CA2028205A1 - Diazabicycloamine compounds and a process for their preparation - Google Patents
Diazabicycloamine compounds and a process for their preparationInfo
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- CA2028205A1 CA2028205A1 CA002028205A CA2028205A CA2028205A1 CA 2028205 A1 CA2028205 A1 CA 2028205A1 CA 002028205 A CA002028205 A CA 002028205A CA 2028205 A CA2028205 A CA 2028205A CA 2028205 A1 CA2028205 A1 CA 2028205A1
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- compound
- formula
- acid
- protecting group
- lower alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
Abstract:
Diazabicycloamine compounds of the general formula I and their acid salts
Diazabicycloamine compounds of the general formula I and their acid salts
Description
HOECHST AKTIENGESELLSCHAFT HOE 89/S 04~ ~ 2 ~3~ ~ Dr. KA/rh Diazabicycloamine co~pounds and a proce~ for their preparation The present invention relates to new diazabicyClo compounds of the following general formula I
~--N R ~
~2~C) (~
wherein m represents an integer of 1 to 3 n represents 1 or 2, and R1 or R2 represents hydrogen or lower alkyl and their ~alts.
These compounds can be used for the preparation of novel guinolone comp~unds having excellent antibacterial activity and can also be used for the preparation of novel cephalosporines and other pharmaceutically interesting compounds. The invention relates further to a process for their preparation.
Since the first introduction of nalidixic acid as a chemotherapeutic agent for urethritis, many guinolone antibacterial agents, especially norfloxacin, ciprofloxacin and ofloxacin are being widely used in hospitals nowadays in a variety of indications.
However, whereas tbese guinolone antibacterial agents have a high antibacterial activity against Gram negative bacteria, these agents have a disadvantage due to their lower antibacterial activity against Gram positive bacteria, such as Staphyiococcus spp. or Streptococcus ~pp.
~--N R ~
~2~C) (~
wherein m represents an integer of 1 to 3 n represents 1 or 2, and R1 or R2 represents hydrogen or lower alkyl and their ~alts.
These compounds can be used for the preparation of novel guinolone comp~unds having excellent antibacterial activity and can also be used for the preparation of novel cephalosporines and other pharmaceutically interesting compounds. The invention relates further to a process for their preparation.
Since the first introduction of nalidixic acid as a chemotherapeutic agent for urethritis, many guinolone antibacterial agents, especially norfloxacin, ciprofloxacin and ofloxacin are being widely used in hospitals nowadays in a variety of indications.
However, whereas tbese guinolone antibacterial agents have a high antibacterial activity against Gram negative bacteria, these agents have a disadvantage due to their lower antibacterial activity against Gram positive bacteria, such as Staphyiococcus spp. or Streptococcus ~pp.
- 2 _ 2 ~ 2 t~
As result of the effort to solve the problems of the existing quinolone antibacterial agents, the following facts have been discovered and have led to the present invention. The novel quinolone antibacterial agents are prepared by introducing the diazabicycloamine compound of the general formula I onto the C-7 or C-10 position of the quinoline nuclei shown in the following general formula (A) or (B) as a substituent R3 F~,COOR~ ~COOR~
R2 J~CH3 (A) ~B) wherein in (A) and (B) X represents C-H, C-F or N, Z represents hydrogen, halogen or amino, R1 represents hydrogen or a pharmaceutically acceptable cation, R2 represents alkyl, halogenated alkyl or hydroxyalkyl having 1 to 4 carbon atoms, vinyl or cycloalkyl having 3 to 6 carbon atoms, R3 represents the introduced group corresponding to the above general formula I. .
While the existing quinolone compounds have only a low antibacterial activity against Gram positive bacteria, the novel quinolone compounds have an excellent antibacterial activity not only against Gram negative bacteria but also against Gram positive bacteria.
The detailed description of the present invention is as follows.
2~2~2~
The present invention consists of the diazabicycloamine compounds of the following general formula I and their acid addition salts wherein m represents an integer of 1 to 3, n represents 1 or 2, and R1 or R2 represents hydrogen or lower alkyl group.
Preferred are diazabicycloamines of the formula I, wherein m denotes 1 or 2, n denotes 1 and R1 and R2 denote hydrogen or lower alkyl, with the proviso that R1 and R2 cannot be lower alkyl simultaneously. These preferred compounds can also be represented by the general formula Ie 1 ~C ~ ~ (Ie) ~oH2 ) wherein m is 1 or 2 and one of R1 and R2 is lower alkyl whereas the other one is hydrogen.
The term "lower alkyl" means alkyl with 1 - 4 carbon atoms, preferably methyl and ethyl.
The present invention relates also to a process for the manufacture of diazabicycloamines of the formula I and their salts Rl--N~_R2 ( I
m~l2C) (~2~
2~,3~5~j wherein m denotes 1 to 3, n denotes 1 to 2 and R1 and R2 denote hydrogen or lower alkyl which comprises (a) reacting tetrakis(halomethyl)ethylene with ammonia, whereby a compound of ~he formula I with m and n = 1 and Rl and R2 = hydrogen is obtained (b) removing from a compound of th~ formula I, wherein one or both nitrogen atoms are protected, the protecting group(s) and - if desired - alkylating one or both nitrogen atoms, (c) removing from a compound of the formula I, wherein one nitrogen atom bears an alkyl group and the other nitrogen atom is protected, the protecting group, or (d) reducing a merimine derivative of the formula Rl or R2~ ~
wherein Rl or R2 is lower alkyl and X(~) is an anion, as e.g. Br(~) or Cl(-).
The term "halo" in variant (a) means chloro, bromo or iod~, preferably bromo.
Preferred is the process for the manufacture of diazabicyclo-amines of the formula I and their salts Rl--N~_R2 ( I ) m(H2C) ~H2 wherein m denotes 1 or 2, n denotes 1 and R1 and R2 denote hydrogen or lower alkyl with the proviso that Rl and R2 cannot be lower alkyl simultaneously, which consists of the same variants (a) to (d) with exception of the dialkylation in variant (b).
The reaction variant (a) is described below in detail.
As protecting groups in variants (b) and (c), in principle each N-protecting group known from literature, e.g. in the field of peptide or ~-lactam chemistry, may be used which can easily be split off in conventional manner, i.e. by solvolysis, including hydrolysis, hydrogenolysis or by reduction.
As examples for protecting groups removable by solvolysis may be mentioned arylsulfonyl, such as p-toluenesulfonyl or phenylsulfonyl; or alkoxycarbonyl such as ethoxy-, t-butoxy-or benzyloxycarbonyl.
The removal of these protecting groups may be carried out in well-known manner in an appropriate solvent between about 0C and elevated temperatures, e.g. up to 160C, in the presence of an acid, such as e.g. hydrochloric or hyrobromic acid, sulfuric acid, acetic acid, trifluoroacetic acid or formic acid, or in the presence of a base, such as e.g.
sodium or potassium hydroxide, sodium or potassium carbonate or sodium acetate. As solvent water can be used, or - if necessary - also an organic solvent, such as e.g. ethanol, dioxane or acetic acid, alone or in mixture with water.
Examples for protecting groups removable by hydrogenolysis are benzyl or substituted benzyl; or arylsulfonyl, such as p-toluenesulfonyl or phenylsulfonyl.
These groups can be split off in customary manner known from literature under different conditions, e.g. in a hydrogen stream in an inert solvent at room temperature or slightly elevated temperatures in the presence of a catalyst, as e.g.
platinum, palladium or Raney nickel; or with e.g. zink in acetic acid or methanol.
It is also possible to remove protecting groups such as e.g.
toluenesulfonyl or phenylsulfonyl by reduction, as for instance by NaAlH2(0CH2CH20CH3)2.
- 6 - 2~2~
Because compounds of the formula I wherein R1 and/or R2 is a protecting group are preferably obtained - as described below - by a cyclization reaction which can be generalized as follows R NH2 + L~ ~ R -N ~
(R = protecting group, L' = leaving group) protecting groups which can be introduced together with the nitrogen atom are therefore preferred, such as for instance arylsulfonyl, as e.g. p-toluenesulfonyl, or alkylsulfonyl as e.g. methanosulfonyl (both introduced in form of the corresponding sulfonamide), alkoxycarbonyl, e.g.
ethoxycarbonyl (introduced as the corresponding urethane) or acetyl (introduced as acetamide), preferably p-toluenesulfonyl.
Some preferred removal conditions can be described as follows. The removal of e.g. toluenesulfonyl may be carried out for example with hydrobromic acid, e.g. 48 % hydrobromic acid in the presence of phenol and reflucing for e.g. 3 - 5 hours, the removal of e.g. ethoxycarbonyl with hydrochloric acid, preferably 20 % hydrochloric acid, and the removal of e.g. the benzyl group by hydrogenolysis in acetic acid solution with 10 % Pd-charcoal/hydrogen, preferably with stirring or refluxing for some hours.
If two protecting groups are to be split off selectively, it is advisable to use one group which can be split off under acid conditions, as e.g. toluenesulfonyl, whereas the other one can be removed by hydrogenolysis, as e.g. benzyl. Thus, toluenesulfonyl can first be removed e.g. by hydrobromic acid and then benzyl subsequently e.g. by Pd-charcoal/
hydrogen.
_ 7 (i~
If an N-alkylation of the compounds of the formula I is to be carried out, the alkyl group can be introduced by conventionyl methods, e.g. with an alkyl halide, for example ethyl iodide in an inert solvent, e.g. in dimethyl formamide in the presence of a base, e.g. potassium carbonate, preferably at lower temperatures, e.g. at room temperature and a reaction time of up to about 24 hours.
A methyl group can for example be introduced by the reaction with formaline, preferably 35 - 37% a~ueous formaline, and formic acid, preferably under reflux for some hours, e.g.
for about 2 to 6 hours.
When a dimethylation or a methylation of a mono-N-protected compound is intended, an excess of formalin/formic acid is used, whereas the monomethylation of an unprotected compound of the formula I re~uires the use of an about equivalent amount of the methylation agent.
The reduction of a merimine, mentioned in the above variant (d) can be carried out in a conventional manner as described in literature for this type of compounds. Thus, hydrogenation can for instance be applied, preferably with Pd/charcoal in an inert solvent, such as a lower alcohol, e.g. methanol or ethanol.
The following more detailed processes are also a part of our invention:
The present invention includes also a process for the preparation of the free diazabicycloamine compound of the following general formula (Ia) ~ ~) - 8 ~ J ? ;3 characterized by heating tetrakis(halomethyl)ethylene, wherein halo is as defined above, and liquid ammonia under increased pressure.
The present invention relates further to a process for the preparation of acid 6alts of the diazabicycloamine compound of in the following general formula (Ib) wherein X represents the anion of an acid, preferably chlorine or bromine, characterized by cyclizing tetrakis(halomethyl)ethylene, wherein halo is as defined above, with 2 mols, pref,erably a slight excess of a compound of the formula R -NH2, wherein R
is a nitrogen-protecting group, such as e.g. methansulfonyl, acetyl or alkoxycarbonyl, e.g. ethoxycarbonyl, preferably toluenesulfonyl, in a polar solvent in the presence of a base, and then removing the nitrogen-protecting group, for instance by treatment with an acid. Preferred examples for the compound R -NH2 are methanesulfonamide, acetamide or an urethane, preferably p-toluene sulfonamide.
The present invention relates also to a method for the preparation of the diazabicycloamine compound of the following formula (Ic) `
Y~ ac) which is characterized by the following steps:
(A) A 3-pyrroline compound is prepared by cyclization of tetrakis(halomethyl)ethylene, wherein halo is as defined above, and 1 mol, preferably a 61ight excess of a - 9 - 2 ~
compound of the formula R -NH~, wherein R is as defined above, preferably p-toluene sulfonamide, in a polar solvent in the presence of a base, (B) one of the two halogens, preferably bromines, of the compound is substituted by a cyanide group, (C) this cyanide group is reduced to the aminomethyl group, (D) a nitrogen protected 3,8-diazabicyclo[4.3.0]non-1(6)-ene is then obtained by cyclizing the compound of step (C) in the presence of a base, and then the protecting group is removed in the presence of an acid or by hydrogenolysis which leads to the compound Id, or (E) a second protecting group selectively removable, e.g. by hydrogenolysis, is introduced to the secondary amine of the above nitrogen protected 3,8-diazabicyclo[4.3.0]non-1(6)-ene, the first protecting group, e.g. the paratoluenesulfonyl group is selectively removed by acid and the second protecting group is removed by hydrogenolysis under acidic conditions, or vice versa, and the acid addition salt of the following formula (Id) ~_ ' wherein X represents the anion of an acid, preferably chlorine or bromine, is obtained and which may then be treated with alkali to give (Ic) The following description is a still more detailed disclosure of the present invention.
Among the diazabicycloamine compounds according to the present invention, the free diazabicycloamine compound of the above formula (Ia), the 3,7-diazabicyclo[3.3.0]oct-1(5)-ene, can e.g. be prepared by adding the well known tetrakis(bromomethyl)ethylene [compound (1) of the reaction ~ ~ 2 ~ ~ ~
scheme] [reference: (1) A. C. Cope, et al., J. Am.
Chem. Soc., 80, 54~9 (1958), (2) P.W. LeQuesne, et al., J.
Org. Chem., 40, 142 (1975)] to the mixture of a solvent, for example a lower alcohol, e.g. methanol, and liquid ammonia, and then heating the reaction mixture in a sealed tube under increased pressure for several hours, for example for about 8 hours in an oil bath of about 180C.
The acid salt of the diazabicycloamine compound of the above general formula (Ib) can e.g. be prepared by cyclization of tetrakistbromomethyl)ethylene [compound ~1)]
and p-toluene sulfonamide, methanesulfonamide, acetamide or an urethane in a polar solvent, as e.g. dimethylformamide in the presence of a base, as e.g. potassium carbonate or sodium hydroxide, preferably at room temperature, followed by heating the cyclized compound in the presence of an acid to remove the nitrogen-protecting groups. Preferred for the removal is the use of hydrobromic acid, e.g. 48 %
hydrobromic acid in the presence of phenol and refluxing of this mixture for several hours, for example 4 hours.
The diazabicycloamine compound of the formula (Ic), the 3,8-diazabicyclo[4.3.0]non-1(6)-ene, can be prepared by the following steps.
