JP6595509B2 - N−スルホニルホモセリンラクトン誘導体、その調製方法及び使用 - Google Patents
N−スルホニルホモセリンラクトン誘導体、その調製方法及び使用 Download PDFInfo
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- JP6595509B2 JP6595509B2 JP2016569948A JP2016569948A JP6595509B2 JP 6595509 B2 JP6595509 B2 JP 6595509B2 JP 2016569948 A JP2016569948 A JP 2016569948A JP 2016569948 A JP2016569948 A JP 2016569948A JP 6595509 B2 JP6595509 B2 JP 6595509B2
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- JP
- Japan
- Prior art keywords
- compound
- oxotetrahydrofuran
- sulfamoyl
- phenyl
- carboxamide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- -1 N-sulfonylhomoserine lactone Chemical class 0.000 title claims description 136
- 238000000034 method Methods 0.000 title claims description 24
- 238000002360 preparation method Methods 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims description 72
- DENPQNAWGQXKCU-UHFFFAOYSA-N thiophene-2-carboxamide Chemical compound NC(=O)C1=CC=CS1 DENPQNAWGQXKCU-UHFFFAOYSA-N 0.000 claims description 55
- 241000894006 Bacteria Species 0.000 claims description 51
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 45
- 201000010099 disease Diseases 0.000 claims description 44
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical compound NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 claims description 42
- 150000003839 salts Chemical class 0.000 claims description 37
- 230000003287 optical effect Effects 0.000 claims description 35
- 239000012453 solvate Substances 0.000 claims description 34
- QJPWUUJVYOJNMH-VKHMYHEASA-N L-homoserine lactone Chemical class N[C@H]1CCOC1=O QJPWUUJVYOJNMH-VKHMYHEASA-N 0.000 claims description 33
- 239000008194 pharmaceutical composition Substances 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 20
- 229940079593 drug Drugs 0.000 claims description 16
- TVFIYRKPCACCNL-UHFFFAOYSA-N furan-2-carboxamide Chemical compound NC(=O)C1=CC=CO1 TVFIYRKPCACCNL-UHFFFAOYSA-N 0.000 claims description 15
- 241000607768 Shigella Species 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 239000003242 anti bacterial agent Substances 0.000 claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
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- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 201000001352 cholecystitis Diseases 0.000 claims description 10
- 206010014665 endocarditis Diseases 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 150000004677 hydrates Chemical class 0.000 claims description 10
- 206010034674 peritonitis Diseases 0.000 claims description 10
- 206010040047 Sepsis Diseases 0.000 claims description 9
- 239000000556 agonist Substances 0.000 claims description 9
- 125000002541 furyl group Chemical group 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000001544 thienyl group Chemical group 0.000 claims description 9
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- 241000606768 Haemophilus influenzae Species 0.000 claims description 8
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- GOLHZPOXCLTFRB-UHFFFAOYSA-N furan-3-carboxamide Chemical compound NC(=O)C=1C=COC=1 GOLHZPOXCLTFRB-UHFFFAOYSA-N 0.000 claims description 8
- 229940047650 haemophilus influenzae Drugs 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
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- 208000035143 Bacterial infection Diseases 0.000 claims description 7
- 241000589242 Legionella pneumophila Species 0.000 claims description 7
- 241000588655 Moraxella catarrhalis Species 0.000 claims description 7
- 208000002606 Paramyxoviridae Infections Diseases 0.000 claims description 7
- 241000607272 Vibrio parahaemolyticus Species 0.000 claims description 7
- 241000607734 Yersinia <bacteria> Species 0.000 claims description 7
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- 229940115932 legionella pneumophila Drugs 0.000 claims description 7
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- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 6
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 6
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- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 5
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- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 claims description 5
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- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims description 4
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- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 claims description 4
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- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 claims description 4
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- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 229960002625 pazufloxacin Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
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- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
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- 235000021317 phosphate Nutrition 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
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- 229920001592 potato starch Polymers 0.000 description 1
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- 229950008679 protamine sulfate Drugs 0.000 description 1
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- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000001047 purple dye Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
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- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960005224 roxithromycin Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
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- 238000013207 serial dilution Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
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- 230000000707 stereoselective effect Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
