接受之鹽、酯、互變異構物或前藥。 In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va or a pharmaceutically acceptable salt, ester, tautomer thereof or A prodrug wherein A is selected from the group consisting of: (a) a 4-7 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (b) 4-7 member saturated , an unsaturated or aromatic carbocyclic ring, and (c) a single bond wherein (a) or (b) is optionally substituted with one or more R 5 groups; or a pharmaceutically acceptable salt, ester or tautomer thereof Structure or prodrug.
在一些具體例中,本發明係關於一種根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中A係選自氮基(azepanyl)、環丁基、環戊基、環己基、環庚基、苯 基、吡啶基、環己烯基、環己二烯基、二氫吡啶基、呋喃基、四氫呋喃基、四氫吡啶基、氮呾基、吡咯啶基、哌啶基及哌啶烯基;其中上述A中任一者隨意地經一或多個R5基團取代;或者A為單鍵。 In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va or a pharmaceutically acceptable salt, ester, tautomer thereof or Prodrug, wherein line A is selected from nitrogen Azepanyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl, cyclohexadienyl, dihydropyridyl, furyl, tetrahydrofuranyl, tetrahydrogen Pyridyl, aziridine, pyrrolidinyl, piperidinyl and piperidinyl; wherein any of the above A is optionally substituted with one or more R 5 groups; or A is a single bond.
在一些具體例中,本發明係關於一種根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中B係選自(a)-(C1-8烷基)-,其中i)上述(a)中的0-4個碳原子隨意地經選自-O-、-S(O)p-、-NR6-、-(C=O)-、-S(O)pNR6-及-NR6S(O)pNR6-之部分替換,ii)上述(a)隨意地經一或多個R5基團取代,及/或iii)上述(a)隨意地經-(C1-8烷基)-R5基團取代;及或者B為單鍵。 In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va or a pharmaceutically acceptable salt, ester, tautomer thereof or a prodrug wherein B is selected from (a)-(C 1-8 alkyl)-, wherein i) 0-4 carbon atoms in (a) above are optionally selected from -O-, -S(O) a partial replacement of p -, -NR 6 -, -(C=O)-, -S(O) p NR 6 - and -NR 6 S(O) p NR 6 -, ii) (a) optionally Substituted by one or more R 5 groups, and/or iii) the above (a) is optionally substituted with a -(C 1-8 alkyl)-R 5 group; and or B is a single bond.
在一些具體例中,本發明係關於一種根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中C係選自(a)NH2,及(b)-NHC(=NH)NH2。 In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va or a pharmaceutically acceptable salt, ester, tautomer thereof or A prodrug wherein C is selected from the group consisting of (a) NH 2 and (b)-NHC (=NH)NH 2 .
在一些具體例中,本發明係關於一種根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中G係選自:(a)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環, (b)3-14員飽和、不飽和或芳族碳環,及(c)單鍵,其中(a)或(b)隨意地經一或多個R5基團取代。 In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va or a pharmaceutically acceptable salt, ester, tautomer thereof or a prodrug wherein G is selected from the group consisting of: (a) a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (b) 3-14 member saturated And an unsaturated or aromatic carbocyclic ring, and (c) a single bond wherein (a) or (b) is optionally substituted with one or more R 5 groups.
在一些具體例中,本發明係關於一種根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中G係選自:(a)含有一或多個選自氮、氧及硫之雜原子的4-7員飽和、不飽和或芳族雜環,(b)4-7員飽和、不飽和或芳族碳環,及(c)單鍵,其中(a)或(b)隨意地經一或多個R5基團取代。 In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va or a pharmaceutically acceptable salt, ester, tautomer thereof or a prodrug wherein G is selected from the group consisting of: (a) a 4-7 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (b) 4-7 member saturated And an unsaturated or aromatic carbocyclic ring, and (c) a single bond wherein (a) or (b) is optionally substituted with one or more R 5 groups.
在一些具體例中,本發明係關於一種根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中G係選自氮基、環丁基、環戊基、環己基、環庚基、苯基、吡啶基、環己烯基、環己二烯基、二氫吡啶基、呋喃基、四氫呋喃基、四氫吡啶基、氮呾基、吡咯啶基、哌啶基、哌啶烯基及單鍵。 In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va or a pharmaceutically acceptable salt, ester, tautomer thereof or Prodrug, wherein G is selected from nitrogen Base, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl, cyclohexadienyl, dihydropyridyl, furyl, tetrahydrofuranyl, tetrahydropyridyl, Aziridine, pyrrolidinyl, piperidinyl, piperidinyl and a single bond.
在一些具體例中,本發明係關於一種具有下式之化合物:
在一些具體例中,本發明係關於一種具有下式之化合物:
在一些具體例中,本發明係關於一種具有下式之化合物:
在一些具體例中,本發明係關於一種具有下式之化合物:
在一些具體例中,本發明係關於一種具有下式之化合物:
在一些具體例中,本發明係關於一種具有式Ia、IIa、IIIa、IVa或Va之化合物:
或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中變體係如式I、II、III、IV及V中所定義。 Or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein the variant system is as defined in formulas I, II, III, IV and V.
在一些具體例中,本發明係關於一種具有下式之化合物:
在一些具體例中,本發明係關於一種具有下式之化合物:
在一些具體例中,本發明係關於一種具有下式之化合物:
在一些具體例中,本發明係關於一種具有下式之化合物:
在一些具體例中,本發明係關於一種具有下式之化合物:
在一些具體例中,本發明係關於一種根據具有式(Ia)之式I、II、III、IV或V之化合物,其中Z為-NR4CONR4-,C-B-A-、-D-E-F及-G-H-J係如式(I)中所定義,或其醫藥上可接受之鹽、酯、互變異構物或前藥。 In some embodiments, the invention relates to a compound according to formula I, II, III, IV or V of formula (Ia) wherein Z is -NR 4 CONR 4 -, CBA-, -DEF and -GHJ As defined in formula (I), or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof.
在一些具體例中,本發明係關於一種具有下式之化合物:
在一些具體例中,本發明係關於一種具有下式之化合物:
在一些具體例中,本發明係關於一種具有下式之化合物:
在一些具體例中,本發明係關於一種具有式:
之化合物,其中C-B-A-係選自:
氫、
在一些具體例中,本發明係關於一種具有式: 之化合物, 其中G係選自:(a)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環,(b)3-14員飽和、不飽和或芳族碳環,及(c)單鍵,其中(a)或(b)隨意地經一或多個R5基團取代,或其醫藥上可接受之鹽、酯、互變異構物或前藥。 In some embodiments, the invention relates to a possessive formula: a compound wherein G is selected from the group consisting of: (a) a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (b) 3-14 member saturated , an unsaturated or aromatic carbocyclic ring, and (c) a single bond wherein (a) or (b) is optionally substituted with one or more R 5 groups, or a pharmaceutically acceptable salt, ester or tautomer thereof Structure or prodrug.
在一些具體例中,本發明係關於一種含有R5之根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,其中R5係選自(a)氫,(b)F,(c)Cl,(d)Br,(e)I,(f)-CF3,(g)-CN,(h)-N3,(i)-NO2,(j)-NH2,(k)-OR6,(l)NHC(NH)NH2,(m)-C1-8烷基,(n)-C1-8烯基,(o)-C1-8炔基,(p)-(C1-8烷基)-(含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環),(q)-(C1-8烷基)-(3-14員飽和、不飽和或芳族碳環),(r)-鹵烷基,(s)烷硫基,(t)-含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環,及(u)-3-14員飽和、不飽和或芳族碳環;或者兩個R5基團一起形成碳環,或其醫藥上可接受之鹽、酯、互變異構物或前藥。 In some embodiments, the invention relates to a compound of the formula R 5 comprising I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va of, wherein R 5 is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) - CF 3 , (g) - CN, (h) - N 3 , (i) - NO 2 , (j) -NH 2 , (k)-OR 6 , (l) NHC(NH)NH 2 , (m)-C 1-8 alkyl, (n)-C 1-8 alkenyl, (o)-C 1- 8 alkynyl, (p)-(C 1-8 alkyl)- (a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur), q)-(C 1-8 alkyl)-(3-14 membered saturated, unsaturated or aromatic carbocyclic ring), (r)-haloalkyl, (s)alkylthio, (t)-containing one or a plurality of 3-14 membered saturated, unsaturated or aromatic heterocyclic rings selected from heteroatoms of nitrogen, oxygen and sulfur, and (u)-3-14 saturated, unsaturated or aromatic carbocyclic rings; or two R The 5 groups together form a carbocyclic ring, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof.
在一些具體例中,本發明係關於一種含有R6之根據 式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,其中R6係選自(a)氫,(b)-C1-8烷基,或者兩個R6基團一起形成碳環,(c)-鹵烷基,(d)-含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環,及(e)-3-14員飽和、不飽和或芳族碳環,或其醫藥上可接受之鹽、酯、互變異構物或前藥。 In some embodiments, the present invention relates to a system comprising of R 6, II, III, IV,, , compound of formula I V Ia IIa, IIIa, IVa or Va of, wherein R 6 is selected from (a) hydrogen, (b)-C 1-8 alkyl, or two R 6 groups together form a carbocyclic ring, (c)-haloalkyl, (d)-containing one or more heteroatoms selected from nitrogen, oxygen and sulfur a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring, and (e)-3-14 membered saturated, unsaturated or aromatic carbocyclic ring, or a pharmaceutically acceptable salt, ester, tautomer thereof or Prodrug.
在一些具體例中,本發明係關於一種具有式:
在一些具體例中,本發明係關於一種具有式:
之化合物,其中-G-H-J係選
自:氫、
在一些具體例中,本發明係關於一種具有式:
之化合物,
其中-G-H-J係選自:氫、
在一些具體例中,本發明係關於一種具有式:
之化合物,
其中-G-H-J係選自:
在一些具體例中,本發明係關於一種含有R5之化合物,其中R5係選自(a)氫,(b)F,(c)Cl,(d)Br,(e)I,(f)-CF3,(g)-CN,(h)-N3,(i)-NO2,(j)-NH2,(k)-OR6,(l)NHC(=NH)NH2,(m)-C1-8烷基,(n)-C1-8烯基,(o)-C1-8炔基,(p)-(C1-8烷基)-(含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環),(q)-(C1-8烷 基)-(3-14員飽和、不飽和或芳族碳環),(r)-鹵烷基,(s)烷硫基,(t)-含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環,及(u)-3-14員飽和、不飽和或芳族碳環;或者兩個R5基團一起形成碳環,或其醫藥上可接受之鹽、酯、互變異構物或前藥。 In some embodiments, the invention relates to a compound containing R 5 wherein R 5 is selected from the group consisting of (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) )-CF 3 , (g)-CN, (h)-N 3 , (i)-NO 2 , (j)-NH 2 , (k)-OR 6 , (l) NHC(=NH)NH 2 , (m)-C 1-8 alkyl, (n)-C 1-8 alkenyl, (o)-C 1-8 alkynyl, (p)-(C 1-8 alkyl)- (containing one or 3-14 member saturated, unsaturated or aromatic heterocyclic ring selected from heteroatoms of nitrogen, oxygen and sulfur, (q)-(C 1-8 alkyl)-(3-14 member saturated, unsaturated) Or an aromatic carbocyclic ring), (r)-haloalkyl, (s)alkylthio, (t)- 3-14 member saturated or unsaturated containing one or more heteroatoms selected from nitrogen, oxygen and sulfur Or an aromatic heterocyclic ring, and (u)-3-14 a saturated, unsaturated or aromatic carbocyclic ring; or two R 5 groups together to form a carbocyclic ring, or a pharmaceutically acceptable salt, ester or tautomer thereof Structure or prodrug.
在一些具體例中,本發明係關於一種含有R6之化合物,其中R6係選自(a)氫,(b)-C1-8烷基,或者兩個R6基團一起形成碳環,(c)-鹵烷基,(d)-含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環,及(e)-3-14員飽和、不飽和或芳族碳環,或其醫藥上可接受之鹽、酯、互變異構物或前藥。 In some embodiments, the invention relates to a compound containing R 6 wherein R 6 is selected from (a) hydrogen, (b)-C 1-8 alkyl, or two R 6 groups together form a carbocyclic ring , (c)-haloalkyl, (d)- a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and (e)-3- A 14-membered saturated, unsaturated or aromatic carbocyclic ring, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof.
在一些具體例中,本發明係關於一種根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中-D-E-F代表氫。 In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester or tautomer thereof Or a prodrug, wherein -DEF stands for hydrogen.
