TW390879B - Optionally substituted 8-cyano-1-cyclopropyl-7-(2,8-diazabicyclo [4.3.0] nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids having antibacterial activities, their preparation and pharmaceutical composition containing the same - Google Patents

Description

Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (;.) The present invention is related to the novel and substituted 8-cyano-1 -fluorenyl-7 — (2,' 8-Diwei Heterobicyclic [4.3.0] non-δ · " yl) -6-fluoro-1,4-digas-4-oxo-3-phospholine carboxylic acid and its derivative, its preparation method and its antibacterial property组合 物。 Composition. The anti-Wei effect of gadolinium 4 carboxylic acid has been revealed. Therefore, oflokaci price, norfloxacin, cffloxaeirr and danofloxaein are active compounds derived from this substance, which are widely used It is used in war medicine. However, its use has not been satisfactory. The present invention is a substituted 8-cyano-1-cyclopropyl-7- (2, t Diaza ring [4.3.Ό] nonyl) -6-fluoro-1,4-dihydro-4-oxo-3, quinolinecarboxylic acid and its derivatives, I…, (Please read the note on the back first (Please fill in this page for matters)

Wherein R 1 represents 氲, any C i-C 4 substituted with cyle, methoxy, amine, methylamino, or diamine, alkynyl, or (5τfluorenyl-2-oxy · ^ 1, 3_4 Sakimao_4_yl) formamidine * R 2 Qin hydrogen, benzyl, Ci-Cg-alkyl, 5-fluorenyloxy "1,3-di-4 fluoren-4-yl) hydrazine, has a continuation- CH = CH-C00R3, -CH2CH2 C00R3, 2 CN,-(; H 2 CH 2 CoCH 3 or -CH 2 coch 3 ^ where R 3 represents methyl or ethyl, or R4-( NH- -3 A paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm), 1T '-Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (2) CHIP -C〇) tt's group, where R4 represents fluorene, "-C3 -fluorenyl or aryl-yango-tri-n-butyl; Rs represents fluorene, Ci-C4, sulfonyl, fluorenyl, amidinyl, amido, Fluorenyl or benzyl, and h is 1 or 2, and Y is oxygen or fluorine. Compounds of formula (P can be purified as racemates or in the form of a chain structure, as a compound, and on their drugs.) The hydrates and sedatives used, as well as their # formulas of the bases, metals, silver, and guanidinium salts. Any substituted 8 "cyano * · 1-cyclopropyl-7, (2,8-diazabicyclo [4.3.〇] nonyl 7-fluoro-1,4-difluorene 4-oxo-37 pyrene 4-carboxylic acid square barley, characterized by the compound of formula (IΪ) IYII cN A where R 1 and Y have the meaning of the above, and X represents halogen, especially fluorine or chlorine, and formula (In) Diazabicyclo [Ho] non-lin • skin 4 丨 6 > τ4- (Please read the precautions on the back before filling in this page) (Π),

(ΠΙ),

This paper size applies the Chinese National Standard (CNS) A4 specification (21 〇 × 297 mm) A7 B7 Member of the Central Bureau of Standards of the Ministry of Economic Affairs and consumer cooperation Du printed 5. Description of the invention (3) Where R2 has the meaning of stopping mystery, such as = appropriate In this case, noodle 1 and helin are under 6 and then thin if the rope is used, and then soil = 之 ⑴ 迹 to find the H material. Compared with this structurally-like Bazi representative, the root compound has more marriage, staphylococcus, streptococcus, salmonella, and genus. Ask him to ride and listen to the defeated and the family. Rapid degradation in the soil after release is advantageous. The more severe (1) compounds are those in which trans-epihydrogen, 'response, methoxy, amine, methano, or dimethylamino are substituted. Ci-C4-alkyl, or (& _methyl "2 ^ oxy-13 ^ di-4-cene-4-methyl) methyl, ^ Table argon, fluorenyl, Ci_C3 ~ graft group> (5-form Oxo-1,3_di-4cene) fluorenyl group, 棬 Cfl ± clH (: 〇〇R3, a CIUcH2 $ q 3 3, CH 2 Cib CN or, CH 2 COCH 3 group, R R 3 epimethyl or fluorenyl f or the general structure C-(hr_CH | ^ -c〇> n-group 'where R 4 represents hydrogen, C i -C 3 -alkane 4 or radical -COO 丄 tertiary Butyl, R epinitrogen, pl_C4 _line grave's scorch group, amine gauge group > sulphur-based or f-based, 1 η is 1 or 2, and Υepioxy and its pharmaceutically usable Hydrate and acid addition, and the -5- + paper wave scale of these carboxylic acids are applicable to China National Standards (CNS) M specifications (2Η) X 297 mm) (Please read the precautions on the back before filling out (The original)) equipment, 1T A7 B7 V. Description of the invention (4) Alkali gold sound, Alkali metal, watch and instantaneous tincture. #Read the precautions on the back before filling this page.) The best formula <] :) fb preparation is 谲, etc. where R 1 expresses oxygen, C; i-dagger- 蟓 秦, or ί5- 甲 秦 彳-oxygen rl , Shitu "4-based" Shen Qin * Cargo 2 epihydrogen, Shen group, 5-methyl "2-oxo-1,3-Nisaki ^ and group) ▼ group, has the structure -o ^ ch- co plus 3, -cl 2 ch, 2 ί ^ οδ3, CHsCNv or πΗ2 (ϋΟ (: the base of Η3, in which mel 3 represents methyl or ethyl, or the general structure R4-(_ < HR s 4〇) η R4 epioxyl, C: wide C3-alkyl or Qin-C0 (M grade butyl, Rs epioxyl, tickyl, hydroxyalkyl, amine alkyl, amidinyl, chlorinyl's, etc., gray h is 1 or 2 * and y are consumption, λ is a pharmaceutically acceptable hydrate and acid and a salt thereof; fluorene metal, earth metal, silver and guanidinium ash of a carboxylic acid are used as main compounds. For the base d, for example, * using 7-gas 4-cyano-dihydro-4-oxo-3-oxolinecarboxylic acid and 2 ^-; azabispyrene [4,3, q] dioxane (J) Chemical products, response: Mai Beng (formed by the following formula): Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (5) Formula u) A compound can also be obtained by queuing step A: where the compound of formula (π) and After the 2,8-diazabicyclo [4.3.QG dealkylation reaction, further reaction of the product can be carried out. As a result, the compound of formula (I) whose Ci +: R2 is the base and CiH: H〒C00 gt can be obtained as follows:

