AU668286B2 - Diazabicyclo(4.3.0)nonane and (3.3.0)octane heterocycles - Google Patents

Description

Our Ref: 505278 Aft Aft

Z

P/00/011 Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT a a

.E

a a a.

a a Applicant(s): Bayer Aktiengesell~schaft D-51368 LEVERKUSEN

GERMANY

Oaa* a a.

a. a Address for Service: DAVIES COtJLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY N'SW 2000 Diazabicyclo(4.3.0]nonane and heterocycles Invention Title: (3.3 .0]octane The following statemient is a full description of this invention, including the best method of performing it known to me:- 5020 The invention of this application relates to new intermediate compounds for use in the synthesis of 7-(l -pyrrolidinyl)-3-quinolone and -naplithyridonecarboxylic acid derivatives.

These derivatives are described in "parent" Patent 650316 (formerly Application No.

10283/92) and in "grandparent" Patent 616277 (formerly Application No. 36594/89).

This application is a divisional of parent application No. 10283/92 (now Patent 650316).

The invention of this divisional application is a compound selected from the group consisting of-, 8-diazabicyclo[4.3 .0]nonane dihydrochloride, trans-2-oxa-5,8-diazabicyclo[4.3 .0]nonane, 5-methyl-2-oxa-5, 8-diazabicyclo[4,3 .O]nonane dihydrochloride, 2,8-diazabicyclo[4.3 .O]nonane, 4,methyl-2,8-diazabicyclo[4.3 .0]nonane, 2-methyl-2,8-diazabicyclo[4. 3 .]nonane, 2zrnethyl-2,7-diazabicyclo [3 0] octane, 3-oxa-2,7-diazabicyclo[3.3.0]octa-ne, 2-methyl-3 Dxa-2,7-diazabicyclo [3 .3 0] octane, 20 2,5 -dimethyl-3 -oxa-2,7-diazabacicylo[3 0] octane, 2,8-dimethyl-3 .oxa..2,7-diazabicyclo[3 .3 .]octane, 2-methyl-4-oxa-2,8-diazabicyclo[4.3 .0]nonane, 3-methyl-2,7-diazabicyclo[3 Ojoctane, 2,3-dimethyl-2,7-diazabicyclo(3.3 .0]octaine, ethyl 2,7-diazabicyclo[3.3.0]octane-2-carboxylate, 9 2-phenyl-2,7-diazabicyclo[3.3 .0]octLane, 0.

4-oxa-2,8-diazabicyco[4.3 .0]nonane, Note: The ensuing description is identical to the description of the specification of "1parent" 650316 (formerly 10283/92). This "parent" description has been fully p:\wpdocs~grs\505278\jgs 71W-r lareadopted to facilitate identification of the parent/divisional relationship. It is reiterated that the invention of this divisional application is as defined above and in the ensuing claims.

A number of 3-quinolone- and naphthyridonecarboxylic acids which are substituted in the 7-position by a pyrrolidinyl ring have already been disclosed. German Patent Application 3,318,145 and European Patent Applications 106,489 and 153,826.

It has been found that the 7-(1-pyrrolidinyl)-3-quinolone- and naphthyridonecarboxylic acid derivatives of the formula (I)

OOR

2 Cr

C

*r C *4S

C.

C

C C

C..

C

C

in which X' represents halogen, 72 represents hydrogen, amino, alkylamino having 1 to 4 carbon atoms, dialkylamino having 1 to 3 carbon atoms per alkyl group, hydroxyl, alkoxy having 1 to 4 carbon atoms, mercapto, alkylthio having 1 to 4 *C.C

CC..

C

*9

C

C.

p X: wpdmtrp15s\52M18\g1 carbon atoms# arylthio or halogen, R' represents alkyl having I to 4 carbon atoms, alkenfyl having 2 to 4 carbon atom.9, cycloalkyl having 3 to 6 carbon atoms, 2-hydroxyethyl, 2-f luoroethyl, methoxys amino, methylamino, ethylamino, dimethylamino or phenyl which is optionally substituted by 1 or 2 fluorine atoms,

R

2 represents hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-l, 3-dioxol-4-yl )-methyl, 10 R 3 represents a radical of the structure P, 1-P 4 R, N~ -N