First, a 3-pyrroline compound [compound (3)] is prepared e.g. by cyclization of tetrakis(bromomethyl)ethylene [compound (1)] and p-tuoluene sulfonamide in the presence of a solvent, e.g. dimethylformamide in the presence of a base, e.g. potassium carbonate, and then the cyanide group is substituted for one of the two bromine atoms by addition of a cyanide, preferably sodium cyanide, to the refluxed solution, e.g. in dimethylsulfoxide, which leads to compound (4). The aminoethyl compound [compound (5)] is obtained by the reduction of the cyanide group, for example with lithium aluminum hydride, and the nitrogen-protected 3,8-diaza-bicyclo[4.3.0]non-1(6)-ene derivative [compound (6)] is then prepared by cyclizing this compound for example in ~11?,~"?~
dimethylformamide solution, by addition of e.g. anhydrous potassium carbonate, preferably at room temperature and stirring for several hours. Thereafter, the compound (7) can be obtained by introducing a second protecting group, for example a benzyl group by adding benzylbromide in the presence of a base, e.g. of sodium hydroxide, to the secondary amine of the compound (6). The compound (8) is then prepared by removing selectively the first protecting group with acid for example with hydrobromic acid, preferably 48 % hydrobromic acid in the presence of phenol under reflux for several hours. The acid salt of the general formula (Id) is obtained by removing the protecting group of the above compound (6) in the presence of an acid, preferably of 48 % hydrobromic acid in the presence of phenol and refluxing for several hours, or by removing the second protecting group of the above compound (8) by hydrogenolysis under acidic condition, e.g. under reflux for several hours in acetic acid solution in the presence of 10 % Pd-charcoal under hydrogen stream. Then the diazabicycloamine of the formula ~Ic) is obtained by treating the compound of the formula (Id) with alkali in usual manner.
In the above steps, each protecting group can - as already described above - be removed for instance by using an acid, e.g. hydrobromic or hydrochloric acid, by alkali such as e.g. sodium hydroxide and potassium hydroxide, Na/NH3 or by hydrogenolysis.
The above described reactions can be summarized in the following reaction scheme using especially the preferred substituents:
Br}cBr ~H
8r Br Ia l s--N~--T6 3 HNX~IH 2HX Rl--N~CN Ra 2HX
~CN Tri--NX~
TS--N~ J~) TS--N~H
--~QH~ X ~`R2 2HX~HN~ ~ _ HN~H- 2HX
~/
le4 2 Ts = CH3~SO2-- , X = Cl, Br, etc.
- 13 _ ~ J ~
Compounds of the general formula I, wherein m - 2 and n = 1 can also be prepared by reduction of a merimine derivative of the following formula X N~ ,N~
Rl or R~' R~
wherein X(~) is an anion, e.g. 8r(~) or Cl(-) and Rl or R2 is lower alkyl, under the above described conditions.
Monoalkyl-3,8-diazabicyclo[4.3.0]non-1(6)-ene compounds such as compounds (Ie2) or (Ie3~ can also be prepared by alkylation of the intermediate (8) or (6), followed by deprotection, using the methods and conditions already described above.
An alternative way to obtain compounds of the type (Ic) or (Id) is the hetero-Diels-Alder reaction of 2,3-bis(halo-methyl)-1,3-butadiene with methylenediurethane (methylene-biscarbamate) in the presence of a Lewis acid, cyclization with an appropriate amine R-NH2 under basic conditions as exemplarily described below and deprotection, e.g. with hydrochloric acid:
X Hal N 1 ~ ~ R-N ~ ---~ R-N ~
wherein Hal is chlorine, bromine or iodine, preferably bromine and R is lower alkyl or optionally also a protecting group.
~ ~' f`J /~ 2 `~ ~
Alkylated diazabicycloamine compounds of the general formula I, especially the preferred ones, can also be prepared by N-mono- or N-di-alkylation of compounds of the general formulae (Ia), (Ib), (Ic) or (Id), using the methods and conditions already described above.
Another way of preparation of N-monoalkyl 3,7-diazabicyclo-[3.3.0]oct-1(5)-ene is the cyclization of the N-protected, preferably of the 1-p-toluenesulfonyl-3,4-bis(halomethyl)-3-pyrroline, wherein halo is as described above, with appropriate alkylamines, e.g. methyl- or ethylamine, under basic conditions, e.g. in the presence of anhydrous potassium carbonate, followed by deprotection, e.g. by hydrolysis with acids, for example with hydrobromic acid/phenol. The reaction scheme with the preferred substituents is as follows:
Rl or R2 R~ os R2 Br--~Br ~N~
wherein Rl or R2 represents lower alkyl, and X represents preferably chlorine or bromine.
The following examples are to illustrate, but not to limit the invention.
2 ~ r Esamples E~amples 1: Prepara~on of 3,7-bi6-p-tolue~e~ulfonyl-3,7-diaza~ic9~10 l3.3.0]
oct-1(Shne ~e of tet~ (~romomet~yl~ethy~ e and ~0~ of p tolu~ ~ulfo~amide ~ere di~solved in 400 ml of dimetllylformamide. 150e of pot~ium ~o~at4 ~y-dride (or 50% sodium hydride 17~) wa~ add~d and t~ tirred at room tempera ture for 24 hours. Therea~er, this reac~os~ ture was di~lilled u~der ~racuum to remove solvents. By addir~g 30 ml of water and lQ0 ~1 of ethylacetate. 17e fthe title compound was obtained a5 pale yello~ powder (yielt 50%).
Mel~ngpoint: 2500C(dec.) IS0-d,s, ~ ppm): 7.65 (4H, d, J . 8.08 Hz), 7.39 (4H, d, J ~ 8.08 Hz), 3.94 (8H, ~), 2.40 (6~1, s).
Er.IS: mlz 418 (M-, 1.3%), mlz 419 (M~ ~1,1.2%).
E~amples 2 : Preparation of 3,7-diazabicyclo~3.3.0]oct-1(5)-ene dihydrobromide 60 ml of 48% hydrobromic acid and 7g of phenol were added to 10.8g 3,7-~is-p-toluenesulfonyl-3,7-diazabicyclo~3.3.0]oct-1(5)-ene, prepar~d ir~ Preparation 1.The mi~ture was reflu~ced for 4 hour~ u~d cooled to room te~perature. The aqueous phase was ~eparated by addisle 100 ml of ~hlorofo~ as~d 50 ~ of water.
The aqueous phase was washed wit}l chlorofo~ (100 ml :~ 4) ~nd decolonzed with acti~e carbon. The aqueous phase was concentrated u~der vacuum a~d the remained solid was washed witll 1: 1 methanol~ yl et~er solvent. 5~ of ~he ~tle compound was o~t~ned as white tolid (~ield 71%).
1 6 ~ ~ J I J . L
Mel~ngpoint: 220C(dec.) N~ (DMSO-D~O, o ppm) 4.06 (8H, s).
MS: m/z llO (M~).
Esamples 3: Preparation of 3,7-diaza~ic~o[3.3.0~oct 1(6)-ene 2.72g of 3,7-diazabicyclo~3.3.0]oct-1(5)-ene dil~ydrobro~ude, prepared ~ Prepara-tion 2, was added to 10 ml of 10% aqueow ~odium hydro~te ~olu~o~ e mis-ture was concentrated under reduced pres6ure to re~nove water, a~d th~ es-kacted with ether several times and concentrated. lg of the ti'de compond was obtained (yield 90%).
'H-N~ (D2O, ~ ppm): 4.02 (8H, s).
MS : m/z 110 tM~).
E~amples 4: Preparation of 3,7-diazabicyclo~3.3.0~oct-1(~)-ene 0.7g of tet~ akis (bromomethyl)ethylene was tissolved in 10 ml of methanol and 4ml of liquid ammonia and sealed and beated in 180C oil bath for 8 hours. ~er cooling the reaction mi~cture to room temperature, ammonia wa~ evaporated.
The mixture was concentrated to remove methanol. lO ml of absolute ethanol was added and the undissolved compound was filitered off to remo~e insoluble material. Ethanol was removed by vacuum dis'dlla~on. 3 ml of 30% aqueous potassium hydro~cide solu~on was added to the oil residue. T~e ~olu~o~
extracted w~th tetrahydro~ (1~, 6 ml s 3) and tl~e o~tained eskates were combined and dried (Na~SO~), co~ce~trated to esve 60mg of t~e ~tle compourld (yield 31%).
IH-N~ (DMSO-d6, ~ ppm): 4.04 (8H, s).
MS: m/z 110 (M-).
- 1 7 - ~ ~ ~ o J ~i, j`
Es nple 5: Preparation of N-~toluenesulfonyl~3,4-bi6(bromomet~yl~
3-pyrroline l9g of tetrakis ~bromome~ylhthylene and 9g of p-toluene sulfonamide were dis-solved in 220 ml of dime~ylfor~amide. 30~ of an~ydrow potas6ium ca~bonate ~as added and then s~drred at room temperature for 20 hour~. Tbere~fter ~ol-~ent was remo-red by vaccum di~tillatiorL 60 ml of et~ylac~ dded to obtain 601it product, a~d ~olid product w purified b~ el column ~roma-to~raphy. 12g of ~e ti~le compound WBB obtained ~ield 60%).
Melting point: 170C
'~^N~ (CDCl3, o ppm): 7.69 (2H, d, J ~ 8.2 Hz), 7.33 (2H, d, J . 8.2 Hz), 4.00 (4H, 6), 3.15 (4~ ), 2.44 (6, 3H).
E~ample 6: PreparationofN-~D-toluenesulfonyl~3-(bromomet~yl)-4-(cyanomethyl)-3-pyrroline lOg of N-(p-toluenesulfonyl~3,~bis(~romomethyl~3-pyrroline, prepared in Prepa-ration ~, was dissolved in 10 ml of d~nethylsulfo~cide (DMS0) and t~en heated inoil bath for 2 hours with reflu~ng. During tlle heating and reflu~iing, 1.5g of sodium cyanide was added by small portion. The reaction mist~ was cooled to room temperature and poured i~to ice water and t~en estracSed ~nth methylene chloride (200 ml s 3). The estracts were combined, dried over Na2SC), and con-centrated. The residue was purified by ~ilica gel column ~romaSograp~y. Sg of the title compound was obtained (yield 57%).
Meltingpoint: 182C
~H-N~ (CDCl3, ~ ppm): 7.71 (2H, d, J ~ 8.2 ~z), 7.36 (2H, d, J . 8.2 Hz), 4.01 (4H, s), 3.20 (2H, s), 3.06 (2H, 6), 2.45 (3H, ~).
, ~ 2 ~
E~cample 7: PreparationofN-~p-tolue~esulfoslyl)-3-(aminoet~yl)-4-(bromomethyl~3-py~roline 4g of N-(p-toluenesulfonyl).3.(bromomet}lyl)~(cya~omet~yl) 3 py~roli~e, pre-pared in Preparation 6, was di~sol~ed ~ 100 ml of e~yl ether. T~e ~olu~on was 610wly added to the su~pension of lg of ~ ium alu~ninum h~dride a~AH) iI~ 20 ml of et~yl ether, and heated with reflu~ for 3 hours. The reaction misture was cooled by ice water. ~fter adding 3 ml of water, it was stirrod for 30 minutes and filtered of ~. The filtrate wa~ concentrated. 2g of the title cor~pound was ob-tained (yield 49%).
Melting point: 18~C
'H~ IR (CDC13, ~ ppm): 7.e~4 (2~I, d, J z 8.2 Hz), 7.46 (2~I, d, J ~ B.2 H z),4.20 (2 H, g, J ~ 7 H z), 4.06 (4~I, 5), 2.45 (3 H,s), 2.26 (2H, t, J - 7 Hz).
x~mple 8: PreparationofN~-~p-toluenesulfonyl~3,8-diazabicyclo [4.3.0]non-1(6)-ene 3.6g of N'-~p-toluenesulfonyl~3-(aminoethyl)~(bromomethyl-3-pyrroline, pre-pared in Preparation 7, was dissolved in 30 ml of rlimethylformamide. 6g of a~hydrous potassium carbo~ate was added to the solution ~d t~e~ stirred at room temperature for 18 bours. After concent~a~g the reac~o~ mistu~ under reduced pressure to remove solverlt, the mist~re ~as estracted wit~ met~ylene chloride (50 ml x 3). After mi~ng the obta~ed e~tracts, it wa6 wa~hed with water and concent~ated. 2.5g of t~e title compound was obtained (~ield 88%).
Meltingpoint: 201C
'H-N~ (CDCl3, o ppm): 7.80 (2H, d, J s 8.2 Hz), 7.44 (2H, d, J 8.2 Hz), 4.05 (4H, s), 3.41 t2H, ~), 2.92 (2~I, t, J ~ 5.8 ~IZ), 2.44 (2H, t, J = 5.8 Hz).
E~ample 9: PreparationofN3-(benzyl~N~ toluenesulfonyl)3.8-diazabicyclo [4.3.0]non-1(6~ene 1.8g of N~ toluenesulfonyl~3,8 dia2abicyclo[4.3.01~on-1(6)~e, prepared in preparation 8, was disgolved in 30 ml of ~e~a~ol. 6 ml of 50% a~lueow ~odium hydroside solution aIld 1.5 ml of benzyl bronude ~ere added to ~e ~olution ~nd ~tirred at room temperature for 5 llourg. T'ne reactio~ mistare wa~ concentratedunder reduced pressure to remove methanol and the~ estracted wit~ methylene c~onde (30 ml s 3). It was dried (Na9S0,) and concentrated a~d t~en dried under reduced pressure. 2g of t~e title compound was obtained (gie~d ~5%).
Melting point: 196C
'H-NMR (CDCl3, ~ ppm): 7.80 (2H, d, J ~ 8.2 Hz), 7.44 (2H, d, J ~ 8.2 Hz), 7.28 (5H, br. s), 4.û1 (4H, s), 3.66 t2H, ~), 3.40(2H, ~), 2.90(2H, d, J = 5.8Hz), 2.22(2H, t, J ~ 5.8 Hz).