在一些具體例中,本發明係關於一種根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中當有W存在時,其為O、NR1、NOR1或S。 In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester or tautomer thereof Or a prodrug, wherein when W is present, it is O, NR 1 , NOR 1 or S.
在一些具體例中,本發明係關於一種根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中當有XY存在時,其為雙鍵,且X為N及Y為碳原子。 In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester or tautomer thereof Or prodrug, which has X When Y is present, it is a double bond, and X is N and Y are carbon atoms.
在一些具體例中,本發明係關於一種根據式I、II、 III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中當有R4a存在時,其為H。 In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester or tautomer thereof Or a prodrug, wherein when R 4a is present, it is H.
在一些具體例中,本發明係關於一種根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中當有Z存在時,其為NR4。 In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester or tautomer thereof Or a prodrug, wherein when Z is present, it is NR 4 .
在一些具體例中,本發明係關於一種根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥,其中R4為H。 In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester or tautomer thereof Or prodrug, wherein R 4 is H.
在一些具體例中,本發明係關於一種根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥,其係與核糖體結合。 In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester or tautomer thereof Or a prodrug that binds to the ribosome.
在一些具體例中,本發明係關於一種根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥,其係與核糖體結合,其中核糖體為細菌核糖體。 In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester or tautomer thereof Or a prodrug that binds to a ribosome, wherein the ribosome is a bacterial ribosome.
在一些具體例中,本發明係關於一種根據表1之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥。 In some embodiments, the invention relates to a compound according to Table 1, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof.
在一些具體例中,本發明係關於一種醫藥組成物,其包含本發明化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥,及醫藥上可接受之載劑。 In some embodiments, the invention relates to a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, and a pharmaceutically acceptable carrier.
在一些具體例中,本發明係關於一種治療、預防人類或動物的疾病狀態或減低其風險之方法,其包含以有效量之本發明化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥投予有此需求之人類或動物。 In some embodiments, the invention relates to a method of treating or preventing a disease state or reducing the risk of a human or animal comprising an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester or tautomer thereof A construct or prodrug is administered to a human or animal in need thereof.
在一些具體例中,本發明係關於一種治療人類或動物的微生物感染之方法,其包含以有效量之本發明化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥投予人類或動物。 In some embodiments, the invention relates to a method of treating a microbial infection in a human or animal comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof To humans or animals.
在一些具體例中,本發明係關於本發明化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造供治療人類或動物的微生物感染之藥劑的用途。 In some embodiments, the invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, for the manufacture of a medicament for the treatment of a microbial infection in a human or animal.
在一些具體例中,本發明係關於一種治療、預防人類或動物的微生物感染或減低其風險之方法,其包含以有效量之本發明化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥投予人類或動物,或關於本發明化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造供治療、預防微生物感染或減低其風險之藥劑的用途,其中該微生物感染係選自:皮膚感染,革蘭氏陽性感染,革蘭氏陰性感染,院內皮膚感染,革蘭氏陽性感染,革蘭氏陰性感染,院內感染肺炎,社區型感染肺炎,後病毒肺炎,醫院型感染肺炎/呼吸器相關肺炎,呼吸道感染,諸如慢性呼吸道感染(CRTI),急性骨盆感染,併發性皮膚及皮膚結構感染,皮膚與軟組織感染(SSTI)包括無併發性皮膚與軟組織感染(uSSTI)及併發性皮膚與軟組織感染,腹部感 染,併發性腹腔內感染,尿道感染,菌血症,敗血症,心內膜炎,心室心房分流感染,血管通路感染,腦膜炎,手術預防感染(surgical prophylaxis),腹膜感染,骨感染,關節感染,二甲苯青黴素抗藥性金黃葡萄球菌感染,萬古黴素抗藥性腸球菌感染,利奈唑德抗藥性有機體感染,炭疽桿菌(Bacillus anthracis)感染,兔熱病桿菌(Francisella tularensis)感染,鼠疫耶氏菌(Yersinia pestis)感染及結核病。 In some embodiments, the invention relates to a method of treating, preventing or reducing the risk of microbial infection in a human or animal comprising an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester or tautomer thereof The construct or prodrug is administered to a human or animal, or to a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, for the manufacture of a medicament for the treatment, prevention or reduction of the risk of microbial infection Use, wherein the microbial infection is selected from the group consisting of: skin infection, Gram-positive infection, Gram-negative infection, nosocomial skin infection, Gram-positive infection, Gram-negative infection, nosocomial infection pneumonia, community-type infection pneumonia, Post-viral pneumonia, hospital-type pneumonia/respirator-associated pneumonia, respiratory infections, such as chronic respiratory infections (CRTI), acute pelvic infections, complicated skin and skin structure infections, skin and soft tissue infections (SSTI) including no concomitant skin and Soft tissue infection (uSSTI) and concomitant skin and soft tissue infections, abdominal sensation Dyeing, complicated intra-abdominal infection, urinary tract infection, bacteremia, sepsis, endocarditis, ventricular atrial shunt infection, vascular infection, meningitis, surgical prophylaxis, peritoneal infection, bone infection, joint infection , xylene penicillin-resistant Staphylococcus aureus infection, vancomycin-resistant enterococci infection, linezolid-resistant organism infection, Bacillus anthracis infection, Francisella tularensis infection, Yersinia pestis ( Yersinia pestis) infection and tuberculosis.
在一些具體例中,本發明係關於一種方法或用途,其中本發明化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥係經耳、眼、鼻、口、非經腸、局部或靜脈內投予。 In some embodiments, the invention relates to a method or use wherein a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, is administered through the ear, eye, nose, mouth, and non-menstrual Intestinal, topical or intravenous administration.
在一些具體例中,本發明係關於一種治療、預防人類或動物的併發性腹腔內感染或減低其風險之方法,其包含以有效量之根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥投予人類或動物,或關於根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造供治療、預防併發性腹腔內感染或減低其風險之藥劑的用途,其中併發性腹腔內感染係選自由於大腸桿菌、梭狀梭菌(Clostridium clostridioforme)、遲緩真桿菌(Eubacterium lentum)、消化鏈球菌屬(Peptostreptococcus spp.)、脆弱擬桿菌(Bacteroides fragilis)、狄氏擬桿菌(Bacteroides distasonis)、卵形擬桿菌(Bacteroides ovatus)、多形擬桿菌(Bacteroides thetaiotaomicron)、單形擬桿菌(Bacteroides uniformis)、咽峽炎鏈球菌(Streptococcus anginosus)、星座鏈球菌(Streptococcus constellatus)、糞腸球菌、奇異變型桿菌(Proteus mirabilis)或產氣莢膜桿菌(Clostridium perfringens)之多種微生物感染,諸如膿腫。 In some embodiments, the invention relates to a method of treating, preventing, or reducing the risk of concurrent intra-abdominal infection in a human or animal comprising administering an effective amount according to Formulas I, II, III, IV, V, Ia, a compound of IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, administered to a human or animal, or in accordance with formulas I, II, III, IV, V, Ia, Use of a compound of IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, for the manufacture of a medicament for the treatment or prevention of concurrent intraperitoneal infection or reducing its risk, wherein concurrent Intra-abdominal infection is selected from Escherichia coli, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus spp., Bacteroides fragilis, Bacteroides diarrhea (Bacteroides Distasonis), Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Streptococcus anginosus, Streptococcus constellatus, fecal intestine A variety of microbial infections, such as abscesses, of cocci, Proteus mirabilis, or Clostridium perfringens.
在一些具體例中,本發明係關於一種治療、預防人類或動物的併發性皮膚與皮膚結構感染或減低其風險之方法,其包含以有效量之根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥投予人類或動物,或關於根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造供治療、預防併發性皮膚與皮膚結構感染或減低其風險之藥劑的用途,其中併發性皮膚與皮膚結構感染係選自由於金黃色葡萄球菌(二甲苯青黴素敏感性及抗藥性分離物)、無乳鏈球菌(Streptococcus agalactiae)、化膿性鏈球菌(Streptococcus pyogenes)、大腸桿菌、克雷伯氏肺炎桿菌(Klebsiella pneumoniae)、奇異變型桿菌(Proteus mirabilis)、脆弱擬桿菌、消化鏈球菌屬、不解糖卟啉單胞菌(Porphyromonas asaccharolytica)或二路普雷沃爾菌(Prevotella bivia)的無骨髓炎之糖尿病足感染。 In some embodiments, the invention relates to a method of treating, preventing, or reducing the risk of complicated skin and skin structure infections in humans or animals, comprising an effective amount according to formulas I, II, III, IV, V, a compound of Ia, IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, administered to a human or animal, or in accordance with Formulas I, II, III, IV, V, a compound of Ia, IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, for the manufacture of a medicament for the treatment or prevention of complications of the skin and skin structure or for reducing its risk Use, wherein the concomitant skin and skin structure infection is selected from the group consisting of Staphylococcus aureus (xylene penicillin sensitive and drug resistant isolate), Streptococcus agalactiae, Streptococcus pyogenes, large intestine Bacillus, Klebsiella pneumoniae, Proteus mirabilis, Bacteroides fragilis, Streptococcus pneumoniae, Porphyromonas asaccharolytica None of osteomyelitis in diabetic two 路普雷沃尔 bacteria (Prevotella bivia) foot infection.
在一些具體例中,本發明係關於一種治療、預防人類或動物的社區型感染肺炎或減低其風險之方法,其包含以 有效量之根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥投予人類或動物,或關於根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造供治療、預防社區型感染肺炎或減低其風險之藥劑的用途,其中社區型感染肺炎係由於包括合併菌血症之病例的肺炎鏈球菌(青黴素敏感性及抗藥性分離物)、流感嗜血桿菌(Haemophilus influenzae)(包括β-內醯胺酶陽性分離物)、卡他莫拉菌(Moraxella catarrhalis)或非典型細菌,如黴漿菌屬。 In some embodiments, the present invention relates to a method of treating, preventing, or reducing the risk of community-type pneumonia in a human or animal, including An effective amount of a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, administered to a human or animal Or for the manufacture of a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, for treatment, Use of a drug to prevent community-type pneumonia or reduce its risk, in which community-type pneumonia is caused by Streptococcus pneumoniae (penicillin-sensitive and drug-resistant isolates), Haemophilus influenzae, including cases of bacteremia (including beta-endoprolinase positive isolates), Moraxella catarrhalis or atypical bacteria such as Mycoplasma.
在一些具體例中,本發明係關於一種治療、預防人類或動物的併發性尿道感染或減低其風險之方法,其包含以有效量之根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥投予人類或動物,或關於根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造供治療、預防併發性尿道感染或減低其風險之藥劑的用途,其中併發性尿道感染係選自由於大腸桿菌、合併菌血症或克雷伯氏肺炎桿菌之腎盂腎炎。 In some embodiments, the invention relates to a method of treating or preventing a concurrent urinary tract infection or reducing the risk in a human or animal, comprising an effective amount according to formulas I, II, III, IV, V, Ia, IIa a compound of, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, administered to a human or animal, or in accordance with formulas I, II, III, IV, V, Ia, IIa Use of a compound of Formula IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, for the manufacture of a medicament for the treatment or prevention of a concurrent urinary tract infection or a reduced risk thereof, wherein the concurrent urethra The infection is selected from pyelonephritis due to Escherichia coli, combined bacteremia or Klebsiella pneumoniae.
在一些具體例中,本發明係關於一種治療、預防人類或動物的急性骨盆感染或減低其風險之方法,其包含以有效量之根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物 或前藥投予人類或動物,或關於根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造供治療、預防急性骨盆感染或減低其風險之藥劑的用途,其中包括產後子宮內膜炎、敗血性流產及手術後婦科感染之急性骨盆感染係由於無乳鏈球菌、大腸桿菌、脆弱擬桿菌、不解糖卟啉單胞菌、消化鏈球菌屬或二路普雷沃爾菌。 In some embodiments, the invention relates to a method of treating, preventing, or reducing the risk of an acute pelvic infection in a human or animal comprising administering an effective amount according to Formulas I, II, III, IV, V, Ia, IIa, a compound of IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester or tautomer thereof Or a prodrug administered to a human or animal, or a compound according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester or tautomer thereof Or the use of prodrugs in the manufacture of a medicament for the treatment, prevention or reduction of acute pelvic infections, including postpartum endometritis, septic abortion and postoperative gynecological infections due to acute pelvic infections due to Streptococcus agalactiae, Escherichia coli , Bacteroides fragilis, P. gingivalis, Peptostreptococcus or P. serrata.
