JP5719312B2 - デオキシアクタガルジン誘導体 - Google Patents
デオキシアクタガルジン誘導体 Download PDFInfo
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- JP5719312B2 JP5719312B2 JP2011545788A JP2011545788A JP5719312B2 JP 5719312 B2 JP5719312 B2 JP 5719312B2 JP 2011545788 A JP2011545788 A JP 2011545788A JP 2011545788 A JP2011545788 A JP 2011545788A JP 5719312 B2 JP5719312 B2 JP 5719312B2
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- Prior art keywords
- compound
- compounds
- deoxyactagardine
- treatment
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- KHPXUQMNIQBQEV-UHFFFAOYSA-N oxaloacetic acid Chemical compound OC(=O)CC(=O)C(O)=O KHPXUQMNIQBQEV-UHFFFAOYSA-N 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 229940074571 peptostreptococcus anaerobius Drugs 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960003040 rifaximin Drugs 0.000 description 1
- NZCRJKRKKOLAOJ-XRCRFVBUSA-N rifaximin Chemical compound OC1=C(C(O)=C2C)C3=C4N=C5C=C(C)C=CN5C4=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O NZCRJKRKKOLAOJ-XRCRFVBUSA-N 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 231100000161 signs of toxicity Toxicity 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000001562 sternum Anatomy 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 210000002438 upper gastrointestinal tract Anatomy 0.000 description 1
- 229940120293 vaginal suppository Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000001238 wet grinding Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/50—Cyclic peptides containing at least one abnormal peptide link
- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Description
式中、Aは-C1-4アルキルであり;Bは-C1-4アルキルであり;Xは-NH(CH2)pNH2であり;pは整数2〜12であり;Zは-NR1R2であり;R1はHまたはC1-4アルキルであり、R2はH、アミノ酸、またはC1-4アルキルである。
[本発明1001]
式(I)の化合物、ならびにその薬学的に許容される塩、水和物、および溶媒和物:
式中、
Aは-C 1-4 アルキルであり;
Bは-C 1-4 アルキルであり;
Xは-NH(CH 2 ) p NH 2 であり;
pは整数2〜12であり;
Zは-NR 1 R 2 であり;
R 1 はHまたはC 1-4 アルキルであり;
R 2 はH、アミノ酸、またはC 1-4 アルキルである。
[本発明1002]
Aが-CH(CH 3 ) 2 および-CH 2 CH(CH 3 ) 2 より選択される、本発明1001の化合物。
[本発明1003]
Aが-CH 2 CH(CH 3 ) 2 である、本発明1002の化合物。
[本発明1004]
Bが-CH(CH 3 ) 2 および-CH(CH 3 )CH 2 CH 3 より選択される、本発明1001〜1003のいずれかの化合物。
[本発明1005]
Bが-CH(CH 3 ) 2 である、本発明1004の化合物。
[本発明1006]
R 2 が-C(O)CH(CH 3 )NH 2 のLまたはD異性体である、本発明1001〜1005のいずれかの化合物。
[本発明1007]
Aが-CH 2 CH(CH 3 ) 2 であり、およびBが-CH(CH 3 ) 2 である、本発明1001〜1005のいずれかの化合物。
[本発明1008]
pが、3、4、5、6、7、8、9、10、11、または12である、本発明1001〜1007のいずれかの化合物。
[本発明1009]
pが、2、3、7、9、または12である、本発明1008の化合物。
[本発明1010]
pが、7、9、または12である、本発明1009の化合物。
[本発明1011]
ZがNH 2 である、本発明1001〜1010のいずれかの化合物。
[本発明1012]
式(II)の本発明1001の化合物、ならびにその薬学的に許容される塩、水和物、および溶媒和物:
。
[本発明1013]
本発明1001〜1012のいずれかの化合物と、薬学的に許容される賦形剤とを含む、薬学的組成物。
[本発明1014]
経口投与のための、本発明1013の組成物。
[本発明1015]
非経口投与のための、本発明1013の組成物。
[本発明1016]
処置における使用のための、本発明1001〜1012のいずれかの化合物、または本発明1013〜1015のいずれかの組成物。
[本発明1017]
微生物感染の処置における使用のための、本発明1016の化合物または組成物。