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- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001608 teicoplanin Drugs 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-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
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- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- QIQITDHWZYEEPA-UHFFFAOYSA-N thiophene-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=CS1 QIQITDHWZYEEPA-UHFFFAOYSA-N 0.000 description 1
- QTWBEVAYYDZLQL-UHFFFAOYSA-N thiophene-3-carbonyl chloride Chemical compound ClC(=O)C=1C=CSC=1 QTWBEVAYYDZLQL-UHFFFAOYSA-N 0.000 description 1
- 229960004089 tigecycline Drugs 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
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- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 1
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- 239000003871 white petrolatum Substances 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
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- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
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Description
本発明は医薬及び化学工業分野に属し、特に、N−スルホニルホモセリンラクトン誘導体、その調製方法、並びにグラム陰性細菌によって引き起こされる疾患の予防及び/又は治療用の薬剤の製造におけるその使用に関する。
菌体密度の増加の間に、細菌は化学シグナル伝達分子(自己誘導因子とも呼ばれる)を絶え間なく生成することができ、その後それらのシグナル伝達分子は細胞外環境に分泌される。シグナル伝達分子の濃度が閾値に達すると、細菌の関連遺伝子、例えば生物発光、バイオフィルムの形成及び病原性に関連する遺伝子の発現が、環境変化に適応するように調節又は活性化される。そのような調節システムは菌体密度感知(bacterial quorum sensing)(QS)システムとして知られている。
第1の態様では、本発明は、式I
のホモセリンラクトン誘導体、あるいはそのラセミ体若しくは光学異性体、薬学的に許容される塩、溶媒和物、又は水和物を提供する。
(S)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物1);
(S)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−3−カルボキサミド(化合物2);
(S)−5−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物3);
(S)−5−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物4);
(S)−5−ニトロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物5);
(S)−4−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物6);
(S)−4−メチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物7);
(S)−3−メチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物8);
(S)−3−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物9);
(S)−3−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物10);
(S)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−2−カルボキサミド(化合物11);
(S)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−3−カルボキサミド(化合物12);
(S)−5−ニトロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−2−カルボキサミド(化合物13);
(S)−5−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−2−カルボキサミド(化合物14);
(S)−2−メチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−3−カルボキサミド(化合物15);
(S)−4,5−ジブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−2−カルボキサミド(化合物16);
(S)−1H−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ピロール−2−カルボキサミド(化合物17);
(S)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ピリジン−4−カルボキサミド(化合物18);
(S)−6−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ピリジン−3−カルボキサミド(化合物19);
(S)−4−フルオロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物20);
(S)−4−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物21);
(S)−4−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物22);
(S)−3−フルオロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物23);
(S)−3−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物24);
(S)−3−メチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物25);
(S)−2−トリフルオロメチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物26);
(S)−2−フルオロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物27);
(S)−2−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物28);
(S)−2−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物29);
(S)−2−メチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物30);
(S)−2−ニトロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物31);
(S)−2,3−ジクロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物32);及び
の中間体をRCOClで表されるアシルクロリドと反応させて、本発明の第1の態様に記載のホモセリンラクトン誘導体、あるいはそのラセミ体若しくは光学異性体、薬学的に許容される塩、溶媒和物、又は水和物を得る、ステップを含む、方法に関する。
のとおりである。
(S)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−2−カルボキサミド(化合物11);
(S)−2−フルオロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物27);及び
(S)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物1);
(S)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−3−カルボキサミド(化合物2);
(S)−5−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物3);
(S)−5−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物4);
(S)−4−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物6);
(S)−4−メチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物7);
(S)−3−メチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物8);
(S)−3−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物9);
(S)−3−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物10);
(S)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−2−カルボキサミド(化合物11);
(S)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−3−カルボキサミド(化合物12);
(S)−5−ニトロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−2−カルボキサミド(化合物13);
(S)−2−メチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−3−カルボキサミド(化合物15);
(S)−1H−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ピロール−2−カルボキサミド(化合物17);
(S)−4−フルオロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物20);及び
(S)−4−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物21)、
からなる群から選択される。
本発明で使用される用語及び語句は当業者に周知の一般的な意味を有するが、それらが本明細書で具体的に定義されている場合、本明細書に定義された意味が優先するものとする。
本発明は、細胞の通常の生理学的機能に干渉することなく病原性細菌の病原性遺伝子の発現を調節することによって病原性細菌から病原性能力を奪い、したがって抗菌剤の開発の新たな方向性と考えられる、一連の新たな菌体密度感知制御剤を提供する。これらの中でも、菌体密度感知阻害剤は、グラム陰性細菌によって引き起こされる様々な疾患、例えば心内膜炎、腹膜炎、胃腸炎、胆嚢炎、膀胱炎、下痢、膿胸、及び敗血症を予防し及び/又は治療するために抗生物質と組み合わせて使用することができ;そして特に、既存の抗生物質に感受性でない薬剤耐性グラム陰性細菌によって引き起こされる疾患の予防及び/又は治療における使用に適している。
本発明はさらに、以下の中間体及び実施例によって説明される。しかしながら、これらの中間体及び実施例は本発明をより詳細に説明するためだけに使用されると理解されるべきであり、いかなる方法によっても本発明を制限するものとして理解されるべきではない。
[中間体1の調製](L)−ホモセリンラクトン臭化水素酸塩
1H-NMR(400MHz, D2O)δppm:8.76(s, 3H), 4.46(t, 1H, J=8.0 Hz,J=7.6Hz), 4.35-4.31(m,2H), 2.56-2.51(m,1H), 2.30-2.27(m,1H); EI-MS(m/z): 102.1 [M+H]+; m.p.220-224℃; [α]D 25= -24.2(c = 0.1, H2O).