在一些具體例中,本發明係關於一種治療、預防人類或動物的醫院型感染肺炎/呼吸器相關肺炎或減低其風險之方法,其包含以有效量之根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥投予人類或動物,或關於根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造供治療、預防醫院型感染肺炎/呼吸器相關肺炎或減低其風險之藥劑的用途,其中醫院型感染肺炎/呼吸器相關肺炎係由於肺炎鏈球菌(青黴素敏感性及抗藥性分離物)、金黃色葡萄球菌(二甲苯青黴素敏感性及抗藥性分離物)、克雷伯氏肺炎桿菌、綠膿桿菌(Pseudomonas aeruginosa)、不動桿菌屬(Acinetobacter spp.)、嗜麥芽窄食單胞菌(Stenotrophomonas maltophilia)、流感嗜血桿菌(包括β-內醯胺酶陽性分離物)或肺炎退伍軍人菌(Legionella pneumophila)。 In some embodiments, the invention relates to a method of treating, preventing, or reducing the risk of hospital-type pneumonia/respirator-associated pneumonia in a human or animal, comprising an effective amount according to formulas I, II, III, IV, a compound of V, Ia, IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, administered to a human or animal, or in accordance with Formulas I, II, III, IV, a compound of V, Ia, IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, for the manufacture or prevention of hospital-type pneumonia/respirator-associated pneumonia or for reducing it The use of drugs for risk, in which hospital-type pneumonia/respirator-associated pneumonia is due to Streptococcus pneumoniae (penicillin-sensitive and drug-resistant isolates), Staphylococcus aureus (xylene penicillin-sensitive and drug-resistant isolates), grams Pseudomonas aeruginosa, Pseudomonas aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia, Haemophilus influenzae (including β-endoprostase-positive separation) ) Or pneumonia Legionnaires bacteria (Legionella pneumophila).
在一些具體例中,本發明係關於一種治療、預防人類 或動物的與好氧性革蘭氏陽性微生物有關的微生物感染或減低其風險之方法,其包含以有效量之根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥投予人類或動物,或關於根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造供治療、預防與好氧性革蘭氏陽性微生物有關的微生物感染或減低其風險之藥劑的用途,其中好氧性革蘭氏陽性微生物係選自:金黃色葡萄球菌(二甲苯青黴素敏感性及抗藥性分離物)、肺炎鏈球菌(青黴素敏感性及抗藥性分離物)、腸球菌屬(萬古黴素敏感性及抗藥性分離物)、無乳鏈球菌、化膿性鏈球菌或上皮葡萄球菌(Staphylococcus epidermidis)(二甲苯青黴素敏感性及抗藥性分離物)。 In some embodiments, the invention relates to a method of treating and preventing humans Or a method of infecting or reducing the risk of an animal associated with an aerobic Gram-positive microorganism, comprising an effective amount according to formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, administered to a human or animal, or in accordance with Formula I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va Use of a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, for the manufacture of a medicament for the treatment or prevention of a microbial infection associated with or associated with aerobic Gram-positive microorganisms, wherein Aerobic Gram-positive microorganisms are selected from the group consisting of: Staphylococcus aureus (xylene penicillin-sensitive and drug-resistant isolates), Streptococcus pneumoniae (penicillin-sensitive and drug-resistant isolates), Enterococcus (vancomycin) Sensitive and drug-resistant isolates, Streptococcus agalactiae, Streptococcus pyogenes or Staphylococcus epidermidis (xylylene penicillin-sensitive and drug-resistant isolates).
在一些具體例中,本發明係關於一種治療、預防人類或動物的與好氧性革蘭氏陰性微生物有關的微生物感染或減低其風險之方法,其包含以有效量之根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥投予人類或動物,或關於根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造供治療、預防與好氧性革蘭氏陰性微生物有關的微生物感染或減低其風險之藥劑的用途,其中好氧性革蘭氏陰性微生物係選自:大腸桿菌(包括ESBL 及KPC產生之分離物)、流感嗜血桿菌(包括β-內醯胺酶陽性分離物)、克雷伯氏肺炎桿菌(包括ESBL及KPC產生之分離物)、弗氏檸檬酸桿菌(Citrobacter freundii)、產氣腸桿菌(Enterobacter aerogenes)、陰溝腸桿菌(Enterobacter cloacae)、摩氏摩根菌(Morganella morganii)、沙雷氏桿菌(Serratia marcescens)、綠膿桿菌、鮑氏不動桿菌(Acinetobacter baumannii)、卡他莫拉菌、奇異變型桿菌、克氏檸檬酸桿菌(Citrobacter koseri)、副流感嗜血桿菌(Haemophilus parainfluenzae)、產酸克雷伯士菌(Klebsiella oxytoca)(包括ESBL及KPC產生之分離物)、普通變形桿菌(Proteus vulgaris)、雷氏普羅威登斯菌(Providencia rettgeri)或普羅非登斯菌(Providencia stuartii)。 In some embodiments, the present invention relates to a method of treating, preventing, or reducing the risk of a microbial infection associated with an aerobic Gram-negative microorganism in a human or animal, comprising an effective amount according to Formulas I, II, a compound of III, IV, V, Ia, IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, administered to a human or animal, or according to formulas I, II, a compound of III, IV, V, Ia, IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, for the manufacture, prevention and aerobic Gram negative The use of microorganism-related microbial infections or agents for reducing the risk thereof, wherein the aerobic Gram-negative microorganisms are selected from the group consisting of Escherichia coli (including ESBL and KPC-derived isolates), Haemophilus influenzae (including β -endogenous sputum) Amino acid-positive isolates, Klebsiella pneumoniae (including isolates produced by ESBL and KPC), Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae Morganella morganii Rganella morganii), Serratia marcescens, Pseudomonas aeruginosa, Acinetobacter baumannii, Moraxella catarrhalis, Phytophthora bacillus, Citrobacter koseri, parainfluenza Haemophilus parainfluenzae, Klebsiella oxytoca (including ESBL and KPC-derived isolates), Proteus vulgaris, Providencia rettgeri or Profolia Providencia stuartii.
在一些具體例中,本發明係關於一種治療、預防人類或動物的與厭氧性微生物有關的微生物感染或減低其風險之方法,其包含以有效量之根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥投予人類或動物,或關於根據式I、II、III、IV、V、Ia、IIa、IIIa、IVa或Va之化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造供治療、預防與厭氧性微生物有關的微生物感染或減低其風險之藥劑的用途,其中厭氧性微生物係選自:脆弱擬桿菌、狄氏擬桿菌、卵形擬桿菌、多形擬桿菌、單形擬桿菌、梭狀梭菌、遲緩真桿菌、消化鏈球菌屬、不解糖卟啉單胞菌、二路普雷沃爾菌、普通擬桿菌(Bacteroides vulgates)、產氣莢膜桿菌或梭桿菌屬(Fusobacterium spp)。 In some embodiments, the present invention relates to a method of treating, preventing, or reducing the risk of a microbial infection associated with an anaerobic microorganism in a human or animal, comprising an effective amount according to Formulas I, II, III, IV, a compound of V, Ia, IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, administered to a human or animal, or in accordance with Formulas I, II, III, IV, a compound of V, Ia, IIa, IIIa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, for the manufacture or prevention of microbial infection associated with anaerobic microorganisms or for reducing thereof The use of a medicament for risk, wherein the anaerobic microorganism is selected from the group consisting of: Bacteroides fragilis, Bacteroides diarrhii, Bacteroides ovum, Bacteroides variabilis, Bacteroides bisporus, Clostridium fusiformis, Lactobacillus retardi, digestive chain Coccus, P. sylvestris, P. vivi, Bacteroides Vulgates), Clostridium perfringens or Fusobacterium spp.
在一些具體例中,本發明係關於一種合成本發明化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥之方法。 In some embodiments, the invention relates to a method of synthesizing a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof.
在一些具體例中,本發明係關於一種含有本發明化合物,或其醫藥上可接受之鹽、酯、互變異構物或前藥之醫學裝置。 In some embodiments, the invention relates to a medical device comprising a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof.
在一些具體例中,本發明係關於一種含有本發明化合物之醫學裝置,其中裝置為血管支架。 In some embodiments, the invention is directed to a medical device comprising a compound of the invention, wherein the device is a vascular stent.
本發明提供用於製造本發明化合物之方法。下列流程1b-5b-描述用於合成本發明化合物的概括來說之示例途徑。更特殊的化學細節提供於實例中。 The invention provides methods for making the compounds of the invention. The following Schemes 1b-5b - describe exemplary pathways for the synthesis of the compounds of the invention. More specific chemical details are provided in the examples.
以上述方法設計、選擇及/或最優化之化合物在一經生產時可使用那些熟諳本技藝者已知的各種檢定法特徵化,以測定化合物是否具有生物活性。例如,可將分子以包括(但不限於此)那些下述檢定法的習知檢定法特徵化,以測定該等分子是否具有預期的活性、結合活性及/或結合特異性。 Compounds designed, selected, and/or optimized in the manner described above can be characterized, upon production, using various assays known to those skilled in the art to determine whether a compound is biologically active. For example, molecules can be characterized by conventional assays including, but not limited to, those assays described below to determine whether such molecules have the desired activity, binding activity, and/or binding specificity.
此外,可使用高產出量篩選加速使用此等檢定法之分析。結果有可能快速篩選本文所述之分子作為例如抗癌症、抗細菌、抗真菌、抗寄生蟲或抗病毒劑之活性。亦有可能使用本技藝中已知的技術檢定化合物如何與核糖體或核糖體次單元交互作用及/或有效作為蛋白質合成之調節劑(例如,抑制劑)。用於執行高產出量篩選的通用方法說 明於例如Devlin(1998)High Throughput Screening,Marcel Dekker;及美國專利第5,763,263號中。高產出量檢定法可使用一或多種不同的檢定技術,包括(但不限於此)那些下述者。 In addition, high throughput screening can be used to speed up the analysis using these assays. As a result, it is possible to rapidly screen the molecules described herein as, for example, anti-cancer, anti-bacterial, anti-fungal, anti-parasitic or anti-viral agents. It is also possible to characterize how a compound interacts with a ribosome or ribosome subunit and/or is effective as a modulator of protein synthesis (e.g., an inhibitor) using techniques known in the art. General method for performing high throughput screening See, for example, Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High throughput assays may use one or more different assay techniques including, but not limited to, those described below.
(1)表面結合研究。各種結合檢定法可用於篩選新型分子的其結合活性。一種方法包括表面電漿子共振(SPR),可使用其評估關注之分子與有關的核糖體、核糖體次單元或其片段之結合性質。 (1) Surface binding studies. Various binding assays can be used to screen for the binding activity of novel molecules. One method includes surface plasmon resonance (SPR), which can be used to assess the binding properties of a molecule of interest to an associated ribosome, ribosome subunit or fragment thereof.
SPR方法係在即時經由量子-機械表面電漿子的產生來測量在二或多種巨分子間的交互作用。一種裝置(來自Pharmacia Biosensor,Piscatawy,N.J.之BIAcore Biosensor RTM)提供多色光之聚焦光束至金膜(提供作為可棄式生物感應器"晶片")與緩衝間隔(可由使用者調整)之間的界面。由提供關注之分析物共價固定的基質之羧基化聚葡萄糖所組成的100奈米厚"水凝膠"與金膜連接。當聚焦光與金膜的游離電子團交互作用時,則增強電漿子共振。使所得反射光於光譜上耗損波長,最優化地釋放出共振。藉由分離反射之多色光成為其組份波長(利用稜鏡)且測定經耗損之頻率,以BIAcore建立光學界面,其精確地記述所產生之表面電漿子共振表現。當設計係如上所述時,則電漿子共振(且因此耗損光譜)對逐漸消失區域(其大致相對應於水凝膠的厚度)之質量具敏感性。若交互作用配對的一種組份係固定至水凝膠,且交互作用夥伴係經由緩衝間隔提供,則在兩種組份之間的交互作用可以在逐漸消失區域中的質 量累積及其相對應之電漿子共振效應(如以耗損光譜所測量)為基準即時測量。此系統容許快速且敏感的分子交互作用即時測量,不需要標記任一種組份。 The SPR method measures the interaction between two or more macromolecules in real time via the generation of quantum-mechanical surface plasmons. A device (BIAcore Biosensor RTM from Pharmacia Biosensor, Piscatawy, NJ) provides an interface between a focused beam of polychromatic light to a gold film (provided as a disposable biosensor "wafer") and a buffer interval (adjustable by the user) . A 100 nm thick "hydrogel" consisting of carboxylated polydextrose, a substrate that provides a covalently immobilized analyte of interest, is attached to the gold film. When the focused light interacts with the free electron cluster of the gold film, the plasmon resonance is enhanced. The resulting reflected light is spectrally depleted in wavelength, and the resonance is optimally released. By separating the reflected polychromatic light into its component wavelength (using 稜鏡) and measuring the frequency of the loss, an optical interface is established with BIAcore, which accurately describes the surface plasmon resonance performance produced. When the design is as described above, the plasmon resonance (and therefore the loss spectrum) is sensitive to the quality of the fading region, which roughly corresponds to the thickness of the hydrogel. If one component of the interaction pair is immobilized to the hydrogel and the interaction partner is provided via a buffer interval, the interaction between the two components can be qualitative in the fading region The amount of accumulation and its corresponding plasmon resonance effect (as measured by the loss spectrum) are measured instantaneously. This system allows for fast and sensitive molecular interactions to be measured in real time without the need to label any of the components.