[本発明1018]
微生物感染がC. ディフィシレ(C. difficile)感染である、本発明1017の化合物または組成物。
[本発明1019]
C. ディフィシレ感染が結腸および/または下部腸管においてである、本発明1018の化合物または組成物。
[本発明1020]
C. ディフィシレなどの微生物感染の処置用の薬剤の製造のための、本発明1001〜1012のいずれかの化合物または本発明1013〜1015のいずれかの組成物の使用。
[本発明1021]
治療的に有効量の、本発明1001〜1012のいずれかの化合物、または本発明1013〜1015のいずれかの組成物を、それを必要とする患者に投与する段階を含む、処置の方法。
[本発明1022]
微生物感染の処置のための、本発明1021の方法。
[本発明1023]
微生物感染がC. ディフィシレである、本発明1021の方法。
[本発明1024]
結腸および/または下部腸管におけるC. ディフィシレ感染の処置のための、本発明1023の方法。
[本発明1025]
微生物感染が小腸細菌異常増殖である、本発明1022の方法。
[本発明1026]
潰瘍性大腸炎の処置のための、本発明1021の方法。
[本発明1027]
過敏性腸症候群の処置のための、本発明1021の方法。
本開示の文脈におけるアルキルとは、直鎖または分岐鎖のアルキル、例えば、メチル、エチル、プロピル、イソプロピル、n-ブチル、またはt-ブチルを指す。
1. 必要とされる量のOPADRY(登録商標)フィルムコーティングシステムを秤量する段階、
2. 混合容器中へ必要とされる量の水または他の溶媒を秤量する段階、
3. 容器の中央およびできるだけ容器の底に近い混合プロペラで、液体中へ空気を引き込むことなく渦を形成するように溶媒を撹拌する段階、
4. 液体表面上の粉末の浮遊を回避し、着実におよび急速にOPADRY(登録商標)粉末を渦に添加する段階、
5. 必要な場合、渦を維持するために撹拌機の速度を増加させる段階、ならびに
6. すべての粉末成分を添加した後、混合機の速度を減少させ、約45分間混合を継続する段階。
デオキシアクタガルジンB(7-アミノ-1-へプチルアミド モノカルボキサミド)
デオキシアクタガルジンB(2.5g)、1,7-ジアミノヘプタン(0.52g)、およびジイソプロピルエチルアミン(0.44ml)を乾燥ジメチルホルムアミド(10ml)に溶解した。乾燥ジメチルホルムアミド(5ml)中のベンゾトリアゾール-1-イル-オキシ-トリス-ピロリジノ-ホスホニウムヘキサフルオロホスフェート(PyBOP)(1.04g)の溶液を2時間に渡って、少しづつ添加した。反応を分析用HPLCにより追跡し(表1参照)、出発物質が消費されるまでPyBOPを添加した(図4および5)。
カラム: Zorbax 5μ C18(2) 150 x 4.6 mm
移動相A: 20 mMリン酸カリウム緩衝液pH 7.0中、30%アセトニトリル
移動相B: 20 mMリン酸カリウム緩衝液pH 7.0中、65%アセトニトリル
流速: 1ml/分
勾配: 時間0分 100% A 0% B
時間10分 0% A 100% B
時間11分 0% A 100% B
時間11.2分 100% A 0% B
サイクル時間 15分
注入容積: 10μl
検出: 210 nm
実施例1の化合物のメタンスルホン酸塩の調製
経口または静脈内投薬に適する溶液を取得する目的で、実施例1の化合物のメタンスルホン酸塩が適当であることが見出された。
デオキシアクタガルジンB[7-(t-ブトキシカルボニルアミド)-1-へプチルアミド モノカルボキサミド]
実施例1の化合物について説明した工程を使用し、デオキシアクタガルジンBおよび7-(t-ブトキシカルボニルアミド)-1-アミノヘプタンより調製した。75% (M+2H)+2 1043、実測値 1044.11。4N塩酸水溶液中、室温で3時間の処理により、t-ブトキシカルボネートを加水分解した。混合物を中和してpH7とし、および実施例1について説明したように精製を実施して、表題の化合物を提供した。収率65%。
デオキシアクタガルジンB(2-アミノ-1-エチルアミド モノカルボキサミド)
実施例1について上述した工程を使用し、デオキシアクタガルジンおよび1,2-エチレンジアミンより調製した。収率96%。質量 計算値(M+2H)+2 958、実測値959.02。
デオキシアクタガルジンB(3-アミノ-1-プロピルアミド モノカルボキサミド)
実施例1について上述した工程を使用し、デオキシアクタガルジンおよび1,3-ジアミノプロパンより調製した。収率87%。質量 計算値 (M+2H)+2 965、実測値 965.04。
デオキシアクタガルジンB(5-アミノ-1-ペンチルアミド モノカルボキサミド)
実施例1について上述した工程を使用し、デオキシアクタガルジンおよび1,5-ジアミノペンタンより調製した。収率83%。質量 計算値 (M+2H)+2 979、実測値 980.06。
デオキシアクタガルジンB(9-アミノ-1-ノニルアミド モノカルボキサミド)
実施例1について上述した工程を使用し、デオキシアクタガルジンおよび1,9-ジアミノノナンより調製した。収率84%。質量 計算値 (M+2H)+2 1007、実測値 1007.51。
デオキシアクタガルジンB(12-アミノ-1-ドデシルアミド モノカルボキサミド)
実施例1について上述した工程を使用し、デオキシアクタガルジンおよび1,12-ジアミノドデカンより調製した。収率74%。質量 計算値 (M+2H)+2 1028、実測値 1027.51。
タイプBランチビオティックの抗菌活性
本発明の化合物は、インビトロおよびインビボで抗菌活性を示す。それらはクロストリジウム・ディフィシレに対して活性を有し、かつデオキシアクタガルジンBと比較して改善された活性を有し得る。
腸液におけるタイプBランチビオティックの安定性
本明細書において提供されるランチビオティックベースの化合物は、ナイシンなどのタイプAランチビオティックと比較し、酵素分解に対して増加した安定性を有し得る。特に、これらの化合物は、タイプAランチビオティックと比較し、腸液に対して改善された安定性を有し得る。
C. ディフィシレ関連盲腸炎のハムスターモデルにおけるタイプB抗生物質のインビボ有効性
C. ディフィシレ感染の処置における本発明の化合物のインビボ有効性を、CDADについての標準的な動物モデルである、ハムスターにおけるクリンダマイシン誘導性盲腸炎において評価した。結果を図2に要約した。