~ple lO: Preparstion of N3-tbenzyl~3,8-diazabicylclo[4.3.0]non-1(6)-ene hydrobrornide 2g of N3-(benzyl)-N~-(p-toluenesulfonyl)-3,8 diazabicyc3o~4.3.0]non-1(6)-ene, pre-pared in Preparation 9, was suspended in 15 ml of 48% hydrobromic acid and 1.5g of phenol, and the reac~on misture was re~u~ed for 3 hours. ~cer cooling tbe reaction misture, 20 ml of water was added tbe misture was wa~hed ~nth chlorofo2m (50 ml s 3). The aqueous phase was taken and decolonzed by active carbon. Tbe aqueous phase was concentrated under reduced pressure asld t}~us resulting SOlia was washed with 1: 1 methanol-etl~ylether ~olve~t. 1.5g of the title compound was obtained (yield 98%).
Meltingpoint: 205C(dec.) 'H~ CDClJ, o ppm): 7.29 (5H, br. s), 4.00 (4H, s), 3.5~ (2~, s), 3.38(2H, ~ ), 2.91(2H, d, J = 5.8Hz), 2.24(2H, t, J ~ 5.8 Hz).
- 2 0 - ~ ~ 2 ~ ~ ~J I `
E~ample 11: Preparation of 3,8 diazabicyclol4.3.03non-1(6)-ene . di~ydrobromide 1.5g of N~D-toluenesulfonyl~3,~diaza~icy~1o[4.3 Olnon-1(6)-e~e. prepared in Preparation 8, was suspended in 15 ml of 48% hy~lro~romio acid and 2~ of phenol,and the reaction misture was re~used fsr 4 hours. ~er cooline the reaction misture, 20 rDl of water was added~ T~e r~isture was wa~d ~nth ~hloroform (40 ml ~ 3). T~e aqueous pba6e was t,ake~ and decolonzed b~ acti~e car~on.
The aqueous phase was concentrated under reduoed pres~ure uld thu~ ul~g ~olid was wasbed witb 1: 1 met~anol-et~ylether Bolvult. O.9g oftl~e ~tle com-pound was obtained (yield 98%).
Mel~ngpoint: 225-2~70C(dec.) Example 12: Prepara~on of 3,8-diazabicyclo~4.3.0~non-1(6~ene . di~ydrobromide 0.7g of N3-(benzyl)-3,8-diazabicyclo[4.3.0]non-1(6~ene hydrobromide, prepared inPreparation 10, was dissolved in 20 ml of 5% aqueous acetic acid colution. 0.5g of 10% palladium charcoalin this solution was 6uspended and the reaction misture was reflu~ted under the hydrogen stream for 7 hours. T~e solid was filtered off.The filtrate was concentrated ur der reduced pressure and dissol~ed ~10 ml of 48C~C bromic acid. By concentrating tbe solution under reduced pressure again, 0.5g of the title compound was obtairled (yield 73%). -Meltingpoint: 225-227C(dec.) ~ample l3: Prepara~on of 3-methyl-3~7~1iazabicy~1O~3.3.0~oct 1(5~ene dihydrobrornide 3,7-Diazabicyclo~3.3.0]oct-1(6~ene dihydrobromide (0.81 g) which was prepared inPreparation 2 was dissol~ed in water (10 ml). To tl~i~ solution 35% fonnaline (0.3 ml) and formic aQd (10 ml) were added arld reflu~ed for 4 hours. Tne ~ ~ f~ J
solvents were distilled of~ d the re~ olid WS,6 waS~ea with ~opropylalco-hol (20 ~nl) ar d ethyle~Lher (20 ml) to ~zive the title compo~t (0.81~, yield 94%).
Melti~g poi~t: 185-187C(dec.) E~ample 14 :Prepara~orlof3-e~yl-3,7diaza~ic:y~10~3.3.0~oct^1(5~e dihytrobFomide To a solution of 1-p-toluene ~u3fonyl-3,~bi~ (bromomet~yl~3-p~ Gline (3Al ~) in acetonitrile (43 ml), 0.73 ml of 70% ethylamine and aD~ydrou6 pota~ium car'Don-ate (8 g) were added and stirred at room te~perature for one hosr. Tne solid was filtered off and the filtrate was purified by ~ilicagel colu~ chromatography(CHCl3-~eOH) to give 3-et~yl-7-~toluene 6ulfonyl-3,7-diazabicy~lo ~3.3.0]oct-1(5)-ene (0.95 g, yield 39%). 0.9 g of this compou~d was hydrolysized in 20 ml of 48~c hydrobromic acid with 1 g of phenol. The hydrolysate ~a~ washed with chloroform (30 ml ~c 3) and decolorized with ~ctive carbon. T~e ~ol~e~t was con-centrated and washed with ethanol to give the ~tle compound (0.57 g, yield 62%).MS m/z (rel. int. %): M~ 138 (32),123 (20),109 (60),108 (100).
~ample 15 : Preparation of 3,7-dimethyl-3,7-diazabicyclo~3.3.0]oct-1(5)-e~e dihydrobromide 3,7-Diazabicyclo~3.3.0]oct-1t5)-ene dihydrobromide (0.644 g) wa~ dis60lved ~
formic acid t5 ml) and 36% fo~naline (5 ml) and t~en re~used for 5 ~oura T'ne ~olvents were evaporated under reduced pre6s~e a~d 20% ~ydro'bromic acid (10 ml) was added to this solid and then refluxed for 30 minutes. Evaporatio~ of 60lvents and washing with isopropanol to give the title comp~u~d (0.54 g, ~neld 90%).
22 2 s ,~
Example 16: Preparation of ~methyl-3~g~ abicyclo[4.3.0]no~-1(6hne dihydrobromide tIe2).
3-Benzyl-3,8-diazabicyclo[4.3.0]no~ l(6) ene dihydrobro~de tO.76 ~) was reflusedin 85% formic acid (10 ml) a~d 37% formalin,e (7 ml) for 5 ~our~. The ~ol~e~ts ~ere removed u~der reduced pre66ure and the ~olid wa~ wasbed wit~ i~opr~panol ethylether (2: 1) to ~pve 3~ uyl-8-methyl-3,8 diazabi~lo~4.3.0~ 1(6)~ene dihydrobromide (0.64 e. ~ield 82%).
'H-N~ (CDCl" ~ ppm): 7.32 (B~I, m), 4.02 (4~ ), 3.57 (2~ .36 (2H, ~), 3.21 (3H, 8), 2.94 (2H, d, J ~.8 ~Iz), 2.25 (2~I, t, J 8 ~.B Hz).
The above compound (0.585 g) was ~rred in 10% acetic a~d in water with lO~o palladium-charcoal (0.05 g) under hydrogen stream. After 5 hours t}le ~olidwas filtered off and 20% hydrobromic acid (~ ml) was added a~d the~ the ~ol~reLts were dis~lled of~. The resul~ng solid was washed with isopropanol-ethylether (2: 1) to obtain the title compound (0.276 g, yield 86%~.
'H-l~ (CDCl3, ~ ppm): 4.01 (4H, ~), 3.30 (2H, ~), 3.20 (3H, 6), 2.86 (2H, d, J~5.8Hz),2.20~2H,t,J~5RHz).
~ample 17: Preparation of 3-methyl-3,8-diazabicyc~ot4.3.0]non-1(6)~ne dihydrobromide (Ie3).
8-p-Toluenesulfonyl-3,8-diazabicy~10[4.3.0~on-1(6)-eDe (0.56 ~) was ~netllylatedwith 8~% fo~ic acid (10 ml) a~d 37% formaline (5 ml) by reflu~g for 5 hour~.
The solvents were distilled o~. To this solid ~% hydrobromic acid (20 ml) a~d phenol (1 g) were added alld refluxed ~or 5 hours. I~e reaction mirture was washed with chloroform (30 ml s 4), decolon~ed with active l:harC4al. The aque-ous layer was concentrated under vacuum and th2 solid was wash~d wit~ ~o-propanol-ether ( 2: 1) to ob~n ~le ~tle compound (0.48 g, yield 83%).
-- 2 3 -- 2 ~ rl s ~
H-NMR (CD30D, o ppm): 4.01 (4H, ~!;), 3.43 (2H, ~), 3.16 (3H, 8), 2.98 (2H, ~5.8Hz~,2.4~6~2H,t,J~5.8Xz).
~c~ple 18: Preparation of 3~7-dimethyl 3~7-diazabicyclol~-3-O]Oct lt5)-ene dihydrobromide 3,7-Diazabicyc3O~3.3.0]oct 1(5).er~e dihydrobromide (0.82 ~) wa~used ~nth formic acid (10 ml) and 35æ formali~e (10 ml) or B hous~ e e~cess r~age~ts were dis~lled of and 20% hydrobromic acid (10 ~1) ~ added a~d refluxed for 1 hour. ~he solvnet was distilled off and washed with etlla~ol-et~ylether (1:1 ) to obtain the title compound (0.95 g, yield 86%).
~H-N~ (CD30D, ~ ppm): 4.36 (8H, s), 3.12 (6H, ~).
xample 19: Prepsration of 3,8-~methyl-3,8-diaza~icyclo[4.3.0]non-1(6)-ene dihydrobromide .
3,8-Diazabicyclo~4.3.0]non-1(6)-ene dihydrobror~ide (0.57 g) was methylated withfo~c acid (8 ml) and 37% formaline ( 8 ml) by reflu~ing for 5 hours. Work-up as in F~ample 18 gave the title compound (0.48 g, ~rield 80%).
'H-N~ (CDJOD, ~ ppm): 4.07 t4H, s), 3.45 (2H, ~), 3.14 (6H, ~), 2.97 (2H, t, J ~ 5.8 ~Iz), 2.48 (2~I, t, J 5.8 ~I2).
~cample 20: Preparation of 3-methyl-3,7 diazabic~o~3.3.0]oct-l(5)~e di~ydrobromide .
To a solution of 1-p-toluenesulfonyl-3~4-bis~bromomethyl) 3-pyrroli~e (6.1 g) was dissol~ed in aoetonitri~e (70 ml), 40% methylamine aqueous ~olutior~ (1.5 ~1) arld anhydrous potassium carbonate powder (16 g) were added and s~ed for 2 hours 2 4 ~, ~ 2 a~ room temperature. The solid w~s filtered off and the filtrate was purified ~ysilicagel column chromato8raphy to yield 3-met~yl-7-p-toluenesulfo~yl-3.7-diazabicyclol3.3.0]oct.1(5)-ene (0.82 ~, ~ield 20%). 0.8 ~ oftl~i~ compou~d and 0.8 ~ of phenol were reflu~ed i~ 48% hyd~obromic ~Q.d (15 ml) fior 5 hour~. The reac-tion ~re was washed with cl~loroform (20 ~1 :c 3), decolonzed ~ active charco~l. The 601vent wafi distilled o~ a~d ~ ed wit~ et~ ol~ ylet~er (1: 1) to give the title compound (O.S g, ~ield 609~).
'H-N~ (CD~OD, o ppm): 4.42 (4H, s), ~.27 (4H, s~, 3.12 (3~I, o~.
sample 21: Preparation of 8-methyl-3,8-dia2abicyclo~4.3.0]non-1~6~ene dihydrochloride.
To a solution of 2,3-bis tbromomethyl~1,3-butadiene (4.8 ~) snd methylenediure-tharle (3.9 g) in dichloroethane ~40 ml), borontriBuoride etherate (0.3 ml) was added. The reaction mixture was reflu~ed for 10 hours and washed with 10%
sodium bicarbonate solution (30 ml x 3). The organic phase was filtered though silicagel and evaporation of the sol~ent to ~pve 1 carboetho~ 4,5-bis~bromo-methyl)-1,2,3,6-tetrahydropyndine (6.14 g, yield 90%) which was cyclized with 40~/c methylamine (1.B ml) and potassium carbonate (15 g) in acetonitrile (50 ml) for 2 hours at room temperature. The solid was filtered of~and the filtrate was purified by silicagel column c~omatography to gi~e 3-carb~ethosy-8-methyl-3,8-dia~abicy~lo~4.3.0] non-1(6~e~e (2.57 g, yield 68%). This ami~e wa~ used in 20% hydrochloric acid (50 ml) aud e~aporatio~l ga~e t~e ~tle compou~d (1.35 g, y~eld 80%).
'H-NMR (CD30D, ~ ppm3: 4.01 (4H, ~), 3.32 (2~ ), 3.20 t3H, s), 2.84 (2H, ~, J = 5.8 ~Iz), 2.21 (2H, t, J = ~.8 Xz~.
-- 2 5 _ f~ f `~ $
By using the diazabicycloamine compo~d~ ~how~l by ~e general for~ula (I~
which were prepared by ~e E~amples, and quinoXo~e oompounds sho~n by the above formula (A) or (B) and their ~ s are prep~red by the follo~ me~o~
rU6e]
Use 1: Preparatio~l of 1-cyclopropyl-7-t3,?~ abi~1O~3.3.o]oct-l(5h~-3-yl]-6,8-difluoro-1,4.dihydro~o:Eoql~inD~ ~3~osyli ~cid (B:R-10~79~
The solution of û.4 g of 1-cyclopropyl-6,7,8-trifluoro L4-d~yd~o:~oline 3 carbo~ylic acid, 0.8 g of 3,7-diazabicy~10~3.3.0]oct-1(5)-e~ ydrobromide, a~d 0.8 ml of 1,8-diazabicyclo[5.4.0~undeo-7~e a~8U) isl 30 ~Dl of aceto~itrile was reflused in oil bath at the temperatllre of 1ûO~ for 8 hour6, a~d t~is reaction ~ture was kept otrer~ight at ~e room temperature. I~e produced precipitate was filtered off and tben ~e residue was washed with metha~ol, to obtaiu 0.35 g of the title compound (yield 67%).
~Ieltingpoint: 220-2220C(dec.) ~H-N~ (CDCl3 ~ CD3COOD, ~ ppm): 8.81 (IH, ~), 7.87 (lH, d, J ~ 14.2, 1.8 Hz), 4.69 (4H, 8), 4.24 (4H, 6), 4.û1 (1H, m), 1.23 (4H, rG).