(2)螢光極化。螢光極化(FP)為一種可輕易地應用於蛋白質-蛋白質、蛋白質-配位體或RNA-配位體交互作用之測量技術,俾以導出兩種分子之間的聯合反應之IC50及Kd。在此技術中,將關注之分子中之一與螢光團共軛。此通常為系統中較小的分子(在此情況中為關注之化合物)。將含有配位體-探針共軛物及核糖體、核糖體次單元或其片段二者之樣品混合物以垂直的極化光激發。光係由探針螢光團吸收,且在短時間之後再發射。測量發射光之極化程度。發射光之極化係取決於許多因素而定,但是最重要在於溶液之黏度及螢光團之視分子量。以適當之控制使發射光之極化程度的變化僅取決於螢光團之視分子量的變化,其依次取決於探針-配位體共軛物是否不存於溶液中,或與受體結合。以FP為基準之結合檢定法具有許多重要的優勢,包括在確實的均相平衡條件下測量IC50及Kd,分析速度與自動化之便利設施,及在混濁懸浮液與有色溶液中的篩選能力。 (2) Fluorescence polarization. Fluorescence polarization (FP) can be readily applied as a protein - protein, protein - Measurement RNA- ligand or ligands that interact, serve to derive IC joint reaction between two molecules of 50 and Kd. In this technique, one of the molecules of interest is conjugated to a fluorophore. This is usually the smaller molecule in the system (in this case the compound of interest). A sample mixture containing both a ligand-probe conjugate and a ribosome, ribosome subunit or a fragment thereof is excited with vertical polarized light. The light system is absorbed by the probe fluorophore and re-emitted after a short time. The degree of polarization of the emitted light is measured. The polarization of the emitted light depends on many factors, but the most important is the viscosity of the solution and the apparent molecular weight of the fluorophore. The change in the degree of polarization of the emitted light with appropriate control depends only on the change in the apparent molecular weight of the fluorophore, which in turn depends on whether the probe-ligand conjugate is not present in solution or binds to the receptor. . The FP-based binding assay has a number of important advantages, including IC 50 and Kd measurement under realistic homogeneous equilibrium conditions, analytical speed and automation facilities, and screening capabilities in turbid suspensions and colored solutions.
(3)蛋白質合成。除了以前述的生化檢定法特徵化以外,預期關注之化合物亦可以核糖體或核糖體次單元之功能活性的調節劑(例如,蛋白質合成抑制劑)特徵化。 (3) Protein synthesis. In addition to being characterized by the aforementioned biochemical assays, compounds of interest are also characterized by modulators of functional activity of ribosomes or ribosomal subunits (eg, protein synthesis inhibitors).
此外,更特殊的蛋白質合成抑制檢定法的執行可藉由將化合物投予整個有機體、組織、器官、細胞器、細胞、 細胞或次細胞萃取物、或純化之核糖體製劑且藉由測定例如其抑制蛋白質合成之抑制常數(IC50)來觀察其藥理及抑制性質。可執行併入3H白胺酸或35S甲硫胺酸或類似的實驗來研究蛋白質合成活性。在關注之分子存在下的細胞中之蛋白質合成量或速度的變化表明分子為蛋白質合成調節劑。蛋白質合成速度及量的減少表明分子為蛋白質合成抑制劑。 In addition, more specific protein synthesis inhibition assays can be performed by administering the compound to an entire organism, tissue, organ, organelle, cell, cell or subcellular extract, or purified ribosome preparation and by measuring, for example, The inhibitory constant (IC 50 ) of protein synthesis was inhibited to observe its pharmacological and inhibitory properties. Incorporation of 3 H leucine or 35 S methionine or similar experiments can be performed to study protein synthesis activity. A change in the amount or rate of protein synthesis in a cell in the presence of a molecule of interest indicates that the molecule is a protein synthesis regulator. A decrease in the rate and amount of protein synthesis indicates that the molecule is a protein synthesis inhibitor.
(4)抗微生物檢定法及其他評估。此外,可以細胞水平檢定化合物的抗增殖或抗感染性質。例如,當目標有機體為微生物時,關注之化合物活性可藉由關注之微生物在含有或缺少化合物之培養基中的生長來檢定。生長抑制可表示分子可作為蛋白質合成抑制劑起作用。更特別地,關注之化合物對抗細菌病原體的活性可藉由化合物抑制限定之人類病原體菌株生長的能力來證明。就此目的而言,可將細菌株培養盤聚集,以包括各種目標病原體物種,一些含有已特徵化之抗藥機制。使用此有機體培養盤容許不僅關於效力及光譜,且亦以排除抗藥機制之觀點來測定結構-活性關係。 (4) Antimicrobial assays and other assessments. In addition, the anti-proliferative or anti-infective properties of the compounds can be assayed at the cellular level. For example, when the target organism is a microorganism, the activity of the compound of interest can be assayed by growth of the microorganism of interest in a medium containing or lacking the compound. Growth inhibition can indicate that the molecule acts as a protein synthesis inhibitor. More particularly, the activity of a compound of interest against a bacterial pathogen can be demonstrated by the ability of the compound to inhibit the growth of a defined human pathogen strain. For this purpose, bacterial strain plates can be aggregated to include a variety of target pathogen species, some containing a characteristic drug resistance mechanism. The use of this organism culture plate allows for the determination of structure-activity relationships not only with respect to potency and spectroscopy, but also with the exclusion of drug resistance mechanisms.
最小抑制濃度(MIC)係根據臨床及實驗室標準協會(Clinical and Laboratory Standards Institute)[CLSI;以前為美國臨床實驗室標準委員會(National Committee for Clinical Laboratory Standards(NCCLS)]所概述之模式以微稀釋法測定,典型係以100微升之最終體積。參見CLSI:Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically;approved standard-fifth edition.Wayne,PA;NCCLS;2000。檢定法亦可根據由CLSI所發表之習知方法於微滴定盤中執行。參見CLSI:Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically;Approved Standard-Seventh Edition.CLSI Document M7-A7[ISBN 1-56238-587-9]CLSI,940 West Valley Road,Suite 1400,Wayne Pennsylvania 19087-1898 USA,2006)。 The minimum inhibitory concentration (MIC) is microdilution according to the model outlined by the Clinical and Laboratory Standards Institute [CLSI; formerly the National Committee for Clinical Laboratory Standards (NCCLS)]. Determined by the method, typically in a final volume of 100 μl. See CLSI: Methods for dilution antimicrobial susceptibility Tests for bacteria that grow aerobically;approved standard-fifth edition.Wayne,PA;NCCLS;2000. The assay can also be performed in a microtiter plate according to conventional methods published by CLSI. See CLSI: Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Seventh Edition. CLSI Document M7-A7[ISBN 1-56238-587-9] CLSI, 940 West Valley Road, Suite 1400, Wayne Pennsylvania 19087- 1898 USA, 2006).
化合物的抗微生物及其他藥物性質可在各種活體內哺乳動物檢定法中進一步評估,諸如小鼠或兔腹膜炎感染模式、皮膚與軟骨組織模式(常被稱為大腿模式)或小鼠肺炎模式。有那些熟諳本技藝者已知的敗血症或器官感染模式。該等效力模式可用作為評估方法的一部分且可用作為在人類中的潛在效力之指南。端點可從減少細菌量改變至殺傷率。就後者的終點而言,結果常以PD50值或防護50%之動物免於死亡之藥物劑量表示。 The antimicrobial and other pharmaceutical properties of the compounds can be further evaluated in various in vivo mammalian assays, such as mouse or rabbit peritonitis infection patterns, skin and cartilage tissue patterns (often referred to as thigh patterns) or mouse pneumonia patterns. There are those patterns of sepsis or organ infection known to those skilled in the art. These modes of effectiveness can be used as part of the assessment method and can be used as a guide to potential efficacy in humans. The endpoint can change from reducing the amount of bacteria to killing rate. For the latter endpoint, the results are often expressed as PD 50 values or drug doses that protect 50% of animals from death.
為了進一步評定化合物的似藥物性質,亦可使用重組的人類酵素系統或更複雜的系統(如人類肝微粒體)測量細胞色素P450酵素及第II期代謝酵素活性之抑制量度。再者,亦可就化合物作為該等代謝酵素活性之基質予以評定。該等活性有用於測定化合物引起藥物-藥物交互作用或產生保留或不具有用的抗微生物活性之代謝物的潛力。 To further assess the drug-like nature of the compound, recombinant human enzyme systems or more complex systems (such as human liver microsomes) can also be used to measure inhibition of cytochrome P450 enzyme and phase II metabolic enzyme activity. Furthermore, the compounds can also be evaluated as a substrate for the activity of such metabolic enzymes. Such activities have the potential to be used to determine whether a compound causes a drug-drug interaction or produces a metabolite with or without useful antimicrobial activity.
為了得到化合物對口服生物利用率的潛在性評估,亦可執行溶解度及Caco-2檢定法。後者為來自人類上皮的 細胞株,其允許測量穿過常在配備有1微米薄膜的24槽孔微滴定盤之槽孔內生長之Caco-2細胞單層的藥物攝取及通過。可在單層的底側面上測量游離藥物濃度,以評定可通過腸單層的藥物量。有必要適當的控制,以確保單層完整性及裂隙接點的緊密性。可使用此相同的系統得到以P-糖蛋白質介導之流出量的評估。P-糖蛋白質為局限至細胞頂膜的幫浦,形成極化單層。此幫浦可取消跨越Caco-2細胞膜的主動或被動攝取,造成較少的藥物通過腸上皮層。該等結果常與溶解度測量一起進行且已知該兩種因素促成在哺乳動物中的口服生物利用率。使用傳統的藥物動力學實驗在動物及最終在人類中的口服生物利用率之測量係測定絕對口服生物利用率。 Solubility and Caco-2 assays can also be performed in order to obtain a potential assessment of the compound's bioavailability. The latter is from the human epithelium A cell line that allows for the measurement of drug uptake and passage of a Caco-2 cell monolayer grown through a well that is often in a 24-well microtiter plate equipped with a 1 micron membrane. The free drug concentration can be measured on the bottom side of the monolayer to assess the amount of drug that can pass through the intestinal monolayer. Appropriate control is necessary to ensure single layer integrity and tightness of the crack joints. This same system can be used to obtain an assessment of P-glycoprotein mediated outflow. The P-glycoprotein is a pump that is localized to the cell's apical membrane, forming a polarized monolayer. This pump can eliminate active or passive uptake across the Caco-2 cell membrane, resulting in less drug passing through the intestinal epithelium. These results are often performed along with solubility measurements and these two factors are known to contribute to oral bioavailability in mammals. Absolute oral bioavailability was determined using conventional pharmacokinetic experiments in the measurement of oral bioavailability in animals and ultimately in humans.
亦可使用實驗結果發展有助於預測促成似藥物性質之物理-化學參數的模式。當此模式經證明屬實時,可歸納出實驗方法,增加對模式可預測性的可信度。 Experimental results can also be used to develop patterns that help predict physico-chemical parameters that contribute to drug-like properties. When this model proves to be real-time, the experimental method can be summarized to increase the credibility of the model predictability.