(s)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))アセトアミド
1H-NMR(400MHz, DMSO)δppm:10.33(s, 1H), 8.16(d, 1H, J=8.0 Hz), 7.75(s, 4H), 4.34-4.30(m, 1H), 4.21(m, 1H), 4.08(m, 1H), 2.08-2.06(m, 4H), 1.80(m, 1H); EI-MS(m/z): 299.34 [M+H]+ ; m.p.174-176℃.
(s)−4−アミノ−N−(2−オキソテトラヒドロフラン−3−イル)ベンゼンスルホンアミド
1H-NMR(400MHz, DMSO)δppm:7.72(d, 1H, J=9.2 Hz), 7.45(d, 2H, J=8.4 Hz), 6.61(d, 2H, J=8.8 Hz), 5.95(m, 2H), 4.21(m, 2H), 4.09(m, 1H), 2.06(m, 1H), 1.78(m, 1H); EI-MS:m/z = 256.4 [M+H]+; m.p.162-165℃.
[実施例1]
(s)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物1)
1H-NMR(400MHz, DMSO)δppm:10.57(s ,1H), 8.25(1H, d, J=8.0 Hz), 8.22(d, 1H, J=8.0 Hz), 8.07(d, 1H, J=8.0 Hz), 7.93(m, 3H), 7.82(d, 2H, J=8.0 Hz), 7.26(d, 1H, J=8.0 Hz), 4.37(m, 1H), 4.23(m, 1H), 4.11(m, 1H), 2.14(m, 1H), 1.84(m, 1H); EI-MS:m/z = 366.9 [M+H]+; m.p.114-119℃.
(s)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−3−カルボキサミド(化合物2)
1H-NMR(400MHz, DMSO)δppm:10.38(s ,1H), 8.42(1H, s), 8.20(d, 1H, J=8.0 Hz), 7.96(d, 2H, J=8.0 Hz), 7.82(m, 2H), 7.68(d, 2H, J=8.0 Hz), 4.37(m, 1H), 4.23(m, 1H), 4.11(m, 1H), 2.14(m, 1H), 1.83(m, 1H); EI-MS:m/z = 367.0 [M+H]+; m.p.212-216℃.
(s)−5−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物3)
1H-NMR(400MHz, DMSO)δppm:10.64(s ,1H), 8.21(d, 1H, J=8.0 Hz), 7.94(m, 3H), 7.82(d, 2H, J=8.0 Hz), 7.32(s, 1H), 4.37(m, 1H), 4.22(m, 1H), 4.10(m, 1H), 2.14(m, 1H), 1.83(m, 1H); EI-MS:m/z = 401.1 [M+H]+; m.p.243-249℃.
(s)−5−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物4)
1H-NMR(400MHz, DMSO)δppm:10.63(s ,1H), 8.21(d, 1H, J=8.0 Hz), 7.91(m, 3H), 7.83(d, 2H, J=8.0 Hz), 7.40(s, 1H), 4.36(m, 1H), 4.22(m, 1H), 4.10(m, 1H), 2.13(m, 1H), 1.83(m, 1H); EI-MS:m/z = 445.0 [M+H]+; m.p.197-199℃.
(s)−5−ニトロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物5)
1H-NMR(400MHz, DMSO)δppm:10.96(s ,1H), 8.23(d, 2H, J=8.0 Hz),8.10(d, 1H, J=8.0 Hz), 7.93(m, 4H), 4.36(m, 1H), 4.21(m, 1H), 4.09(m, 1H), 2.13(m, 1H), 1.83(m, 1H); EI-MS:m/z = 434.2 [M+Na]+; m.p.208-220℃.