ラットモデルにおけるADME
実施例1の化合物を経口でラットに7日間投与し、メタノールでの抽出により糞から回収した。図3は、ラットに投与された量に対する、回収された物質の量を示す。回収された物質の量は抽出の数に依存する一方で、データは、GI管の通過後に、実施例1の化合物の少なくとも60〜70%を変化せずに回収することができ、かつ実施例1の化合物が結腸において高濃度に達し得ることを示す。
ラットモデルにおける毒性学
実施例1の化合物を、ラットモデルでの7日間の毒性実験にて試験した。1つの研究は、7日間静脈内に投与される50mg/kg/日の物質を使用した。もう1つの研究は、7日間経口投与される200mg/kg/日の物質を使用した。静脈内及び経口用量の両方とも、予測される臨床的用量レベル(経口投薬により約3〜30mg/kg/日)を有意に超過する。実験の間に有意な毒性学的効果は観察されず、剖検は器官の損傷が無いことを示した。
Claims (11)
- デオキシアクタガルジンB 7-アミノ-1-へプチルアミド モノカルボキサミド、ならびにその薬学的に許容される塩、水和物、または溶媒和物。
- 請求項1記載の化合物と、薬学的に許容される賦形剤とを含む、薬学的組成物。
- 経口投与または非経口投与のための、請求項2記載の組成物。
- 処置における使用のための、請求項1記載の化合物、または請求項2もしくは3記載の組成物。
- 微生物感染の処置における使用のための、請求項1記載の化合物、または請求項2もしくは3記載の組成物。
- 微生物感染がC. ディフィシレ(C. difficile)感染である、請求項5記載の化合物または組成物。
- C. ディフィシレ感染が結腸および/または下部腸管においてである、請求項6記載の化合物または組成物。
- 微生物感染が小腸細菌異常増殖である、請求項5記載の化合物または組成物。
- 潰瘍性大腸炎または過敏性腸症候群の処置における使用のための、請求項1記載の化合物、または請求項2もしくは3記載の組成物。
- 請求項1記載のデオキシアクタガルジンB 7-アミノ-1-へプチルアミド モノカルボキサミドを調製する方法であって、ジメチルホルムアミド(DMF)中、ジイソプロピルエチルアミンおよびベンゾトリアゾール-1-イル-オキシ-トリス-ピロリジノ-ホスホニウムヘキサフルオロホスフェート(PyBOP)の存在下で、デオキシアクタガルジンBと1,7-ジアミノヘプタンを反応させる工程を含む、方法。
- デオキシアクタガルジンBが、A. リグリアエ(Actinoplanes liguriae)において合成される、請求項10記載の方法。
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US14449009P | 2009-01-14 | 2009-01-14 | |
US61/144,490 | 2009-01-14 | ||
PCT/GB2010/000042 WO2010082018A1 (en) | 2009-01-14 | 2010-01-12 | Deoxyactagardine derivatives |
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Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0600928D0 (en) | 2006-01-17 | 2006-02-22 | Novacta Biosystems Ltd | Improvements relating to lantibiotics |
GB0714029D0 (en) | 2007-07-18 | 2007-08-29 | Novacta Biosystems Ltd | Lantibiotic-based compounds having antimicrobial activity |
GB0714030D0 (en) | 2007-07-18 | 2007-08-29 | Novacta Biosystems Ltd | The use of type-B lantibiotic-based compounds having antimicrobial activity |
PT2387580E (pt) | 2009-01-14 | 2014-10-30 | Novacta Biosystems Ltd | Derivativos da desoxiactagardina |
BRPI1007884A2 (pt) | 2009-02-04 | 2016-09-06 | Novacta Biosystems Ltd | derivados de actagardina |
WO2011061748A1 (en) * | 2009-11-19 | 2011-05-26 | Strides Arcolab Limited | Rifaximin premix |
GB201001688D0 (en) | 2010-02-02 | 2010-03-17 | Novacta Biosystems Ltd | Compounds |
GB201013509D0 (en) * | 2010-08-11 | 2010-09-22 | Novacta Biosystems Ltd | Compounds |
GB201013507D0 (en) * | 2010-08-11 | 2010-09-22 | Novacta Biosystems Ltd | Compounds |
GB201013513D0 (en) * | 2010-08-11 | 2010-09-22 | Novacta Biosystems Ltd | Formulations |
GB201013508D0 (en) * | 2010-08-11 | 2010-09-22 | Novacta Biosystems Ltd | Compounds |
GB201213434D0 (en) | 2012-07-27 | 2012-09-12 | Novacta Biosystems Ltd | The use of type-B lantibiotic-based compounds having antimicrobial activity |