R

6

I

wherein R4 can represent H, C,-C-alkyll aryl or CI-C-acyle can represent He C,-C-alkyle OH or 0CH., it also being possible for R' and R 5 together to 5 denote A CI-C 3 -alkylene bridge which is optionally mono- or disubstituted by methyl, Re can represent H, optionally hydroxyl-substituted CI"C 4 -alkyl, as well as aryl, heteroaryl, benzyl, Di2 h 26 -2- 2

C

1 -C4-alkoxycarbonyll CI-C 4 -acyl, (5-methy1 -2oxo-1, 3-dioxol-4-yl )-methyl, Or C 3 -CS-CYC1oalkyll R7 can represent H or C-C 4 -alkylr RF can represent H, CH 3 or phenyl, Ro can represent He CH 3 or phenyl, Rol can represent H or CH,, Y can represent 0, CH 2 CH2CH 2 or CH2-0, it being possible for the CH2-0 group to be linked to 10 the nitrogen either via 0 or via CH 2 and Z can represent 0 or S, and A represents N or C-Rt wherein RI represents H, halogen, methyl, cyanol nitro, hydroxyl or methoxy or, together with can form a bridge having the structure -0-CHZ-CH-CH 3 1 -S-CH 2

-CH-CH

3 or I I and pharmaceutically usable hydrates and acid addition salts thereof and the alkali metals alka- 3line earth metal, silver and guanidinium salts of the underlying carboxylic acids, have a high antibacterial action, in particular in the Grampositive regioh.

Preferred compounds are those of the formula (1) X1 COOR2

R

3

(II

:in which x 1 represents fluorine or chlorine, x2 represents hydrogen, amino, alkylamino having 1 or 2 carbon atoms, dimethylamino, hydroxyl, methoxy, mercaptol methylthio, phenylthio, fluorine or chlorine, represents alkyl having 1 to 3 carbon atomsj alkenyl having 2 or 3 carbon atoms, cycloalkyl having 3 to 5 carbon atoms, 2-hydroxysthyl, 2-f luoroethyl, methoxy, amino, methylanino, ethylamino, dimethylamino or phw.nyl which iv~ optionally substituted by 1 or 2 fluorine atoms, W~ represents hydrogen, alkyl having I to 3 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-y1)-nbthyl, -4 R 3 represents a radical having the structure R. Z-P 4 wherein R4 can represent H, Cl-C 3 -alkyl Or Cl-C 2 -aCYl,

R

5 can represent H, C 1

-C

3 -alkyl, OH or OCH 3 it also being possible for R' and R 5 together to denote a C-C-alkylene bridge which is optionally mono- or disubstituted by methyl, RG can represent He optionally hydxoxyl-oubstituted. C-C 3 -alkyl, as well as phenyl, benzyl, Cp.CC.lkoxy..

ses 10 carbonyl, C-C-acyl, (5-methyl-2-oxo-1,3.

dioxol-4-yl) -methyl, or C 3 -C-cycloalkyll R' can represent H or C,-C-alkyl, *49 *RO can represent H Or CE 3 R* can represent R or CH 3 Roo can rpresent R or CHI, T can represent 0, CE 3

CH

2

CE

1 2 or C92-0,, it being I& A 261011-5 5 possible for the CH 2 -O group to be linked to the nitrogen either via 0 or via CH 2 1 and z can represent 0 or S, and A represents N or C-Rj wherein RA represents H, fluorine, chlorine, bromine# methyl, nitro, hydroxyl or methoxy or together with R' can form a bridge having the structure on0-CH 2

CHCH

Particularly preferred compounds are those of the formula 2 ol *000 !00R 2 (1) in which X1 repvesents fluorine, 12 represents hydrogen, amino, umothylanino or fluorine, RI represents &ikyl baying 1 or 2 carbon atms, vinyl, cyclopropyll 2-hydxoxyethyle 2-flu1-roethyl, aethoxy, nethylazino~ 4-f luorophenyl or 2 ,4-difluorophenyl,, Lf A 21- -1-68 6

R

2 representi hydrogen or alkyl having 1 or 2 carbon atomI

R

3 represents a radical having the struct,.ire R- Z-Ft 4 R'4 .N N N R' P 6 8 wherein Sa can represent H, CI-CI-alkyl or acetyl, can represent H or C,-C-allkyl, it also beinq possible for R4 and R 5 together to form a aljylene bridge which is optionally substituted by methyl, RH can represent H, C 3

C

2

H

5

HOCHICH

2 benzyl, Cl- C,-alkoxycarbonyl or CI-Ca-.acyl R can represent H or CX3,s R# can represent H or CH,, ReO can represent H or CH3,I Rol can represent H or CH3.

