JPS61126082A - Aminopyrrolidone derivative, its ester and its salt - Google Patents
Aminopyrrolidone derivative, its ester and its saltInfo
- Publication number
- JPS61126082A JPS61126082A JP59247629A JP24762984A JPS61126082A JP S61126082 A JPS61126082 A JP S61126082A JP 59247629 A JP59247629 A JP 59247629A JP 24762984 A JP24762984 A JP 24762984A JP S61126082 A JPS61126082 A JP S61126082A
- Authority
- JP
- Japan
- Prior art keywords
- dihydro
- carboxylic acid
- ester
- compound
- methyl
- 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.)
- Granted
Links
- 150000002148 esters Chemical class 0.000 title claims abstract description 19
- 150000003839 salts Chemical class 0.000 title claims description 14
- LSROBYZLBGODRN-UHFFFAOYSA-N 1-aminopyrrolidin-2-one Chemical class NN1CCCC1=O LSROBYZLBGODRN-UHFFFAOYSA-N 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 125000005843 halogen group Chemical group 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- SBMSLRMNBSMKQC-UHFFFAOYSA-N pyrrolidin-1-amine Chemical class NN1CCCC1 SBMSLRMNBSMKQC-UHFFFAOYSA-N 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 46
- 239000002253 acid Substances 0.000 abstract description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 abstract description 7
- 239000003242 anti bacterial agent Substances 0.000 abstract description 3
- 125000000524 functional group Chemical group 0.000 abstract description 3
- 239000012442 inert solvent Substances 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- 150000001735 carboxylic acids Chemical class 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- -1 1 Chemical compound 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 238000007796 conventional method Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- WGOWOSXVPSBDEY-UHFFFAOYSA-N 3-methylpyrrolidin-3-amine Chemical compound CC1(N)CCNC1 WGOWOSXVPSBDEY-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XNIVKSPSCYJKBL-UHFFFAOYSA-N 2h-1,2-benzoxazine-6-carboxylic acid Chemical compound O1NC=CC2=CC(C(=O)O)=CC=C21 XNIVKSPSCYJKBL-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- YCAZALSUJDPQPP-UHFFFAOYSA-N 4-oxo-3h-quinoline-3-carboxylic acid Chemical compound C1=CC=C2C(=O)C(C(=O)O)C=NC2=C1 YCAZALSUJDPQPP-UHFFFAOYSA-N 0.000 description 1
- UNVQHSVRIOLLPZ-UHFFFAOYSA-N 5-methylpyrrolidin-3-amine Chemical compound CC1CC(N)CN1 UNVQHSVRIOLLPZ-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 208000010824 fish disease Diseases 0.000 description 1
- 239000005452 food preservative Substances 0.000 description 1
- 235000019249 food preservative Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 150000003388 sodium compounds Chemical class 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は優れた抗菌活性を示す新規アミノピロリジン誘
導体、そのエステルおよびその塩に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel aminopyrrolidine derivatives, esters thereof and salts thereof which exhibit excellent antibacterial activity.
更に詳しくは、本発明の化合物は下記一般式（式中、Ｘ
はハロゲン原子を意味し、
Ｙは窒素原子またはＣ−Ｒを意味し、ここにＲは水素原
子、・・ロゲン原子を表わし、あるいはＲ５と共に５〜
６員環を形成してもよく、Ｒ＋およびＲ２は同一まだは
異なって、水素原子または低級アルキル基を意味し、あ
るいはＲ１およびＲ２が互に結合して３〜７員環を形成
してもよく、
Ｒ３およびＲ４は同一または異なって、水素原子または
低級アルキル基を意味し、
Ｒ５は低級アルキル基、低級アルケニル基、／クロプロ
ピル基または低級アルキルアミノ基を意味する。More specifically, the compound of the present invention has the following general formula (wherein X
means a halogen atom, Y means a nitrogen atom or C-R, where R represents a hydrogen atom,...a halogen atom, or together with R5, 5 to
A 6-membered ring may be formed, and R+ and R2 are the same or different and represent a hydrogen atom or a lower alkyl group, or R1 and R2 may be combined with each other to form a 3- to 7-membered ring. Often, R3 and R4 are the same or different and represent a hydrogen atom or a lower alkyl group, and R5 represents a lower alkyl group, a lower alkenyl group, a /clopropyl group, or a lower alkylamino group.
但し、Ｙが窒素原子である場合には、Ｒ５は低級アルキ
ルアミノ基であり、Ｙが式Ｃ−Ｒで表わされる基であっ
てかつＲ５が７クロプロピル基または低級アルキルアミ
ノ基でない場合には、Ｒ３は低級アルキル基である。）
で表わされるアミノピロリジン誘導体、そのエステルお
よびその塩である。However, when Y is a nitrogen atom, R5 is a lower alkylamino group, and when Y is a group represented by the formula CR and R5 is not a 7-chloropropyl group or a lower alkylamino group, , R3 is a lower alkyl group. ) Aminopyrrolidine derivatives, esters thereof, and salts thereof.
式〔１〕において、ＲとＲ５が結合して５〜６員環を形
成する場合の例は、下記の構造を有する一般式で示され
る。In formula [1], an example where R and R5 combine to form a 5- to 6-membered ring is shown by the general formula having the following structure.
（式中、ｎは整数ｌまたば２を意味し、Ｘ、Ｒｒ。(In the formula, n means an integer l or 2, X, Rr.
Ｒ２、Ｒ３およびＲ４は前掲と同じ。）本発明の化合物
の塩は、酢酸、乳酸、コノ・り酸。R2, R3 and R4 are the same as above. ) The salts of the compounds of the present invention are acetic acid, lactic acid, cono-phosphoric acid.
メタンスルホン酸、マレイン酸、マロン酸、クルコン酸
等の有機酸との塩、ア、スパラギ／酸、グルタミン酸等
のアミノ酸との塩、或いは塩酸、リン酸等の無機酸との
塩、成いは式〔１〕の化合物のナトＩＪウム。Salts with organic acids such as methanesulfonic acid, maleic acid, malonic acid, curconic acid, etc., salts with amino acids such as acetic acid, glutamic acid, or salts with inorganic acids such as hydrochloric acid, phosphoric acid, etc. A sodium compound of formula [1].