(s)−4−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物6)
1H-NMR(400MHz, DMSO)δppm:10.66(s ,1H), 8.24(d, 1H, J=8.0 Hz), 8.12(d, 2H, J=8.0 Hz), 7.94(m, 2H), 7.86(m, 2H), 4.38(m, 1H), 4.23(m, 1H), 4.11(m, 1H), 2.14(m, 1H), 1.84(m, 1H); EI-MS:m/z = 445.0[M+H]+; m.p.197-203℃.
(s)−4−メチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物7)
1H-NMR(400MHz, DMSO)δppm:10.50(s ,1H), 8.23(d, 1H, J=8.0 Hz), 7.94(m, 3H), 7.81(d, 2H, J=8.0 Hz),7.51(d, 1H, J=8.0 Hz), 4.37(m, 1H), 4.23(m, 1H), 4.11(m, 1H), 2.14(m, 1H), 1.83(m, 1H);EI-MS(m/z):381.1[M+H]+; m.p.187-188℃.
(s)−3−メチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物8)
1H-NMR(400MHz, DMSO)δppm:10.36(s ,1H), 8.23(d, 1H, J=8.0 Hz), 7.88(d, 2H, J=8.0 Hz), 7.79(d, 2H, J=8.0 Hz),7.72(m, 1H), 7.06(d, 1H, J=8.0 Hz), 4.36(m, 1H), 4.23(m, 1H), 4.11(m, 1H), 2.14(m, 1H), 1.83(m, 1H); EI-MS:m/z = 381.0[M+H]+; m.p.176-178℃.
(s)−3−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物9)
1H-NMR(400MHz, DMSO)δppm:10.63(s ,1H), 8.23(d, 1H, J=8.0 Hz), 7.96(m, 1H),7.87(d, 2H, J=8.0 Hz), 7.82(d, 2H, J=8.0 Hz), 7.24(d, 1H, J=8.0 Hz), 4.37(m, 1H), 4.23(m, 1H), 4.11(m, 1H), 2.13(m, 1H), 1.83(m, 1H); EI-MS:m/z = 401.3[M+H]+; m.p.219-221℃.
(s)−3−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物10)
1H-NMR(400MHz, DMSO)δppm:10.71(s ,1H), 8.24(d, 1H, J=8.0 Hz), 7.92(m, 1H),7.87(d, 2H, J=8.0 Hz), 7.83(d, 2H, J=8.0 Hz), 7.27(d, 1H, J=8.0 Hz), 4.37(m, 1H), 4.23(m, 1H), 4.11(m, 1H), 2.13(m, 1H), 1.83(m, 1H); EI-MS:m/z = 444.9[M+H]+; m.p.151-154℃.
(s)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−2−カルボキサミド(化合物11)
1H-NMR(400MHz, DMSO)δppm:10.49(s ,1H), 8.18(d, 1H, J=8.0 Hz), 7.96(m, 3H),7.82(d, 2H, J=8.0 Hz), 7.40(d, 1H, J=8.0 Hz), 6.72(d, 1H, J=8.0 Hz), 4.36(m, 1H), 4.23(m, 1H), 4.11(m, 1H), 2.17(m, 1H), 1.86(m, 1H); EI-MS:m/z = 351.1[M+H]+; m.p.195-196℃.
(s)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−3−カルボキサミド(化合物12)
1H-NMR(400MHz, DMSO)δppm:10.28(s ,1H), 8.44(s, 1H), 8.21(d, 1H, J=8.0 Hz), 7.92(m, 5H), 7.02(d, 1H, J=8.0 Hz), 4.36(m, 1H), 4.23(m, 1H), 4.10(m, 1H), 2.13(m, 1H), 1.82(m, 1H); EI-MS:m/z = 351.1[M+H]+; m.p.202-209℃.
(s)−5−ニトロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−2−カルボキサミド(化合物13)
1H-NMR(400MHz, DMSO)δppm:10.97(s ,1H), 8.26(d, 1H, J=8.0 Hz), 7.95(d, 2H, J=8.0 Hz),7.85(m, 3H), 7.71(d, 1H, J=8.0 Hz), 4.37(m, 1H), 4.23(m, 1H), 4.10(m, 1H), 2.13(m, 1H), 1.86(m, 1H); EI-MS:m/z = 396.0[M+H]+; m.p.113-120℃.
(s)−5−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−2−カルボキサミド(化合物14)
1H-NMR(400MHz, DMSO)δppm:10.56(s ,1H), 8.24(d, 1H, J=8.0 Hz), 7.94(d, 2H, J=8.0 Hz), 7.81(d, 2H, J=8.0 Hz), 7.45(d, 1H, J=8.0 Hz), 6.87(d, 1H, J=8.0 Hz),4.36(m, 1H), 4.23(m, 1H), 4.10(m, 1H), 2.13(m, 1H), 1.83(m, 1H); EI-MS:m/z = 453.1[M+Na]+; m.p.190-196℃.