I& A 26 108 7 y can represent 0, CH 2

CH

2 CH, or CH 2 it being possible for the CH 2 -0 group to be linked to the nitrogen either via 0 or via CH 2 and Z can represent 0 or St and A represents N or C-Rj wherein R' represents H, fluorine or chlorine, or together with R' also can form a bridge having the atructure too -0-CHa-CH-CH 3 it has furthermore been f tund that the compounds of the formula are obtained by a process in which compounds of the formula (II)

X

2 0 x0 COOR2 in which i's. 1 R 1

R

2 Y1 and X2 have the abovementloned mieaning and i represents halogon, in particular fluorin, or chlorine, are reacted with compounds of the formula (III) JAImA -6810 8

R

3 -H

(III)

in which

R

3 has the abovementioned meaning, if appropriate in the presence of acid entrainers, and if appropriate protective groups contained in R 3 are removed (method A).

Compounds of the formula according to the invention

*A

*X represents amino, alkylamino having 1 to 4 carbon atoms, dialkylamino having 1 to 3 carbon atoms per alkyl group, hydroxyl, alkoxy having 1 to 4 carbon atoms, mercapto, alkylthio having I to 4 carbon atocs or caylthio, can also be obtained by reacting a compound of the formula (IV) -9- F 0 x I I C0R 2

R

3 A N

(IV)

ii which

X

1 R, R' and A have the abovementioned meaning, with compounds of the formula tV)

S

*5 4

I.

*4

S

0e*4 4 *5SS 0*

S

*55* 12in which x 2 has the abovementioned meaning, if appropriate in the presence of acid entrainers (method B).

Compounds of the formula (1a) according to the invention in which lX, 12, R and A have the aboveueontionod meaning and R3 reprebents a radical having the structure Le A26, &f 10 or

J

I R6 wherein IW, RO, RI, Y ar&i 3 have the abovementioned meaning, can also be obtained by a process in which a compound of the formula (VI) 5

C

C

C.

9 6C*

C

*9 O0R 2

(VI)

9C*C

C

C. a a

.CO*

C C C. C C* CC C in which X20 X 2 R' ard A have the abovementioned meaning and 3* 10 R represents a radical having the structure R, Z-R 4 or

-N

IR"

H

H

11 where in RA, R 5 RI, RN, R-1, Y and Z have the abovementioned meaning, is reacted with compounds of the formula (VII)

R

6 1V (VII) in which Re has the abovementioned meaning and XG represents chlorine, bromine, iodine, hydroxyl or acyloxy, *se 10 if appropriate in the presence of acid entrainers (method

C).

if, for example, l-cyclopropyl-6,7, 8-trifluoro-1,4dihydro-4-.oxo-3-quinolinecarboxylic acid and 1-methylactahydropy-rroloE3,4-b]pyridine are used as starting 5 substances, the course of the reaction can be represented by the following equation: 12 COOH Base

COH

CM3 If o xmle -hoo6-lool9*furpey) 1 iyr--x-18nptyrdn--abxlcai n c 9 a9 tr.-uoyabnlain-4-ohx-yr dn r used assatn usacs.hecus fterato can berpeetd yteflown qain ItoA 2~ -113 13 cH, 3 0 Bs ID -HC1

(CH

3 3

C-O-CO-H

9.

I S 9@ 4 9 9 94 9 9 9 9*49 94

HCI

(CH

3 3

C-O-CO-NI

x HCI 14 If, for example, l-cyclopropyl-5,6,8-trifluoro-,4dihydro-7-( 2-methyl-2, 7-diazbicyclo( 3.3. ]oct-3-yl)-4oxo-3-quinlinecarboxylic acid and ammonia are used as starting substances, the course of the reaction can be represented by the following equation: NH 3 .0.

boo 0 sob* 00e *001 Se *0*S SO

H

3

C-

SI

NH

2 0

COOH

F' I F zs If, for example, l-cyclopropyl-7-(2 ,7-diazabicyclo- [3.3.0]oct-7-yl)-6-fluor-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid and ethanool/hydrogen chloride are used as starting substances, the course of the reaction can be represented by the following equation: 5000 *e 0 LtA 26 108 15 :00H

MCI

4C 2

H

5

OH

*4 X MCI The compounds of the formula (II) used as starting substances are known or can be prepared by known methods.