カリウム、亜鉛、銀等の金属塩、或いは有機塩基との塩
である。These are metal salts such as potassium, zinc, and silver, or salts with organic bases.
弐〔１〕の化合物のエステルとは、化合物（、Ｉ）のメ
チルエステル、エチルエステル等の低級アルキルエステ
ル、或いは加水分解することによシ又は生体内で容易に
脱離されて化合物（１）になる様な公知のエステル、例
えばピバロイルオキシメチルエステル。The ester of the compound (2) [1] refers to a lower alkyl ester such as methyl ester or ethyl ester of the compound (I), or a compound (1) that is easily eliminated by hydrolysis or in vivo. Known esters such as pivaloyloxymethyl ester.
エトキンカルボニルオキシエチルエステル、ジメチルア
ミンエチルエステルや１−ヒペリシニルエチルエステル
等のアミノエチルエステル類、５−インダニルエステル
、フタリジルエステル等を意味する。Etquin carbonyloxyethyl ester, aminoethyl esters such as dimethylamine ethyl ester and 1-hypericinylethyl ester, 5-indanyl ester, phthalidyl ester, and the like.
本発明の化合物は、また水和物としても存在しうる。従
って、この様な形のものも当然本発明の化合物に包含さ
れる。Compounds of the invention may also exist as hydrates. Therefore, such forms are naturally included in the compounds of the present invention.
本発明の化合物は、そのピロリジン環上に不斉炭素原子
を有するので、光学異性体として存在し得る。The compound of the present invention has an asymmetric carbon atom on its pyrrolidine ring and therefore can exist as optical isomers.
従って、これらの光学異性体は本発明の化合物に包含さ
れる。Therefore, these optical isomers are included in the compounds of the present invention.
更にまた、本発明化合物のある種のものは、そのピロリ
ジノ環上に２個の不斉炭素原子を有することができ、従
って異なる立体異性体（／ス型、トランス型）として存
在し得る。これらの立体異性体もまた、本発明の化合物
に包含される。Furthermore, certain of the compounds of the present invention may have two asymmetric carbon atoms on their pyrrolidino ring and therefore may exist as different stereoisomers (/s, trans). These stereoisomers are also included in the compounds of the present invention.
本発明の化合物の中で、好ましい化合物は次のようなも
のである。Among the compounds of the present invention, preferred compounds are as follows.
７−（３−アミノ−３−メチル−１−ピロリジニル）−
６，８−ジフルオロ−１−エチル−１，４−ジヒドロ−
４−オキツキノリ／−３−カルボン酸７−（３−アミノ
−４−メチル−１−ピロリジニル）−６，８−ジフルオ
ロ−１−エチル−１，４−ジヒドロ−４−オキソキノリ
ノ−３−カルボン酸７−（３−アミノ−３−メチル−１
−ピロリジニル）−６−フルオロ−１−メチルアミノ−
１，４−ジヒドロ−４−オキシキノリンー３−カッＣホ
゛ン酸７−（３−アミノ−４−メチル−１−ピロリジニ
ル）−６、８−ジフルオロ−１−メチルアミノ−１゜４
−ジヒドロ−４−オキソキノリン−３−カルボン酸
７−（３−アミノ−３−メチル−１−ピロリジニル）−
６−フルオロ−１−メチルアミノ−１，４−ジヒドロ−
４−オキソ−１，８−ナフチリジン−３−カルボン酸
７−（３−アミノ−１−ピロリジニル）−６−フルオロ
−１−メチルアミノ−１，４−ジヒドロ−４−オキソ−
１，８−ナフチリジン−３−カルボン酸７−（３−アミ
ノ−１−ピロリジニル）−１−７クロプロピルー６−フ
ルオロー１．４−ジヒドロ−４−オキソキノリン−３−
カルボン酸
７−（３−アミノ−４−メチル−１−ピロリジニル）−
６−フルオロ−１−ビニル−１，４−ジヒドロ−４−オ
キソキノリン−３−カルボン酸１Ｏ−（３−アミノ−３
−メチル−１−ピロリジニル）−２、３−ジヒドロ−９
−フルオロ−３−メチル−７−オキンー７Ｈ−ピリド（
１，２，３−ｄｅ）［１，４］ベンゾオキサジ／−６−
カルボン酸８−（３−アミノ−４−メチル−１−ピロリ
ンニル）−９−フルオロ−５−メチル−６，７−ジヒド
ロ−ｌ−オキソ−ＩＨ，５Ｈ−ベンゾ〔ＩＪ〕キノリジ
ン−２−カルボン酸
およびそれらのエステルおよびそれらの塩。7-(3-amino-3-methyl-1-pyrrolidinyl)-
6,8-difluoro-1-ethyl-1,4-dihydro-
4-oxoquinolino/-3-carboxylic acid 7-(3-amino-4-methyl-1-pyrrolidinyl)-6,8-difluoro-1-ethyl-1,4-dihydro-4-oxoquinolino-3-carboxylic acid 7 -(3-amino-3-methyl-1
-pyrrolidinyl)-6-fluoro-1-methylamino-
1,4-dihydro-4-oxyquinoline-3-kacphonic acid 7-(3-amino-4-methyl-1-pyrrolidinyl)-6,8-difluoro-1-methylamino-1゜4
-dihydro-4-oxoquinoline-3-carboxylic acid 7-(3-amino-3-methyl-1-pyrrolidinyl)-
6-Fluoro-1-methylamino-1,4-dihydro-
4-oxo-1,8-naphthyridine-3-carboxylic acid 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-methylamino-1,4-dihydro-4-oxo-
1,8-Naphthyridine-3-carboxylic acid 7-(3-amino-1-pyrrolidinyl)-1-7 clopropyl-6-fluoro1,4-dihydro-4-oxoquinoline-3-
Carboxylic acid 7-(3-amino-4-methyl-1-pyrrolidinyl)-
6-Fluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1O-(3-amino-3
-methyl-1-pyrrolidinyl)-2,3-dihydro-9
-Fluoro-3-methyl-7-okine-7H-pyrido (
1,2,3-de)[1,4]benzoxadi/-6-
Carboxylic acid 8-(3-amino-4-methyl-1-pyrrolinyl)-9-fluoro-5-methyl-6,7-dihydro-l-oxo-IH,5H-benzo[IJ]quinolidine-2-carboxylic acid and their esters and their salts.