Use 2 : Preparation of 5-amino 1-cyclopropyl-7-t3~7-diazabicyclo~3.3.0~oct 1(5) en-3-yl]-6,8-difluoro-1,4-dihydro~soquinoline-3-carbos~lic acid (KR-10747) The solutio~ of 0.4 g of 5 amino-1~clopropyl~,7,~triliuoro~ dihydro~4~oxoqui noline-3-carboxylic acid, 0.8 ~ of 3,7-diazabicy~lo~3.3.û]oct~1(5) e~e ~ihyd~obro mide, and 0.6 ml of 1~diazabicydo[5.4.oh~dec-7~e a:~BU) in 40 ~1 of acetoni-trile was reflu~ed at t~e reac~on temperature of 100~C for 7 ~ours. T~is reaction ture was kept oven~ight at the room temperature, and the produced precipi-tate was filtered and then the residue was washed with ethanol to obtai~ 0.3 g of the tit]e compound (yield 57%).
2 6 ~ " j~ !
Meltingpoint: 220-225DC(dec.) H-N~ (CDCl3 ~ CD3COC)D, ~ ppm): 8.6~ (lH. 6), 4.6~ (4H, 8), 4-24 (4H, ~), 3.91 (lH"n), 1.18 (4H, m).
Use 3: Preparation of 1-cyclopropyl-7-~7-~e~yl~3,7-diazabicyclo~3.3.0]oCt 1 S~ en~3-yl]-6,8-difluoro 1~ hyaro4-o~:o~oli~3-carbosylic acid hydrochlonide t~R-10755) 0.1 g of 1-cyclopropyl 7 [3~?-diazabicyclor3.3.0]oc~1(5)-en-3-gl~6~difluoro-1/4-~ihydro-~o~oquinoline-3-carboxylic acid, prepared i~ e U~e 1, wa~ assol~ed in the solu~on mi~ture of ~ ml of 3B% aqueous fon~aline solution a~d 1.5 ml of foImic acid, and then this reactio~ ~ture was feflwced at tlle reactioII tempera-ture of 120C for 2 hours and it w8s concentrated u~der the reduced pressure to remove solvent. 1 ml of isopropyl alcohol and 1 ml of 20% hydrochlonc acid W85 added herein and then it was reflu~ced more for 1 hour. The solve~t was removed under the reduced pressure t~ remove the solvent arld washed ~ith 1: 1 ~nisture solvent of methanol-ether, to obtai~ 0.082 g of the ~tle compound (~ield 78%).
Mel~ngpoint: 210-213~C(dec.) ~H-N~ (CDCl3 ~ CD3COOD, o ppm): 8.82 (lH, s), 7.85 (lH, d, J =14.3Hz), 4.83 (2H, m), 4.67 (4H, ~r. s), 3.98 (lH, m), 3.8~ (2H, m), 3.16 (3H, B), 1.24 (4H, m).
U6e 4: Preparation of 1-cydopropyl-7-r3,7-diazabicy~1O~3.3.0]oct-1(5). e~-3-yl]- 5,6,8-trifluoro-1,4-dihydro~osoquinolin~3-carbosylic acid tgR-10768) 0.6 g of 1-cyclopropyl-~6~7~8-tetrafiuoro-l~4-dihydro~o~oq~oli~carbosylic acid, 1.2 g of 3,7-diazabicyclo~3.3.0]oct-1(5) ene dihydro~romide a~d 1.3 ml of 1,8-- 27 - ~$' Ji~i ~
di~abicyclo[5.4.0]undec-7~ne (DBU) were eu~pe~ded ir~ 20 ml of acetonitrile, and then the reac~on mi~cture was renu~ed ~or 10 hours. ~i5 reactiaa misture was kept o~ren~ight at the room tempera~e, ancl ~e prDducet precipitate was filtered and then the residue wafi washed wi~ etharlol ~o obtain 0.58 g the title compound (yield 74%).
Meltingpoint: 226-228DC(dec') 'H-N~ (CDCl, I CD,COOD, ~ ppm): 8.71 (l~ ), 4.68 (4EI, o), 4.18 (~H, 1~), 4.00 (lH, m), 1.22 (4~, ~n).
Use 5: Preparation of (-~9-~uoro-3-(5~10-~3,7-diszabicyclot3.3.0]oct 1(5) en-3-yl]-7-o~o-2 ,3-dihydro-7H-pyndo~1.2.3~e]-1,4-benzosazi~e~car~o~cylic acid (~-10759) 0.28 g of (-)-9,10-difluoro-3(5~methyl-7-o~o-2,3-dihydro-7~I-pyndo~1.2.3-de]-1,4-~enzo~azine-6-carbo~cylic acid was dissolved in 3 ml of pyridine, and tllen 0.5 g of 3,7-diazabicyclo[3.3.0]oct-l(~)-ene dihydrobromice was added herein, ne~t the reaction mi2ture was refllL~ed for 10 houss. This reaction mir~rue wa~ concen-trated under the reduced pressure tllree ~mes, a~d the residue was washed with 1: 1 mi~ture solvent of ethanol-ether to obtain 0.32 g of the title compound (yield 8~c).
Meltingpoint: 196C(dec.) ~H-N~ (CDCl3 ~ CD~COOD, ~ ppm): 8.85 (lR, B), 7.69 (lH, d, J ~14.2 ~z), 4.60 (4H, s), 4.51 (lH, m3, 4.31 (2~ r. s), 4.21 (4~, s), 1.65 (3H, d, J 6.6 Hz~.
Use 6: Preparation of l-cyclopropyl-7 ~3~7-diazabicydo~3.3.0]oct-1(5)~e~l~3~yl~6~8-difluoro-1,4-dihydro~-osoquinoline-3-carbo~cylic acid (ER-10679) 2 ~ ) r~ d i /
0.28 g of 1-cyclopropyl-6,7,8-~ifluoro-1,4-dihydro-~o~oquinolin~3-Car'DOSy~ic acid, 0.16 g of 3,7-diazabicyclo-~3.3.0]oct-1(5)-ene ,~d 0.3 ml of 1,8~iaz~icy~1o-[5.4.0]unde-7-ene (DBU) ~ere su6pended in 20 ml of acetonitrile, a~d the~ the reaction mixture was fefl~ed in oil bath at ~he re~io~ tempcrature of 100C for 6 hours. This reactioD ~e wa~ Icept ove2~ught at the r~om temperature, the produced precipits~e wa6 filtered a~d the reE idue w~ hed wit~ t mis-ture of ethanol-ether (1: 1) to obtain 0.3 g oiE t~e title compou~d (~rield 809~).
Meltingpoi~t: 220-223~C(dec.) Use 7: Preparation of l-cyclopropyl-6,R~ luor~7-t3,8-diazabicy~10[4.3.0] Ilon-1(6)-en-3-yl)-1,4-dihydro4~soq~oline-3-carbo~ylic a~:id hydrobromide 0 3 g of 1-cyclopropyl-6,7,B-trifluoro-1,4-dihydro4-o~coquinoline-3-carbDsylic aQd and 0.42 g of 8-p-toluenes~fonyl-3,8-diazabicyclo[4.3.0]non-1(6~e~e were dis-solved in 20 ml of acetonitrile. 0.3 ml of 1,8-diazabicyclo~5.4.0]undec-7-ene (DBU) were added and then reflua~ed for 5 hour~. The reaction misture was kept overnight at room temperature. The produced precipitate was filtered and 5U5-pended in the mi~lture of 20 ml of 40% hydrobromi~ acid and 1 g of phe~ol. The suspension was reflu~ed for 5 hours. The reaction misture was c~oled to room temperature and then washed five ti~es with met~ylene ~hlonde (30 ml s B).
The aqueous phase was eoncentrated under reduced pressue a~t wad~ed ~itl~ tbe ethanol-ethylether (1: 1) solvent. 0.34 g of t~e title compou~d (yield 68%).
Meltingpoint: 287-291C(dec.) 'H-NMR tCDCl3 I CD3COOD, ~ ppm): 8.89 (lH, 6), 7.88 (lH, d, J ~ 14 Hz), 4.10 (4H, ~), 4.00 (lH, m), 3.40 (2~, , br). 2.94 (2H, t, J z 5.8 ~Iz), 2.31 (2~I, t, J c 5.8 Hz), 1.25 (4H, m).
~ 29 - ~ ~r; ~
Use 8: Preparation of 1-cyclopropyl-6,~-di1uoro-7 (3~8-dia~abic~rdo[4~3~o]
non-1(6)-en 8-yl]-1l4-dihydro~osoqu~olille-3-caT'Dosylic acid 0.3 g of 1-cyclopropyl-6,7,8.~ifluo~1,4 dihydro~)~oq~oli~e-3-car'Do~ c acid ~d 0.6 g of 3-be~zyl-3,8-dia;cabicydo~.3.0~non-1(6h~e ~ydrobromide were ~uspended in 30 ml of acetonitrile. 0.6 ~ of 1,8~iazabicyclo[5.4.0h~dec-7~e tDBU) was added to the suspen6ion. T~e ~action mist~ wa~ ed for 6 boun ar~d then kept overnight at room te~pera~ure. T~e pr~duced precapitate was filtered a~d dissolved in 30 ml of 5% aee~c Rcid ~ et~a~ol. ~ter ad~ing 0.5 g of 10~ Palladium chareoal, the reactio~ ture was ~tined ~der hyd~ogen ~tream for 6 hours and then filtered. T~e filtrate was conce~trated u~ter ~e-duced pressu~e. 0.25 g of the title compound (~ielt 61%).
~Ieltingpoint: 270C(dec.) IR (CDCl3 I CD ,COOD, ô ppm) : 8.84 ~lH, s), ~.89 (lH, d, J ~ 14. Hz), 4.60 (4H, s), 4.02 (lH, m), 3.41 (2H, s), 2.94 (2H, t, J 6.8 Hz~, 2.27 (2H, t, J ~ 5.~ ~z), 1.27 (~I, m).
The antibacterial activity of the quinolone compoun~ prepared ~ ~e pren-ously descnbed Uses accordi~ to tbe present inven~on i6 I;~OWn in the follo~g Table I and Table II.
~ he quinolone compo~ds ~ow~ by the above ~erlera~ forDlula (A) a~d (B) which were prepared by using t~e diazabicy~loE~mine compou~dr ~own ~ t~e above general fo~nula ~I) according to tbe pre~ent u~vention have r~uc~ bett~r antibacten~l ac~vity against the Gram po~itive ba~teria ~uch as Stt~phylo~s spp. spP .
and Streptoc~ccu~ ~an the t~aditional q~olone compou~ds ~uch a~ o~osa~
and norflo~acin, and they have ~milar or better asl~bacterial ac~ an cip-roflo~acin.
- 3c - ~ g ~ c~
These qui~olone compou~ds accordi~g to the present iIl~e~o~ were proved to ~ave superior an~bacterial ac~ to the trad:i~o~al quinolone a~ibacterisl agents agai~st methicilli~ resistant Staphy~ococcl s a~reus.
- 31 - f~ ~J~ f'. ', ~J \'i~ ' ~t ~ X ~ o ~
~ tD~ooo~o~joo~-i-oooooo .S ._ _~____ __ # ~ C!~
~ c~ ~ 3 ~ 8 ~ ~ 8 ~ i~ ~ oooo VOI~ V VOOOO V V VO V
As result of the effort to solve the problems of the existing quinolone antibacterial agents, the following facts have been discovered and have led to the present invention. The novel quinolone antibacterial agents are prepared by introducing the diazabicycloamine compound of the general formula I onto the C-7 or C-10 position of the quinoline nuclei shown in the following general formula (A) or (B) as a substituent R3 F~,COOR~ ~COOR~
R2 J~CH3 (A) ~B) wherein in (A) and (B) X represents C-H, C-F or N, Z represents hydrogen, halogen or amino, R1 represents hydrogen or a pharmaceutically acceptable cation, R2 represents alkyl, halogenated alkyl or hydroxyalkyl having 1 to 4 carbon atoms, vinyl or cycloalkyl having 3 to 6 carbon atoms, R3 represents the introduced group corresponding to the above general formula I. .
While the existing quinolone compounds have only a low antibacterial activity against Gram positive bacteria, the novel quinolone compounds have an excellent antibacterial activity not only against Gram negative bacteria but also against Gram positive bacteria.
The detailed description of the present invention is as follows.
2~2~2~
The present invention consists of the diazabicycloamine compounds of the following general formula I and their acid addition salts wherein m represents an integer of 1 to 3, n represents 1 or 2, and R1 or R2 represents hydrogen or lower alkyl group.
Preferred are diazabicycloamines of the formula I, wherein m denotes 1 or 2, n denotes 1 and R1 and R2 denote hydrogen or lower alkyl, with the proviso that R1 and R2 cannot be lower alkyl simultaneously. These preferred compounds can also be represented by the general formula Ie 1 ~C ~ ~ (Ie) ~oH2 ) wherein m is 1 or 2 and one of R1 and R2 is lower alkyl whereas the other one is hydrogen.
The term "lower alkyl" means alkyl with 1 - 4 carbon atoms, preferably methyl and ethyl.
The present invention relates also to a process for the manufacture of diazabicycloamines of the formula I and their salts Rl--N~_R2 ( I
m~l2C) (~2~
2~,3~5~j wherein m denotes 1 to 3, n denotes 1 to 2 and R1 and R2 denote hydrogen or lower alkyl which comprises (a) reacting tetrakis(halomethyl)ethylene with ammonia, whereby a compound of ~he formula I with m and n = 1 and Rl and R2 = hydrogen is obtained (b) removing from a compound of th~ formula I, wherein one or both nitrogen atoms are protected, the protecting group(s) and - if desired - alkylating one or both nitrogen atoms, (c) removing from a compound of the formula I, wherein one nitrogen atom bears an alkyl group and the other nitrogen atom is protected, the protecting group, or (d) reducing a merimine derivative of the formula Rl or R2~ ~
wherein Rl or R2 is lower alkyl and X(~) is an anion, as e.g. Br(~) or Cl(-).
The term "halo" in variant (a) means chloro, bromo or iod~, preferably bromo.
Preferred is the process for the manufacture of diazabicyclo-amines of the formula I and their salts Rl--N~_R2 ( I ) m(H2C) ~H2 wherein m denotes 1 or 2, n denotes 1 and R1 and R2 denote hydrogen or lower alkyl with the proviso that Rl and R2 cannot be lower alkyl simultaneously, which consists of the same variants (a) to (d) with exception of the dialkylation in variant (b).
The reaction variant (a) is described below in detail.
As protecting groups in variants (b) and (c), in principle each N-protecting group known from literature, e.g. in the field of peptide or ~-lactam chemistry, may be used which can easily be split off in conventional manner, i.e. by solvolysis, including hydrolysis, hydrogenolysis or by reduction.