本發明化合物可用於預防或治療各種人類或其他動物(包括哺乳動物及非哺乳動物)之病症,包括例如細菌感染、真菌感染、病毒感染、腹瀉、寄生蟲疾病及癌症。一經鑑證時,預期本發明的活性分子可在使用之前併入任何適當的載劑中。活性分子的劑量、投予模式及適合的載劑使用係取決於意欲之接受者及目標有機體而定。根據本發明的化合物之調配物(用於獸醫學及人類醫學二者)典型地 包括與醫藥上可接受之載劑結合的此等化合物。 The compounds of the invention are useful in the prevention or treatment of a variety of conditions in humans or other animals, including mammals and non-mammals, including, for example, bacterial infections, fungal infections, viral infections, diarrhea, parasitic diseases, and cancer. Upon verification, it is contemplated that the active molecules of the invention can be incorporated into any suitable carrier prior to use. The dosage of the active molecule, the mode of administration, and the proper carrier use will depend on the intended recipient and the target organism. Formulations of compounds according to the invention (for both veterinary and human medicine) typically These compounds are included in combination with a pharmaceutically acceptable carrier.
載劑應為"可接受之",具有與調配物的其他成分可相容且不對接受者有害之意義。關於此點,醫藥上可接受之載劑意欲包括與醫藥投予可相容的任何及所有的溶劑、分散介質、包膜、抗細菌與抗真菌劑、等張與吸收延遲劑及類似物。用於醫藥活性物質的此等介質及劑為本技藝中已知。除了在任何習知的介質或劑與活性化合物不可相容的範圍以外,可預期其他在組成物中的用途。亦可將補充的活性化合物(根據本發明及/或在本技藝中已知的經鑑證或經設計者)併入組成物中。調配物可方便以單位劑型呈現且可以藥學/微生物學技藝中熟知的任何方法製備。通常一些調配物可藉由將化合物與液體載劑或細碎的固體載劑或與二者達成結合且接著若必要時將產物定形成所欲調配物而製備。 The carrier should be "acceptable" and have the meaning of being compatible with the other ingredients of the formulation and not deleterious to the recipient. In this regard, pharmaceutically acceptable carriers are intended to include any and all solvents, dispersion media, capsules, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are compatible with pharmaceutical administration. Such media and agents for pharmaceutically active substances are known in the art. Other uses in the composition are contemplated, except in the range in which any conventional medium or agent is incompatible with the active compound. Supplementary active compounds (in accordance with the invention and/or certified or designer known in the art) may also be incorporated into the compositions. Formulations may be conveniently presented in unit dosage form and may be prepared by any methods known in the pharmacy/microbiology art. Generally, some formulations may be prepared by combining the compound with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, formulating the product to the desired formulation.
應將本發明的醫藥組成物調配成與其意欲之投予途徑可相容。投予途徑的實例包括經口、耳、眼、鼻或非經腸(例如,靜脈內、皮膚內、吸入、穿透皮膚(局部)、穿透黏膜及直腸)投予。用於非經腸、皮膚內或皮下施予之溶液或懸浮液可包括下列組份:無菌稀釋劑,諸如注射用水、食鹽水溶液、固定油、聚乙二醇、甘油、丙二醇或其他合成溶劑;抗細菌劑,諸如苄醇或對羥基苯甲酸甲酯;抗氧化劑,諸如抗壞血酸或亞硫酸氫鈉;螯合劑,諸如乙二胺四乙酸;緩衝劑,諸如乙酸鹽、檸檬酸鹽或磷酸鹽,及張力調節劑,諸如氯化鈉或葡萄糖。pH可以酸或鹼調整, 諸如鹽酸或氫氧化鈉。 The pharmaceutical compositions of the present invention should be formulated to be compatible with the intended route of administration. Examples of routes of administration include oral, otic, ocular, nasal or parenteral (e.g., intravenous, intradermal, inhalation, penetration through the skin (topical), penetrating mucosa, and rectal administration). Solutions or suspensions for parenteral, intradermal or subcutaneous administration may include the following ingredients: sterile diluents, such as water for injection, aqueous saline, fixed oil, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents; An antibacterial agent such as benzyl alcohol or methylparaben; an antioxidant such as ascorbic acid or sodium hydrogen sulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetate, citrate or phosphate, And a tonicity modifier such as sodium chloride or glucose. pH can be adjusted by acid or alkali, Such as hydrochloric acid or sodium hydroxide.
有用於經口或非經腸投予之溶液可以醫藥技藝中熟知的任何方法製備,例如在Remington’s Pharmaceutical Sciences,(Gennaro,A.,ed.),Mack Pub.,(1990)中所描。用於非經腸投予之調配物亦可包括用於頰內投予之甘膽酸鹽、用於直腸投予之甲氧基水楊酸鹽或用於***投予之檸檬酸。非經腸製劑可封裝於玻璃或塑膠所製成之安瓶、可棄式注射器或多劑小瓶中。用於直腸投予之栓劑可藉由將藥物與無刺激性賦形劑(諸如在室溫下為固體及在體溫下為液體之可可奶油、其他甘油酯或其他組成物)混合而製備。調配物亦可包括例如聚伸烷二醇(諸如聚乙二醇)、蔬菜來源之油類及氫化萘。用於直接投予之調配物可包括甘油及其他高黏度組成物。其他潛在有用於該等藥物的非經腸載劑包括乙烯-乙酸乙烯酯共聚物粒子、滲透幫浦、可植入之灌注系統及脂質體。用於吸入投予之調配物可含有如賦形劑(例如,乳糖),或可為含有例如聚氧基伸乙基-9-月桂醚、甘膽酸鹽及去氧膽酸鹽之水溶液,或以鼻滴劑形式投予之油性溶液,或為經鼻內塗抹之凝膠。留滯型灌腸劑亦可用於直腸輸送。 Solutions for oral or parenteral administration can be prepared by any of the methods well known in the art, for example, as described in Remington's Pharmaceutical Sciences, (Gennaro, A., ed.), Mack Pub., (1990). Formulations for parenteral administration may also include glycocholate for buccal administration, methoxysalicylate for rectal administration or citric acid for vaginal administration. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Suppositories for rectal administration can be prepared by mixing the drug with non-irritating excipients such as cocoa butter, other glycerides or other compositions which are solid at room temperature and liquid at body temperature. Formulations may also include, for example, polyalkylene glycols (such as polyethylene glycol), vegetable derived oils, and hydrogenated naphthalenes. Formulations for direct administration may include glycerin and other high viscosity compositions. Other parenteral vehicles potentially useful for such drugs include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable perfusion systems, and liposomes. The formulation for administration by inhalation may contain, for example, an excipient (for example, lactose), or may be an aqueous solution containing, for example, polyoxyethylidene-9-lauryl ether, glycocholate, and deoxycholate, or An oily solution administered as a nasal drop, or a gel applied intranasally. A stagnation enema can also be used for rectal delivery.
適合於口服投於予之本發明調配物可呈以下形式:分立單位,諸如膠囊、明膠膠囊、小藥囊、錠劑、菱形錠或喉糖錠,每個含有預定量之藥物;粉末或顆粒組成物;在水性液體或非水性液體中的溶液或懸浮液;或油水型乳液或水油型乳液。藥物亦可以大藥丸、糖果劑或糊劑形式投 予。錠劑可藉由將藥物隨意地與一或種多種附屬成分壓縮或模製而製得。經壓縮之錠劑可藉由將呈自由流動形式之藥物(諸如粉末或顆粒)在適合的機器中壓縮且隨意地與黏合劑、潤滑劑、惰性稀釋劑、表面活性或分散劑混合而製備。經模製之錠劑可藉由將粉末狀藥物與以惰性液體稀釋劑弄濕之適合的載劑之混合物在適合的機器中模製而製得。 Formulations of the invention suitable for oral administration can be in the form of discrete units such as capsules, gelatin capsules, sachets, lozenges, lozenges or lozenges, each containing a predetermined amount of the drug; powder or granules a composition; a solution or suspension in an aqueous liquid or a non-aqueous liquid; or an oil-water emulsion or a water-oil emulsion. The drug can also be administered in the form of a large pill, candy or paste. Give. Tablets can be prepared by compressing or molding the drug with one or more accessory ingredients. Compressed lozenges can be prepared by compressing, in a suitable machine, a drug (such as a powder or granules) in a free-flowing form, and optionally admixed with a binder, lubricant, inert diluent, surface active or dispersing agent. The molded lozenge can be prepared by molding a mixture of the powdered medicament with a suitable carrier which is moistened with an inert liquid diluent in a suitable machine.
口服組成物通常包括惰性稀釋劑或可食用載劑。以口服治療投予為的目,可將活性化合物與賦形劑合併。使用液體載劑所製備而用作為漱口水之口服組成物包括在流體載劑中的化合物,且經口施予,並漱口且吐出或吞下。醫藥上可相容之黏合劑及/或佐劑材料可包括為組成物的一部分。錠劑、丸劑、膠囊、菱形錠及類似物可含有任何下列成分或類似本性之化合物:黏合劑,諸如微結晶纖維素、黃蓍膠或明膠;賦形劑,諸如澱粉或乳糖;崩散劑,諸如藻酸、普姆膠(Primogel)或玉米澱粉;潤滑劑,諸如硬脂酸鎂或史特羅(Sterotes);助滑劑,諸如膠體二氧化矽;甜味劑,諸如蔗糖或糖精;或調味劑,諸如薄荷、水楊酸甲酯或柳橙口味。 Oral compositions typically include an inert diluent or an edible carrier. The active compound can be combined with excipients for the purpose of oral administration. An oral composition prepared as a mouthwash using a liquid carrier is included in a fluid carrier and administered orally, and rinsed and spit or swallowed. Pharmaceutically compatible adhesives and/or adjuvant materials can be included as part of the composition. Tablets, pills, capsules, diamonds and the like may contain any of the following ingredients or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth or gelatin; excipients such as starch or lactose; disintegrating agents, Such as alginic acid, Primogel or corn starch; lubricants such as magnesium stearate or Strotes; slip agents such as colloidal cerium oxide; sweeteners such as sucrose or saccharin; Flavoring agents such as mint, methyl salicylate or orange flavor.
適合於注射使用的醫藥組成物包括無菌水性溶液(於此可溶於水)或分散液及即席製備無菌可注射溶液或分散液的無菌粉末。適合於靜脈內投予的載劑包括生理食鹽水、制菌水、Cremophor ELTM(BASF,Parsippany,N.J.)或磷酸鹽緩衝食鹽水(PBS)。其在製造及貯存條件下應該為 穩定的且應該以對抗微生物(諸如細菌和真菌)的污染作用予以保存。載劑可為含有例如水、乙醇、多元醇(例如,甘油、丙二醇及液體聚乙二醇)及其適合的混合物之溶劑或分散介質。適當的流動性可例如藉由使用包膜(諸如卵磷脂),藉由在分散液的情況中維持必需的粒徑及藉由使用界面活性劑來維持。在許多情況中,較佳的是在組成物中包括等張劑(例如,糖)、多元醇(諸如甘露醇、山梨醇)或氯化鈉。延長可注射組成物的吸收可藉由在組成物中包括延遲吸收之劑而引起,例如單硬脂酸鋁及明膠。 Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (wherein water soluble) or dispersions and sterile powders in the preparation of sterile injectable solutions or dispersions. Carriers suitable for intravenous administration include physiological saline, bacteriostatic water, Cremophor EL (TM) (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of an envelope such as lecithin, by the maintenance of the necessary particle size in the case of dispersions and by the use of surfactants. In many cases, it is preferred to include an isotonic agent (e.g., a sugar), a polyhydric alcohol (such as mannitol, sorbitol), or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by the inclusion of agents which delay absorption in the compositions, such as aluminum monostearate and gelatin.
無菌可注射溶液可藉由將活性化合物以必需的量與若必需時的上述列舉之成分中之一或其組合併入適當的溶劑中及接著過濾滅菌而製備。通常分散液係藉由將活性化合物併入含有基本分散介質及來自那些上述列舉之必需的其他成分的無菌媒劑中而製備。在用於製備無菌可注射溶液之無菌粉末的情況中,製備方法包括真空乾燥及凍乾,得到活性成分加上來自先前其經無菌過濾之溶液的任何額外所欲成分之粉末。 Sterile injectable solutions can be prepared by incorporating the active compound in the required amount, together with one or a combination thereof, if necessary, in a suitable solvent, followed by filtration sterilization. Generally, the dispersion is prepared by incorporating the active compound into a sterile vehicle containing the base dispersion medium and the other ingredients necessary from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation comprises vacuum drying and lyophilization yielding the active ingredient plus a powder of any additional desired ingredient from a previously sterile filtered solution thereof.