本発明の化合物の製造法につき以下に説明する。The method for producing the compound of the present invention will be explained below.
本発明の化合物は、下記一般式
（式中Ｚは後記ピＣＩ ＩＪレジン類置換しうる官能基
を意味し、ｘ、ｙおよびＲ５は前掲と同じ。）で表わさ
れるカルボン酸またはそのエステル（好ましくは低級ア
ルキルエステル）と下記一般式（式中Ｒｒ 、 Ｒ２、
Ｒ３およびＲ４は前掲と同じ。）で表わされるピロリジ
ン類を反応せしめ、生成物を常法により単離することに
より製造することができるＯ
式〔■〕のＺで示した反応性官能基としては、アリール
スルホニル、低級アルキルスルホニル、ノｈロゲン原子
、低級アルコキン、低級アルキルチオ、低級アルキルス
ルフィニル、アリールスルホニルオキシ。The compound of the present invention is a carboxylic acid or an ester thereof (preferably is a lower alkyl ester) and the following general formula (in the formula Rr, R2,
R3 and R4 are the same as above. ) can be produced by reacting pyrrolidines represented by O and isolating the product by a conventional method. The reactive functional group represented by Z in formula [■] includes arylsulfonyl, lower alkylsulfonyl, Norogen atom, lower alkokene, lower alkylthio, lower alkylsulfinyl, arylsulfonyloxy.
低級アルキルスルホニルオキシ等が挙げられる。Examples include lower alkylsulfonyloxy.
本反応は、エタノール、アセトニトリル、ジオキサン、
ジメチルホルムアミド、トルエン、キ７レンの如き不活
性溶媒中、１０〜１８０°Ｃ１好ましくは２０〜１５０
°Ｃにおいて、原料化合物〔■〕またはそのエステルと
（［）とを５〜１２０分間、通常は２０〜６０分間混合
攪拌することにより実施できる。原料化合物（［）の原
料化合物（ＩＩ）またはそのエステルに対する使用量は
当量ないしや＼過剰量である。原料化合物（ｎ）または
そのエステルのＺの官能基の種類により、反応の結果塩
酸等の酸が副生ずるので、かかる場合には酸受容体を使
用するのが一般的であるが、原料化合物（１）を過剰に
用い、酸受容体としての役割を兼ねさせてもよい。This reaction uses ethanol, acetonitrile, dioxane,
In an inert solvent such as dimethylformamide, toluene, xylene, 10 to 180°C, preferably 20 to 150°C.
This can be carried out by mixing and stirring the raw material compound [■] or its ester and ([) at °C for 5 to 120 minutes, usually for 20 to 60 minutes. The amount of starting compound ([) to be used is equivalent to or in excess of starting compound (II) or its ester. Depending on the type of functional group Z in the starting compound (n) or its ester, an acid such as hydrochloric acid may be produced as a by-product as a result of the reaction. In such cases, it is common to use an acid acceptor; 1) may be used in excess to serve as an acid acceptor.
また、本反応で使用される原料化合物（［）は、可能な
らば、そのＲ２ンＮ一部をアセチル等で保護した形で用
い、反応完了後常法によりその保護基を除去してもよい
。In addition, if possible, the raw material compound ([) used in this reaction may be used in a form where its R2-N is partially protected with acetyl, etc., and after the completion of the reaction, the protecting group may be removed by a conventional method. .
更にまた、Ｒ５が低級アルキルアミノ基である原料化合
物（Ｉｔ）は、そのＲ５の低級アルキルアミノ部分をホ
ルミル等で保護した形で用い、反応完了後常法によりそ
の保護基を除去してもよい。Furthermore, the starting compound (It) in which R5 is a lower alkylamino group may be used with the lower alkylamino moiety of R5 protected with formyl, etc., and the protecting group may be removed by a conventional method after the reaction is completed. .
原料化合物〔１〕は、参考例１に記載の方法あるい（以
下 余 白）
この様にして得られる本発明化合物がエステルである場
合、そのエステル部分を常法により加水分解することに
よって、式〔］〕の化合物に変換することができる。更
には、必要に応じ式〔（〕の化合物を常法によりエステ
ル化し、式〔１〕の化合物のエステルに導くこともでき
る。Starting compound [1] can be prepared by the method described in Reference Example 1 (see below) or, if the compound of the present invention obtained in this way is an ester, by hydrolyzing the ester moiety by a conventional method. It can be converted into a compound of formula []]. Furthermore, if necessary, the compound of formula [(] can be esterified by a conventional method to lead to an ester of the compound of formula [1].
この様にして製造される本発明の化合物は、常法に従い
単離、精製される。単離、精製条件によって、塩の形、
遊離カルボン酸や遊離アミンの形で得られるが、これら
は、目的に応じて相互に変換され、目的とする形の本発
明の化合物が製造される。The compound of the present invention produced in this manner is isolated and purified according to conventional methods. Depending on the isolation and purification conditions, the salt form,
Although it is obtained in the form of a free carboxylic acid or a free amine, these can be mutually converted depending on the purpose to produce the compound of the present invention in the desired form.
本発明の化合物の立体異性体（７ス型、トランス型）は
、通常の方法、例えば分別結晶、クロマトグラフィ分離
等により、互いに分離することができる。Stereoisomers (7s form, trans form) of the compounds of the present invention can be separated from each other by conventional methods, such as fractional crystallization, chromatographic separation, etc.
尚、ンス型あるいはトランス型の配置を有する化合物（
［１）を用い、上記方法（１）によって、それぞれンス
型、トランス型の配置を有する本発明の化合物を製造す
ることもできる。 。In addition, compounds with nce-type or trans-type configuration (
[1) can also be used to produce compounds of the present invention having trans-type and trans-type configurations, respectively, by the above method (1). .
本発明の化合物の光学異性体は、公知の方法を適用する
ことによって、分離することが可能である。Optical isomers of the compounds of the present invention can be separated by applying known methods.