As examples for protecting groups removable by solvolysis may be mentioned arylsulfonyl, such as p-toluenesulfonyl or phenylsulfonyl; or alkoxycarbonyl such as ethoxy-, t-butoxy-or benzyloxycarbonyl.
The removal of these protecting groups may be carried out in well-known manner in an appropriate solvent between about 0C and elevated temperatures, e.g. up to 160C, in the presence of an acid, such as e.g. hydrochloric or hyrobromic acid, sulfuric acid, acetic acid, trifluoroacetic acid or formic acid, or in the presence of a base, such as e.g.
sodium or potassium hydroxide, sodium or potassium carbonate or sodium acetate. As solvent water can be used, or - if necessary - also an organic solvent, such as e.g. ethanol, dioxane or acetic acid, alone or in mixture with water.
Examples for protecting groups removable by hydrogenolysis are benzyl or substituted benzyl; or arylsulfonyl, such as p-toluenesulfonyl or phenylsulfonyl.
These groups can be split off in customary manner known from literature under different conditions, e.g. in a hydrogen stream in an inert solvent at room temperature or slightly elevated temperatures in the presence of a catalyst, as e.g.
platinum, palladium or Raney nickel; or with e.g. zink in acetic acid or methanol.
It is also possible to remove protecting groups such as e.g.
toluenesulfonyl or phenylsulfonyl by reduction, as for instance by NaAlH2(0CH2CH20CH3)2.
- 6 - 2~2~
Because compounds of the formula I wherein R1 and/or R2 is a protecting group are preferably obtained - as described below - by a cyclization reaction which can be generalized as follows R NH2 + L~ ~ R -N ~
(R = protecting group, L' = leaving group) protecting groups which can be introduced together with the nitrogen atom are therefore preferred, such as for instance arylsulfonyl, as e.g. p-toluenesulfonyl, or alkylsulfonyl as e.g. methanosulfonyl (both introduced in form of the corresponding sulfonamide), alkoxycarbonyl, e.g.
ethoxycarbonyl (introduced as the corresponding urethane) or acetyl (introduced as acetamide), preferably p-toluenesulfonyl.
Some preferred removal conditions can be described as follows. The removal of e.g. toluenesulfonyl may be carried out for example with hydrobromic acid, e.g. 48 % hydrobromic acid in the presence of phenol and reflucing for e.g. 3 - 5 hours, the removal of e.g. ethoxycarbonyl with hydrochloric acid, preferably 20 % hydrochloric acid, and the removal of e.g. the benzyl group by hydrogenolysis in acetic acid solution with 10 % Pd-charcoal/hydrogen, preferably with stirring or refluxing for some hours.
If two protecting groups are to be split off selectively, it is advisable to use one group which can be split off under acid conditions, as e.g. toluenesulfonyl, whereas the other one can be removed by hydrogenolysis, as e.g. benzyl. Thus, toluenesulfonyl can first be removed e.g. by hydrobromic acid and then benzyl subsequently e.g. by Pd-charcoal/
hydrogen.
_ 7 (i~
If an N-alkylation of the compounds of the formula I is to be carried out, the alkyl group can be introduced by conventionyl methods, e.g. with an alkyl halide, for example ethyl iodide in an inert solvent, e.g. in dimethyl formamide in the presence of a base, e.g. potassium carbonate, preferably at lower temperatures, e.g. at room temperature and a reaction time of up to about 24 hours.
A methyl group can for example be introduced by the reaction with formaline, preferably 35 - 37% a~ueous formaline, and formic acid, preferably under reflux for some hours, e.g.
for about 2 to 6 hours.
When a dimethylation or a methylation of a mono-N-protected compound is intended, an excess of formalin/formic acid is used, whereas the monomethylation of an unprotected compound of the formula I re~uires the use of an about equivalent amount of the methylation agent.
The reduction of a merimine, mentioned in the above variant (d) can be carried out in a conventional manner as described in literature for this type of compounds. Thus, hydrogenation can for instance be applied, preferably with Pd/charcoal in an inert solvent, such as a lower alcohol, e.g. methanol or ethanol.
The following more detailed processes are also a part of our invention:
The present invention includes also a process for the preparation of the free diazabicycloamine compound of the following general formula (Ia) ~ ~) - 8 ~ J ? ;3 characterized by heating tetrakis(halomethyl)ethylene, wherein halo is as defined above, and liquid ammonia under increased pressure.
The present invention relates further to a process for the preparation of acid 6alts of the diazabicycloamine compound of in the following general formula (Ib) wherein X represents the anion of an acid, preferably chlorine or bromine, characterized by cyclizing tetrakis(halomethyl)ethylene, wherein halo is as defined above, with 2 mols, pref,erably a slight excess of a compound of the formula R -NH2, wherein R
is a nitrogen-protecting group, such as e.g. methansulfonyl, acetyl or alkoxycarbonyl, e.g. ethoxycarbonyl, preferably toluenesulfonyl, in a polar solvent in the presence of a base, and then removing the nitrogen-protecting group, for instance by treatment with an acid. Preferred examples for the compound R -NH2 are methanesulfonamide, acetamide or an urethane, preferably p-toluene sulfonamide.
The present invention relates also to a method for the preparation of the diazabicycloamine compound of the following formula (Ic) `
Y~ ac) which is characterized by the following steps:
(A) A 3-pyrroline compound is prepared by cyclization of tetrakis(halomethyl)ethylene, wherein halo is as defined above, and 1 mol, preferably a 61ight excess of a - 9 - 2 ~
compound of the formula R -NH~, wherein R is as defined above, preferably p-toluene sulfonamide, in a polar solvent in the presence of a base, (B) one of the two halogens, preferably bromines, of the compound is substituted by a cyanide group, (C) this cyanide group is reduced to the aminomethyl group, (D) a nitrogen protected 3,8-diazabicyclo[4.3.0]non-1(6)-ene is then obtained by cyclizing the compound of step (C) in the presence of a base, and then the protecting group is removed in the presence of an acid or by hydrogenolysis which leads to the compound Id, or (E) a second protecting group selectively removable, e.g. by hydrogenolysis, is introduced to the secondary amine of the above nitrogen protected 3,8-diazabicyclo[4.3.0]non-1(6)-ene, the first protecting group, e.g. the paratoluenesulfonyl group is selectively removed by acid and the second protecting group is removed by hydrogenolysis under acidic conditions, or vice versa, and the acid addition salt of the following formula (Id) ~_ ' wherein X represents the anion of an acid, preferably chlorine or bromine, is obtained and which may then be treated with alkali to give (Ic) The following description is a still more detailed disclosure of the present invention.
Among the diazabicycloamine compounds according to the present invention, the free diazabicycloamine compound of the above formula (Ia), the 3,7-diazabicyclo[3.3.0]oct-1(5)-ene, can e.g. be prepared by adding the well known tetrakis(bromomethyl)ethylene [compound (1) of the reaction ~ ~ 2 ~ ~ ~
scheme] [reference: (1) A. C. Cope, et al., J. Am.
Chem. Soc., 80, 54~9 (1958), (2) P.W. LeQuesne, et al., J.
Org. Chem., 40, 142 (1975)] to the mixture of a solvent, for example a lower alcohol, e.g. methanol, and liquid ammonia, and then heating the reaction mixture in a sealed tube under increased pressure for several hours, for example for about 8 hours in an oil bath of about 180C.
The acid salt of the diazabicycloamine compound of the above general formula (Ib) can e.g. be prepared by cyclization of tetrakistbromomethyl)ethylene [compound ~1)]
and p-toluene sulfonamide, methanesulfonamide, acetamide or an urethane in a polar solvent, as e.g. dimethylformamide in the presence of a base, as e.g. potassium carbonate or sodium hydroxide, preferably at room temperature, followed by heating the cyclized compound in the presence of an acid to remove the nitrogen-protecting groups. Preferred for the removal is the use of hydrobromic acid, e.g. 48 %
hydrobromic acid in the presence of phenol and refluxing of this mixture for several hours, for example 4 hours.
The diazabicycloamine compound of the formula (Ic), the 3,8-diazabicyclo[4.3.0]non-1(6)-ene, can be prepared by the following steps.
First, a 3-pyrroline compound [compound (3)] is prepared e.g. by cyclization of tetrakis(bromomethyl)ethylene [compound (1)] and p-tuoluene sulfonamide in the presence of a solvent, e.g. dimethylformamide in the presence of a base, e.g. potassium carbonate, and then the cyanide group is substituted for one of the two bromine atoms by addition of a cyanide, preferably sodium cyanide, to the refluxed solution, e.g. in dimethylsulfoxide, which leads to compound (4). The aminoethyl compound [compound (5)] is obtained by the reduction of the cyanide group, for example with lithium aluminum hydride, and the nitrogen-protected 3,8-diaza-bicyclo[4.3.0]non-1(6)-ene derivative [compound (6)] is then prepared by cyclizing this compound for example in ~11?,~"?~
dimethylformamide solution, by addition of e.g. anhydrous potassium carbonate, preferably at room temperature and stirring for several hours. Thereafter, the compound (7) can be obtained by introducing a second protecting group, for example a benzyl group by adding benzylbromide in the presence of a base, e.g. of sodium hydroxide, to the secondary amine of the compound (6). The compound (8) is then prepared by removing selectively the first protecting group with acid for example with hydrobromic acid, preferably 48 % hydrobromic acid in the presence of phenol under reflux for several hours. The acid salt of the general formula (Id) is obtained by removing the protecting group of the above compound (6) in the presence of an acid, preferably of 48 % hydrobromic acid in the presence of phenol and refluxing for several hours, or by removing the second protecting group of the above compound (8) by hydrogenolysis under acidic condition, e.g. under reflux for several hours in acetic acid solution in the presence of 10 % Pd-charcoal under hydrogen stream. Then the diazabicycloamine of the formula ~Ic) is obtained by treating the compound of the formula (Id) with alkali in usual manner.
In the above steps, each protecting group can - as already described above - be removed for instance by using an acid, e.g. hydrobromic or hydrochloric acid, by alkali such as e.g. sodium hydroxide and potassium hydroxide, Na/NH3 or by hydrogenolysis.
The above described reactions can be summarized in the following reaction scheme using especially the preferred substituents:
Br}cBr ~H
8r Br Ia l s--N~--T6 3 HNX~IH 2HX Rl--N~CN Ra 2HX
~CN Tri--NX~
TS--N~ J~) TS--N~H
--~QH~ X ~`R2 2HX~HN~ ~ _ HN~H- 2HX
~/
le4 2 Ts = CH3~SO2-- , X = Cl, Br, etc.
- 13 _ ~ J ~
Compounds of the general formula I, wherein m - 2 and n = 1 can also be prepared by reduction of a merimine derivative of the following formula X N~ ,N~
Rl or R~' R~
wherein X(~) is an anion, e.g. 8r(~) or Cl(-) and Rl or R2 is lower alkyl, under the above described conditions.
Monoalkyl-3,8-diazabicyclo[4.3.0]non-1(6)-ene compounds such as compounds (Ie2) or (Ie3~ can also be prepared by alkylation of the intermediate (8) or (6), followed by deprotection, using the methods and conditions already described above.
An alternative way to obtain compounds of the type (Ic) or (Id) is the hetero-Diels-Alder reaction of 2,3-bis(halo-methyl)-1,3-butadiene with methylenediurethane (methylene-biscarbamate) in the presence of a Lewis acid, cyclization with an appropriate amine R-NH2 under basic conditions as exemplarily described below and deprotection, e.g. with hydrochloric acid:
X Hal N 1 ~ ~ R-N ~ ---~ R-N ~
wherein Hal is chlorine, bromine or iodine, preferably bromine and R is lower alkyl or optionally also a protecting group.
~ ~' f`J /~ 2 `~ ~
Alkylated diazabicycloamine compounds of the general formula I, especially the preferred ones, can also be prepared by N-mono- or N-di-alkylation of compounds of the general formulae (Ia), (Ib), (Ic) or (Id), using the methods and conditions already described above.
Another way of preparation of N-monoalkyl 3,7-diazabicyclo-[3.3.0]oct-1(5)-ene is the cyclization of the N-protected, preferably of the 1-p-toluenesulfonyl-3,4-bis(halomethyl)-3-pyrroline, wherein halo is as described above, with appropriate alkylamines, e.g. methyl- or ethylamine, under basic conditions, e.g. in the presence of anhydrous potassium carbonate, followed by deprotection, e.g. by hydrolysis with acids, for example with hydrobromic acid/phenol. The reaction scheme with the preferred substituents is as follows:
Rl or R2 R~ os R2 Br--~Br ~N~
wherein Rl or R2 represents lower alkyl, and X represents preferably chlorine or bromine.
The following examples are to illustrate, but not to limit the invention.
2 ~ r Esamples E~amples 1: Prepara~on of 3,7-bi6-p-tolue~e~ulfonyl-3,7-diaza~ic9~10 l3.3.0]
oct-1(Shne ~e of tet~ (~romomet~yl~ethy~ e and ~0~ of p tolu~ ~ulfo~amide ~ere di~solved in 400 ml of dimetllylformamide. 150e of pot~ium ~o~at4 ~y-dride (or 50% sodium hydride 17~) wa~ add~d and t~ tirred at room tempera ture for 24 hours. Therea~er, this reac~os~ ture was di~lilled u~der ~racuum to remove solvents. By addir~g 30 ml of water and lQ0 ~1 of ethylacetate. 17e fthe title compound was obtained a5 pale yello~ powder (yielt 50%).
Mel~ngpoint: 2500C(dec.) IS0-d,s, ~ ppm): 7.65 (4H, d, J . 8.08 Hz), 7.39 (4H, d, J ~ 8.08 Hz), 3.94 (8H, ~), 2.40 (6~1, s).
Er.IS: mlz 418 (M-, 1.3%), mlz 419 (M~ ~1,1.2%).
E~amples 2 : Preparation of 3,7-diazabicyclo~3.3.0]oct-1(5)-ene dihydrobromide 60 ml of 48% hydrobromic acid and 7g of phenol were added to 10.8g 3,7-~is-p-toluenesulfonyl-3,7-diazabicyclo~3.3.0]oct-1(5)-ene, prepar~d ir~ Preparation 1.The mi~ture was reflu~ced for 4 hour~ u~d cooled to room te~perature. The aqueous phase was ~eparated by addisle 100 ml of ~hlorofo~ as~d 50 ~ of water.