(s)−2−メチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−3−カルボキサミド(化合物15)
1H-NMR(400MHz, DMSO)δppm:10.05(s ,1H), 8.21(d, 1H, J=8.0 Hz), 7.94(d, 2H, J=8.0 Hz), 7.79(d, 2H, J=8.0 Hz), 7.63(d, 1H, J=8.0 Hz), 7.09(d, 1H, J=8.0 Hz),4.36(m, 1H), 4.23(m, 1H), 4.11(m, 1H), 2.53(s, 3H), 2.13(m, 1H), 1.83(m, 1H); EI-MS:m/z = 365.0[M+H]+; m.p.185-187℃.
(s)−4,5−ジブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−2−カルボキサミド(化合物16)
1H-NMR(400MHz, DMSO)δppm:10.66(s ,1H), 8.23(d, 1H, J=8.0 Hz), 7.94(d, 2H, J=8.0 Hz), 7.82(d, 2H, J=8.0 Hz), 7.69(d, 1H, J=8.0 Hz), 4.36(m, 1H), 4.23(m, 1H), 4.11(m, 1H), 2.14(m, 1H), 1.85(m, 1H); EI-MS:m/z = 529.0[M+Na]+; m.p.217-219℃.
(s)−1H−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ピロール−2−カルボキサミド(化合物17)
1H-NMR(400MHz, DMSO)δppm:11.79(d ,1H, J=8.0 Hz), 10.10(s ,1H),8.17(d, 1H, J=8.0 Hz), 7.95(d, 2H, J=8.0 Hz), 7.80(d, 2H, J=8.0 Hz), 7.12(d, 1H, J=8.0 Hz), 7.02(d, 1H, J=8.0 Hz), 6.20(d, 1H, J=8.0 Hz),4.36(m, 1H), 4.23(m, 1H), 4.11(m, 1H), 2.13(m, 1H), 1.83(m, 1H); EI-MS:m/z = 365.0[M+H]+; m.p.170-174℃.
(s)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ピリジン−4−カルボキサミド(7−19)(化合物18)
1H-NMR(400MHz, DMSO)δppm:10.86(s ,1H), 8.81(m, 2H), 8.23(d, 1H, J=8.0 Hz), 7.97(d, 2H, J=8.0 Hz), 7.86(m, 4H), 4.36(m, 1H), 4.23(m, 1H), 4.11(m, 1H), 2.14(m, 1H), 1.83(m, 1H); EI-MS:m/z = 362.1[M+H]+; m.p.174-185℃.
(s)−6−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ピリジン−3−カルボキサミド(化合物19)
1H-NMR(400MHz, DMSO)δppm:10.85(s ,1H), 8.96(d, 1H, J=8.0 Hz), 8.36(d, 1H, J=8.0 Hz), 8.25(d, 1H, J=8.0 Hz), 7.96(d, 2H, J=8.0 Hz), 7.85(d, 2H, J=8.0 Hz), 7.76(d, 1H, J=8.0 Hz), 4.38(m, 1H), 4.23(m, 1H), 4.09(m, 1H), 2.14(m, 1H), 1.83(m, 1H); EI-MS:m/z = 396.1[M+H]+; m.p.190-191℃.
(S)−4−フルオロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物20)
1H-NMR(400MHz, DMSO)δppm:10.58(s ,1H), 8.18(d, 1H, J=8.0 Hz), 7.77(m, 4H), 7.36(d, 2H, J=8.0 Hz), 7.17(dd, 2H, J=8.0 Hz), 4.34(m, 1H), 4.20(m, 1H), 4.09(m, 1H), 3.69(s, 2H),2.09(m, 1H), 1.80(m, 1H); EI-MS:m/z = 393.1[M+H]+ ; m.p.187-194℃.
(S)−4−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物21)
1H-NMR(400MHz, DMSO)δppm:10.57(s ,1H), 8.16(d, 1H, J=8.0 Hz), 7.76(m, 4H), 7.37(m, 4H), 4.33(m, 1H), 4.21(m, 1H), 4.09(m, 1H), 3.70(s, 2H),2.10(m, 1H), 1.80(m, 1H); EI-MS:m/z = 409.2[M+H]+; m.p.169-180℃.