COOH

(Please read the notes on the back before filling out this page) Which? 1 The compound of formula (J) in Table 1 can be chemically basicized in a known method, N-enezine low or N-halide. For: TN-alkyl group, do you use halogenated R2 halogenated or hydroxide or is it more common than R $? For 7 «-enenization, a pyridine group corresponding to 衿 R 2 is used. For the sake of 艢 基佑, the test should be applied to the Nanhua 醢 长, which is 2 in length, Continue to 4 gas, or anhydride. The domes that can be selected are: benzyl fluoride * C ^ 3 alkyl iodide, bromide or chloride * gas ethane carboxylic acid methyl or ethyl Λ and gas _; alkenyl or missing Bases; methyl propynyl carboxylates into 6 esters, acrylic acid 6 醅 and dienenitrile; and printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. , Gasification of special fluorene and N-tertiary butoxyl Qin-L-propionate carboxylic acid age. The N-alkylation of Fu Yongyi alkane is preferably used in dilute transfer agents, for example, Lishenyi Ν * Ν, Ν-χ Shinky A brewing 腠, ring T 额 I or acetonitrile -7 7- This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (6) Can be converted to acetic acid, oolitic agent, Zhizhiku inorganic and organic acid combined sodium For example, alkali metal oxides, toad metal rhenium carbonate or organic rides. Reverse temperature can be a substantial internal coup of the fungus. General • The reaction is performed between 20 and 200 phantoms, compared to 50 and 150 ¾. Use the fentai of 幡 衿 β 2 and the alkynyl N ~ alkenyl cone corresponding to R 2 in the dilution fee j, for example, Wujia helmet maple ^ Ν, Ν ▲ 二甲Methylamine, well, methylpyrrolidine, 0 diferment, mecoferment or diglycol. The reaction temperature can be changed within the range of quality + quality. In general, the bottom should be carried out at 2Q '200 ° C. * It is better to be in the range of 50 ° C to 8 ° C. The halogenation of ginseng or anhydride corresponding to R2 is used to perform the hydration reaction rather than dilute copper. In, for example, lead infusion [, U-dimethylformamide * or D-diamine or H-methylqinweiluo concealed reaction is performed in the absence of an acid binder or is also poor in the presence of the test The available acids are mixtures of inorganic and organic acid recording agents known in the United States, such as trisamine, 1,4_diazabicyclo ring 2 than octane and diazapyridine ring. 4.〇Η 7 ～ ene〇 Here the anti-killing degree can be changed within the real mouth fan circle. Once lost, the reaction is -10 1C ^ 20〇K_, compared with the silk starter ^ ^ starting compound The formula (ID compound from the United States specifically No. 4 9 mesh 0 S17; is known or can be prepared by known methods. An example of an inch boat is: 7-fluorocyanocycloxin-fluoro ^ , Heptaoxyhydroxancarboxylic acid-8- —. ^ --- Γ ---- 5 $-/ —. (Please read the notes on the back before filling this page) Quasi / 檩 家 格 规 I centimeter 7 9. 2 A7 B7 V. Description of the invention (7) • Oxygen-8-cyanocylenyl-6 -Fluoro-1,4- 工 氲 "4, oxy-3- 嗉 ## 失 甲 甲 _ δ ^ · • 气 秦 _i- 环 高 泰 -6,7_difluoro_1,4_dihydro, 4 ; -Ga-3_peak <#Hexanoic acid 8-cyanocyclopropyl-6,7-buffluro-1,4-dihydro-4-gas "3-Hexylcarboxylic acid 〇_ Here, the formula ( II) Compounds * For example, Yoshikazu (IV) will also deduct the formula IV) ridge 〇 (—methylamino-propionic acid Λ and reaction formula (VI) obtained from the shame and cyclopropyl face Produced by the formula (VIp compound, trout obtained after the combination # M): COOR " NMe2 NH. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page).

(VI) 〇

COCI F CN (IV) (V)

COOR. (VII) In the above formula, X means ϋ, special shave is fluorine or gas, and JTS means ^: 4 alkyl, especially Shenbian -9- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 (Mm) A7 B7 V. Description of the invention (8) Take me 0 It can also directly react the adduct of formula (IV) with monocyclopropylamino-pinene!. Ester reaction:

X CN Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page) 〇

COOR6 .COOR6 COCI / ΝΗ

(IV) (II) (In the formula, X and R6 have the meaning of being addicted). In Yuanqing Shen, the intermediate product [such as the formula αν of * where kd ·) can be prepared according to the following formula: F F

Br: (VIII) F.

COF 1. MeOH -Ψ F] ^ WC〇2Me F 2. CuCN CN COCI 'F-2. SOCI2' CN & (iv)