Family Cites Families (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3710795A (en) | 1970-09-29 | 1973-01-16 | Alza Corp | Drug-delivery device with stretched, rate-controlling membrane |
GB8507528D0 (en) * | 1985-03-22 | 1985-05-01 | Lepetit Spa | Basis monocarboxyamide derivatives |
US5304540A (en) | 1988-06-22 | 1994-04-19 | Applied Microbiology, Inc. | Pharmaceutical bacteriocin compositions and methods for using the same |
IN167138B (ja) | 1988-08-17 | 1990-09-01 | Hoechst India | |
GB8926639D0 (en) | 1989-11-24 | 1990-01-17 | Agricultural & Food Res | Delayed release formulations |
US5376645A (en) | 1990-01-23 | 1994-12-27 | University Of Kansas | Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof |
KR0166088B1 (ko) | 1990-01-23 | 1999-01-15 | . | 수용해도가 증가된 시클로덱스트린 유도체 및 이의 용도 |
IT1260505B (it) | 1992-06-01 | 1996-04-09 | Poli Ind Chimica Spa | Sistemi farmaceutici orali a cessione ritardata per il rilascio specifico nel colon |
IL107887A (en) | 1992-12-08 | 2003-07-06 | Ambi Inc | Stabilized lanthionine containing bacteriocin compositions |
US5512269A (en) | 1993-06-09 | 1996-04-30 | Burroughs Wellcome, Co. | Method of treating retained pulmonary secretions |
EP0700998B1 (en) | 1994-09-12 | 2003-11-26 | Aventis Pharma Deutschland GmbH | Recombinant mersacidin and a method for production |
EP0833657B1 (en) | 1995-06-23 | 2003-08-27 | AMBI Inc. | A method for the control of antibiotic-resistant gram positive bacteria and treatment of infection |
GB9711643D0 (en) | 1997-06-05 | 1997-07-30 | Janssen Pharmaceutica Nv | Glass thermoplastic systems |
US5958873A (en) | 1997-06-09 | 1999-09-28 | University Of Cincinnati | Oral formulation for treatment of bacteria-induced diseases of the colon |
US5985823A (en) | 1997-06-09 | 1999-11-16 | Ambi Inc. | Method for the treatment of diarrheal disease and for eliminating particular bacterial populations from the colon |
DE19745583A1 (de) | 1997-10-15 | 1999-04-22 | Hoechst Marion Roussel De Gmbh | Neues Lantibiotikum verwandt mit Actagardine, Verfahren zur Herstellung und Verwendung derselben |
US6569830B1 (en) | 1999-03-05 | 2003-05-27 | Ambi, Inc. | Compositions and methods for treatment of staphylococcal infection while suppressing formation of antibiotic-resistant strains |
SI1294358T1 (en) | 2000-06-28 | 2004-12-31 | Smithkline Beecham Plc | Wet milling process |
GB0110432D0 (en) | 2001-04-27 | 2001-06-20 | Plant Bioscience Ltd | Lantibiotic production |
WO2002103010A1 (en) | 2001-06-14 | 2002-12-27 | Plant Bioscience Limited | Methods and materials for targeted gene disruption in actinomycete bacteria |
US6861236B2 (en) | 2002-05-24 | 2005-03-01 | Applied Nanosystems B.V. | Export and modification of (poly)peptides in the lantibiotic way |
WO2004033706A2 (en) | 2002-10-10 | 2004-04-22 | Molichem Medicines, Inc. | Nucleic acids encoding duramycin |