かくして得られる化合物〔１〕、そのエステルおよびそ
の塩はいずれも新規化合物である。特に化合物〔１〕は
極めて優れた抗菌活性を示すので、抗菌剤として価値あ
るものである。化合物（１）まだはその塩はこれを人体
および、動物用医薬は勿論のこと、魚病薬、農薬、食品
の保存剤等としても使用することが可能である。また、
化合物（１）のエステル体は化合物〔］〕の合成原料と
して勿論価値あるものであるが、その他にこの化合物が
生体内において容易に化合物〔１〕に変換する場合には
、化合物ＣＩ）と同等の作用効果を発揮しうるので、製
剤的見地からも有用な化合物である。Compound [1] thus obtained, its ester, and its salt are all new compounds. In particular, compound [1] exhibits extremely excellent antibacterial activity and is therefore valuable as an antibacterial agent. Compound (1) and its salts can be used not only as medicines for humans and animals, but also as medicines for fish diseases, agricultural chemicals, food preservatives, and the like. Also,
The ester form of compound (1) is of course valuable as a raw material for the synthesis of compound []], but if this compound is easily converted into compound [1] in vivo, it is equivalent to compound CI). It is a useful compound from a pharmaceutical standpoint as well.
次に本発明の化合物の抗菌活性について、以下に７−′
″−″′ｉｆｆ 、”、°（以７．８゜案）に準じて行
ない、その結果を上記表中に示した。Next, regarding the antibacterial activity of the compounds of the present invention, 7-'
The results are shown in the table above.
本発明の化合物を人に抗菌剤として使用する場合、その
投与量は、年令１体重、症状、投与経路、投与回数等に
よシ異なるが、１日当り５■〜５ｙを１回ないし数回に
分けて投与することが推奨される。投与経路は経口、非
経口のいずれでもよい。When the compound of the present invention is used as an antibacterial agent in humans, the dosage varies depending on age, body weight, symptoms, route of administration, number of administrations, etc., but the dosage is 5 to 5 years once to several times per day. It is recommended that the drug be administered in separate doses. The route of administration may be either oral or parenteral.
本発明の化合物は原末のままでもよいが、通常製剤用担
体と共に調製された形で投与される。その具体例として
は、錠剤、カプセル剤、顆粒剤、細粒剤。Although the compound of the present invention may be administered as a bulk powder, it is usually administered in a prepared form together with a pharmaceutical carrier. Specific examples include tablets, capsules, granules, and fine granules.
散剤、シロップ剤、注射剤等が挙けられる。これらの製
剤は常法に従って調製される。経口用製剤担体トシては
、デンプン、マンニット、結晶セルロース。Examples include powders, syrups, injections, etc. These formulations are prepared according to conventional methods. Carriers for oral preparations include starch, mannitol, and crystalline cellulose.
ＣＭＣＮａ等の製剤分野において常用され、かつ本発明
の化合物と反応しない物質が用いられる。注射用担体と
しては、水、生理食塩水、グルコース溶液。A substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention, such as CMCNa, is used. Injectable carriers include water, saline, and glucose solutions.
輸液剤等の注射剤の分野で常用される担体が挙げられる
。Examples include carriers commonly used in the field of injections such as infusion solutions.
次に実施例および参考例を挙げて本発明化合物の製造法
を更に具体的に説明する。Next, the method for producing the compound of the present invention will be explained in more detail with reference to Examples and Reference Examples.
（以下余白）
実施例１
７−（３−アミノ−３−メチル−１−ピロリジニル）−
６、８−ジフルオロ−１−エチル−１，４−ジヒドロ−
４−オキソキノリン−３−カルボン酸１−エチル−６，
７，８−トリフルオロ−】、４ジヒドロ−４−オキソキ
ノリン−３−カルボン酸１．３６ｙ、３−アミノ−３−
メチルピロリジン０．７５Ｆ！。(Left below) Example 1 7-(3-amino-3-methyl-1-pyrrolidinyl)-
6,8-difluoro-1-ethyl-1,4-dihydro-
1-ethyl-6 4-oxoquinoline-3-carboxylate,
7,8-trifluoro-], 4dihydro-4-oxoquinoline-3-carboxylic acid 1.36y, 3-amino-3-
Methylpyrrolidine 0.75F! .
重炭酸ナトリウムｉ、ｏｓｐ、アセトニトリル３０ｒｎ
ｅの混合物を９０〜１００°Ｃで２．５時間加熱攪拌す
る。溶媒を減圧で留去した後、水を加え、酢酸でｐＨ８
〜９に調製する。今後、析出結晶をＰ取する。この結晶
を１０チ酢酸に溶かし、活性炭処理した後、２８チアン
モニア水でｐＨ８〜９に調製する。今後、析出結晶を戸
数し、７−（３−アミノ−３−メチル−１−ピロリジニ
ル）−６，８−）フルオロ−１−エチル−１，４−ジヒ
ドロー４−オキンキノリン−３−カルボン酸１．２５Ｐ
を得るａ ｍ、ｐ、 ２５１ ２５３°Ｃ０実施例２
１０−（３−アミノ−３−メチル−１−ピロリジニル）
−９−フルオロ−３−メチル−２，３−ジヒドロ−７−
オキンー７Ｈ−ピリド（１，２，３−ｄｅ）（１，４）
ベンゾオキサジン−６−カルボン酸９．１０−ジフルオ
ロ−３−メチル−２，３−ジヒドロ−７−オキンー７Ｈ
−ピリド〔１，２，３−ｄｅ）（１，４）ベンゾオキサ
ジ／−６−カルボン酸５６０ｍｇと３−アミノ−３−メ
チルピロリジン３００ｒｎｇを実施例１と同様に反応処
理して、１Ｏ−（３−アミノ−３−メチル−１−ピロリ
ジニル）−９−フルオロ−３−メチル−２，３−ジヒド
ロ−７−オキソ−７Ｈ−ピリド（１，２，３−ｄｅ）（
１，４）ベンゾオキサジン−６−カルボン酸５０Ｍを得
る。クロロホルム−エタノールから再結晶スる。ｍ、ｐ
、２５４−２５５”Ｃ０
実施例３
７−（３−アミン−３−メチル−１−ピロリジニル）−
６−フルオロ−１−メチルアミノ−１，４−ジヒドロ−
４−オキソキノリ／−３−カルボン酸（１）６．７−ジ
フルオロ−１−メチルアミノ−１゜４−ジヒドロ−４−
オキソキノリン−３−カルボン酸エチルエステル１．０
ｙ、３−アミノ−３−メチルピロリジン０．５３ｐ、）
リエチルアミン１．５ ｍｅ 、エタノール２０ｄの混
合物を９０〜１００°Ｃで３時間加熱攪拌する。溶媒を
減圧で留去した後、残渣に水を加え、クロロホルムで抽
出する。抽出液を無水硫酸ナトリウムで乾燥した後、溶
媒を減圧で留去する。残渣をアセトニトリルより再結晶
して、７−（３−アミノ−３−メチル−１−ピロリジニ
ル）−６−フルオロ−１−メチルアミノ−１，４−ジヒ
ドロ−４−オキソキノリン−３−カルボン酸エチルエス
テル０．５２０ｍｅの混合物を９０〜１００”Ｃで５分
間加熱攪拌する。反応液を活性炭で処理した後、酢酸で
ｐＨ６〜７に調整する。今後、析出結晶を戸数して、７
−（３−アミノ−３−メチル−１−ピロリジニル）−６
−フルオロ−１−メチルア、ミノ−１，４−ジヒドロ−
４−オキソキノリ／−３−カルボン酸３３０〜を得る。Sodium bicarbonate i, osp, acetonitrile 30rn
The mixture in e is heated and stirred at 90 to 100°C for 2.5 hours. After distilling off the solvent under reduced pressure, water was added and the pH was adjusted to 8 with acetic acid.