The starting material of formula 0III is known from DE 3 631 90fe. The reaction of a compound of formula (Π) with a compound of formula (III), wherein compound (III) can also be used in their salt form, for example, hydrazone, and is preferably performed in a dilute solution, such as dimethylarsine, NJ- Dimethylformamide, N-fluorenylpyrrolidone, tartarium hexamethyl phosphate, butanidine, acetonitrile, water, alcohol-10- This paper size applies to China National Standard (CNS) A4 (210X297 (Mm) A7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs __—_ B7_______ 5. Description of the invention (9), such as methanol, ethanol, n-propanol, isopropanol, ethylene di_monomethyl_, or slightly different. Also &gt; A mixture of these diluents can be fun. The acid binding agents that can be used are all conventional and organic acid binding agents. These soaps include, for example, alkali metal hydroxides, alkali metal rot, heptogen carbonate, dome knees, and cymbals. Special mention is made of special fillers. The combined reagents are true ethyl 1,4-diazabicyclo [2.2.2], umane (plus 8 (: 0) 1,8-diazabicyclo [5.4. 0] eleven "7-cockroach ( DBtt) or chloramine (III). The reaction temperature is severe and changes in the garden. Generally, the reaction is performed between 0 and 0 t: * is more than between 20 and 180 ¾. The tail should be carried out under normal pressure. However, it can also be performed under increased friction. Generally, the reaction is performed under the acoustic force between 1 color and 100 bar, rather than between 1 and 10 bar. '' In the port line according to the present invention In the formula, 1 to 15 moles are used for each molecule (Π), preferably 1, to mole, compound (III). The free amidine group may be protected by an appropriate amine protecting group, For example, by using tricolor butoxyquinyl * during the reaction and when the reaction has ended, it can be released again by treatment with an appropriate acid, such as trifluoroacetic acid, such as acetic acid (see g. HpuBen-Weyl »Methoden der Qrggiiisch en Chemi &gt; [Organization method], Vol. E4, p. 144 (1983,); and JFW, Mc0, "mie, Yucheng Chemicals Zhongjun Protection Group (1973), etc. p. 43) The ester can also be obtained by the reaction of an alkali metal salt of a carboxylic acid (on which the compound is a base), which can be preserved by an arbitrary layer on N Fengzi, such as three-butoxycarbonyl * and in Appropriate odontyl derivatives in solvents, such as trimethylformamidine, dimethylacetamidine, and methylline-pyrrolidine-11. This paper size applies to China National Standard (CNS) A4 (210X297 mm) ) IJ --- Γ ----- 4)-^ 11111— ——, ----}: 1'- ...... (Please read the notes on the back before filling this page) A7 B7 V. Description of the invention (10) Ketones, dioxan bricks or tetrashens-at temperatures of about 0 to 100 ° C, compared to about 0 to 50 ° C. Acid addition salts of the compounds according to the invention It can be prepared by known methods, for example, by dissolving betaine in an appropriate amount of an aqueous acid solution and an organic solvent such as methanol, ethyl acetate, acetone, or acetonitrile, which can be easily mixed with water. An equivalent amount of betaine and Water or alcohol For example, the step of ethylene glycol monoethyl ether * and then 'evaporate the mixture to dry or pomegranate over the plaques of tartar. The pharmacologically used trousers are special, such as hydrochloric acid, sulfuric acid, acetic acid, spasm Glycolic acid, lactic acid, succinic acid, arsenic acid, tartaric acid, sulphonic acid, 4-toluenesulfonic acid, epicuronic acid, glucosinolate, pamoic acid, glutamic acid, or aspartic acid In addition, the compound Yang according to the present invention can be combined with the sulfonium ion exchange agent. The acid addition of the te compound according to the present invention can also be made by hydrolyzing the carboxylic esters of the formula (1 &gt;, where R i is, for example, fluorenyl or ethyl, and is quite acidic with dangdang to produce a carboxylic acid of formula (1) * and monoisoacid addition kang obtained from R1 in hydrogen. Printed by the Consumer Cooperative of the Shiyang Standard Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) The alkali metal or alkaline earth metal of carboxyphosphorus according to the present invention can be obtained by, for example, _ 觯 is less than the same amount Alkali takes betaine of the genus or alkaline earth hydroxide solution, which is obtained by filtering undissolved betaine and evaporating the filtrate to dryness. Sodium, potassium or calcium salts are pharmaceutically suitable for private use. These corresponding silver salts are obtained by the reaction of bee metal or alkaline earth with a suitable silver deficiency, such as silver nitrate. Alkali horses or alkaline earth metals according to the present invention can also be obtained by hydrolyzing a few acid esters of formula (I) with a suitable alkali metal or alkaline lambda metal hydroxide solution, where R1 is * Umbrella, methyl ethyl or ethyl, and single-isolated anti-mold-ia- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) A7 B7 V. Metal inspection or acid earth gold (U) Off the salt. These grains according to this # 明 之 化合 # have the effect of being bacteria and a wide range of anti-growth plants that show positive and Gram-staining bacteria, especially against these different antibiotics. For example, cyanobacteria, chrysanthemum, amine f, sulfonamide, and cyclin bacteria, with double low toxicity. These valuable properties make paper bamboo pupa like chemical treatment in medicine and veterinary medicine. Activated preparations are used to preserve inorganic and organic sealants, especially all types of organic materials, such as polymers, lubricants, paints, fiber greens, leather, paper and wood, and food and water. . It is understood that according to the present invention, the ‘thing countermeasure’ is often widely used. With the help of these compounds, school-made, single-lane staining negative and Gram-staining bacteria and bacterial-like symptoms can be spared, and the diseases caused by P. pneumoniae can be reduced and treated. According to the present invention, the most important thing is to remove cockroaches. The difference in role between tadpole bacteria and tadpole waste. The effect of the compounds according to the invention on painful bacteria (which is classified as <Comparative Matter Paperlessness, especially on resistance to Staphylococcus aureus and wood wins) (shows a surprising increase. Central Standard of the Ministry of Economic Affairs) Printed by the Bureau's Consumer Cooperative (please read the precautions on the back before filling out this page) The compounds of the invention according to the present invention which have anti-cellulite and dendritic bacteria have 9 in particular, so they are specially filled for diagnosis due to these pathogens. The high k and systemic infection prevention and chemical therapy, the method of sighing and the furnace of sighs 4 These chemical compounds are also used to wave protozoa and worms. According to the present invention, various kinds of chemical compounds can be used. This week's pharmaceutical age preparation. Compared with -13- this paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) Printed by A7 B7 of the Consumer Cooperatives of the China National Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (Λ /) The pharmaceutical formulations mentioned by Jin Ke are lozenges, lozenges, gum barley, pills, small v. Granules, medicaments, injection solutions, suspensions and emulsions, and solutions prepared by delicious thieves. Tincture and emulsion Gels, creams, lotions, powders and sprays. Those active compounds are fortunate enough to develop bacterial diseases that affect animal and pet animals, pets, pets, pets, pets, and pets, It really has a tendency to be beneficial to the blood and the food. Here we are active against all or individual stages of development and resistance to antibiotics and normal singing. The use of baht compounds should be reduced; &gt;, 4 diseases that attack bacteria, disease, death, and reduced fertility (such as meat * milk * wool, rawhide, eggs * honey and similar car production), so economic and easy animal husbandry is possible. Home and feeding animals include mammals such as cattle, horses, sheep, pigs, goats, camels, buffalo, donkeys, birds, deer, perch, hairy animals, such as mule, millet And Wan bears and birds, such as chickens, turkeys, turkeys, ducks, pigeons, and black birds as pets and Qinyang Garden. They include domestic breeding, and decorative fishes, greedy animals, and anchor animals. , Rat, sky silicon rat, golden rat, dog _1. Post some pet soaps including dogs and bismuth. Π-like * has been proven to be beneficial in the amount of bran per kilogram of smoked body per day (K5 to about 50 mg, preferably 1 to 29 ¾ grams, active compounds are The active composition can also be administered to feed with feed or rose water-14- (Please read the precautions on the back before filling this page) This paper applies the Chinese national standard ( CNS) A4 size (210X297 mm)