(S)−4−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物22)
1H-NMR(400MHz, DMSO)δppm:10.57(s ,1H), 8.16(d, 1H, J=8.0 Hz), 7.77(m, 4H), 7.52(d, 2H, J=8.0 Hz), 7.29(d, 2H, J=8.0 Hz), 4.33(m, 1H), 4.20(m, 1H), 4.09(m, 1H), 3.68(s, 2H), 2.10(m, 1H), 1.80(m, 1H); EI-MS:m/z = 453.3[M+H]+; m.p.184-186℃.
(S)−3−フルオロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物23)
1H-NMR(400MHz, DMSO)δppm:10.58(s ,1H), 8.16(d, 1H, J=8.0 Hz), 7.76(m, 4H), 7.37(m, 1H), 7.18(m, 3H), 4.32(m, 1H), 4.21(m, 1H), 4.09(m, 1H), 3.73(s, 2H),2.10(m, 1H), 1.80(m, 1H); EI-MS:m/z = 393.2[M+H]+; m.p.175-177℃.
(S)−3−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物24)
1H-NMR(400MHz, DMSO)δppm:10.59(s ,1H), 8.18(d, 1H, J=8.0 Hz), 7.76(m, 4H), 7.37(m, 4H), 4.33(m, 1H), 4.21(m, 1H), 4.09(m, 1H), 3.73(s, 2H),2.10(m, 1H), 1.80(m, 1H); EI-MS:m/z = 409.1[M+H]+; m.p.188-190℃.
(S)−3−メチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物25)
1H-NMR(400MHz, DMSO)δppm:10.58(s ,1H), 8.18(d, 1H, J=8.0 Hz), 7.78(m, 4H), 7.16(m, 4H), 4.33(m, 1H), 4.20(m, 1H), 4.08(m, 1H), 3.73(s, 2H),2.11(m, 1H), 1.80(m, 1H); EI-MS:m/z = 389.1[M+H]+; m.p.191-193℃.
(S)−2−トリフルオロメチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物26)
1H-NMR(400MHz, DMSO)δppm:10.63(s ,1H), 8.18(d, 1H, J=8.0 Hz), 7.74(m, 6H), 7.53(m, 2H), 4.33(m, 1H), 4.22(m, 1H), 4.08(m, 1H), 3.98(s, 2H),2.10(m, 1H), 1.81(m, 1H); EI-MS:m/z = 443.3[M+H]+; m.p.197-198℃.
(S)−2−フルオロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物27)
1H-NMR(400MHz, DMSO)δppm:10.62(s ,1H), 8.17(d, 1H, J=8.0 Hz), 7.76(m, 4H), 7.19(m, 4H), 4.32(m, 1H), 4.21(m, 1H), 4.06(m, 1H), 3.78(s, 2H), 2.11(m, 1H), 1.80(m, 1H); EI-MS:m/z = 393.3[M+H]+; m.p.185-186℃.
(S)−2−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物28)
1H-NMR(400MHz, DMSO)δppm:10.64(s ,1H), 8.18(d, 1H, J=8.0 Hz), 7.78(m, 4H), 7.44(m, 4H), 4.33(m, 1H), 4.21(m, 1H), 4.08(m, 1H), 3.89(s, 2H), 2.11(m, 1H), 1.81(m, 1H); EI-MS:m/z = 409.2[M+H]+; m.p.223-228℃.
(S)−2−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物29)
1H-NMR(400MHz, DMSO)δppm:10.65(s ,1H), 8.18(d, 1H, J=8.0 Hz), 7.79(m, 4H), 7.62(d, 1H, J=8.0 Hz), 7.42(m, 2H), 7.22(m, 1H), 4.34(m, 1H), 4.22(m, 1H), 4.08(m, 1H), 3.91(s, 2H), 2.13(m, 1H), 1.83(m, 1H); EI-MS:m/z = 475.2[M+Na]+; m.p.227-229℃.
(S)−2−メチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物30)
1H-NMR(400MHz, DMSO)δppm:10.56(s ,1H), 8.17(d, 1H, J=8.0 Hz), 7.78(m, 4H), 7.16(m, 4H), 4.35(m, 1H), 4.21(m, 1H), 4.08(m, 1H), 3.73(s, 2H), 2.10(m, 1H), 1.81(m, 1H); EI-MS:m/z = 389.2[M+H]+; m.p.208-210℃.
(S)−2−ニトロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物31)
1H-NMR(400MHz, DMSO)δppm:10.66(s ,1H), 8.18(d, 1H, J=8.0 Hz), 8.08(d, 1H, J=8.0 Hz),7.75(m, 5H), 7.59(m, 2H), 4.34(m, 1H), 4.21(m, 1H), 4.18(s, 2H), 4.08(m, 1H), 2.11(m, 1H), 1.81(m, 1H); EI-MS:m/z = 420.4[M+H]+; m.p.216-219℃.