The aqueous phase was washed wit}l chlorofo~ (100 ml :~ 4) ~nd decolonzed with acti~e carbon. The aqueous phase was concentrated u~der vacuum a~d the remained solid was washed witll 1: 1 methanol~ yl et~er solvent. 5~ of ~he ~tle compound was o~t~ned as white tolid (~ield 71%).
1 6 ~ ~ J I J . L
Mel~ngpoint: 220C(dec.) N~ (DMSO-D~O, o ppm) 4.06 (8H, s).
MS: m/z llO (M~).
Esamples 3: Preparation of 3,7-diaza~ic~o[3.3.0~oct 1(6)-ene 2.72g of 3,7-diazabicyclo~3.3.0]oct-1(5)-ene dil~ydrobro~ude, prepared ~ Prepara-tion 2, was added to 10 ml of 10% aqueow ~odium hydro~te ~olu~o~ e mis-ture was concentrated under reduced pres6ure to re~nove water, a~d th~ es-kacted with ether several times and concentrated. lg of the ti'de compond was obtained (yield 90%).
'H-N~ (D2O, ~ ppm): 4.02 (8H, s).
MS : m/z 110 tM~).
E~amples 4: Preparation of 3,7-diazabicyclo~3.3.0~oct-1(~)-ene 0.7g of tet~ akis (bromomethyl)ethylene was tissolved in 10 ml of methanol and 4ml of liquid ammonia and sealed and beated in 180C oil bath for 8 hours. ~er cooling the reaction mi~cture to room temperature, ammonia wa~ evaporated.
The mixture was concentrated to remove methanol. lO ml of absolute ethanol was added and the undissolved compound was filitered off to remo~e insoluble material. Ethanol was removed by vacuum dis'dlla~on. 3 ml of 30% aqueous potassium hydro~cide solu~on was added to the oil residue. T~e ~olu~o~
extracted w~th tetrahydro~ (1~, 6 ml s 3) and tl~e o~tained eskates were combined and dried (Na~SO~), co~ce~trated to esve 60mg of t~e ~tle compourld (yield 31%).
IH-N~ (DMSO-d6, ~ ppm): 4.04 (8H, s).
MS: m/z 110 (M-).
- 1 7 - ~ ~ ~ o J ~i, j`
Es nple 5: Preparation of N-~toluenesulfonyl~3,4-bi6(bromomet~yl~
3-pyrroline l9g of tetrakis ~bromome~ylhthylene and 9g of p-toluene sulfonamide were dis-solved in 220 ml of dime~ylfor~amide. 30~ of an~ydrow potas6ium ca~bonate ~as added and then s~drred at room temperature for 20 hour~. Tbere~fter ~ol-~ent was remo-red by vaccum di~tillatiorL 60 ml of et~ylac~ dded to obtain 601it product, a~d ~olid product w purified b~ el column ~roma-to~raphy. 12g of ~e ti~le compound WBB obtained ~ield 60%).
Melting point: 170C
'~^N~ (CDCl3, o ppm): 7.69 (2H, d, J ~ 8.2 Hz), 7.33 (2H, d, J . 8.2 Hz), 4.00 (4H, 6), 3.15 (4~ ), 2.44 (6, 3H).
E~ample 6: PreparationofN-~D-toluenesulfonyl~3-(bromomet~yl)-4-(cyanomethyl)-3-pyrroline lOg of N-(p-toluenesulfonyl~3,~bis(~romomethyl~3-pyrroline, prepared in Prepa-ration ~, was dissolved in 10 ml of d~nethylsulfo~cide (DMS0) and t~en heated inoil bath for 2 hours with reflu~ng. During tlle heating and reflu~iing, 1.5g of sodium cyanide was added by small portion. The reaction mist~ was cooled to room temperature and poured i~to ice water and t~en estracSed ~nth methylene chloride (200 ml s 3). The estracts were combined, dried over Na2SC), and con-centrated. The residue was purified by ~ilica gel column ~romaSograp~y. Sg of the title compound was obtained (yield 57%).
Meltingpoint: 182C
~H-N~ (CDCl3, ~ ppm): 7.71 (2H, d, J ~ 8.2 ~z), 7.36 (2H, d, J . 8.2 Hz), 4.01 (4H, s), 3.20 (2H, s), 3.06 (2H, 6), 2.45 (3H, ~).
, ~ 2 ~
E~cample 7: PreparationofN-~p-tolue~esulfoslyl)-3-(aminoet~yl)-4-(bromomethyl~3-py~roline 4g of N-(p-toluenesulfonyl).3.(bromomet}lyl)~(cya~omet~yl) 3 py~roli~e, pre-pared in Preparation 6, was di~sol~ed ~ 100 ml of e~yl ether. T~e ~olu~on was 610wly added to the su~pension of lg of ~ ium alu~ninum h~dride a~AH) iI~ 20 ml of et~yl ether, and heated with reflu~ for 3 hours. The reaction misture was cooled by ice water. ~fter adding 3 ml of water, it was stirrod for 30 minutes and filtered of ~. The filtrate wa~ concentrated. 2g of the title cor~pound was ob-tained (yield 49%).
Melting point: 18~C
'H~ IR (CDC13, ~ ppm): 7.e~4 (2~I, d, J z 8.2 Hz), 7.46 (2~I, d, J ~ B.2 H z),4.20 (2 H, g, J ~ 7 H z), 4.06 (4~I, 5), 2.45 (3 H,s), 2.26 (2H, t, J - 7 Hz).
x~mple 8: PreparationofN~-~p-toluenesulfonyl~3,8-diazabicyclo [4.3.0]non-1(6)-ene 3.6g of N'-~p-toluenesulfonyl~3-(aminoethyl)~(bromomethyl-3-pyrroline, pre-pared in Preparation 7, was dissolved in 30 ml of rlimethylformamide. 6g of a~hydrous potassium carbo~ate was added to the solution ~d t~e~ stirred at room temperature for 18 bours. After concent~a~g the reac~o~ mistu~ under reduced pressure to remove solverlt, the mist~re ~as estracted wit~ met~ylene chloride (50 ml x 3). After mi~ng the obta~ed e~tracts, it wa6 wa~hed with water and concent~ated. 2.5g of t~e title compound was obtained (~ield 88%).
Meltingpoint: 201C
'H-N~ (CDCl3, o ppm): 7.80 (2H, d, J s 8.2 Hz), 7.44 (2H, d, J 8.2 Hz), 4.05 (4H, s), 3.41 t2H, ~), 2.92 (2~I, t, J ~ 5.8 ~IZ), 2.44 (2H, t, J = 5.8 Hz).
E~ample 9: PreparationofN3-(benzyl~N~ toluenesulfonyl)3.8-diazabicyclo [4.3.0]non-1(6~ene 1.8g of N~ toluenesulfonyl~3,8 dia2abicyclo[4.3.01~on-1(6)~e, prepared in preparation 8, was disgolved in 30 ml of ~e~a~ol. 6 ml of 50% a~lueow ~odium hydroside solution aIld 1.5 ml of benzyl bronude ~ere added to ~e ~olution ~nd ~tirred at room temperature for 5 llourg. T'ne reactio~ mistare wa~ concentratedunder reduced pressure to remove methanol and the~ estracted wit~ methylene c~onde (30 ml s 3). It was dried (Na9S0,) and concentrated a~d t~en dried under reduced pressure. 2g of t~e title compound was obtained (gie~d ~5%).
Melting point: 196C
'H-NMR (CDCl3, ~ ppm): 7.80 (2H, d, J ~ 8.2 Hz), 7.44 (2H, d, J ~ 8.2 Hz), 7.28 (5H, br. s), 4.û1 (4H, s), 3.66 t2H, ~), 3.40(2H, ~), 2.90(2H, d, J = 5.8Hz), 2.22(2H, t, J ~ 5.8 Hz).
~ple lO: Preparstion of N3-tbenzyl~3,8-diazabicylclo[4.3.0]non-1(6)-ene hydrobrornide 2g of N3-(benzyl)-N~-(p-toluenesulfonyl)-3,8 diazabicyc3o~4.3.0]non-1(6)-ene, pre-pared in Preparation 9, was suspended in 15 ml of 48% hydrobromic acid and 1.5g of phenol, and the reac~on misture was re~u~ed for 3 hours. ~cer cooling tbe reaction misture, 20 ml of water was added tbe misture was wa~hed ~nth chlorofo2m (50 ml s 3). The aqueous phase was taken and decolonzed by active carbon. Tbe aqueous phase was concentrated under reduced pressure asld t}~us resulting SOlia was washed with 1: 1 methanol-etl~ylether ~olve~t. 1.5g of the title compound was obtained (yield 98%).
Meltingpoint: 205C(dec.) 'H~ CDClJ, o ppm): 7.29 (5H, br. s), 4.00 (4H, s), 3.5~ (2~, s), 3.38(2H, ~ ), 2.91(2H, d, J = 5.8Hz), 2.24(2H, t, J ~ 5.8 Hz).
- 2 0 - ~ ~ 2 ~ ~ ~J I `
E~ample 11: Preparation of 3,8 diazabicyclol4.3.03non-1(6)-ene . di~ydrobromide 1.5g of N~D-toluenesulfonyl~3,~diaza~icy~1o[4.3 Olnon-1(6)-e~e. prepared in Preparation 8, was suspended in 15 ml of 48% hy~lro~romio acid and 2~ of phenol,and the reaction misture was re~used fsr 4 hours. ~er cooline the reaction misture, 20 rDl of water was added~ T~e r~isture was wa~d ~nth ~hloroform (40 ml ~ 3). T~e aqueous pba6e was t,ake~ and decolonzed b~ acti~e car~on.
The aqueous phase was concentrated under reduoed pres~ure uld thu~ ul~g ~olid was wasbed witb 1: 1 met~anol-et~ylether Bolvult. O.9g oftl~e ~tle com-pound was obtained (yield 98%).
Mel~ngpoint: 225-2~70C(dec.) Example 12: Prepara~on of 3,8-diazabicyclo~4.3.0~non-1(6~ene . di~ydrobromide 0.7g of N3-(benzyl)-3,8-diazabicyclo[4.3.0]non-1(6~ene hydrobromide, prepared inPreparation 10, was dissolved in 20 ml of 5% aqueous acetic acid colution. 0.5g of 10% palladium charcoalin this solution was 6uspended and the reaction misture was reflu~ted under the hydrogen stream for 7 hours. T~e solid was filtered off.The filtrate was concentrated ur der reduced pressure and dissol~ed ~10 ml of 48C~C bromic acid. By concentrating tbe solution under reduced pressure again, 0.5g of the title compound was obtairled (yield 73%). -Meltingpoint: 225-227C(dec.) ~ample l3: Prepara~on of 3-methyl-3~7~1iazabicy~1O~3.3.0~oct 1(5~ene dihydrobrornide 3,7-Diazabicyclo~3.3.0]oct-1(6~ene dihydrobromide (0.81 g) which was prepared inPreparation 2 was dissol~ed in water (10 ml). To tl~i~ solution 35% fonnaline (0.3 ml) and formic aQd (10 ml) were added arld reflu~ed for 4 hours. Tne ~ ~ f~ J
solvents were distilled of~ d the re~ olid WS,6 waS~ea with ~opropylalco-hol (20 ~nl) ar d ethyle~Lher (20 ml) to ~zive the title compo~t (0.81~, yield 94%).
Melti~g poi~t: 185-187C(dec.) E~ample 14 :Prepara~orlof3-e~yl-3,7diaza~ic:y~10~3.3.0~oct^1(5~e dihytrobFomide To a solution of 1-p-toluene ~u3fonyl-3,~bi~ (bromomet~yl~3-p~ Gline (3Al ~) in acetonitrile (43 ml), 0.73 ml of 70% ethylamine and aD~ydrou6 pota~ium car'Don-ate (8 g) were added and stirred at room te~perature for one hosr. Tne solid was filtered off and the filtrate was purified by ~ilicagel colu~ chromatography(CHCl3-~eOH) to give 3-et~yl-7-~toluene 6ulfonyl-3,7-diazabicy~lo ~3.3.0]oct-1(5)-ene (0.95 g, yield 39%). 0.9 g of this compou~d was hydrolysized in 20 ml of 48~c hydrobromic acid with 1 g of phenol. The hydrolysate ~a~ washed with chloroform (30 ml ~c 3) and decolorized with ~ctive carbon. T~e ~ol~e~t was con-centrated and washed with ethanol to give the ~tle compound (0.57 g, yield 62%).MS m/z (rel. int. %): M~ 138 (32),123 (20),109 (60),108 (100).
~ample 15 : Preparation of 3,7-dimethyl-3,7-diazabicyclo~3.3.0]oct-1(5)-e~e dihydrobromide 3,7-Diazabicyclo~3.3.0]oct-1t5)-ene dihydrobromide (0.644 g) wa~ dis60lved ~
formic acid t5 ml) and 36% fo~naline (5 ml) and t~en re~used for 5 ~oura T'ne ~olvents were evaporated under reduced pre6s~e a~d 20% ~ydro'bromic acid (10 ml) was added to this solid and then refluxed for 30 minutes. Evaporatio~ of 60lvents and washing with isopropanol to give the title comp~u~d (0.54 g, ~neld 90%).
22 2 s ,~
Example 16: Preparation of ~methyl-3~g~ abicyclo[4.3.0]no~-1(6hne dihydrobromide tIe2).
3-Benzyl-3,8-diazabicyclo[4.3.0]no~ l(6) ene dihydrobro~de tO.76 ~) was reflusedin 85% formic acid (10 ml) a~d 37% formalin,e (7 ml) for 5 ~our~. The ~ol~e~ts ~ere removed u~der reduced pre66ure and the ~olid wa~ wasbed wit~ i~opr~panol ethylether (2: 1) to ~pve 3~ uyl-8-methyl-3,8 diazabi~lo~4.3.0~ 1(6)~ene dihydrobromide (0.64 e. ~ield 82%).
'H-N~ (CDCl" ~ ppm): 7.32 (B~I, m), 4.02 (4~ ), 3.57 (2~ .36 (2H, ~), 3.21 (3H, 8), 2.94 (2H, d, J ~.8 ~Iz), 2.25 (2~I, t, J 8 ~.B Hz).