EP1646646B1 (en) | 2003-07-18 | 2007-03-07 | Vicuron Pharmaceuticals, Inc. | Antibiotic 107891, its factors a1 and a2, pharmaceutically acceptable salts and compositions, and use thereof. |
US7351687B2 (en) | 2003-07-18 | 2008-04-01 | Vicuron Pharmaceuticals, Inc. | Antibiotic 107891, its factors A1 and A2, pharmaceutically acceptable salts and compositions, and use thereof |
GB0406870D0 (en) | 2004-03-26 | 2004-04-28 | Novacta Biosystems Ltd | Improvements relating to the production of lantibiotics |
WO2007036706A1 (en) | 2005-09-27 | 2007-04-05 | Novacta Biosystems Limited | Variants of the lantibiotic mersacidin and their use |
GB0600928D0 (en) | 2006-01-17 | 2006-02-22 | Novacta Biosystems Ltd | Improvements relating to lantibiotics |
AU2007310534A1 (en) | 2006-10-27 | 2008-05-02 | Capsugel Belgium Nv | Hydroxypropyl methyl cellulose hard capsules and process of manufacture |
US20110150917A1 (en) | 2007-06-12 | 2011-06-23 | The University Of British Columbia | Small Cationic Antimicrobial Peptides |
GB0714030D0 (en) | 2007-07-18 | 2007-08-29 | Novacta Biosystems Ltd | The use of type-B lantibiotic-based compounds having antimicrobial activity |
GB0714029D0 (en) | 2007-07-18 | 2007-08-29 | Novacta Biosystems Ltd | Lantibiotic-based compounds having antimicrobial activity |
WO2010058238A1 (en) | 2008-11-24 | 2010-05-27 | Sentinella Pharmaceuticals, Inc. ("Sentinella") | Lantibiotic carboxyamide derivatives with enhanced antibacterial activity |
GB0900599D0 (en) | 2009-01-14 | 2009-02-18 | Novacta Biosystems Ltd | Treatment |
PT2387580E (pt) | 2009-01-14 | 2014-10-30 | Novacta Biosystems Ltd | Derivativos da desoxiactagardina |
BRPI1007884A2 (pt) | 2009-02-04 | 2016-09-06 | Novacta Biosystems Ltd | derivados de actagardina |
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CN102348718A (zh) | 2012-02-08 |
ZA201104991B (en) | 2013-10-31 |
EA021683B1 (ru) | 2015-08-31 |
WO2010082018A1 (en) | 2010-07-22 |
RS53586B1 (en) | 2015-02-27 |
CA2749278A1 (en) | 2010-07-22 |
DK2387580T3 (da) | 2014-10-13 |
SG172944A1 (en) | 2011-08-29 |
TW201029661A (en) | 2010-08-16 |
CN102348718B (zh) | 2015-06-03 |
PT2387580E (pt) | 2014-10-30 |
ES2520165T3 (es) | 2014-11-11 |
EP2387580A1 (en) | 2011-11-23 |
AU2010205472A1 (en) | 2011-07-28 |
US8283371B2 (en) | 2012-10-09 |
US20100179207A1 (en) | 2010-07-15 |
AU2010205472B2 (en) | 2013-03-14 |
EA201190071A1 (ru) | 2012-06-29 |
MX2011007313A (es) | 2011-08-04 |
PL2387580T3 (pl) | 2015-01-30 |
SI2387580T1 (sl) | 2014-11-28 |
US8741945B2 (en) | 2014-06-03 |
JP2012515195A (ja) | 2012-07-05 |
IL213927A0 (en) | 2011-07-31 |
EP2387580B1 (en) | 2014-08-13 |
TWI453029B (zh) | 2014-09-21 |
NZ594011A (en) | 2013-12-20 |
KR20110119699A (ko) | 2011-11-02 |
HRP20141084T1 (hr) | 2015-02-13 |
US20120277145A1 (en) | 2012-11-01 |
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