(S)−2,3−ジクロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物32)
1H-NMR(400MHz, DMSO)δppm:10.67(s ,1H), 8.17(d, 1H, J=8.0 Hz), 7.77(m, 4H), 7.56(d, 1H, J=8.0 Hz),7.36(m, 2H), 4.34(m, 1H), 4.20(m, 1H), 4.08(m, 1H), 3.97(s, 2H), 2.11(m, 1H), 1.81(m, 1H); EI-MS:m/z = 443.3[M+H]+; m.p.230-237℃.
本発明の菌体密度感知制御剤の活性は以下の方法により測定することができる。
1.1 調製作業:試験すべき化合物(実施例1〜32で調製された化合物1〜32及び中間体1〜3)を秤量し、次いで200μlのDMSO(ジメチルスルホキシド)に個別に溶解して、0.065Mの濃度で溶液を調製した。5.0mgのインデューサーである、N−ヘキサノイルホモセリンラクトン(C6−HSL、Sigma Companyから購入した)を秤量し、200μlのDMSOに(0.125Mの濃度で)溶解し、化合物及びインデューサーをその後の使用のためにすべて4℃で保存した。C.ビオラセウム(C.violaceum)CV026(テキサス州立大学のMcLean J C教授から提供された、細菌は野生型クロモバクテリウム・ビオラセウム(Chromobacterium violaceum)ATCC31532のTn−5突然変異体である;Latifi、A.ら、Mol.Microbiol、17,333〜343(1995)及びWinson、M.K.ら、Proc.Natl.Acad.Sci.USA,92,9427〜9431(1995)を参照のこと)を30℃、200rpmでシェーカーで振とうしながら培養した。
2.1 12ウェルプレートのウェルを、初期濃度群、2、4、8、16、32、64、128、及び256倍希釈群、DMSO群、ならびにブランク対照群として、左から右へそして上から下へ、それぞれマークした。
Claims (19)
- Rがチエニル、フリル、ピロリル、ピリジル及びベンジルから選択される基であり、ここで、
当該チエニル、フリル、ピロリル、及びピリジルは、任意に、ハロゲン、トリフルオロメチル、ニトロ、及びC1~6アルキルからなる群から選択される置換基によって一置換又は多置換(例えば、二置換若しくは三置換)されており;かつ
当該ベンジルは、ハロゲン、トリフルオロメチル、ニトロ、及びC 1~6 アルキルからなる群から選択される置換基によって一置換又は多置換(例えば、二置換若しくは三置換)されている、
請求項1に記載のホモセリンラクトン誘導体、あるいはそのラセミ体若しくは光学異性体、薬学的に許容される塩、溶媒和物、又は水和物。 - Rが、チエニル、クロロチエニル、ブロモチエニル、ニトロチエニル、メチルチエニル、フリル、ニトロフリル、ブロモフリル、メチルフリル、ジブロモフリル、ピロリル、ピリジル、クロロピリジル、フルオロベンジル、クロロベンジル、ブロモベンジル、メチルベンジル、ニトロベンジル、トリフルオロメチルベンジル、及びジクロロベンジルからなる群から選択される、請求項1に記載のホモセリンラクトン誘導体、あるいはそのラセミ体若しくは光学異性体、薬学的に許容される塩、溶媒和物、又は水和物。
- 前記ホモセリンラクトン誘導体が、以下:
(S)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物1);
(S)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−3−カルボキサミド(化合物2);
(S)−5−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物3);
(S)−5−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物4);
(S)−5−ニトロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物5);
(S)−4−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物6);
(S)−4−メチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物7);
(S)−3−メチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物8);
(S)−3−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物9);
(S)−3−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))チオフェン−2−カルボキサミド(化合物10);
(S)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−2−カルボキサミド(化合物11);
(S)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−3−カルボキサミド(化合物12);
(S)−5−ニトロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−2−カルボキサミド(化合物13);
(S)−5−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−2−カルボキサミド(化合物14);
(S)−2−メチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−3−カルボキサミド(化合物15);
(S)−4,5−ジブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))フラン−2−カルボキサミド(化合物16);