5. Description of the invention (13). Hook materials and foods contain 0.01 to 1 ⑽ppm, preferably 0.5 to 50 p⑽ of active hydrazone compounds, which are combined with common edible materials. The food and food can be used for treatment purposes and prevention purposes. The feed or food is prepared from a concentrated starting material or a mash mixture, which contains 0.5 to 3 p% * preferably 1 to 20% by weight of the active compound mixed with an edible organic or inorganic carrier, and conventional hook materials . The harsh foods are, for example, the main noodle soup or maize and soybean flour or minerals, which contain less roots than the plant: inch edible dust-proof oil, such as maize oil or soybean oil. The resulting pre-mix can then be ingested completely before it is fed to the animals. The minimum inhibitory price of the compounds according to the invention i) is determined by * serial dilution method on isa-Sensitest agar (0xο i d). For each test substance, a series of petri dishes containing active compounds, each of which was diluted by a double dilution, were prepared. Agar m was inoculated with a multi-point inoculator (Dertley). The pathogen was cultured so well that it was previously diluted so that each inoculated tadpole contained approximately 10 'colony-forming particles for defeating gold. Agar blood was inoculated at 37 ° C: cultured and recorded for bacterial growth after about 20 hours. The MIC image (g / ml) picked up with the naked eye indicates the minimum concentration of activated substances _ washed and found to grow. After 5 to 7 days of incubation period, the MIC value of Eupatorium was recorded under the apparent chain. The MI (; value of one of the compounds according to the present invention is compared with the love and ertrof 1 oxacjiη) of the compound Qin Kao Nian, which is shown in the table below.豕 Standard (CNS) Α4 specification (210 × 297 mm) ----- ^ -----, / ίχ (Please read the notes on the back before filling out this page) Order printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economy A7 B7 V. Description of the invention (14) Table 1 Hie value (sign A / ml) Species strain Example 1 Rufusler E. coli Ec 9658 0. 004 0. 03 Salmonella S 9659 0.06 0.5 Pseudomonas aeruginosa P 9503 0 25 1.0 B. bronchitis B 9610 0.125 0. 5 pleuropneumoniae Actinomycete App 0 6/94 0. 008 0.06 Staphylococcus aureus St 2941 0.015 0.125 S. aureus See 9549 0.03 0.5 S. suis See 9593 0.06 0.5 pyogenes Am 9602 0. 25 1.0 b 0 V i Mycoplasma H 9548 0.015 0.25 i 〇 Mycoplasma M 95144 0.06 0.5 Mycoplasma hominis H 9557 0.004 0.06 Clostridium Ao 9620 0.03 4.0 Clostridium perfringens Ct 9606 0.25 4.0 ▼

--------- τ ^-— —, ((Please read the notes on the back before filling out this page), 1T Printed on the Blood Dynamics of the Consumer Cooperatives of the Central Standards Bureau Staff of the Ministry of Economic Affairs f, compared with the test paper composition iridfloxacin, _ Ming Deshao, the substance of the substance, the metabolic kinetic properties of the substance according to Example 1 of the present invention. The substance was tested at 5 mg per kg. The body-child-like agent fainted in a message for 6 beagles &lt; dogs. Intravenous (iy) t Intramuscular (i.ni.) and mouth gland rescue modal use and Jian Pingjiao Suppose that the fiber can be used for all proofs of morality. It can be used from the material poor condition of the collection example 1 according to the present invention. The percentage image (C_ax) of the high and high field of Taiqing and Qingyuan. Long life survey (ti 2) And _ long residence time (MRT) 'and the larger chapter 16 ^ This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm)

7 A

B V. Description of the invention (15) The quality is effective to the organism (below the serum content curve, AUC.-2 4). k__2_ Pharmacokinetic data Example 1 Intramuscular Oral Intramuscular Oral Cmax [Neck / ml] / 2.4 1.3 / 2.1 1.0 [hour] 10.5 6.9 9.5 3.7 2.9 4.3 MRT [hour] 11.5 8.5 14.7 4.2 3.9 7.3 'auc〇_24 [Nike · Hours / ml] 20.0 19.8 17.4 10.4 8.4 7.0 By feeding 20 kg of young pigs with 150 ppm of anatomical manure, and enrof (enrof 1 oxac iη) comparatively proves the improved consumption acceptance of the compound according to the inventive example \ 1. When the animals refused to consume only 50 ppm of the food containing avian rufoss, the substance according to the invention was eaten without problems within 15 minutes without any residue. Preparation of Active Compounds Example 1

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) 8-cyano-cyclopropyl-7- ((1S.6S) -2,8-diazabicyclo [ 4.3.0] non-8-yl) -6-fluoro-1,4, dihydro-4-oxo-3-quinoline [4-carboxylic acid-17- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 Mm)