Prepare to 9. From now on, the precipitated crystals will be subjected to P extraction. The crystals are dissolved in 10-thiacetic acid, treated with activated carbon, and then adjusted to pH 8-9 with 28-thiammonium water. From now on, the precipitated crystals will be counted, and 1. 25P
obtain am, p, 251 253°C0 Example 2 10-(3-amino-3-methyl-1-pyrrolidinyl)
-9-fluoro-3-methyl-2,3-dihydro-7-
Okin-7H-pyrido(1,2,3-de)(1,4)
Benzoxazine-6-carboxylic acid 9.10-difluoro-3-methyl-2,3-dihydro-7-okine-7H
560 mg of -pyrido[1,2,3-de)(1,4)benzoxadi/-6-carboxylic acid and 300 rng of 3-amino-3-methylpyrrolidine were reacted in the same manner as in Example 1. -amino-3-methyl-1-pyrrolidinyl)-9-fluoro-3-methyl-2,3-dihydro-7-oxo-7H-pyrido(1,2,3-de)(
1,4) 50M of benzoxazine-6-carboxylic acid is obtained. Recrystallize from chloroform-ethanol. m, p
, 254-255"C0 Example 3 7-(3-amine-3-methyl-1-pyrrolidinyl)-
6-Fluoro-1-methylamino-1,4-dihydro-
4-oxoquinol/-3-carboxylic acid (1) 6.7-difluoro-1-methylamino-1゜4-dihydro-4-
Oxoquinoline-3-carboxylic acid ethyl ester 1.0
y, 3-amino-3-methylpyrrolidine 0.53p,)
A mixture of 1.5 me of ethylamine and 20 d of ethanol is heated and stirred at 90 to 100°C for 3 hours. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying the extract over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. The residue was recrystallized from acetonitrile to give ethyl 7-(3-amino-3-methyl-1-pyrrolidinyl)-6-fluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate. A mixture of 0.520 me of ester is heated and stirred at 90-100"C for 5 minutes. After treating the reaction solution with activated carbon, the pH is adjusted to 6-7 with acetic acid.
-(3-amino-3-methyl-1-pyrrolidinyl)-6
-Fluoro-1-methyla,mino-1,4-dihydro-
4-oxoquinol/-3-carboxylic acid 330~ is obtained.
ｍ、ｐ、 ２６８ ２７１°Ｃ（分解）。m, p, 268 271°C (decomposed).
実施例４
７−（４−アミノ−２−メチル−１−ピロリジニル）−
６，８−ジフルオロ−１−エチル−１，４−ジヒドロ−
４−オキソキノリン−３−カルボン酸１−エチル−６，
７，８−１−リフルオロ−１，４−ジヒドロ−４−オキ
ソキノリン−３−カルボン酸と４−アミノ−２−メチル
ピロリジンを実施例１と同様に反応処理して、７−（４
−アミノ−２−メチル−１−ピロリジニル）−６，８−
ジフルオロ−１＝エチル−１，４−ジヒドロ−４−オキ
ソキノリ／−３−ｆｔｋカルボン酸る。ｍ、ｐ、 １２
２−１２４°Ｃ０実施例５
７−（３−アミノ−４−メチル−１−ピロリジニル）−
６、８−ジフルオロ−１−エチル−１，４−ジヒドロ−
４−オキソキノリン−３−カルボン酸塩酸塩
（１）１−エチル−６，７，８−１−リフルオロ−１゜
４−ジヒドロ−４−オキツキノリ／−３−カルボン酸１
．５ｐ、３−アセチルアミノ−４−メチルピロリジンｉ
、ｓｙ、重炭酸ナトリウム１．０Ｐ、アセトニトリル３
０ｄの混合物を、攪拌下に８時間加熱還流する。今後、
析出結晶をＰ取する。Ｐ夜に水と酢酸を加えて酸性とし
た後、結晶をＰ取し水洗して、７−（３−アセチルアミ
ノ−４−メチル−１−ピロリジニル）−６、８−ジフル
オロ−１−エチル−１，４−ジフルオロ−４−オキソキ
ノリン−３−カルボン酸合計１．７ｙを得る。ジメチル
ホルムアミドから再結晶する。ｍ、ｐ、２６５−２６８
℃。Example 4 7-(4-amino-2-methyl-1-pyrrolidinyl)-
6,8-difluoro-1-ethyl-1,4-dihydro-
1-ethyl-6 4-oxoquinoline-3-carboxylate,
7,8-1-Lifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 4-amino-2-methylpyrrolidine were reacted in the same manner as in Example 1 to obtain 7-(4
-amino-2-methyl-1-pyrrolidinyl)-6,8-
Difluoro-1=ethyl-1,4-dihydro-4-oxoquinol/-3-ftk carboxylic acid. m, p, 12
2-124°C0 Example 5 7-(3-amino-4-methyl-1-pyrrolidinyl)-
6,8-difluoro-1-ethyl-1,4-dihydro-
4-Oxoquinoline-3-carboxylic acid hydrochloride (1) 1-ethyl-6,7,8-1-refluoro-1°4-dihydro-4-oxoquinoline/-3-carboxylic acid 1
．． 5p,3-acetylamino-4-methylpyrrolidine i
, sy, sodium bicarbonate 1.0P, acetonitrile 3
The mixture of 0d is heated under reflux for 8 hours while stirring. from now on,
The precipitated crystals are collected by P. After making it acidic by adding water and acetic acid overnight, the crystals were collected and washed with water to give 7-(3-acetylamino-4-methyl-1-pyrrolidinyl)-6,8-difluoro-1-ethyl- A total of 1.7y of 1,4-difluoro-4-oxoquinoline-3-carboxylic acid is obtained. Recrystallize from dimethylformamide. m, p, 265-268
℃.