The above compound (0.585 g) was ~rred in 10% acetic a~d in water with lO~o palladium-charcoal (0.05 g) under hydrogen stream. After 5 hours t}le ~olidwas filtered off and 20% hydrobromic acid (~ ml) was added a~d the~ the ~ol~reLts were dis~lled of~. The resul~ng solid was washed with isopropanol-ethylether (2: 1) to obtain the title compound (0.276 g, yield 86%~.
'H-l~ (CDCl3, ~ ppm): 4.01 (4H, ~), 3.30 (2H, ~), 3.20 (3H, 6), 2.86 (2H, d, J~5.8Hz),2.20~2H,t,J~5RHz).
~ample 17: Preparation of 3-methyl-3,8-diazabicyc~ot4.3.0]non-1(6)~ne dihydrobromide (Ie3).
8-p-Toluenesulfonyl-3,8-diazabicy~10[4.3.0~on-1(6)-eDe (0.56 ~) was ~netllylatedwith 8~% fo~ic acid (10 ml) a~d 37% formaline (5 ml) by reflu~g for 5 hour~.
The solvents were distilled o~. To this solid ~% hydrobromic acid (20 ml) a~d phenol (1 g) were added alld refluxed ~or 5 hours. I~e reaction mirture was washed with chloroform (30 ml s 4), decolon~ed with active l:harC4al. The aque-ous layer was concentrated under vacuum and th2 solid was wash~d wit~ ~o-propanol-ether ( 2: 1) to ob~n ~le ~tle compound (0.48 g, yield 83%).
-- 2 3 -- 2 ~ rl s ~
H-NMR (CD30D, o ppm): 4.01 (4H, ~!;), 3.43 (2H, ~), 3.16 (3H, 8), 2.98 (2H, ~5.8Hz~,2.4~6~2H,t,J~5.8Xz).
~c~ple 18: Preparation of 3~7-dimethyl 3~7-diazabicyclol~-3-O]Oct lt5)-ene dihydrobromide 3,7-Diazabicyc3O~3.3.0]oct 1(5).er~e dihydrobromide (0.82 ~) wa~used ~nth formic acid (10 ml) and 35æ formali~e (10 ml) or B hous~ e e~cess r~age~ts were dis~lled of and 20% hydrobromic acid (10 ~1) ~ added a~d refluxed for 1 hour. ~he solvnet was distilled off and washed with etlla~ol-et~ylether (1:1 ) to obtain the title compound (0.95 g, yield 86%).
~H-N~ (CD30D, ~ ppm): 4.36 (8H, s), 3.12 (6H, ~).
xample 19: Prepsration of 3,8-~methyl-3,8-diaza~icyclo[4.3.0]non-1(6)-ene dihydrobromide .
3,8-Diazabicyclo~4.3.0]non-1(6)-ene dihydrobror~ide (0.57 g) was methylated withfo~c acid (8 ml) and 37% formaline ( 8 ml) by reflu~ing for 5 hours. Work-up as in F~ample 18 gave the title compound (0.48 g, ~rield 80%).
'H-N~ (CDJOD, ~ ppm): 4.07 t4H, s), 3.45 (2H, ~), 3.14 (6H, ~), 2.97 (2H, t, J ~ 5.8 ~Iz), 2.48 (2~I, t, J 5.8 ~I2).
~cample 20: Preparation of 3-methyl-3,7 diazabic~o~3.3.0]oct-l(5)~e di~ydrobromide .
To a solution of 1-p-toluenesulfonyl-3~4-bis~bromomethyl) 3-pyrroli~e (6.1 g) was dissol~ed in aoetonitri~e (70 ml), 40% methylamine aqueous ~olutior~ (1.5 ~1) arld anhydrous potassium carbonate powder (16 g) were added and s~ed for 2 hours 2 4 ~, ~ 2 a~ room temperature. The solid w~s filtered off and the filtrate was purified ~ysilicagel column chromato8raphy to yield 3-met~yl-7-p-toluenesulfo~yl-3.7-diazabicyclol3.3.0]oct.1(5)-ene (0.82 ~, ~ield 20%). 0.8 ~ oftl~i~ compou~d and 0.8 ~ of phenol were reflu~ed i~ 48% hyd~obromic ~Q.d (15 ml) fior 5 hour~. The reac-tion ~re was washed with cl~loroform (20 ~1 :c 3), decolonzed ~ active charco~l. The 601vent wafi distilled o~ a~d ~ ed wit~ et~ ol~ ylet~er (1: 1) to give the title compound (O.S g, ~ield 609~).
'H-N~ (CD~OD, o ppm): 4.42 (4H, s), ~.27 (4H, s~, 3.12 (3~I, o~.
sample 21: Preparation of 8-methyl-3,8-dia2abicyclo~4.3.0]non-1~6~ene dihydrochloride.
To a solution of 2,3-bis tbromomethyl~1,3-butadiene (4.8 ~) snd methylenediure-tharle (3.9 g) in dichloroethane ~40 ml), borontriBuoride etherate (0.3 ml) was added. The reaction mixture was reflu~ed for 10 hours and washed with 10%
sodium bicarbonate solution (30 ml x 3). The organic phase was filtered though silicagel and evaporation of the sol~ent to ~pve 1 carboetho~ 4,5-bis~bromo-methyl)-1,2,3,6-tetrahydropyndine (6.14 g, yield 90%) which was cyclized with 40~/c methylamine (1.B ml) and potassium carbonate (15 g) in acetonitrile (50 ml) for 2 hours at room temperature. The solid was filtered of~and the filtrate was purified by silicagel column c~omatography to gi~e 3-carb~ethosy-8-methyl-3,8-dia~abicy~lo~4.3.0] non-1(6~e~e (2.57 g, yield 68%). This ami~e wa~ used in 20% hydrochloric acid (50 ml) aud e~aporatio~l ga~e t~e ~tle compou~d (1.35 g, y~eld 80%).
'H-NMR (CD30D, ~ ppm3: 4.01 (4H, ~), 3.32 (2~ ), 3.20 t3H, s), 2.84 (2H, ~, J = 5.8 ~Iz), 2.21 (2H, t, J = ~.8 Xz~.
-- 2 5 _ f~ f `~ $
By using the diazabicycloamine compo~d~ ~how~l by ~e general for~ula (I~
which were prepared by ~e E~amples, and quinoXo~e oompounds sho~n by the above formula (A) or (B) and their ~ s are prep~red by the follo~ me~o~
rU6e]
Use 1: Preparatio~l of 1-cyclopropyl-7-t3,?~ abi~1O~3.3.o]oct-l(5h~-3-yl]-6,8-difluoro-1,4.dihydro~o:Eoql~inD~ ~3~osyli ~cid (B:R-10~79~
The solution of û.4 g of 1-cyclopropyl-6,7,8-trifluoro L4-d~yd~o:~oline 3 carbo~ylic acid, 0.8 g of 3,7-diazabicy~10~3.3.0]oct-1(5)-e~ ydrobromide, a~d 0.8 ml of 1,8-diazabicyclo[5.4.0~undeo-7~e a~8U) isl 30 ~Dl of aceto~itrile was reflused in oil bath at the temperatllre of 1ûO~ for 8 hour6, a~d t~is reaction ~ture was kept otrer~ight at ~e room temperature. I~e produced precipitate was filtered off and tben ~e residue was washed with metha~ol, to obtaiu 0.35 g of the title compound (yield 67%).
~Ieltingpoint: 220-2220C(dec.) ~H-N~ (CDCl3 ~ CD3COOD, ~ ppm): 8.81 (IH, ~), 7.87 (lH, d, J ~ 14.2, 1.8 Hz), 4.69 (4H, 8), 4.24 (4H, 6), 4.û1 (1H, m), 1.23 (4H, rG).
Use 2 : Preparation of 5-amino 1-cyclopropyl-7-t3~7-diazabicyclo~3.3.0~oct 1(5) en-3-yl]-6,8-difluoro-1,4-dihydro~soquinoline-3-carbos~lic acid (KR-10747) The solutio~ of 0.4 g of 5 amino-1~clopropyl~,7,~triliuoro~ dihydro~4~oxoqui noline-3-carboxylic acid, 0.8 ~ of 3,7-diazabicy~lo~3.3.û]oct~1(5) e~e ~ihyd~obro mide, and 0.6 ml of 1~diazabicydo[5.4.oh~dec-7~e a:~BU) in 40 ~1 of acetoni-trile was reflu~ed at t~e reac~on temperature of 100~C for 7 ~ours. T~is reaction ture was kept oven~ight at the room temperature, and the produced precipi-tate was filtered and then the residue was washed with ethanol to obtai~ 0.3 g of the tit]e compound (yield 57%).
2 6 ~ " j~ !
Meltingpoint: 220-225DC(dec.) H-N~ (CDCl3 ~ CD3COC)D, ~ ppm): 8.6~ (lH. 6), 4.6~ (4H, 8), 4-24 (4H, ~), 3.91 (lH"n), 1.18 (4H, m).
Use 3: Preparation of 1-cyclopropyl-7-~7-~e~yl~3,7-diazabicyclo~3.3.0]oCt 1 S~ en~3-yl]-6,8-difluoro 1~ hyaro4-o~:o~oli~3-carbosylic acid hydrochlonide t~R-10755) 0.1 g of 1-cyclopropyl 7 [3~?-diazabicyclor3.3.0]oc~1(5)-en-3-gl~6~difluoro-1/4-~ihydro-~o~oquinoline-3-carboxylic acid, prepared i~ e U~e 1, wa~ assol~ed in the solu~on mi~ture of ~ ml of 3B% aqueous fon~aline solution a~d 1.5 ml of foImic acid, and then this reactio~ ~ture was feflwced at tlle reactioII tempera-ture of 120C for 2 hours and it w8s concentrated u~der the reduced pressure to remove solvent. 1 ml of isopropyl alcohol and 1 ml of 20% hydrochlonc acid W85 added herein and then it was reflu~ced more for 1 hour. The solve~t was removed under the reduced pressure t~ remove the solvent arld washed ~ith 1: 1 ~nisture solvent of methanol-ether, to obtai~ 0.082 g of the ~tle compound (~ield 78%).
Mel~ngpoint: 210-213~C(dec.) ~H-N~ (CDCl3 ~ CD3COOD, o ppm): 8.82 (lH, s), 7.85 (lH, d, J =14.3Hz), 4.83 (2H, m), 4.67 (4H, ~r. s), 3.98 (lH, m), 3.8~ (2H, m), 3.16 (3H, B), 1.24 (4H, m).
U6e 4: Preparation of 1-cydopropyl-7-r3,7-diazabicy~1O~3.3.0]oct-1(5). e~-3-yl]- 5,6,8-trifluoro-1,4-dihydro~osoquinolin~3-carbosylic acid tgR-10768) 0.6 g of 1-cyclopropyl-~6~7~8-tetrafiuoro-l~4-dihydro~o~oq~oli~carbosylic acid, 1.2 g of 3,7-diazabicyclo~3.3.0]oct-1(5) ene dihydro~romide a~d 1.3 ml of 1,8-- 27 - ~$' Ji~i ~
di~abicyclo[5.4.0]undec-7~ne (DBU) were eu~pe~ded ir~ 20 ml of acetonitrile, and then the reac~on mi~cture was renu~ed ~or 10 hours. ~i5 reactiaa misture was kept o~ren~ight at the room tempera~e, ancl ~e prDducet precipitate was filtered and then the residue wafi washed wi~ etharlol ~o obtain 0.58 g the title compound (yield 74%).
Meltingpoint: 226-228DC(dec') 'H-N~ (CDCl, I CD,COOD, ~ ppm): 8.71 (l~ ), 4.68 (4EI, o), 4.18 (~H, 1~), 4.00 (lH, m), 1.22 (4~, ~n).
Use 5: Preparation of (-~9-~uoro-3-(5~10-~3,7-diszabicyclot3.3.0]oct 1(5) en-3-yl]-7-o~o-2 ,3-dihydro-7H-pyndo~1.2.3~e]-1,4-benzosazi~e~car~o~cylic acid (~-10759) 0.28 g of (-)-9,10-difluoro-3(5~methyl-7-o~o-2,3-dihydro-7~I-pyndo~1.2.3-de]-1,4-~enzo~azine-6-carbo~cylic acid was dissolved in 3 ml of pyridine, and tllen 0.5 g of 3,7-diazabicyclo[3.3.0]oct-l(~)-ene dihydrobromice was added herein, ne~t the reaction mi2ture was refllL~ed for 10 houss. This reaction mir~rue wa~ concen-trated under the reduced pressure tllree ~mes, a~d the residue was washed with 1: 1 mi~ture solvent of ethanol-ether to obtain 0.32 g of the title compound (yield 8~c).
Meltingpoint: 196C(dec.) ~H-N~ (CDCl3 ~ CD~COOD, ~ ppm): 8.85 (lR, B), 7.69 (lH, d, J ~14.2 ~z), 4.60 (4H, s), 4.51 (lH, m3, 4.31 (2~ r. s), 4.21 (4~, s), 1.65 (3H, d, J 6.6 Hz~.
Use 6: Preparation of l-cyclopropyl-7 ~3~7-diazabicydo~3.3.0]oct-1(5)~e~l~3~yl~6~8-difluoro-1,4-dihydro~-osoquinoline-3-carbo~cylic acid (ER-10679) 2 ~ ) r~ d i /
0.28 g of 1-cyclopropyl-6,7,8-~ifluoro-1,4-dihydro-~o~oquinolin~3-Car'DOSy~ic acid, 0.16 g of 3,7-diazabicyclo-~3.3.0]oct-1(5)-ene ,~d 0.3 ml of 1,8~iaz~icy~1o-[5.4.0]unde-7-ene (DBU) ~ere su6pended in 20 ml of acetonitrile, a~d the~ the reaction mixture was fefl~ed in oil bath at ~he re~io~ tempcrature of 100C for 6 hours. This reactioD ~e wa~ Icept ove2~ught at the r~om temperature, the produced precipits~e wa6 filtered a~d the reE idue w~ hed wit~ t mis-ture of ethanol-ether (1: 1) to obtain 0.3 g oiE t~e title compou~d (~rield 809~).