2. Description of the invention (w 6 ^ ° mg (2. yesterday Moore) of Buqi-8, cyano-1-pyridyl fluoride '' k-year-old Qin, oxyquinoline carboxylic acid and 31? Mg pf Mo Ear) (1 heart, BU 2 * 8-diazabicyclo &amp; · 3 · 0] nonane and 5 (H mg (4.50: mmol-U-diazapyridine ring [2.2.2] _ Xin _ (MBC intends to slash the & ^ shank with 6 liters of red cyanide, 6 milliliter of red nitrile to combine the wealth-from room temperature expansion to remove all Solution to 邡 7, pumping and removing is not wrong, to: air hoodie turn, and the recording line merges like the organic phase of the foot and thicken under the real home. Repeat rate: 650 耷 first (beat%) Bright zero: 246 ^ 24 $ tr (decomposed) tMM ^ 2 8: cyano-Η, *-? 刼 刼 心 书 双环 ⑽p] -kplug) -6 ^ fluoro-1,4-earthine-4-oxo-3-jun Geocarboxylic acid ridges are filled with 5.00 g of U2.6 millimolar) of 8,6-amino-n-cyclopropylu (1S, 6S) U-diazabifluorene [々., (^ Non ^ "group Fabry ^ heptahydrogen ^ oxygen-3-44 carboxylic acid was stirred in 95 ml of 4N hydrochloric acid / -oxane (1 i) at t for two hours. The anti-horse mixture was rolled under vacuum, and ethanol was removed from the mixture. Re_Crystal Residue. In a single U.4S beam (82% of theory) Melting point: 280t: (Tiller) Huiwei Example 3 8-Cyano-Qin-1-Hydroxypropyl "7-((H &amp; S) -2, δ-; azabicyclo [4,3,0] non-8 diyl) -6-fluoro -1,4-'di-A-4-oxo t3-Sakirin after acid and acid -18- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) Employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the cooperative A7 _____ ^ _ B7__ 5. Description of the invention (17) 獠 250 mg (0. q 亳 years) 8-cyano-1-cyclopropyl-7- ((13, 6 capacity) -2, § -Diazepine heterobicyclo [4,3Ά] 4-S · yl) "6-air dioxo, 4-ox ^ 3-xanthroline was dissolved in 2 ml of this solution, and isomethylsulfonic acid was added. The solution was stirred at room temperature. The 30-minute turn is then injected into 20% wells of alcohol. The formed precipitate is removed by suction pumping, and dried after boiling. Rate: 201 mg (theoretical 6S) Ficus point: U8-124 ° C Example 4 8-Cyanoid-cyclopropyl ((H6S)-厶 δ "diazepine ring [4.3jQQ Non" fluorenyl group> -6-fluorene "1,4-dioxoline 50 mg (0 A3 mmol) of 8-cyano-1 j-cyclopropyl_7-((1S, '/ \' diazabicyclo 3, .0]今 -δ- 基) -6 ^ • Ga-1,4-dihydro-4 "oxygen-3-fluorene 4 carboxylic acid No ^ mM, green water, and as the equivalent amount of methanesulfonic acid baicalensis. Ning mix was stirred at room temperature and then poured into Bin min 2〇_ liter hexanol. Recognize radon gas and remove the formed phosphorus, then dry. Yield: 309 Cork (theoretical jealousy) Doped: 2 ^ -23 ° C Example 5 8-cyano. ^ 1τcyclopropyl-7- (0S, 6S) diazabicyclo [ 4 · 3 · 0] -8-8-yl) fluorohydro-4-oxofluorene 4 carboxyhydroxanthlofluoroacetate 塩 f-20Q millibeam ((^ 5p deaf mole) 8-cyano-i-cyclopropane ((IS, Di) -2,8-diazabifluorene U,. 3.0] ΐ -δ- 奉) -6-fluoro-U ^ Dihydrogen 4 ″ oxygen-3-azolin carboxylic acid suspended in 3mL of Z etc. was added in the amount of trifluorodonic acid. The formed sulphate was heated under a stream of neodymium for 30 minutes and then cooled #. Zhufu fluoride-19 ^ ^ 1- n ^ — — ^ 1 ι ^ ϋ .1 ^^ 1 mt n \ nyi m ^ n— mm ·· m ^ — \ i, next to f, words /, _ \. (Please read the notes on the back before filling this page) This paper size is applicable to China Standard rate (CNS) A4 specification (210X2.97 mm) A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs “Five-kilometers Shen Shu and washed with ether. Repeat rate: 208 grams (not to mention the machine钐) 璿 点 17¾¾ Example 6 ^ Cyano-1τcycloyuyl-7, [(1Melon 6 &gt;) -2- (2, ethoxycarbonyl-ethenyl) A &gt; diazepine bicyclic [4U] Non-δ-yl] -6-fluoro-ί, 4-dioxo 4-phosphonocarboxylic acid

COOH 400 mg (1.01 mmol) of 8-cyano-I-fluorenyl, 6S) -2,8-present aza double-stroke tC 3.0] non-8-yl) -δ-fluoro4,4 ^ · Hydrogen, 4-oxy-3-44 after beryllium and 1.03 liters (10.1 Binmol J propanoic acid ester in H0 ° C? · 5mmol #_ 秦 乙 孑 醇Small special. The reaction is melted and concentrated in a vacuum, the anti-residue is touted with water and pumped over. Please change the production parameters from ethanol # knot A 9 Yield: 30E mg (61% of theory) Melting point: 180 -18lt! R2〇- This paper size is applicable to China National Standard (CNS) A4 specification (210X297mm) (Please read the precautions on the back before filling this page) • Packing. Order A7 B7 V. Description of Invention (19) Supervisor Example 7

COOH

8-cyano is printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. Cyclopyryl-7-U1S, 6S) -2- (5-methyl-2-oxo-1,3 molybdenum f group) -2,8-diazabifluorene [4.3.0] non- 8t-based) -6-fluoro-1,4-dihydro-present-oxy-3 ^ 4line carboxyl marginal 100 mg (25 millimoles) 8-cyano-bucyclopropyl-74 (1S, 6S) 1, δ-Diazabispyridine [4,3,0] non-8 ^ Qin Bu 6- 氱 4,4-Dipyridine-4-oxo-3 · 1 Sakirin post enzyme '59 mg (0.30 Φ Mo Ear) of 4-Ajia tomb 丄 5-methine-1,3-di-imazamo-2-one and 30 mg potassium potassium bicarbonate Table 140 ° C in 2 ml of dimethylformamide to heat the work clock. The reaction solution was concentrated in vacuum, the salty residue was treated in S gas level and alkane, and the mixture was washed with water. The organic phase was scaled with nickel persulfate and dried in a vacuum. The resulting residue was stirred with water, filtered with suction and dried. Yield: 99 mg (thin T7 谛) Melting point: 175aC (Unknown solution) -21- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) ---- Γ ---- f ' -装 l ·-(Please read the precautions on the back before filling this page) Order A7 B7 0

COOH V. Description of the invention (10) Example 8 You will be less \ vp 8-cyanoτ cyclopropyl-7-[(find, 65, 2 ~ (3, ma-methyl) -2,8-benzyl Heterobicyclo [4.3.0] de-8-yl &gt; 8-cyano-6-fluoro-1,4-dihydro-4-oxo-3-post-leaching acid 300 mg (0.7 &amp; 1-fluorenyl-7-((15,65) di-2,8-molazabicyclo [4.3.0] non.8.yl) -6-fluoro, 1,4-dihydro-4-oxofluorene Hemolyte and 0.63 ml (7.6 millimolar) of 'methaqin vinyl' were instantaneously heated under reflux in 5 liters of methyl ethylene glycol for 2 hours. The anti-shaming solution was shrinked in vacuum, and the residue and Water τ from alkali mixed with pomegranate gas. Yield: 2 milligrams (% of shovel theory)

Melting point: 158-1 &amp; 0 ° C Example 9 (Please read the notes on the back before filling this page) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 〇

COOH

8-cyano-1-cyclopropyl-7, [(1S, 6S) -2- (? -Cyanofluorenyl) -2, exhaust-diaza-22- This paper applies Chinese national standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (21) Bicyclic [4.3.0] nonyl) -β-fluoro-1,4, dihydro, -4-oxolinate acid '00 millibeam (1 , (Η 亳 mol) the helyl-1-cyclopropanine "7 _ ((1S3S) -2,?-Diazabifluorene [4.3.0] non-8" feng) fluororl, 4-di Hydrogen-4.oxy-3-hydrazone &lt; 4-acetic acid and 1.03 ml (10.1 mmol 4) of acrylonitrile were finally heated. C was heated in 7.5 ml of methyl ethyl alcohol for 1 hour. The reaction was dissolved in a vacuum. f \ Concentration, and the residue is stirred with water and dried up. The crude product produced is recrystallized from ethanol. Yield; 136 mg (theoretical nail percentage). Point: 250 ¾ Example 10 (please first (Read the notes on the back and fill out this page)