（２）７−（３−アセチルアミノ−４−メチル−１−ピ
ロリジニル）−６，ｓ−ジフルオロ−１−エチル−１，
４−ジヒドロ−４−オキソキノリン−３−カルボン酸１
．０７と２０％塩酸１０−の混合物を１．５時間加熱還
流する。反応液を減圧濃縮し、残漬にエタノールを加え
、結晶をデ取する。水−エタノールより再結晶して、７
−（３−アミノ−４−メチル−１−ピロリジニル）−’
）＋８−ジフルオロ−１−エチル−１，４−ジヒドロ−
４−オキノキノリンー３−カルボン酸塩酸塩０．４８ｙ
を得る。ｍ、ｐ、２７４−２８１°Ｃ０
実施例６
７−（３−アミ７−３−メチル−１−ピロリジニル）−
６−フルオロ−１−メチルアミノ−１，４−ジヒドロ−
４−オキンー１，８−ナフチリジン−３−カルボン酸
７〜クロａ−５−フルオロ−１−ホルミルメチルアミ／
−１、４−ジヒドロ−４−オキソ−１，８−カッチリジ
ン−３−カルボン酸エチルエステル０，６２１．３−ア
ミン−３−メチルピロリシフ０．２３ｙ、 トリエチル
アミン０．３５ｍｅ、アセトニトリル２０ｍ１！の混合
物を室温で１時間攪拌する。溶媒を減圧で留去した後、
残渣に１０チ塩酸Ｌ５ｒｎｅを加えて、９０’Ｃで３時
間加熱する。反応液を減圧で濃縮乾固した後、残漬を水
１０ｒｎｅに溶かし、２８チアンモニア水でアルカリ性
とする。析出結晶をＰ取し、水洗後、乾燥して、７−（
３−アミノ−３−メチル−１−ピロリジニル）−６−フ
ルオロ−１−メチル７ミ／−１。(2) 7-(3-acetylamino-4-methyl-1-pyrrolidinyl)-6,s-difluoro-1-ethyl-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid 1
．． A mixture of 07 and 20% hydrochloric acid 10- is heated to reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, ethanol was added to the residue, and the crystals were collected. Recrystallized from water-ethanol, 7
-(3-amino-4-methyl-1-pyrrolidinyl)-'
)+8-difluoro-1-ethyl-1,4-dihydro-
4-Oquinoquinoline-3-carboxylic hydrochloride 0.48y
get. m, p, 274-281°C0 Example 6 7-(3-ami7-3-methyl-1-pyrrolidinyl)-
6-Fluoro-1-methylamino-1,4-dihydro-
4-Oquine-1,8-naphthyridine-3-carboxylic acid 7-chloroa-5-fluoro-1-formylmethylamine/
-1,4-dihydro-4-oxo-1,8-cathyridine-3-carboxylic acid ethyl ester 0,621.3-amine-3-methylpyrrolisif 0.23y, triethylamine 0.35me, acetonitrile 20ml! The mixture is stirred at room temperature for 1 hour. After distilling off the solvent under reduced pressure,
Add 10% hydrochloric acid L5rne to the residue and heat at 90'C for 3 hours. After the reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in 10 rne of water and made alkaline with 28 thiammonium aqueous solution. The precipitated crystals were collected, washed with water, and dried to give 7-(
3-amino-3-methyl-1-pyrrolidinyl)-6-fluoro-1-methyl 7mi/-1.
４−ジヒドロ−４−オキソ−１，８−ナフチリジン−３
−カルボン酸０．２５ｙを得る。ｍ、ｐ、 ２６０−２
６２°Ｃ０
実施例７
７−（３−アミノ−１−ビロリンニル）−６−フルオロ
−１−メチルアミノ−１，４−ジヒドロ−４−オキソ−
１，８−ナフチリジン−３−カルボン酸７−クロロ−６
−フルオロ−１−ホルミルメチルアミノ−１，４−ジヒ
ドロ−４−オキソ−１，８’−ナフチリジン−３−カル
ボン酸エチルエステルと３−アセチルアミノビロリジン
を、実施例６と同様に反応処理して、７−（３−アミノ
−１−ピロリジニル）−６−フルオロ−１−メチルアミ
ノ−１，４−ジヒドロ−４−オキソ−１，８−ナフチリ
ジン−３−カルボン酸を得る。ｍ、ｐ、２５７−２５９
℃。4-dihydro-4-oxo-1,8-naphthyridine-3
-0.25y of carboxylic acid is obtained. m, p, 260-2
62°C0 Example 7 7-(3-amino-1-virolinyl)-6-fluoro-1-methylamino-1,4-dihydro-4-oxo-
1,8-naphthyridine-3-carboxylic acid 7-chloro-6
-Fluoro-1-formylmethylamino-1,4-dihydro-4-oxo-1,8'-naphthyridine-3-carboxylic acid ethyl ester and 3-acetylaminovirolidine were reacted in the same manner as in Example 6. Thus, 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-methylamino-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained. m, p, 257-259
℃.