適合於關節內投予之調配物可呈藥物的無菌水性製劑形式,其可呈微結晶形式,例如呈水性微結晶懸浮液形式。亦可使用脂質體調配物或可生物降解之聚合物系統,以提供用於關節內及眼部投予二者之藥物。 Formulations suitable for intra-articular administration may be in the form of a sterile aqueous preparation of the drug, which may be in a microcrystalline form, for example in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems can also be used to provide drugs for both intra-articular and ocular administration.
適合於局部投予(包括眼部治療)之調配物包括液體或半液體製劑,諸如擦劑、洗劑、凝膠、敷劑、油水型或水油型乳液(諸如乳霜、軟膏或糊劑);或溶液或懸浮液(諸如 滴劑)。用於局部投予皮膚表面之調配物可藉由將藥物以皮膚學上可接受之載劑(諸如洗劑、乳霜、軟膏或肥皂)分散而製備。特別有用的載劑為能夠在皮膚上形成膜或層之載劑,以局限施予且禁止移除。可將用於局部投予內部組織表面之劑分散在液體組織黏著劑或已知的其他物質中,以增強吸附至組織表面。例如,可有利於使用羥丙基纖維素或纖維蛋白原/凝血酶溶液。或者可使用組織塗佈溶液,諸如含果膠之調配物。 Formulations suitable for topical administration, including ocular treatment, include liquid or semi-liquid preparations such as liniments, lotions, gels, dressings, oil-water or water-oil emulsions (such as creams, ointments or pastes). ); or a solution or suspension (such as Drops). Formulations for topical administration to the skin surface can be prepared by dispersing the drug in a dermatologically acceptable carrier such as lotion, cream, ointment or soap. A particularly useful carrier is a carrier capable of forming a film or layer on the skin for limited administration and forbidden removal. The agent for topical administration of the internal tissue surface can be dispersed in a liquid tissue adhesive or other known substance to enhance adsorption to the tissue surface. For example, it may be advantageous to use a hydroxypropylcellulose or fibrinogen/thrombin solution. Alternatively, a tissue coating solution, such as a formulation containing pectin, can be used.
可使用以噴霧罐、噴灑器或霧化器配送之粉末吸入(自行-推進或噴霧調配物)用於吸入治療。此等調配物可從粉末吸入裝置或自行-推進粉末-配送調配物而呈用於肺部投予的細粉末形式。在自行-推進溶液及噴霧調配物之情形中,此效果可藉由選擇具有所欲噴霧特徵之閥(亦即能夠產生具有所欲粒徑之噴霧)或藉由併入活性成分作為粒徑受控制之懸浮粉末而達成。以吸入投予之化合物亦可以氣溶膠噴霧形式從含有適合的推進劑(例如,氣體,諸如二氧化碳)或噴灑劑之加壓容器或配送器輸送。 Powder inhalation (self-propelled or spray formulations) delivered in a spray can, spray or atomizer can be used for inhalation therapy. Such formulations may be in the form of a fine powder for pulmonary administration from a powder inhalation device or a self-propelled powder-delivery formulation. In the case of self-propelled solutions and spray formulations, this effect can be achieved by selecting a valve having the desired spray characteristics (i.e., capable of producing a spray having the desired particle size) or by incorporating the active ingredient as a particle size. This is achieved by controlling the suspension of the powder. The compound administered by inhalation may also be delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant (e.g., a gas such as carbon dioxide) or a spray.
全身性投予亦可以穿透黏膜或穿透皮膚的方式。以適合於穿透障壁的穿透劑用於穿透黏膜或穿透皮膚投予的調配物中。此等穿透劑通常為本技藝中已知,且包括例如用於穿透黏膜投予的清潔劑及膽鹽。穿透黏膜投予可經由使用鼻噴霧劑或栓劑而實現。穿透皮膚投予的活性化合物典型地調配成通常為本技藝中已知的軟膏、油膏、凝膠或乳霜。 Systemic administration can also penetrate the mucous membrane or penetrate the skin. A penetrant suitable for penetrating the barrier is used to penetrate the mucosa or penetrate the skin for administration. Such penetrants are generally known in the art and include, for example, detergents and bile salts for penetrating mucosal administration. Penetrating mucosal administration can be accomplished via the use of nasal sprays or suppositories. The active compound administered through the skin is typically formulated into ointments, salves, gels or creams which are generally known in the art.
活性化合物可以防護化合物免於從身體快速消除的醫藥上可接受之載劑製備,諸如控制釋放調配物,包括植入劑及微囊封輸送系統。可使用可生物降解且可生物相容之聚合物,諸如乙烯乙酸乙烯酯、聚酐、聚乙醇酸、膠原蛋白、聚原酸酯及聚乳酸。此等調配物之備製方法為那些熟諳本技藝者顯而易見。微脂體懸浮液亦可用作為醫藥上可接受之載劑。該等可根據那些熟諳本技藝者已知的方法製備,例如在美國專利案第4,522,811號中所述。 The active compound can be formulated to protect the compound against pharmaceutically acceptable carriers which are rapidly eliminated from the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable and biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. The preparation of such formulations is apparent to those skilled in the art. The liposome suspension can also be used as a pharmaceutically acceptable carrier. Such can be prepared by methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.
口服或非經腸組成物可調配成容易投予且劑量均勻的單位劑型。單位劑型係指適合作為用於欲治療之對象的單一劑量的物理分立單位;每個單位含有與必需之醫藥載劑結合的經計算以產生所欲療效之預定量活性化合物。本發明的單位劑型規格係由且直接取決於活性化合物的獨特特徵及欲達成之特別療效而指定,且取決於在化合用於治療個體的此活性化合物之技藝中的固有限制。此外,投予可為以大藥丸之定期注射,或可從外部儲存器(例如,靜脈注射袋)更連續以靜脈內、肌肉內或腹腔內投予而達成。 The oral or parenteral compositions can be formulated in unit dosage forms for ease of administration and uniformity. Dosage unit form refers to a unit of physically discrete unit suitable as a unit of the subject to be treated; each unit contains a predetermined amount of active compound in association with the required pharmaceutical carrier, which is calculated to produce the desired therapeutic effect. The unit dosage form of the present invention is specified by, and directly dependent on, the particular characteristics of the active compound and the particular <RTIgt; </ RTI> </ RTI> desired effect, and is dependent upon the inherent limitations in the art of compounding the active compound for treating the subject. In addition, the administration may be carried out by regular injection of a large pill, or may be administered continuously, intravenously, intramuscularly or intraperitoneally from an external reservoir (for example, an intravenous bag).
在希望黏附於組織表面處,組成物可包括分散於纖維蛋白原/凝血酶組成物或其他生物黏著劑中的藥物。接著可將化合物塗敷、噴灑或以另外方式塗抹於所欲組織表面。或者藥物可經調配而以例如治療有效量經耳、眼、鼻、非經腸或口投予人類或其他動物,例如該有效量提供適當的藥物濃度至目標組織,經足夠的時間誘發所欲效果。 Where it is desired to adhere to the surface of the tissue, the composition may include a drug dispersed in a fibrinogen/thrombin composition or other bioadhesive. The compound can then be applied, sprayed or otherwise applied to the desired tissue surface. Alternatively, the medicament may be formulated to be administered to a human or other animal by ear, eye, nose, parenteral or oral administration, for example, in a therapeutically effective amount, for example, the effective amount provides an appropriate concentration of the drug to the target tissue, and sufficient time is induced to induce effect.
在活性化合物欲用作為移植程序的一部分時,其可在組織或器官自捐贈者移出之前先提供至欲移植之活組織或器官。可將化合物提供至捐贈宿主。或者或另外,一經自捐贈者移出時,可將器官或活組織放入含有活性化合物的保存溶液中。在所有情況中,可將活性化合物直接投予所欲組織,如藉由注射至組織中,或可使用本文所述及/或本技藝中已知的任何方法及調配物經全身提供,例如藉由耳、眼、鼻、口或非經腸投予。在藥物包含組織或器官保存溶液的一部分時,可有利於使用任何市售可取得的保存溶液。例如,在本技藝中已知的有用溶液包括可林(Collins)溶液、威斯康辛(Wisconsin)溶液、貝爾惹(Belzer)溶液、優可林(Eurocollins)溶液及乳酸化之林格(Ringer)溶液。 Where the active compound is to be used as part of a transplant procedure, it can be provided to the living tissue or organ to be transplanted prior to removal of the tissue or organ from the donor. The compound can be provided to a donor host. Alternatively or additionally, upon removal from the donor, the organ or living tissue can be placed in a preservation solution containing the active compound. In all cases, the active compound can be administered directly to the desired tissue, such as by injection into a tissue, or can be provided systemically, for example, by any of the methods and formulations described herein and/or as known in the art. It is administered by ear, eye, nose, mouth or parenteral. Where the drug comprises a portion of a tissue or organ preservation solution, it may be advantageous to use any commercially available preservation solution. For example, useful solutions known in the art include Collins solution, Wisconsin solution, Belzer solution, Eucollins solution, and lactated Ringer solution.
本發明化合物可藉由將化合物施加在與組織接觸安置的醫學裝置中而直接投予組織所在地。醫學裝置的實例為血管支架,其含有或被塗以一或多種本發明化合物。 The compounds of the invention can be administered directly to the site of the tissue by application of the compound to a medical device placed in contact with the tissue. An example of a medical device is a vascular stent containing or coated with one or more compounds of the invention.
例如,可將活性化合物施加在血管受傷位置的血管支架中。血管支架可以醫藥技術中熟知的任何方法製備。參見例如Fattori,R.and Piva,T.,“Drug-Eluting Stents in Vascular Intervention," Lancet,2003,361,247-249;Morice,M.C.,“A New Era in the Treatment of Coronary Disease?”European Heart Journal,2003,24,209-211;及Toutouzas,K.等人之”Sirolimus-Eluting Stents:A Review of Experimental and Clinical Findings,”Z.Kardiol.,2002, 91(3),49-57。血管支架可由不銹鋼或其他生物可相容之金屬製作,或其可以生物可相容之聚合物製得。活性化合物可與血管支架表面連結,嵌入塗佈在血管支架上的聚合物材料且從該材料釋放,或由塗佈或跨橋血管支架之載劑圍繞且經由該載劑釋放。可使用血管支架投予單一或多重活性化合物至鄰近於血管支架之組織。 For example, the active compound can be applied to a vascular stent at the site of the vessel injury. Vascular stents can be prepared by any method well known in the art of medicinal techniques. See, for example, Fattori, R. and Piva, T., "Drug-Eluting Stents in Vascular Intervention," Lancet, 2003, 361, 247-249; Morice, MC, "A New Era in the Treatment of Coronary Disease?" European Heart Journal, 2003, 24, 209-211; and Toutouzas, K. et al. "Sirolimus-Eluting Stents: A Review of Experimental and Clinical Findings," Z. Kardiol., 2002, 91(3), 49-57. The vascular stent can be made of stainless steel or other biocompatible metal, or it can be made from a biocompatible polymer. The active compound can be attached to the surface of the vascular stent, embedded in and released from the polymeric material coated on the vascular stent, or surrounded by and coated with a carrier that coats or bridges the vascular stent. A single or multiple active compound can be administered to a tissue adjacent to a vascular stent using a vascular stent.
可將如本文所述之方法鑑證且設計之活性化合物可投予個體以治療病症(預防或治療)。可將藥物基因學(亦即研究個體基因型與個體對外來化合物或藥物的反應之間的關係)與此治療一起考慮。治療法的代謝差異可藉由改變藥理活性藥物的劑量與血液濃度之間的關係而造成嚴重的毒性或治療失敗。因此,醫師或臨床醫師可考慮應用在測定是否投予藥物以及修改以藥物治療的劑量及/或治療系統之相關藥物基因學研究中所獲得的知識。 The active compound ascertained and designed as described herein can be administered to an individual to treat the condition (prevention or treatment). The pharmacogenetics (i.e., the relationship between the study of individual genotypes and the response of an individual to a foreign compound or drug) can be considered in conjunction with this treatment. Metabolic differences in therapy can result in severe toxicity or treatment failure by altering the relationship between the dose of the pharmacologically active drug and the blood concentration. Thus, the physician or clinician may consider the knowledge gained in the pharmacology studies of the relevant pharmacology for determining whether to administer the drug and modifying the dose and/or treatment system for the drug treatment.