Examples which may be mentioned are& 7 -chloro-l-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo-3quinol inecarboxyl ic acid (German Patent Application 3,142,854), 1-cyc lopropyl-6, 7-dif luoro- 1, 4-dihydro-4 -oxo-3-quino7linecarboxylic acid (Ziiopean Patent Application 113,0Q91), 6-chloro-1-toyclopropyl-7 ,8-dfluoz~o-1,4-dihydro-4-oxo-3quinolncavcbxyric acid (GermAn Patent Application 30420,1743), 0 16 8-chloro-1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3quinolinecarbaxylic acid (German Patent Application 3,420,743), 1-cyclopropyl-6,7 ,8-trifluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid (German Patent Application 3,318,145), 6,8-dichloro-l-cyclopropyI-7-fluoro-1, 4-dihydro-4-oxo-3quinolinecarboxylic acid (German Patent Application 3,420,743), 10 1 -cyc lopropyl 6 j7-dif 1uoro -11,4-d ihydro 8-met hyl- 4 -oxo-3 quinolinecarboxyIlic acid, 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-8-nitro-4oxo-3-quinolinecarboxylic acid, 6, -di l -6 uoro ethyl -1 4 -diydro- 4- oxo -3-qu inoIine carboxylic acid, 7 -c h 1oro- 6 -fluoro 1 4-yl1hy ydX- 1X-3(2q-hiflxyel 3-quinolinecaxboxylic acid, 6 j7 -d if luoro- 2- f1 u oroe thy111,4- d ihyd ra- 4- oxO -3 quinolinecarboxylic acid, 17 8-chloro-1- (2,4-dif luorophenyl) -6#7-difluoro-I, 4-dihydro- 4-oxo-3-quinolinecarbaxylic acid (European Patent Application 235,762), 7-chloro-6-fluoro-1,4-dihydro-l-mothoxy-4-oxo-3-quinolinecarboxylic acid, 7-chloro-6-fluoro-l,4-dihydro-l-methylamino-4-oxo-3quinolinecarboxylic acid, 6,7-difluoro-114-dihydro-4-oxo-l-phenyl-3-quinoline- :carboxylic acid, 7-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-1,8naphthyridine-3-carboxylic acid, 6, 7-dichloro-l-cyclopropyl-1, 4-dihydro-4-oxo-1, 8naphthyridine-3-carboxylic acid, ethyl 1-cyclopropyl-6, 7,8-trif luoro-1, 4-dihydro-4-oxo-3quinolinecarboxylate (German Patent Application 3,318,145), 9, lO-difluoro-2,3-dmydro-3-Othyl-7-oxo-7H-pyrido(1,2,3- 0 do] (1,4 ]benzoxazino-6-carboxylic acid (European Patent Application 47,005), 8,9-difluoro-o6,7-dihydro-5-3othyl-l-oxo.1H,5H-bflzo[iojJquinoliz!~ne-2-carboxylic acid, IL&A i 26 180is 7-chloro-6-f luoro-1-phanyl-l, 4-dihydro-4-oxo-l, 8-naphthyridina-3-carboxylic acid (European P~ltent Application 153,580), 7-chloro-6-fluoro-1- (4-f luoropherayl) -1 ,4-dihydro-4-oxo- 1, 8-naphthyridine-3-carboxylic acid (European Patent Application 153,580), 6,7 ,8-trifluoro-114-dihydro-l-methyla~mirno-4-oxo-3-quinolinecarboxylic acid (German Patent Application 0*06 3t4091922), 10 1 aino 6 178 -t r iflu oro 1 4- dihydro- 4 -oxo 3-qu ino 11ne carboxylic acid (German Patent Application 3,409,922), 6,7, 8-trifluoro-l,4-dihydro-l-dimethylamino-4-oxo-3quinolinecarboxylic acid (German Pattdnt Application 7- c hloro- 6 -f 1uoro 114-d ihydro 8-n itro 4-o xo 1-phe nyl -3 quinolinecarboxylic acid, 7 -c hloro -6 fluoro- 1-(4 fluorophanyl 1, 4 -dihydro- 8-nitro- 4-oxo-3-quinolinecarboxylic acid, 6,g 7 -d ifluoro-1- (4 fluorophnyl) Ij4 -dihydro- 8 -nthyl-4 ozo-3-quinolinecarboxylic acid, 6 -chloro -7 fluoro-l1- (4 -f luorophenyl I 4 -dikiydro- 4-oxo- 3-quinolincarboxylic acid (European Patent Application 19 131,839), 5,6,j 7 r 8 -tetra f luoro-1- 4-dif luorophenyl 4-dihydro- 4 -oxo-3-quinolinecarboxylic acid, t7-cdich1oro-6-f luoro-l-(2f4-dif luorophenyl) 4-dihydro- 4-oxo-3-qiuinolinecarboxylic acid, 5,7-dichloro-1-cycloprzpyl-6-f luoro-1 j4-dihydro-4-oxo-3se. )q12inolinecarboxylic acid# .x 6-chlor-fluoro--(,4-difluorophenyl dr4- xdo-4- 1 ox3quinolinecarb xyli acid (European Patant Applica-o 6:40 6 17 8 -tri fluoro- 1- (24 -di f lophopyl) 14-d..hy ro--OXO- 0 3quinolinecarboxylic acid (European Patent Application :154,780), 6,7 ,8-trifluoro--24dfiohn-1,4-d.-hydo-4-oxo-l-hry--ioie 1 3quoincarbxylic acid (European Patent Application 470, 67, 8oo-tthy -luoro1 -iyro-4-dihy-1-ny4-quInoSnpthynidine-3-carboxylic acid, 6 ,7-ditluoro-1, 4-dihydro-4-oxo-l-vinyl-3-quinol-in.- Le A 2 108 20 carboxylic acid, 1-cyclopropy1-51, -tetra f luoro-l 4-dihydro-4-oxo-3quinoinecarboxylic acid, 5-amino-l-cyclopropyl-6,7,8-trifluoro-1 4-dihydro-4-oxo- 3-quinolLnecarboxylic acid, 1-cyclopropyl-6, 7 8-trifluoro-l, 4-dihydro-5-hydroxy-4oxo-3.quinolinecarboxylic acid, and 1-cyclopropy' -6 i7-dif luoro-1;4-dihydro-9-methoxs5v-4-oxo 3-quinolinecarboxylic acid.