参考例１
７−クロロ−６−フルオロ−１−ホルミルメチルアミノ
−１，４−ジヒドロ−４−オキソ−１，８−−１，８−
ナフチリジン−３−カルボン酸エチルエステル５．４１
Ｐ、無水炭酸カリウム５．５２ｐ、ジメチルホルムアミ
ド８０ｍｅの混合物を６０℃で３０分攪拌する。今後、
室温で０−（２，４−）ニトロフェニル）ヒドロキシル
アミン５．２０ｐを加えて一夜攪拌し、不溶物を濾過し
て除く。Ｐ液を５０°Ｃで減圧濃縮し、残渣に水を加え
る。析出結晶をＰ取して、１−アミ／−７−クロロ−６
−フルオロ−１，４−ジヒドロ−４−オキソ−１，８−
ナフチリジン−３−カルボ／酸エチルエステル４．８１
７を得る。アセトニトリルから再結晶する。ｍ、ｐ、
１９８−１９９°Ｃ０（２）水冷下、無水酢酸１０．２
ｍｔ’にぎ酸５．３ ｍＩ！を滴下し、室温で３０分攪
拌する。この溶液に上記化合物４．１０５１’を加えて
室温で２時間攪拌後、反応液を氷水１５０ｍｔ’中に注
ぎ込み、３０分攪拌する。析出結晶をｉｒ取ｔ、水洗し
て、７−クロロ−６−フルオロ−１−ホルミルアミノ−
１，４−ジヒドロ−４−オキソ−１，８−カッチリジン
−３−カルボン酸エチルエステル３．４０ｙを得る。エ
タノールから再結晶する。Reference example 1 7-chloro-6-fluoro-1-formylmethylamino-1,4-dihydro-4-oxo-1,8--1,8-
Naphthyridine-3-carboxylic acid ethyl ester 5.41
A mixture of P, 5.52 p of anhydrous potassium carbonate, and 80 me of dimethylformamide was stirred at 60° C. for 30 minutes. from now on,
Add 5.20 p of 0-(2,4-)nitrophenyl)hydroxylamine at room temperature, stir overnight, and remove insoluble matter by filtration. Concentrate the P solution under reduced pressure at 50°C, and add water to the residue. The precipitated crystals were collected as 1-amino/-7-chloro-6
-Fluoro-1,4-dihydro-4-oxo-1,8-
Naphthyridine-3-carbo/acid ethyl ester 4.81
Get 7. Recrystallize from acetonitrile. m, p,
198-199°C0(2) Under water cooling, acetic anhydride 10.2
mt' formic acid 5.3 mI! was added dropwise and stirred at room temperature for 30 minutes. The above compound 4.1051' was added to this solution and stirred at room temperature for 2 hours, then the reaction solution was poured into 150 mt' of ice water and stirred for 30 minutes. The precipitated crystals were collected by IR and washed with water to give 7-chloro-6-fluoro-1-formylamino-
3.40y of 1,4-dihydro-4-oxo-1,8-cathyridine-3-carboxylic acid ethyl ester is obtained. Recrystallize from ethanol.
ｍ、ｐ、 ２３９ ２４１”Ｃ。m, p, 239 241”C.
（３）上記化合物３．０ｙ、無水炭酸カリウム２．６５
ｙ。(3) The above compound 3.0y, anhydrous potassium carbonate 2.65
y.
ジクロルエタン１５０＋＋＋ｔ’の混合物を１５分間加
熱還流した後、ヨウ化メチル７．５ｄを加えて、更に３
時間加熱還流する。今後、不溶物を濾過して除き、Ｐ液
にクロロホルム５０ｒｒＬｅと水５０ｒｎｌを加える。A mixture of 150+++t' of dichloroethane was heated under reflux for 15 minutes, then 7.5d of methyl iodide was added, and a further 3.5d of methyl iodide was added.
Heat to reflux for an hour. From now on, insoluble matters are removed by filtration, and 50 rrLe of chloroform and 50 rnl of water are added to the P solution.
クロロホルム層を分け、無水硫酸マグネシウムで乾燥後
、溶媒を留去する。残虐を酢酸エチルから再結晶して、
７−４０ロー６−フルオロ−１−ホルミルメチルアミノ
−１，４−ジヒドロ−４−オキノー１，８−ナフチリジ
ン−３−カルボン酸エチルエステル１．８６ｙを得る。The chloroform layer is separated, dried over anhydrous magnesium sulfate, and then the solvent is distilled off. Recrystallize the brutality from ethyl acetate,
7-40 rho 6-fluoro-1-formylmethylamino-1,4-dihydro-4-okino-1,8-naphthyridine-3-carboxylic acid ethyl ester 1.86y is obtained.
ｍ、ｐ、 ２００−２０１’Ｃ。m, p, 200-201'C.