在治療或對抗哺乳動物中的細菌感染之治療用途中,將化合物或其醫藥組成物以獲得及維持濃度的劑量經耳、眼、鼻、口、非經腸及/或局部投予,亦即該濃度為活性組份在進行治療之動物中的抗微生物有效量或血液或組織水平。活性組份劑量的有效量通常係在從約0.1至約100,更佳為從約1.0至約50毫克/公斤體重/天之範圍內。所投予之量亦同樣取決於諸如欲治療之疾病或徵兆類型和程度、特殊病患的整體健康狀態、所輸送之化合物的相關生物效力、藥物的調配、調配物中的賦形劑存在和類型及投予途徑之變數而定。亦應了解所投予之初劑量可增 加超越上述的上水平,俾以快速達到所欲血液水平或組織水平,或初劑量可小於最優值且日劑量可在治療期間取決於特殊狀況而循序增加。若有要求時,亦可將日劑量分成多重劑量投予,例如每天2至4次。 In a therapeutic use for treating or combating a bacterial infection in a mammal, the compound or a pharmaceutical composition thereof is administered at a concentration to achieve and maintain a concentration, which is administered by ear, eye, nose, mouth, parenteral and/or topical, ie The concentration is the antimicrobially effective amount or blood or tissue level of the active ingredient in the animal being treated. An effective amount of the active ingredient dose will generally be in the range of from about 0.1 to about 100, more preferably from about 1.0 to about 50 mg/kg body weight per day. The amount administered will also depend, for example, on the type and extent of the disease or condition to be treated, the overall state of health of the particular patient, the biological effectiveness of the compound being delivered, the formulation of the drug, the presence of excipients in the formulation, and The type and the variables of the route of administration depend on the variables. It should also be understood that the initial dose administered may be increased. Adding above the above upper level, the sputum can quickly reach the desired blood level or tissue level, or the initial dose can be less than the optimal value and the daily dose can be sequentially increased during the treatment depending on the particular condition. The daily dose can also be divided into multiple doses, if desired, for example 2 to 4 times per day.
人類和其他哺乳動物的各種疾病狀態或症狀經發現係由無意義或錯義突變所引起或介導。該等突變係由於例如蛋白質合成、摺疊、運輸及/或功能受到不利影響而引起或介導疾病狀態或症狀。疾病狀態或症狀(其中相當高百分比的疾病症狀咸信係由無意義或錯義突變所造成)的實例包括血友病(因子VIII基因)、神經纖維瘤病(NF1和NF2基因)、色素沉著性視網膜炎(人類USH2A基因)、大皰性皮膚病,如大皰性表皮鬆解症(COL7A1基因)、囊性纖維變性(囊性纖維變性透膜調節基因)、乳癌和卵巢癌(BRCA1和BRCA2基因)、裘馨氏肌肉萎縮症(肌肉萎縮蛋白基因)、結腸癌(誤配基因,以MLH1和MSH2佔優勢)及溶小體醣脂類儲積症,諸如尼曼匹克症(Neimann-Pick disease)(酸性鞘磷脂酶基因)。參見Sanders CR,Myers JK.Disease-related misassembly of membrane proteins.Annu Rev Biophys Biomol Struct.2004;33:25-51;National Center for Biotechnology Information(U.S.)Genes and Disease Bethesda,MD;NCBI,NLM ID:101138560;及Raskó,István,Downes,C S Genes in medicine:molecular biology and human genetic disorders 1st ed.London;New York;Chapman & Hall,1995.NLM ID:9502404。可使用本發明化合物治療或預防哺乳動物中由此等無意義或錯義突變所引起或介導之疾病狀態,其係藉由將有效量之本發明化合物投予有此需求之哺乳動物,以抑制涉入疾病狀態中的無意義或錯義突變。 Various disease states or symptoms of humans and other mammals have been found to be caused or mediated by nonsense or missense mutations. Such mutations cause or mediate disease states or symptoms due to, for example, adverse effects of protein synthesis, folding, transport, and/or function. Examples of disease states or symptoms (of which a significant percentage of disease symptoms are caused by meaningless or missense mutations) include hemophilia (Factor VIII gene), neurofibromatosis (NF1 and NF2 genes), pigmentation Retinitis (human USH2A gene), bullous skin disease such as bullous epidermolysis (COL7A1 gene), cystic fibrosis (cystic fibrosis transmembrane regulatory gene), breast cancer and ovarian cancer (BRCA1 and BRCA2 gene), Muscle's muscular dystrophy (muscle atrophin gene), colon cancer (mismatched genes, predominating with MLH1 and MSH2) and lytic glycolipidosis, such as Neimann-Pick Disease) (acid sphingomyelinase gene). See Sanders CR, Myers JK. Disease-related misassembly of membrane proteins. Annu Rev Biophys Biomol Struct. 2004; 33:25-51; National Center for Biotechnology Information (US) Genes and Disease Bethesda, MD; NCBI, NLM ID: 101138560 And Raskó, István, Downes, CS Genes in medicine: molecular biology and human genetic disorders 1st ed. London; New York; Chapman & Hall, 1995. NLM ID: 9502404. The compounds of the invention may be used to treat or prevent a disease state caused or mediated by such nonsense or missense mutations in a mammal by administering an effective amount of a compound of the invention to a mammal in need thereof. Inhibition of meaningless or missense mutations involved in disease states.
核磁共振(NMR)光譜係在Bruker Avance 300或Avance 500分光計上獲得,或在一些情況中於GE-Nicolet 300分光計上獲得。常見的反應溶劑具有高性能液相層析術(HPLC)等級或美國化學學會(American Chemical Society)(ACS)等級,且此為從製造商所獲得的無水物,除非另有其他註明。"層析術"或"以矽膠純化"係指使用矽膠(EM Merck,Silica Gel 60,230-400篩網)之快速管柱層析術,除非另有其他註明。 Nuclear magnetic resonance (NMR) spectroscopy was obtained on a Bruker Avance 300 or Avance 500 spectrometer or, in some cases, on a GE-Nicolet 300 spectrometer. Common reaction solvents are high performance liquid chromatography (HPLC) grades or American Chemical Society (ACS) grades, and this is an anhydride obtained from the manufacturer unless otherwise noted. "Chromatography" or "purified with tannin" refers to flash column chromatography using tannin gel (EM Merck, Silica Gel 60, 230-400 mesh) unless otherwise noted.
本發明化合物可使用適應於手邊的特殊情況之已知的化學轉變來製備。 The compounds of the invention can be prepared using known chemical transformations adapted to the particular conditions at hand.
在下列實例合成的實驗細節中所使用的一些縮寫係定義如下:h或hr=小時;min=分鐘;mol=莫耳;mmol=毫莫耳;M=莫耳;μM=微莫耳;g=公克;μg=微克;rt=室溫;L=公升;mL=毫升;Et2O=二***;THF=四氫呋喃;DMSO=二甲亞碸;EtOAc=乙酸乙酯;Et3N=三乙胺;i-Pr2NEt或DIPEA=二異丙基乙胺;CH2Cl2=二氯甲烷;CHCl3=氯仿;CDCl3=氘化氯仿;CCl4=四氯化碳;MeOH= 甲醇;CD3OD=氘化甲醇;EtOH=乙醇;DMF=二甲基甲醯胺;BOC=第三丁氧基羰基;CBZ=苯甲氧基羰基;TBS=第三丁基二甲基矽烷基;TBSC1=第三丁基二甲基矽烷基氯;TFA=三氟乙酸;DBU=二氮雜雙環十一烯;TBDPSC1=第三丁基二苯基氯矽烷;胡尼格氏(Hunig’s)鹼=N,N-二異丙基乙胺;DMAP=4-二甲基胺基吡啶;CuI=碘化銅(I);MsCl=甲烷磺醯氯;NaN3=疊氮化鈉;Na2SO4=硫酸鈉;NaHCO3=碳酸氫鈉;NaOH=氫氧化鈉;MgSO4=硫酸鎂;K2CO3=碳酸鉀;KOH=氫氧化鉀;NH4OH=氫氧化銨;NH4Cl=氯化銨;SiO2=二氧化矽;Pd-C=鈀/碳;Pd(dppf)Cl2=二氯[1,1’-雙(二苯膦基)二茂鐵]鈀(II)。 Some of the abbreviations used in the experimental details synthesized in the following examples are defined as follows: h or hr = hour; min = minute; mol = mole; mmol = millimolar; M = mole; μM = micromolar; = gram; μg = microgram; rt = room temperature; L = liter; mL = milliliter; Et 2 O = diethyl ether; THF = tetrahydrofuran; DMSO = dimethyl hydrazine; EtOAc = ethyl acetate; Et 3 N = triethyl Amine; i-Pr 2 NEt or DIPEA = diisopropylethylamine; CH 2 Cl 2 = dichloromethane; CHCl 3 = chloroform; CDCl 3 = deuterated chloroform; CCl 4 = carbon tetrachloride; MeOH = methanol; CD 3 OD=deuterated methanol; EtOH=ethanol; DMF=dimethylformamide; BOC=third butoxycarbonyl; CBZ=benzyloxycarbonyl; TBS=t-butyldimethylmethylalkyl; TBSC1 = tert-butyldimethylsilyl chloride; TFA = trifluoroacetic acid; DBU = diazabicycloundecene; TBDPSC1 = tert-butyldiphenylchlorodecane; Hunig's base = N,N-diisopropylethylamine;DMAP=4-dimethylaminopyridine; CuI=copper iodide (I); MsCl=methanesulfonium chloride; NaN 3 = sodium azide; Na 2 SO 4 = sodium sulfate; NaHCO 3 = sodium bicarbonate; NaOH = sodium hydroxide; MgSO 4 = magnesium sulfate; K 2 CO 3 = carbonic acid Potassium; KOH = potassium hydroxide; NH 4 OH = ammonium hydroxide; NH 4 Cl = ammonium chloride; SiO 2 = cerium oxide; Pd-C = palladium / carbon; Pd (dppf) Cl 2 = dichloro [1 , 1'-bis(diphenylphosphino)ferrocene]palladium (II).
將依照本發明所合成之示例化合物陳列於表1中。所顯示之黑體鍵或虛線鍵係標示在手性中心的特殊立體化學,而波形鍵標示取代基可在定位上或化合物為其混合物。亦應知道為了節省空間而將一些化合物的化學結構***成具有兩個連接點的兩個部分,每個連接點以波形線交叉的鍵標示。參見例如化合物1345,將其繪製成如以下的兩個部分:
可將本發明化合物製備、調配成鹽、酯及前藥且以其輸送。為方便起見,通常顯示化合物而不標示特殊的鹽、酯或前藥形式。 The compounds of the invention may be prepared, formulated, and delivered as salts, esters, and prodrugs. For convenience, the compounds are usually shown without the particular salt, ester or prodrug form.
將本發明化合物顯示於表1中。提供可取得的LCMS(液相層析術質譜)數據。當不可取得數據時,則以"NA"標示。LCMS數據係使用具有格式[M+H]+之m/z為常規提供,除非另有其他標示。 The compounds of the invention are shown in Table 1. Available LCMS (liquid chromatography mass spectrometry) data is available. When data is not available, it is marked with "NA". The LCMS data is routinely provided using m/z with the format [M+H] + unless otherwise indicated.