*fee The compounds of the formula (III) used as starting compounds are new in some cases. They can be prepared by the following procasaes.

S.

1. Startinq from the N-protected 314-epoxypyrrolidine (German Offenlegungschrift (German Published Specification) 11929,237 and U.S, Patent 41254,135), which can optionally also carry one or two nethyl or phenyl radicals, the starting compounds of the formula (IIIA).(II) are prepared ZL2 i Iflo A2 14. 1 HN 6 MS 1~removat of fI77 ,SN6 Protective goups Ho" (1) I II a)

I,.

0* removaL of protective groups IIXb n benzyll acyl, alkoxyr~bonyl, benzyloxycarbonyl, trialkylsityl or suiphonyl (examples of protectivo gjroups):~ a lebving group, such as halogen, or alkyl- or arylaulphor~yloxy

X

04 0 111," 1 a a 22

N-

HON ~d 3 Base

R

4 0 ol#0 #t4id3

R

9 Otto a R 4 C) ~F(dH2

R

9

P

4 O~,-~~4IPQOCH 3 3

H

(111c)

R

4 0- R4 0 kl a a. a a a a p4%1[ rH2 713

I

R

4 0 N 6 H KN0

H

2 0

~-R

R

4

I-

K

(I I I) I H 2 /Pd.

(111d) 0 0 4 too.S 0 S 2. Starting compounds of the formula (IIlt) are obtained from 112-dichloroethyl)-oxirane via the following reaction sequences

S

S45* 55 C5 5 C1 HO C1

U--C'

fON t 4 0 0~ Lt A 26.1lQJ 24

R

4 0

H

2 R40 N H -R6

H

(1lI()

C

Ce er~g.