Claims (1)
子、ハロゲン原子を表わし、あるいはＲ＿５と共に５〜
６員環を形成してもよく、Ｒ＿１およびＲ＿２は同一ま
たは異なつて、水素原子または低級アルキル基を意味し
、あるいはＲ＿１およびＲ＿２が互に結合して３〜７員
環を形成してもよく、 Ｒ＿３およびＲ＿４は同一または異なつて、水素原子ま
たは低級アルキル基を意味し、 Ｒ＿５は低級アルキル基、低級アルケニル基、シクロプ
ロピル基または低級アルキルアミノ基を意味する。 但し、Ｙが窒素原子である場合には、Ｒ＿５は低級アル
キルアミノ基であり、Ｙが式Ｃ−Ｒで表わされる基であ
つてかつＲ＿５がシクロプロピル基または低級アルキル
アミノ基でない場合には、Ｒ＿３は低級アルキル基であ
る。） で表わされるアミノピロリジン誘導体、そのエステルお
よびその塩。[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, X means a halogen atom, Y means a nitrogen atom or C-R, where R is a hydrogen atom, a halogen atom, Represents an atom or together with R_5 5~
A 6-membered ring may be formed, and R_1 and R_2 are the same or different and represent a hydrogen atom or a lower alkyl group, or R_1 and R_2 may be bonded to each other to form a 3- to 7-membered ring. , R_3 and R_4 are the same or different and mean a hydrogen atom or a lower alkyl group, and R_5 means a lower alkyl group, a lower alkenyl group, a cyclopropyl group or a lower alkylamino group. However, when Y is a nitrogen atom, R_5 is a lower alkylamino group, and when Y is a group represented by the formula CR and R_5 is not a cyclopropyl group or a lower alkylamino group, R_3 is a lower alkyl group. ) Aminopyrrolidine derivatives, esters thereof and salts thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59247629A JPH0670032B2 (en) | 1984-11-22 | 1984-11-22 | Aminopyrrolidine derivative, its ester and its salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59247629A JPH0670032B2 (en) | 1984-11-22 | 1984-11-22 | Aminopyrrolidine derivative, its ester and its salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61126082A true JPS61126082A (en) | 1986-06-13 |
| JPH0670032B2 JPH0670032B2 (en) | 1994-09-07 |
Family
ID=17166350
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP59247629A Expired - Lifetime JPH0670032B2 (en) | 1984-11-22 | 1984-11-22 | Aminopyrrolidine derivative, its ester and its salt |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0670032B2 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS624284A (en) * | 1985-06-28 | 1987-01-10 | Kyorin Pharmaceut Co Ltd | Pyridonecarboxylic acid derivative and production thereof |
| US4692454A (en) * | 1986-02-03 | 1987-09-08 | Warner-Lambert Company | Opthalmic use of quinolone antibiotics |
| US4771055A (en) * | 1986-07-28 | 1988-09-13 | Warner-Lambert Company | 7-[[3-(aminomethyl)-3-alkyl]-1-pyrrolidinyl]-quinoline-carboxylic acids |
| US4855292A (en) * | 1986-02-25 | 1989-08-08 | Otsuka Pharmaceutical Company, Limited | 1-cyclopropyl-6-fluoro-8-alkyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid derivatives |
| FR2644455A1 (en) * | 1989-03-16 | 1990-09-21 | Esteve Labor Dr | Azetidinyl-substituted pyridonecarboxylic acid derivatives, their preparation and their application as medicaments |
| FR2649106A2 (en) * | 1989-06-29 | 1991-01-04 | Esteve Labor Dr | Derivatives of azetidinyl-substituted pyridonecarboxylic acids, their preparation and their application as medicaments |
| EP0924213A4 (en) * | 1996-09-27 | 2002-10-23 | Daiichi Seiyaku Co | Pyridobenzoxazine derivatives |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5872589A (en) * | 1981-10-28 | 1983-04-30 | Dai Ichi Seiyaku Co Ltd | Pyrido(1,2,3-de)(1,4)benzoxazine derivative |
| JPS591489A (en) * | 1982-06-29 | 1984-01-06 | Dai Ichi Seiyaku Co Ltd | Pyridobenzoxazine derivative |
| JPS5978189A (en) * | 1982-10-26 | 1984-05-04 | Otsuka Pharmaceut Co Ltd | Pyrrolo(3,2,1-ij)quinoline-5-carboxylic acid derivative |
| JPS59106488A (en) * | 1982-12-10 | 1984-06-20 | Dai Ichi Seiyaku Co Ltd | Benzoquinolizine derivative |
| JPS60214773A (en) * | 1984-02-17 | 1985-10-28 | ワ−ナ−−ランバ−ト・コンパニ− | Antibacterial |
| JPS6137781A (en) * | 1984-07-20 | 1986-02-22 | ワーナー‐ランバート・コンパニー | Antibacterial-iii |
-
1984
- 1984-11-22 JP JP59247629A patent/JPH0670032B2/en not_active Expired - Lifetime
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5872589A (en) * | 1981-10-28 | 1983-04-30 | Dai Ichi Seiyaku Co Ltd | Pyrido(1,2,3-de)(1,4)benzoxazine derivative |
| JPS591489A (en) * | 1982-06-29 | 1984-01-06 | Dai Ichi Seiyaku Co Ltd | Pyridobenzoxazine derivative |
| JPS5978189A (en) * | 1982-10-26 | 1984-05-04 | Otsuka Pharmaceut Co Ltd | Pyrrolo(3,2,1-ij)quinoline-5-carboxylic acid derivative |
| JPS59106488A (en) * | 1982-12-10 | 1984-06-20 | Dai Ichi Seiyaku Co Ltd | Benzoquinolizine derivative |
| JPS60214773A (en) * | 1984-02-17 | 1985-10-28 | ワ−ナ−−ランバ−ト・コンパニ− | Antibacterial |
| JPS6137781A (en) * | 1984-07-20 | 1986-02-22 | ワーナー‐ランバート・コンパニー | Antibacterial-iii |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS624284A (en) * | 1985-06-28 | 1987-01-10 | Kyorin Pharmaceut Co Ltd | Pyridonecarboxylic acid derivative and production thereof |
| US4692454A (en) * | 1986-02-03 | 1987-09-08 | Warner-Lambert Company | Opthalmic use of quinolone antibiotics |
| US4855292A (en) * | 1986-02-25 | 1989-08-08 | Otsuka Pharmaceutical Company, Limited | 1-cyclopropyl-6-fluoro-8-alkyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid derivatives |
| US4771055A (en) * | 1986-07-28 | 1988-09-13 | Warner-Lambert Company | 7-[[3-(aminomethyl)-3-alkyl]-1-pyrrolidinyl]-quinoline-carboxylic acids |
| FR2644455A1 (en) * | 1989-03-16 | 1990-09-21 | Esteve Labor Dr | Azetidinyl-substituted pyridonecarboxylic acid derivatives, their preparation and their application as medicaments |
| FR2649106A2 (en) * | 1989-06-29 | 1991-01-04 | Esteve Labor Dr | Derivatives of azetidinyl-substituted pyridonecarboxylic acids, their preparation and their application as medicaments |
| EP0924213A4 (en) * | 1996-09-27 | 2002-10-23 | Daiichi Seiyaku Co | Pyridobenzoxazine derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0670032B2 (en) | 1994-09-07 |
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