8-cyanocyclopropyl-7, [(1S, 6 $) (2-oxypropylbuth 2,8-diazabicyclo [4.3.0]), printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, 8-yl) fluoro-1 * 4-dioxo-4-oxo-3-phospholine carboxylic acid was similar to Example 7 to obtain the title compound by reacting φ with oxyacetone. Melting: 74-75¾ A 23- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (22) Example 11 0

.COOH Η

Name-Cyano-Cyclopropyl 4-((iS, 6Sp2-a-Ethylcarbonylcarbonyl) -2,8-shirazine ring_ [4. 泰] _6-fluororl, 4, Dihydro-4 -列 -3 ^ 峰 "## Compilation is similar to Example 8. Example 8 The title compound was obtained by anti-friction with ethyl acrylic acid. Molten green: U3, 150 ° C Supervision 12

COOH (Read the precautions on the back before filling this page) xHCl Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Static Economics 8-cyanopin 4-Chuo Ruiji-7-[(13,65) 4 ((5)- Propionyl> -2, Heart blanket / Nitrogen-free bicyclo [4.3, Q] non-Qin] -Mr-I, 'Jiang Hydrogen-Cardio oxygen_3_Zolinoline carboxylic acid hydrazone will be 50 deaf grams (0 · 63 millimoles) -fang-Cyclobutanyl_7, dl $, 6S) -2 'Gas heterobicyclo [4.3,0 | &gt; non 48-yl _}-6-fluoro-1,4- Dihydro-4- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X 297 mm) A7 B7 V. Description of the invention (23) Gas-3-carboxine acid, 1 Qiu, 4 g (0:69 Millimoles) N-tertiary butyryl-alanine-N-_Suyan and 12.5 mg of H, N-dimethylaminopyridine were dissolved in 7.5 ml of difamidamine. The solution was stirred at room temperature for 3 hours and then concentrated in true asparagus. 20 liters of 4N hydrochloric acid / f f, alkane (1: 1) were added to the residue and the mixture was added at 50 ° C for 3 hours. Reaction rosette 秦 真 食 中 浓 # Then the residue of the produced product was recrystallized from acetonitrile. Yield: 164 mg (theoretical 涔 52) Melting point; 2pt: (decomposition) Example: Example 13 8-cyano-1-cyclopropyl-7- [(1S, 6H-2, (〇〇- 尚 胺Fluorenyl) -2,8-fluorenazaazabicyclo [4 &lt; 3,0: 1non-8-yl] -6-fluoro-1,4-dioxo-4-oxoline ferrate ferrite similar In Example 12, the standard hydrazone compound was obtained by reacting 4N-tertiary butyloxy group and k-propanoic acid N-carboxylic anhydride. Melting point: 213 ° G (decomposition) Example 14 8-cyano-1-cyclopropane K (li 6S) -2, ((S) -Valamine group) -2,8-diazabicyclo [4.3 · 0] nonan-4] -6-fluoro-1,4-dihydro- 4-Oxygen-3-4 Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, Linoleic Acid, Phosphoric Acid and Sodium Phosphate (please read the precautions on the back before filling out this page) Scale similar to Example 12 The reaction of fluorenyl-L-valeric acid with carboxylic acid anhydride gave the title compound. I 黠: 255 ° C (decomposition will give 15 cyano-1-cyclopropyl-t-[(l · S, 6S) -2-((S) -Benzylamine-Tab 2, §- The standard of this paper is Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (24) Each azapine U. 3.0] non-8-yl] -6-an-1,4-dihydro-4-oxygen peak Similar to the following: In Example 12, the title compound was obtained from N-tertiary butoxyfluorenyl-L-like alanine N-carboxylic acid. The melting point: 23 (TC (decomposition) Example 16.: 8-cyano-1-cyclopropyl-7-[(1§, 舫) «(Phenyl-leucine amidinoyl 2,8-diazabicyclo [4 JO] non-8-yl] The acid field of the 6-fluoro-U4-dioxo-4-oxo-3-ol carboxylic acid is similar to that in Example 1. By combining with N-trioxo-oxo-L-myramine Acid anhydride tile should obtain the standard hydrazone compound. Melting point: 270-274 ° C (decomposition) f Example If δ-cyano-1-fluorenyl 4-[&lt; 15,65) -2,8-diazabicyclo [4,3, 〇1] nonyl] -fen-fluoro. 1,4-dioxo, 4-oxo-3-jun acid acid vinegar &quot; 〇 〇

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

(Please read the precautions on the back before filling out this page) 200 mg (0.625 mol) of 8-cyano-1-cyclopropyl ^ 7-chloro- &amp; -fluoro_1,14 hydrogen, heart palpitations Lin Lin Methyl Carboxylate, Mirolone (0.683 mmol) &lt; 1S, 6S) -2, S-Diazabispyrene [4.3.0] nonane and 150 mg rare books Paper size applies Chinese national standard (CNS) A4 specification (210X 297 mm) A7 B7 V. Description of the invention (25 (1TM: 鸯 Mor) H azabipyridine [2.2.2] Xin 粽 at the room temperature in the examination and promotion Stir for 48 small spans. After that, evaporate the mixture, and distribute the residue between 15 liters of gas and 20 gram of saturated sodium sulphate solution. The sample phase is separated, and the water phase is oxyformed again-agricultural — Take the sum, and use the combined solution of Pycnogenol, which is dried with sulfur and sodium, steamed, etc. In order to purify, the phosphorus residue is passed through the silica gel using cardioacetate / ditol / 2% sharpness 4 permanent surface solution Bu Xing color analysis. Yield: 1 ^ 0 mg town water: 23 Γ (decomposition &gt; Du Shi 18 18-cyano-1, ciprofen-7 gas (1§, 6 magic-2, mason nitrogen Heterobicyclo [4.3.〇] 壬 ▲ δ- 举 ·], -4 * ·· P: Oxygen 4 &quot; oxygen ~~ 3_ peak scared after acid fermentation (please first Note Complete this page and then read it back)