3. By addition of a:ides onto N-benzylmaleimiden which are optionally substituted by one or two methyl or phenyl radicals, starting compounds of the formula (1I 9) can be prepared:

R

9 ~n 0 0: 0-R

-R

9 reduction R 4 00, 7N CC C LS&a 26l 25 (IIIg) Rio H, alkyl or benzyl.

4. From the 3,4-epoxypyrrolidines (1)r the starting compounds of the formula (III h) are obtained via cyclization with thionyl chlorides 8 0 HO' ,sr--~NIdN-~ -SOC12 R9 R 9 R'7

R

7 R H (111 h) By reaction of the 3,4-ejxuypyrrolidines with ethanolanines, the atarting compounds of th3 formula (III L) are-obtained by intramolecular etherification i L:2 -A 26 hOQQ 26

R

6

N

Ii-6 HO

HO

R

9

H

0 N -R 6

I

o @0 0 9* 0001 6 (III i).

6. The starting compounds of the formula (TIII J) are obtained from aminoacetaldehyde dimethyl acetal via intramolecular 1, 3-dipolar cycloaddition.

ACH

3 OCH 3 3

H

2 Ne ,.-NAOCH 3 R9Ne" H H 2 CgN.-X Base 00 @0 0000** 0 OCH3 R9-N 3 4H2 R 0 H* e*--,CHO R 6

-NH-OH

9 RNIt4 H2 Ls A L-101- 27

N-R

7. Starting from pyridine-2, 3-dicarboxylic acid Nbenzylimide, starting compounds (III k) or (111 1) are prepared via the reaction steps shown.

S

0

N-CH

2

-C

6

H

0 jH 2 /Ru-C or IPd -C alkyt iodide

[-CH

2

-C

6

H

Alikyl I H 2 iPt.0 2 ILiAlH o Bir CAH) 2 0 Alkyl QCl NCH 2 -C6H Hi 28 I AH 4

IH

2 /Pd-C

NJ-CH

2

C

6

H

5

NH

H

Alkyl (111 1)

H

2 IPd-C Alkyl (III k) 8. N-Benzyl-maleilmide adds onto 2-chloroethylaine to give 3-(2-chloroethy amino) -UCCinimides which are converted into the starting compounds of the formula 0 IN CH2-C 6

H

5 C1-CH 2

CH

2

NH-R

6 i C 10 NaH 1

H

2 J NH CH 2 -C6HS 00 -iA1H 4 29

H

2 1lP-C

~Z

4

H

I.

(111 M) .e 44..

9 4.

*44

S

S 4 9. 2-Methyl-2-propenal-dimethylhydxrazone reacts with Nbenzylmaleimide to give a cycloadductr which cpn be converted into the starting compound (Illn) by the reaction sequence shown.

N

C-H

3 0 0

CH

3

~N-CH

2 -Ph C2-I o N 0 t CH 3

CM

3 0

-(CH

3 2 NH CH 3 .1H 2 1 0 0 CH3,-*

-CH

2 -Ph 0 L16A1H 4 -CH3*-W-H-hH/d H (III H 30 Starting compounds of the formulae (I110),s (Ilp) or (IXtIq) can be obtained in the following way, starting from N-protected 2,5-dihydropyrroles (3-pyrrolines) by addition of suiphenyl chlorides:

S.

S*

S* S

S.

S

S

S .5.5 S S 55 5 S S Le 101~ 31

R

9 0 4-S-e 1. *R-NH 2

(R

1

CH

2

CH

2

-HI

2. Removal o R R N S

H

C1 I N S-R 1

R

9 4R-NH R6a RR9 a.

a a. So

I

K

SH RemovaL o-f R

(RI

1 x Acyl, Alkoxy- H carbonyl) (1I1P) (111q) R" C,-C,-alkyl which is optionally substituted by halogen or phenyl, which is optionally substituted by halogen, nitro, alkyl or alkoxy, as well as acyl or alkoxycarbonyl.

The folloving starting compounds, for example, cam be prepared in accordance with thens general equations. They Ls AI2618 32 can be prepared and employed an diantereomer mixtures or in the diastereomerically pure or onantiomerically pure f orm,.