Meltingpoi~t: 220-223~C(dec.) Use 7: Preparation of l-cyclopropyl-6,R~ luor~7-t3,8-diazabicy~10[4.3.0] Ilon-1(6)-en-3-yl)-1,4-dihydro4~soq~oline-3-carbo~ylic a~:id hydrobromide 0 3 g of 1-cyclopropyl-6,7,B-trifluoro-1,4-dihydro4-o~coquinoline-3-carbDsylic aQd and 0.42 g of 8-p-toluenes~fonyl-3,8-diazabicyclo[4.3.0]non-1(6~e~e were dis-solved in 20 ml of acetonitrile. 0.3 ml of 1,8-diazabicyclo~5.4.0]undec-7-ene (DBU) were added and then reflua~ed for 5 hour~. The reaction misture was kept overnight at room temperature. The produced precipitate was filtered and 5U5-pended in the mi~lture of 20 ml of 40% hydrobromi~ acid and 1 g of phe~ol. The suspension was reflu~ed for 5 hours. The reaction misture was c~oled to room temperature and then washed five ti~es with met~ylene ~hlonde (30 ml s B).
The aqueous phase was eoncentrated under reduced pressue a~t wad~ed ~itl~ tbe ethanol-ethylether (1: 1) solvent. 0.34 g of t~e title compou~d (yield 68%).
Meltingpoint: 287-291C(dec.) 'H-NMR tCDCl3 I CD3COOD, ~ ppm): 8.89 (lH, 6), 7.88 (lH, d, J ~ 14 Hz), 4.10 (4H, ~), 4.00 (lH, m), 3.40 (2~, , br). 2.94 (2H, t, J z 5.8 ~Iz), 2.31 (2~I, t, J c 5.8 Hz), 1.25 (4H, m).
~ 29 - ~ ~r; ~
Use 8: Preparation of 1-cyclopropyl-6,~-di1uoro-7 (3~8-dia~abic~rdo[4~3~o]
non-1(6)-en 8-yl]-1l4-dihydro~osoqu~olille-3-caT'Dosylic acid 0.3 g of 1-cyclopropyl-6,7,8.~ifluo~1,4 dihydro~)~oq~oli~e-3-car'Do~ c acid ~d 0.6 g of 3-be~zyl-3,8-dia;cabicydo~.3.0~non-1(6h~e ~ydrobromide were ~uspended in 30 ml of acetonitrile. 0.6 ~ of 1,8~iazabicyclo[5.4.0h~dec-7~e tDBU) was added to the suspen6ion. T~e ~action mist~ wa~ ed for 6 boun ar~d then kept overnight at room te~pera~ure. T~e pr~duced precapitate was filtered a~d dissolved in 30 ml of 5% aee~c Rcid ~ et~a~ol. ~ter ad~ing 0.5 g of 10~ Palladium chareoal, the reactio~ ture was ~tined ~der hyd~ogen ~tream for 6 hours and then filtered. T~e filtrate was conce~trated u~ter ~e-duced pressu~e. 0.25 g of the title compound (~ielt 61%).
~Ieltingpoint: 270C(dec.) IR (CDCl3 I CD ,COOD, ô ppm) : 8.84 ~lH, s), ~.89 (lH, d, J ~ 14. Hz), 4.60 (4H, s), 4.02 (lH, m), 3.41 (2H, s), 2.94 (2H, t, J 6.8 Hz~, 2.27 (2H, t, J ~ 5.~ ~z), 1.27 (~I, m).
The antibacterial activity of the quinolone compoun~ prepared ~ ~e pren-ously descnbed Uses accordi~ to tbe present inven~on i6 I;~OWn in the follo~g Table I and Table II.
~ he quinolone compo~ds ~ow~ by the above ~erlera~ forDlula (A) a~d (B) which were prepared by using t~e diazabicy~loE~mine compou~dr ~own ~ t~e above general fo~nula ~I) according to tbe pre~ent u~vention have r~uc~ bett~r antibacten~l ac~vity against the Gram po~itive ba~teria ~uch as Stt~phylo~s spp. spP .
and Streptoc~ccu~ ~an the t~aditional q~olone compou~ds ~uch a~ o~osa~
and norflo~acin, and they have ~milar or better asl~bacterial ac~ an cip-roflo~acin.
- 3c - ~ g ~ c~
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Claims (7)
1. Diazabicycloamines of the general formula I
(I) wherein m denotes 1 to 3, n denotes 1 to 2 and R1 and R2 denote hydrogen or lower alkyl and their salts.
(I) wherein m denotes 1 to 3, n denotes 1 to 2 and R1 and R2 denote hydrogen or lower alkyl and their salts.
2. Diazabicycloamines as claimed in claim 1, wherein m denotes 1 or 2, n denotes 1 and R1 and R2 denote hydrogen or lower alkyl, with the proviso that R1 and R2 cannot be lower alkyl simultaneously.
3. A process for the manufacture of diazabicycloamines of the formula I and their salts (I) wherein m denotes 1 to 3, n denotes 1 to 2 and R1 and R2 denote hydrogen or lower alkyl which comprises (a) reacting tetrakis(halomethyl)ethylene, wherein halo is chloro, bromo or iodo, with ammonia, whereby a compound of the formula I with m and n = 1 and R1 and R2 = hydrogen is obtained;
(b) removing from a compound of the formula I, wherein one or both nitrogen atoms are protected, the protecting group(s) and - if desired - alkylating one or both nitrogen atoms;
(c) removing from a compound of the formula I, wherein one nitrogen atom bears an alkyl group and the other nitrogen atom is protected, the protecting group, or (d) reducing a merimine derivative of the formula wherein R1 or R2 is lower alkyl and X(-) is an anion.
(b) removing from a compound of the formula I, wherein one or both nitrogen atoms are protected, the protecting group(s) and - if desired - alkylating one or both nitrogen atoms;
(c) removing from a compound of the formula I, wherein one nitrogen atom bears an alkyl group and the other nitrogen atom is protected, the protecting group, or (d) reducing a merimine derivative of the formula wherein R1 or R2 is lower alkyl and X(-) is an anion.
4. A process as claimed in claim 3 for the manufature of diazabicycloamines of the formula I and their salts (I) wherein m denotes 1 or 2, n denotes 1 and R1 and R2 denote hydrogen or lower alkyl with the proviso that R1 and R2 cannot be lower alkyl simultaneously, which comprises (a) reacting tetrakis(halomethyl)ethylene, wherein halo is chloro, bromo or iodo, with ammonia, whereby a compound of the formula I with m and n = 1 and R1 and R2 = hydrogen is obtained, (b) removing from a compound of the formula I, wherein one or both nitrogen atoms are protected, the protecting group(s) and - if desired - alkylating one of the nitrogen atoms, (c) removing from a compound of the formula I, wherein one nitrogen atom bears an alkyl group and the other nitrogen atom is protected, the protecting group, or (d) reducing n merimine derivative of the formula wherein R1 or R2 is lower alkyl and X(-) is an anion.
5. A process for the manufacture of compounds of the general formula I as claimed in claim 3, which comprises the following variants of (a) heating tetrakis(halomethyl)ethylene of the formula wherein Hal means chlorine, bromine or iodine, and liquid ammonia under increased pressure whereby a compound of the formula Ia (Ia) is obtained, (b) cyclization of tetrakis(halomethyl)ethylene with 2 mols, preferably a slight excess a compound of the formula R*-NH2, wherein R is a nitrogen-protecting group, in the presence of a base, and removing the nitrogen-protecting group by treatment with an acid or by hydrogenolysis under acidic conditions, whereby a compound of the formula Ib (Ib) wherein X is the anion of the acid, is obtained, (c) (c1) cyclization of tetrakis(halomethyl)ethylene and 1 mol, preferably a slight excess of a compound of the formula R*-NH2, wherein R* is a nitrogen-protecting group, in the presence of a base, whereby a compound of the formula is obtained, (c2) replacing one bromine atom by the cyanide group, (c3) reducing the cyanide group to the aminomethyl group, (c4) cyclizing this compound in the presence of a base, whereby a compound of the formula is obtained, and then removing the protective group in the presence of an acid or by hydrogenolysis under acidic conditions, whereby a compound of the formula Id wherein X is the anion of the acid, is obtained, which may be treated with alkali to lead to a compound of the formula Ic (Ic) or (C5) introducing to the only free nitrogen atom of the N-protected compound obtained in step t4 a second protecting group, removing selectively the group R* by addition of an acid, whereby a compound of the formula wherein X is the anion of the acid and "prot.gr." is a protecting group removable by hydrogenolysis, is obtained, and removing the second protecting group by hydrogenolysis under acidic conditions, whereby a compound of the formula 1d is obtained, (d) subjecting 2,3-bis(halomethyl)-1,3-butadiene of the formula wherein Hal means chlorine, bromine or iodine, to a hetero-Diels-Alder reaction with methylene-diurethane (methylene-biscarbamate) leading to a compound of the formula which is cyclized with an amine of the formula R-NH2, wherein R is lower alkyl or a protecting group, under basic conditions and deprotection under acidic conditions (e) reduction of a merimine of the formula which leads to a compound of the formula or carrying out the following reactions with some of the above-mentioned intermediates a) treating compound Ib with alkali to obtain compound Ia, b) subjecting compound Ib to a mono- or dialkylation, .lambda.) cyclizing the compound obtained in step c1 with an amine R1NH2 in the presence of a base to obtain a compound of the formula which after removing the protective group with a strong acid or by hydrogenolysis under acidic conditions leads to the monoalkyl compound of the formula wherein X is the anion of the acid, .delta.) alkylating the protected compound of step c4) and deprotecting the resulting product under acidic conditions or by hydrogenolysis under acidic conditions, whereby a compound of the formula wherein X is the anion of the acid, is obtained, subjecting the compound of step c5 which still contains the second protecting group to an alkylation and deprotection by hydrogenolysis under acidic conditions to obtain a compound of the formula wherein X is the union of the acid or ?) subjecting the compound 1d to a dialkylation reaction which leads to a compound of the formula
6. The use of the compounds of claims 1 and 2 for the manufacture of new quinolone antibiotics.
7. The diazabicycloamines as claimed in claim 1 and substantially as described herein.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019890015204A KR910009331B1 (en) | 1989-10-23 | 1989-10-23 | Diazabicycloamine compounds and the preparation process thereof |
| KR89-15204 | 1989-10-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2028205A1 true CA2028205A1 (en) | 1991-04-24 |
Family
ID=19290921
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002028205A Abandoned CA2028205A1 (en) | 1989-10-23 | 1990-10-22 | Diazabicycloamine compounds and a process for their preparation |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US5089621A (en) |
| EP (1) | EP0424852A1 (en) |
| JP (1) | JPH03193779A (en) |
| KR (1) | KR910009331B1 (en) |
| CN (1) | CN1051177A (en) |
| CA (1) | CA2028205A1 (en) |
| FI (1) | FI905173A0 (en) |
| HU (1) | HUT56366A (en) |
| IL (1) | IL96090A0 (en) |
| IN (1) | IN171604B (en) |
| YU (1) | YU198190A (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR940001770B1 (en) * | 1991-10-15 | 1994-03-05 | 재단법인 한국화학연구소 | Azabicyclo compound derivatives |
| DE4339134A1 (en) * | 1993-11-16 | 1995-05-18 | Bayer Ag | 1- (2-fluorocyclopropyl) quinolone and naphthyridonecarboxylic acid derivatives |
| US5457121A (en) * | 1994-09-02 | 1995-10-10 | Eli Lilly And Company | Cis-hexahydro-5-(1,2,3,4-tetrahydro-2-naphthalenyl)pyrrolo<3,4-c>pyrroles as inhibitors of serotonin reuptake |
| WO2016046837A1 (en) | 2014-09-22 | 2016-03-31 | Cadila Healthcare Limited | An improved process for preparation of pyrrolo[3,4- c] pyrrole compounds and intermediates thereof |
| EP3448859B1 (en) | 2017-03-20 | 2019-07-10 | Forma Therapeutics, Inc. | Pyrrolopyrrole compositions as pyruvate kinase (pkr) activators |
| JP7450610B2 (en) | 2018-09-19 | 2024-03-15 | ノヴォ・ノルディスク・ヘルス・ケア・アーゲー | Activation of pyruvate kinase R |
| EP3853206B1 (en) | 2018-09-19 | 2024-04-10 | Novo Nordisk Health Care AG | Treating sickle cell disease with a pyruvate kinase r activating compound |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE55898B1 (en) * | 1982-09-09 | 1991-02-14 | Warner Lambert Co | Antibacterial agents |
| JP2844079B2 (en) * | 1988-05-23 | 1999-01-06 | 塩野義製薬株式会社 | Pyridonecarboxylic acid antibacterial agent |
-
1989
- 1989-10-23 KR KR1019890015204A patent/KR910009331B1/en not_active IP Right Cessation
-
1990
- 1990-09-19 IN IN745/MAS/90A patent/IN171604B/en unknown
- 1990-10-19 FI FI905173A patent/FI905173A0/en not_active Application Discontinuation
- 1990-10-19 US US07/598,888 patent/US5089621A/en not_active Expired - Fee Related
- 1990-10-20 HU HU906520A patent/HUT56366A/en unknown
- 1990-10-22 YU YU198190A patent/YU198190A/en unknown
- 1990-10-22 CA CA002028205A patent/CA2028205A1/en not_active Abandoned
- 1990-10-22 CN CN90108666A patent/CN1051177A/en active Pending
- 1990-10-22 JP JP2282069A patent/JPH03193779A/en active Pending
- 1990-10-22 EP EP90120242A patent/EP0424852A1/en not_active Withdrawn
- 1990-10-23 IL IL96090A patent/IL96090A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL96090A0 (en) | 1991-07-18 |
| US5089621A (en) | 1992-02-18 |
| FI905173A0 (en) | 1990-10-19 |
| KR910007932A (en) | 1991-05-30 |
| KR910009331B1 (en) | 1991-11-11 |
| JPH03193779A (en) | 1991-08-23 |
| EP0424852A1 (en) | 1991-05-02 |
| YU198190A (en) | 1993-05-28 |
| HUT56366A (en) | 1991-08-28 |
| CN1051177A (en) | 1991-05-08 |
| HU906520D0 (en) | 1991-04-29 |
| IN171604B (en) | 1992-11-21 |
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