〇c2h5

Printed by the Consumers' Cooperative of the China Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China 14.32 (1-milk)-1-cyano boxer **-瓖 Huiji-6 乂 difluoro-1 4-dihydro-4-oxo-3-_4 carboxyl Ethyl Acetate, Alcohol) (1S, J6 S), -2,8_; Azabispyrene [4.3.〇] Alcohol and 10 * 22 g () 0 1 mmol) triethylamine in # 0 ml Boil in reflux for 4 hours. The reaction mixture is left to stand in the whole plague for several hours and it is crystallized out after evacuation. # 厨 体 ， $ 乙 棍 沣 Wash and dry. Obtained 1 L6 g of light brown solid (probably from &amp;

Melting point: 209 to M0 ° C -Z1- This paper standard uses China National Standard (CNS) A4 size (21 OX297 mm) A7 A7 COONa

B7

V. Description of the invention (26) f Example 1Q δ-cyano-cyclopropane 44, [(IS, 6S) -2,8-diazabicyclo [4.1heart] nonyl] -6-fluoro4,4- Sodium dioxo-4-oxo-3-carboxylcarboxylate 萆 0

Will. 12 g (Price 耄 Mor &gt; Hong Hong Cyan 4--cyclopropyl [CIS, 6S> -2, 8-Azabicyclo [4.?. 〇] ren "3-Tomb] Fluoro- L4-dihydroxy-3-quinolinecarboxylic acid hexane and g (5.2 mmol) of sodium hydride were heated under reflux in 10 ml of ethanol for 2 hours. Then most of the ethanol was stripped in vacuum 6 # Hexane was added to the residue, and the resulting solids were filtered and masked to dryness. # Grams of light plum solids were obtained (9 theoretical 9. 9%). Melting point: 235 "(decihertz) Example 20 8-cyanide -Cyclopropyl-6,7_wenfluoro-1,4-dihydroxide, ethyl 3-phosphonium carboxylic acid step phosphorus *: 3 · bromo-2V4,5_trifluorobenzoic acid methyl ester Fxi— 772 g of fluorinated &gt; bromo-2,4, &amp; -trioxo-extracted formamidine was dropped into 1460 ml of methanol and 34Q g of triethylamine, and then cooled with ice. The mixture was cooled at t 28- Standards are applicable to China National Standard (CNS) A4 specifications (210X297 mm) -----------installed l · ii — ordered (please read the precautions on the back before filling this page) Central Bureau of Standards, Ministry of Economic Affairs Printed by the staff consumer cooperative V. Description of the invention (27- A7 B7 Stir for 1 hour at warm temperature. The reaction mixture is concentrated in a vacuum * The raw residue was treated with water and dioxane. The water was taken again with dichloromethane. The organic phase was dried over Na2CO3 and concentrated in vacuo. The resulting residue was distilled in vacuo. Yield : 752.4 g; boiling point: 122 ° C / 20 mbar. Step b: methyl 3-cyano-2,4,5-trifluorobenzoate

The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed a mixture of 269 g of methyl 3-bromo-2,4,5-trifluorobenzoate, 108 g of steel cyanide (I) and 400 ml of diamidinofluoride in Heat under reflux for 5 hours. All the volatile components were distilled off in a vacuum. Fractionation of the resulting mixture gave 133 g of the title compound. Boiling point: 88 * 89 ° C / 0.01 mbar. Step c: Cyano-2,4,5-trifluoro-phenylarsinic acid :. %, CN ^ 156, a solution of 3-cyano-2,4,5-trifluoro-benzoic acid Y ester in a mixture of 960 ml of glacial acetic acid, 140 ml of water and 69 ml of concentrated sulfuric acid was heated to reflux over 8 hour. Hexanoic acid was removed by distillation, and the resulting radon residue was treated with water. The precipitate was filtered under suction, washed with water and dried. Yield: 118.6 g of white solid. Melting point: 137-190 ° C.

Reference, (Please read the notes on the back before filling this page) 29- This paper size is applicable to China National Standard (CNS) 8 4 specifications (210 × 297 mm) A7 B7 V. Description of the invention (28) Step d: Gasification 3 -Cyano-2,4,5-trifluoro "benzidine

F. ^ .COCI

111 g of 3-cyano-2,4,5 "trifluoro-phenylarsinic acid, 84 g of ethylenedicyanide, and a few drops of dimethylamidamine were stirred in 930 ml of dry dichloromethane at room temperature for 5 hours. The reaction mixture was concentrated by evaporation, and the residue was distilled in vacuo. Yield: 117.6 g of a yellow oil. Step e: 2- (3-cyano-2,4,5-trifluoro-benzylidene) -3-dimethylamino-ethyl acrylate (Please read the precautions on the back before filling in this page)

A solution printed by 55 g of 3-cyano-2,4,5-trifluoro-benzidine in 50 ml of methylbenzyl printed by a consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs at a temperature between 50 and 55 ° C Add dropwise to a solution of 36.5 g of diamido-ethyl acrylate and 26.5 g of triethylamine in 14 ml of toluene. After stirring at 50 ° C for 2 hours, the reaction mixture was concentrated in vacuo. The crude product was used in the next step without further purification. Step f: ^-(3-cyano-2,4,5-trifluoro-phenylfluorenyl) -3-cyclopropylamino-ethyl acrylate-30- This paper is sized for China National Standard (CNS) A4 (210X 297 mm) 390879 V. Description of the invention (29) η

Add the sealed bottle to the crude product from step e at 20 t! Then a solution of 15.75 grams of cyclopropylamine in 30 liters of toluene was added dropwise. The reaction mixture was stirred at TC for 1 hour. 9 After adding eight 200 milliliters of water, the mixture was stirred for 15 minutes. The organic phase was separated, extracted with 100 ml of water, dried over Na 2 CO 3; and scaled up in vacuo. The crude yield is less than 4 steps, 4 steps of purification, and 4 steps of one month. Step 骅 g: 8-cyano, cyclopropyl% ^, 7-difluoro 43-1hydro-4, oxo-phospholine-?-Carboxybase ethyl ester

The crude product from step f, a mixture of ^ 7.6 g of R ^ COa and 80 ml of dimethylformamidine phenylene was stirred in a chamber for hours. At this time, the reaction mixture was mainly 750 liters of ice / water, and filtered by suction, and washed with 30 ml of cold methanol and dried. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Yield: 47, grams of Chu compounds.婊 黩: 2Q9-211 ° C q -31- This paper size applies to China National Standard (CNS) A4 (210X297 mm)

Claims (1)