4-amino-3-hydroxypyrrolidine, 3-hydxoxy-4-methylaminopyrrolidine, 4 -d imethyl amino- 3-hydroxypyrrol1idine, 4 -ethylamino-3-hydzoxypyrrolidine, 3-amtino-4-methoxypyrrolidine, 4 -methoxy- 3-rethylaminopy-rrol idine, 10 3-dimethylamino-4-methoxypyrrolidine, 3 -ethyl axino-4 -methl-oxypyrrol id ine, 00 a, 3-amino-4-ethoxypyrrolidinot 4 -ethoxy-3-methylaminopyrrolidine, 3 -dimethylamino-4 -ethoxypyrrolidine, 4-ethoxy-3-ethylaminopyrrolidineI 3 -hydroxy- 4-hydro xyami nopyrrol1idi no, 3-hydroxy-4-methoxyaminopyrrolidine, 3 hydroxyam ino -4 -me thozxypyrrol1 id ine 4 -methoxy-3-mthoxyaminopyrrolidineI 3-benzylamin-4-methoxypyrrolidine, 4 -m e th ox y -3 -me th y I- 2-o xo 1,3 -d iox o I- 4- yI)-methyl- *tooamino) -pyrrolidine# "*Q:O,3-amino-4-mthylinrcaptopyrrolidino, 3 -acetoxy-4 -dimthylaminopyrrolidin., 25 3 -acetamido- 4-methoypyrrl idina 4 -mettboxy- 3-me thoxycarbonylami~opyrro1 1dim I 3-f oraido-4-aetboxypyrxvlidin. 3 -amino-4 -methoxy- 2-mothylpyrrol dins, 3- amino- 4 -mothoxy- 5 -mthylpyrrol 1din., 33 4-methoxy-2-mthy-3-miothyaminopyrrolidine, 4-methoxy-5-methyl-3-methylaminopyrrolidine, 3 -amino- 4-methoxy- 2-phenylpyrro lid ine, 4 -methoxy- 3 -iet yamino- 5-phenylpyrro1 idine, 3-methyl-2,7-dlazabicyclo[ 3.3. 0]octane, 4-methyl-2, 7-diazabicyclo[ 3. 3. 0 ]octane.

5-me'thyl-2 ,7-diazabicyclo[3. 3. 0O]octane, 3 ,54'.OU~thY1-2 e 7-4iAzabicyclo[ 3.3.-0 ]oct~mm, I, 5-dimethyl-2, 7-diazabicyclof 3.3. 0 ]octano, 2-oxe-4,7-diazabicydloE3.3.0]octane, 3,j 3-dimethyl-2-oxa-4, 7-diazabicyclo( 3.3.0 ]octanej 3 -oxa -217 -diaz abicyc lo 13.3. 0 octane I 1, 2-dimethyl-3-oxa-2, 7-d Lazabicyclo ]octane, 2 ,5-dimethyl-3-oxa-2,7-diazabicyclo[3..3 .0]octiane, 15 2,8-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octatne, 5-xiethy-3-oxa-217-diazabicyclo(3. 3. 0O]octane, 2-oxa-4,7-diazabicyclL%( 3.3.*0 3oct-3-en., 3-methyl-2-oxa-4, 7-diazabicyclo (3.3.0 ]oct-3-eie# 3-phenyl-2-oxa-4,7-diazabicyclo[3. 3.0]oct-3-ene, 6-ehl2oa47daabcco330*t3ee 6-methyl-2-oxa-4,7-diazabicyclo[3.3.0]oct-3-ene, 8-methyl-2-dia-4e -iycbioc(4 3.3 ]ct-3one 3-methyl-2,8-diazabicyclo(4 .3.O]nonane# 4 -methyl-2,8-diazabicyclo nonan., -mthyl28-dazabcyclo[4.*3 0 nonazw, 6-methyl-2-5,8-diazaycyc 4.3.0]nonan 3-mothyl-2-oxa-5,8-diazabicyclo[4o.3.0]nonaras, 4-uot1hyl-2-oxa-5,8-diazabicyclo[4.3.03nonane,, 3,5-diam~thyl-2-oxa-5,8-diazabicyclo[4 2-thia-5,8-diazabicyclo(4.3.0]nonan,# Ls A 26-.8. 34 5-met.1 -2-thia-5 8-diaza-bicyclo(~4 .3.0 Ononane, 3,5-dimethyl-2-thia-5,8-diaz$Abicyclo(4.3.0]nonane, 3-oxa-2,8-diazabicycloE4.3.0]nonanri, 2-methyl-9-oxa-2, 8-diazabicycloE4 .3 .0]nonaneI 4-methyl-3-oxa-2B-diazabicyclo4.3.lflolalO 2.5-dimethyl-3-oxa-2,8-diazabicyclo(4.3.0]nonanO, 8-diazabicyclo(4 O]nonane, 5-iiithyl-3-oxa-5, 8-diazabicyclo(4 .3 .Ononane, 1,5,.dimethyl-3-oxa-5,8-diazabicyclo[4.3,01nonanO and 4,4-dimethyl-3-oxa-58-diazbicyclo4.3.0]olaS.