Claims (25)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US25247809P | 2009-10-16 | 2009-10-16 | |
US31428710P | 2010-03-16 | 2010-03-16 | |
US35820110P | 2010-06-24 | 2010-06-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW201726630A true TW201726630A (en) | 2017-08-01 |
Family
ID=43876906
Family Applications (8)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW99135286A TW201125566A (en) | 2009-10-16 | 2010-10-15 | Antimicrobial compounds and methods of making and using the same |
TW106131448A TW201825495A (en) | 2009-10-16 | 2010-10-15 | Antimicrobial compounds and methods of making and using the same |
TW104135849A TWI618707B (en) | 2009-10-16 | 2010-10-15 | Antimicrobial compounds and methods of making and using the same |
TW104131806A TWI621439B (en) | 2009-10-16 | 2010-10-15 | Antimicrobial compounds and methods of making and using the same |
TW106102658A TWI629277B (en) | 2009-10-16 | 2010-10-15 | Antimicrobial compounds and methods of making and using the same |
TW099135283A TWI589294B (en) | 2009-10-16 | 2010-10-15 | Antimicrobial compounds and methods of making and using the same |
TW106101234A TW201726630A (en) | 2009-10-16 | 2010-10-15 | Antimicrobial compounds and methods of making and using the same |
TW099135287A TWI612048B (en) | 2009-10-16 | 2010-10-15 | Antimicrobial compounds and methods of making and using the same |
Family Applications Before (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW99135286A TW201125566A (en) | 2009-10-16 | 2010-10-15 | Antimicrobial compounds and methods of making and using the same |
TW106131448A TW201825495A (en) | 2009-10-16 | 2010-10-15 | Antimicrobial compounds and methods of making and using the same |
TW104135849A TWI618707B (en) | 2009-10-16 | 2010-10-15 | Antimicrobial compounds and methods of making and using the same |
TW104131806A TWI621439B (en) | 2009-10-16 | 2010-10-15 | Antimicrobial compounds and methods of making and using the same |
TW106102658A TWI629277B (en) | 2009-10-16 | 2010-10-15 | Antimicrobial compounds and methods of making and using the same |
TW099135283A TWI589294B (en) | 2009-10-16 | 2010-10-15 | Antimicrobial compounds and methods of making and using the same |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW099135287A TWI612048B (en) | 2009-10-16 | 2010-10-15 | Antimicrobial compounds and methods of making and using the same |
Country Status (9)
Country | Link |
---|---|
JP (6) | JP2016121171A (en) |
KR (3) | KR20120101392A (en) |
CN (5) | CN104628729B (en) |
AR (3) | AR080617A1 (en) |
EA (1) | EA201500913A1 (en) |
MY (2) | MY161870A (en) |
NZ (2) | NZ623384A (en) |
SG (3) | SG10201406635QA (en) |
TW (8) | TW201125566A (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2010306647B9 (en) | 2009-10-16 | 2016-11-17 | Melinta Therapeutics, Inc. | Antimicrobial compounds and methods of making and using the same |
CN102725274A (en) | 2009-10-16 | 2012-10-10 | Rib-X制药公司 | Antimicrobial compounds and methods of making and using the same |
CN104628729B (en) * | 2009-10-16 | 2018-11-06 | 梅琳塔治疗公司 | Antimicrobe compound and its preparation and application |
JP6317669B2 (en) * | 2011-04-15 | 2018-04-25 | メリンタ セラピューティクス インコーポレイテッド | Antibacterial compounds and methods of making and using the same |
MX2016002975A (en) | 2013-09-09 | 2016-10-21 | Melinta Therapeutics Inc | Antimicrobial compunds and methods of making and using the same. |
AU2014315045A1 (en) | 2013-09-09 | 2016-03-24 | Melinta Therapeutics, Inc. | Antimicrobial compounds and methods of making and using the same |
CA2979342A1 (en) | 2015-03-11 | 2016-09-15 | Melinta Therapeutics, Inc. | Antimicrobial compounds and methods of making and using the same |
CN110312722A (en) | 2016-05-06 | 2019-10-08 | 生物验证***股份公司 | Antimicrobial and its preparation and application |
Family Cites Families (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3980781A (en) * | 1966-03-31 | 1976-09-14 | Imperial Chemical Industries Limited | Fungicidal composition and method containing 2-amino-pyrimidines |
US3673184A (en) * | 1970-09-02 | 1972-06-27 | Dainippon Pharmaceutical Co | Certain 2-substituted-5,8-dihydro-5-oxopyrido{8 2,3-d{9 pyrimidine-6-carboxylic acid derivatives |
EP0067610A1 (en) * | 1981-06-16 | 1982-12-22 | Beecham Group Plc | Penicillins, a process for their preparation and compositions containing them |
ZA835684B (en) * | 1982-08-27 | 1985-03-27 | Roussel Uclaf | Imidazo(1,2-a)pyrimidines |
IT1197876B (en) * | 1986-10-15 | 1988-12-21 | Pharmachim Engineering Srl | PROCEDURE FOR THE PREPARATION OF 5,8-DIHYDRO-8-ETHYL-5-BONE-2- (1-PIPERAZINYL) PYRID (2,3-D) PYRIMIDIN-6-CARBOXYLIC |
JP2549931B2 (en) * | 1990-01-12 | 1996-10-30 | 株式会社大塚製薬工場 | Pyrimidobenzimidazole derivative |
JP2991382B2 (en) * | 1990-07-18 | 1999-12-20 | 大日本製薬株式会社 | Fused tricyclic compounds and salts thereof |
US5208141A (en) * | 1990-10-09 | 1993-05-04 | Konica Corporation | Silver halide color photographic light-sensitive material |
JP2811230B2 (en) * | 1990-10-17 | 1998-10-15 | コニカ株式会社 | New photographic coupler |
US6451968B1 (en) * | 1991-05-24 | 2002-09-17 | Isis Pharmaceuticals, Inc. | Peptide nucleic acids |
US5434257A (en) * | 1992-06-01 | 1995-07-18 | Gilead Sciences, Inc. | Binding compentent oligomers containing unsaturated 3',5' and 2',5' linkages |
US5646163A (en) * | 1992-10-30 | 1997-07-08 | The Procter & Gamble Company | Quinolone 5-(N-heterosubstituted amino) antimicrobials |
IT1263804B (en) * | 1993-01-22 | 1996-09-03 | Luso Farmaco Inst | PYRIMIDINONIC DERIVATIVES MELT WITH NITROGEN HETEROCYCLES ACTIVATED IN II ANTAGONIST |
EP0698013B1 (en) * | 1993-05-12 | 2001-10-04 | E.I. Du Pont De Nemours And Company | Fungicidal fused bicyclic pyrimidinones |
US5502177A (en) * | 1993-09-17 | 1996-03-26 | Gilead Sciences, Inc. | Pyrimidine derivatives for labeled binding partners |
US5668127A (en) * | 1995-06-26 | 1997-09-16 | Pathogenesis Corporation | Nitroimidazole antibacterial compounds and methods of use thereof |
ATE284407T1 (en) * | 1997-11-07 | 2004-12-15 | Isis Pharmaceuticals Inc | PYRIMIDINE DERIVATIVES AS LABELED BINDING PARTNERS |
DE19838998A1 (en) * | 1998-08-27 | 2000-03-09 | Bayer Ag | New natural product derivatives |
SE9903894D0 (en) * | 1999-10-28 | 1999-10-28 | New Pharma Research Ab | Novel compounds |
KR20040028657A (en) * | 2000-10-18 | 2004-04-03 | 파마셋, 리미티드 | Modified nucleosides for treatment of viral infections and abnormal cellular proliferation |
DE10061542A1 (en) * | 2000-12-11 | 2002-06-13 | Bayer Ag | New alkanoylamino-pyrimidine derivatives used as antibacterial agents, especially for prevention and control of Staphylococcal infections |
DE10061538A1 (en) * | 2000-12-11 | 2002-06-20 | Bayer Ag | New ureido-substituted dihydropyrimidinone derivatives, useful as broad-spectrum antibacterial agents with strong activity against Gram positive bacteria |
ES2249489T3 (en) * | 2000-12-14 | 2006-04-01 | THE PROCTER & GAMBLE COMPANY | ANTIMICROBIAL QUINOLONES. |
ATE465739T1 (en) * | 2001-01-29 | 2010-05-15 | Bio Rad Laboratories | NUCLEIC ACID DERIVATIVES |
TWI248936B (en) * | 2001-03-21 | 2006-02-11 | Merck Sharp & Dohme | Imidazo-pyrimidine derivatives as ligands for GABA receptors |
US20030207804A1 (en) * | 2001-05-25 | 2003-11-06 | Muthiah Manoharan | Modified peptide nucleic acids |
CA2452458A1 (en) * | 2001-07-03 | 2003-01-16 | Isis Pharmaceuticals, Inc. | Nuclease resistant chimeric oligonucleotides |
JP4306206B2 (en) * | 2001-09-04 | 2009-07-29 | 住友化学株式会社 | Imidazo [1,2-a] pyrimidine, its use and production intermediate |
GB0205165D0 (en) * | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
WO2004080466A1 (en) * | 2003-03-07 | 2004-09-23 | Ribapharm Inc. | Cytidine analogs and methods of use |
JP5147237B2 (en) * | 2003-08-12 | 2013-02-20 | アキリオン ファーマシューティカルズ,インコーポレーテッド | Isothiazoloquinolones and related compounds as antiinfectives |
WO2007014308A1 (en) * | 2005-07-27 | 2007-02-01 | Achillion Pharmaceuticals, Inc. | 8-methoxy-9h-isothiazolo[5,4-b]quinoline-3,4-diones and related compounds as anti-infective agents |
WO2007101871A1 (en) * | 2006-03-08 | 2007-09-13 | Basf Se | Substituted imidazolopyrimidines, method for the production thereof and use thereof for controlling parasitic fungi and agents containing the latter |
WO2008082440A2 (en) * | 2006-08-25 | 2008-07-10 | Emory University | Fluorescent nucleoside analogues |
EP1964841A1 (en) * | 2007-02-28 | 2008-09-03 | sanofi-aventis | Imidazo[1,2-a]azine and their use as pharmaceuticals |
KR20090098710A (en) * | 2008-03-14 | 2009-09-17 | 주식회사 씨티아이바이오 | Peptide nucleic acid derivatives with good cell penetration and affinity for nucleic acid |
CN104628729B (en) * | 2009-10-16 | 2018-11-06 | 梅琳塔治疗公司 | Antimicrobe compound and its preparation and application |
-
2010
- 2010-10-15 CN CN201510018490.2A patent/CN104628729B/en not_active Expired - Fee Related
- 2010-10-15 TW TW99135286A patent/TW201125566A/en unknown
- 2010-10-15 CN CN201710499962.XA patent/CN107266470A/en active Pending
- 2010-10-15 MY MYPI2012001696A patent/MY161870A/en unknown
- 2010-10-15 TW TW106131448A patent/TW201825495A/en unknown
- 2010-10-15 SG SG10201406635QA patent/SG10201406635QA/en unknown
- 2010-10-15 SG SG10201406634VA patent/SG10201406634VA/en unknown
- 2010-10-15 SG SG10201406631TA patent/SG10201406631TA/en unknown
- 2010-10-15 NZ NZ623384A patent/NZ623384A/en not_active IP Right Cessation
- 2010-10-15 TW TW104135849A patent/TWI618707B/en not_active IP Right Cessation
- 2010-10-15 CN CN201710499688.6A patent/CN107445976A/en active Pending
- 2010-10-15 TW TW104131806A patent/TWI621439B/en not_active IP Right Cessation
- 2010-10-15 CN CN201610065325.7A patent/CN105646370A/en active Pending
- 2010-10-15 EA EA201500913A patent/EA201500913A1/en unknown
- 2010-10-15 TW TW106102658A patent/TWI629277B/en not_active IP Right Cessation
- 2010-10-15 KR KR1020127012676A patent/KR20120101392A/en active Application Filing
- 2010-10-15 MY MYPI2012001651A patent/MY165011A/en unknown
- 2010-10-15 CN CN201810372366.XA patent/CN108456211A/en active Pending
- 2010-10-15 KR KR1020127012702A patent/KR101857694B1/en active IP Right Grant
- 2010-10-15 TW TW099135283A patent/TWI589294B/en not_active IP Right Cessation
- 2010-10-15 TW TW106101234A patent/TW201726630A/en unknown
- 2010-10-15 NZ NZ713357A patent/NZ713357A/en not_active IP Right Cessation
- 2010-10-15 TW TW099135287A patent/TWI612048B/en not_active IP Right Cessation
- 2010-10-15 KR KR1020127012700A patent/KR20120099435A/en not_active Application Discontinuation
- 2010-10-18 AR ARP100103803 patent/AR080617A1/en unknown
- 2010-10-18 AR ARP100103804 patent/AR080558A1/en unknown
- 2010-10-18 AR ARP100103805 patent/AR080559A1/en unknown
-
2016
- 2016-01-29 JP JP2016015912A patent/JP2016121171A/en active Pending
- 2016-02-29 JP JP2016037911A patent/JP2016153405A/en not_active Withdrawn
- 2016-03-17 JP JP2016054375A patent/JP2016172733A/en not_active Withdrawn
-
2017
- 2017-07-31 JP JP2017148521A patent/JP2018039784A/en active Pending
- 2017-07-31 JP JP2017148530A patent/JP2018024653A/en active Pending
-
2018
- 2018-09-27 JP JP2018182217A patent/JP2019038808A/en active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI621439B (en) | Antimicrobial compounds and methods of making and using the same | |
KR101972992B1 (en) | Antimicrobial compounds and methods of making and using the same | |
TWI656123B (en) | Antimicrobial compound and its manufacture and use method | |
US9845297B2 (en) | Antimicrobial compounds and methods of making and using the same | |
US11999739B2 (en) | Antimicrobials methods of making and using the same | |
KR20180051676A (en) | Antimicrobial compounds and methods of making and using the same | |
TW201808956A (en) | Antimicrobials and methods of making and using same |