Patent Application No. 86101994 ROC Patent Appln. No. 86101994 Amended Application I 彘 ® + Text 1 Attachment (1) Amended Claims in Chinese-Enel (I) ❽ 平 Submitted on August 18) (Submitted on August 18? 1999) Printed by a member of the Intellectual Property Bureau of the Ministry of Economic Affairs and a Consumer Cooperative. 1 · A substituted 8-amino group ~ 1 -cyclopropyl. Radical_7_, (2, B-diaza-heterobicyclo [ 4 3 〇] non_8_yl) each gas], ^^ R1 represents hydrogen, any CrC4-alkyl group substituted with a 'hydroxy, fluorenyloxy, amine, fluorenylamino or difluorenylamino group, or (5-methyl-2-oxo-1,3-di. Isocene-4-yl) methyl, R2 epihydrogen, benzyl, C3-C3-alkyl, (5-methyl-2-oxo: 1,3-difluorenyl4-yl) fluorenyl, having Structure-= C OOR3, -CH2CH2COOR3, -CH2CH2CN, -CH2CH2C0CH3 or -CH2C ^ O_CH3 (where R3 represents methyl or ethyl), or general structure. Structure r4- (nh-chr5-co) -Radicals (where R4 represents hydrogen, CVCV alkyl, or aryl-CQO-tertiary butyl, R5 represents hydrogen, CVCV alkyl, or benzyl), and this paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) ΙΓΙΙ „------- 〇 Loading -------- Order --------- Begin (Please read the precautions on the back before filling this page) Patent Application No. 86101994 ROC Patent Appln. No. 86101994 Amended Application I 彘 ® + Text 1 Attachment (1) Amended Claims in Chinese-Enel (I) ❽ 平 Submitted on August 18) (Submitted on August 18? 1999) Printed by a member of the Intellectual Property Bureau of the Ministry of Economic Affairs and a Consumer Cooperative. 1 · A substituted 8-amino group ~ 1 -cyclopropyl. Radical_7_, (2, B-diaza-heterobicyclo [ 4 3 〇] non_8_yl) each gas], ^^ R1 represents hydrogen, any CrC4-alkyl group substituted with a 'hydroxy, fluorenyloxy, amine, fluorenylamino or difluorenylamino group, or (5-methyl-2-oxo-1,3-di. Isocene-4-yl) methyl, R2 epihydrogen, benzyl, C3-C3-alkyl, (5-methyl-2-oxo: 1,3-difluorenyl4-yl) fluorenyl, having Structure-= C OOR3, -CH2CH2COOR3, -CH2CH2CN, -CH2CH2C0CH3 or -CH2C ^ O_CH3 (where R3 represents methyl or ethyl), or general structure. Structure r4- (nh-chr5-co) -Radicals (where R4 represents hydrogen, CVCV alkyl, or aryl-CQO-tertiary butyl, R5 represents hydrogen, CVCV alkyl, or benzyl), and this paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) ΙΓΙΙ „------- 〇Installation -------- Order --------- Begin (Please read the precautions on the back before filling in this page) S90819 The scope of patent application A8 B8 C8 D8 and Y are oxygen, and their pharmaceutically acceptable acid addition salts and alkali metal salts. 2 · — #Method for preparing and preparing a compound of formula (1) according to item 1 of the scope of patent application (Π), (Please read the precautions on the back before filling out this page) 4. Install R1 and Y with the definition of the first order of the scope of the patent application and the X table element, especially fluorine or chlorine, and the formula ( III) of 2,8-Azabicyclo [4J, 0] nonane reaction (mx order --------- 婵 'printed by the consumer co-operatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, where R2 has the definition as defined in item 1 of the scope of patent application, if appropriate, then split_ The purpose of the carboxylic acid is g; if appropriate, then R2 epihydrogen is a ⑴ compound &amp; alkylated, acylated or tritiated. „-33- This paper is based on the national standard (CNS) A4 specification of the paper. Love ^ Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 39081¾ 〇ι__ VI. Application for Patent 3. The method of applying for the second item of the patent, in which the compound of formula (II) is __ · in acid In the presence of a binding agent, it reacts with a compound of formula (III). 4. The compound of formula ⑴ according to item 1 of the scope of patent application, wherein R1 represents hydrogen, amenoryl, methoxy, amine, and fluorenyl. CrC4-alkyl substituted with amino or diamidoamino, or (5-methyl, 2-oxo-1,3-difluoren-4-enyl) fluorenyl., R2 epioxy, benzyl, CrC3 -Alkyl., (5-methyl-2-oxo-1,3-dihumo-4 -yl) methyl, having the structure dH = C Η-C Ο OR 3--CH2CH2C00I ^, -ch2ch2cn, Or: CH2CM in which R3 represents methyl or ethyl), or a general structure of R4- (NH-CHR5-CO) _v (where R4 represents hydrogen, CrC3-alkyl, or radical -COO-tertiary butyl'R Cousin-Hyun "base or octyl", · ... and Y are oxygen, / and "they are medically acceptable for acid addition salts and metal test salts. 5. The compound of formula (I) according to item 1 of the scope of the patent application, wherein R1 represents hydrogen, CrC4-alkyl, or (5-methyl-2-oxo, 1,3-difluorenyl-4- base). .Methenyl '&gt; R2 epihydrogen, methyl, (5: methyl-2-oxo-1,3-dioxocenyl) methyl, having structure -CH = CH-COOR3, -CH2CH2COOR3, -CH2CH2CN Or a group of -CH2COCH3 (where R3 is methyl or ethyl), or a group of general structure R4- (NH-CHR5-CO)-(where R4 represents hydrogen,... _, CrC3- ^ group or group -COO -Tertiary butyl, R5 epihydrogen, Cl-CV good, basic or octyl), -34- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (Please read the note on the back first Please fill in this page for more details) ^ Installation -------- Order --------- 0V VI. S90819 ----- Shen Jing's patent scope and -Y for oxygen, and its medical application Accepted acid addition salts and metal test salts. 6 · According to the formula 1 of the scope of the patent application, the compound ⑴ of the formula r is 8_cyano_.1% • propyl-7_ (2,8 -__: azabij, .3 ... 0.) Nonan-8-yl 1-6-fluoro 〇. 氲 .-4-oxo-3 喳 咁 carboxylic acid and esters thereof. 7. A pharmaceutical composition for treating bacillus infections, including The compound of formula (1) according to the scope of the patent application. According to the compound of the scope of the patent application, the compound is used in an antibacterial composition. 9. A compound having the formula COOH 10 · —A compound with the formula: &lt; _ (丨 F ^^^ / COOMe I 师 人 i (Please read the precautions on the back before filling this page) -------- Order-- ------- # Intellectual Property Office of the Ministry of Economic Affairs 11. A compound having the formula -35- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)