(S)−1H−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ピロール−2−カルボキサミド(化合物17);
(S)−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ピリジン−4−カルボキサミド(化合物18);
(S)−6−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ピリジン−3−カルボキサミド(化合物19);
(S)−4−フルオロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物20);
(S)−4−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物21);
(S)−4−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物22);
(S)−3−フルオロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物23);
(S)−3−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物24);
(S)−3−メチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物25);
(S)−2−トリフルオロメチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物26);
(S)−2−フルオロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物27);
(S)−2−クロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物28);
(S)−2−ブロモ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物29);
(S)−2−メチル−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物30);
(S)−2−ニトロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物31);及び
(S)−2,3−ジクロロ−N−(4−(N−(2−オキソテトラヒドロフラン−3−イル)スルファモイル)フェニル))ベンゼンアセトアミド(化合物32);
から選択される、請求項1に記載の式Iのホモセリンラクトン誘導体、あるいはそのラセミ体若しくは光学異性体、薬学的に許容される塩、溶媒和物、又は水和物。 - 前記式3の中間体が、ホモセリンラクトン臭化水素酸塩をアセチルスルファニリルクロリド(acetylsulianilyl chloride)と反応させることによって調製される、請求項5に記載の方法。
- 請求項1〜4のいずれか一項に記載のホモセリンラクトン誘導体、あるいはそのラセミ体若しくは光学異性体、薬学的に許容される塩、溶媒和物、又は水和物、及び、任意に1又は複数の薬学的に許容される担体又は賦形剤を含有する、医薬組成物。
- 少なくとも1つの抗生物質をさらに含有する、請求項7に記載の医薬組成物。
- 菌体密度感知制御剤(例えば、菌体密度感知阻害剤又はアゴニスト)としての使用のための、請求項1〜4のいずれか一項に記載のホモセリンラクトン誘導体、あるいはそのラセミ体若しくは光学異性体、薬学的に許容される塩、溶媒和物、又は水和物を含有する医薬組成物。
- 細菌の感染によって引き起こされる疾患の予防及び/又は治療における使用のための、請求項1〜4のいずれか一項に記載のホモセリンラクトン誘導体、あるいはそのラセミ体若しくは光学異性体、薬学的に許容される塩、溶媒和物、又は水和物を含有する医薬組成物。
- 前記細菌がグラム陽性細菌又はグラム陰性細菌である、請求項10に記載の医薬組成物。
- 前記細菌がグラム陰性細菌である、請求項10に記載の医薬組成物。
- 前記グラム陰性細菌が、大腸菌、バチルス・ニューモニエ、バチルス・プロテウス、赤痢菌、ブルセラ菌、インフルエンザ菌、パラインフルエンザ菌、モラクセラ・カタラーリス、アシネトバクター属、エルシニア属、パスツレラ属、赤痢菌属、百日咳菌、パラ百日咳菌、腸炎ビブリオ、レジオネラ・ニューモフィラ、及びコレラ菌からなる群から選択される、請求項11又は12に記載の医薬組成物。
- 前記細菌の感染によって引き起こされる疾患が、心内膜炎、腹膜炎、胃腸炎、胆嚢炎、膀胱炎、下痢、膿胸、及び敗血症から選択される、請求項10に記載の医薬組成物。
- 菌体密度感知によって引き起こされる疾患の予防及び/又は治療における使用のための、請求項1〜4のいずれか一項に記載のホモセリンラクトン誘導体、あるいはそのラセミ体若しくは光学異性体、薬学的に許容される塩、溶媒和物、又は水和物を含有する医薬組成物。
- 前記菌体密度感知によって引き起こされる疾患が、グラム陰性細菌、例えば大腸菌、バチルス・ニューモニエ、バチルス・プロテウス、赤痢菌、ブルセラ菌、インフルエンザ菌、パラインフルエンザ菌、モラクセラ・カタラーリス、アシネトバクター属、エルシニア属、パスツレラ属、赤痢菌属、百日咳菌、パラ百日咳菌、腸炎ビブリオ、レジオネラ・ニューモフィラ、又はコレラ菌によって引き起こされる疾患である、請求項15に記載の医薬組成物。
- 前記グラム陰性細菌によって引き起こされる疾患が、心内膜炎、腹膜炎、胃腸炎、胆嚢炎、膀胱炎、下痢、膿胸、及び敗血症から選択される、請求項16に記載の医薬組成物。
- 前記疾患が、抗生物質に感受性でない細菌の薬剤耐性株によって引き起こされる疾患である、請求項16又は17に記載の医薬組成物。
- イン・ビボ又はイン・ビトロで菌体密度感知制御機構を研究するためのツール薬としての使用のための、請求項1〜4のいずれか一項に記載のホモセリンラクトン誘導体、あるいはそのラセミ体若しくは光学異性体、薬学的に許容される塩、溶媒和物、又は水和物を含有する医薬組成物。
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