*h recto of ih(I) accoun tomthdAi which the compounds (III) can also be employed in the :form of their hydrochlorides, is preferably carried out in a diluent, such as dimethyl suiphoxide, NN-dimethyl- 15 f orniamidej N-methylpyrroc.idono, hexaznethyl-phosphoric acid triamide, ouipholane, acetonitrile, water# an alcohol, ouch as wathanolt ethanol, n-propanol or isopropanol, glycol monomethyl ether or pyridine. Mixtures of these diluents can also be used or the reaction can be carried out without any solvent, 20 Acid-b~inding agents which can be used are all the cuetomary inorganic and organic acid-binding agents. These include, preferably, the alkali metal hydroxides, alkali laxly suitable acid-binding agents which may be mentioned specifically ares triethylamine, 1,4-diazabicyclo(2.2.2]octane (DAM3C), 1*,8-diazabicyclo(5,,4]un!ec-7-ene (DBU) or excess amino (III).

35 The reaction temperatures can be varied within a substantial range. The reaction is in general carried out between about 20 and 200 0 C, preferably between 80 and 180 0

C.

The reaction can be carried out under normal pressure, but also under elevated pressure. It is in general carried out under pressures between about 1 and 100 bar, preferably between 1 and 10 bar.

In carrying out the process according to the invertlon, 10 1 to 15 mol, preferably 4 to 6 mol, of the compound (III) a'e employed per mel of the carboxylic acid (II).

Free hydroxyl groups can be protected during the reaction by a suitable hydroxyl-protective group, for example by the tetrahydropyranyl radical and can be liberated again when the reaction has ended (see Mcmie, Protective Groups in Organic Chemistry (1973), page 104).

Free amino functlon can be protected during the reaction by a suitable arino-protective group, for exaziple by the ethoxycarbonyl or tert.-butoxycarbonyl radical, and liberated again when the reaction has ended by treatment with a suitable aciW, such as hydrochloric acid or trifluoroacetic acid (sea Houben-Waylt Methoden der organischen Cheaie (Metho4s of Organic Chemistry), Volume 84, page 144 (1983); and JIMW. c(maie, Protective Groups in Organic Chemistry (173), page 43).

36 The ri ,ction of (IV) with according to method B is preferably carried out in a diluent, such as dimethyl suiphoside, dio~ane, N,N-dimethyli ormamide, N-methylpyrrolidone, hexamethyi-phoephsz~ic acid triamide, suipholane, water# an alcohol, such a. methanol, ethanol#, propanol or isoprcipanol, glycol monomethyl. ether or pyridline. Mixtures of these diluenits can also be used.

Acid-binding agents which can be used are all the customary inorganic c4nd organic acid-binding agents. These include, preferably, the alkali metal 'c iroxides, alkali metal carbonates, organic amines and amidines. Particula~ly suitable acid-binding agents which may be mentione~d a opecifically ares triethylamine, 1,4-di-AzabicycloJ2.2.2 oct;Lne (DWCBO) or 1,8-diazabicyclo(5. 4. 0]undec-7-ene is1 (DBU).

The reaction temperatures can be varied within a substanease tial range. The reaction is in general carried out between about 70 araA about 200 0 C, preferably between 100 and 180 0

C.

T'Aae rt-ction can be carried out under norwaL prosisure, ee:S *but also vvidar increased pressoxe. It is in general carried out ii~der pres~ures of bwtween about I ba~r and about 100 bar, preferah-4.y between I and 10 bar.

XIn carrying out th~e process according to the invention by method B, I tej 50 mol, preferably I to 30 mol, of the compound axce employed per aol of the compound (IV).

1d) A2§ 190 37 To prepare the eaters according to the invention, tho car' xylic: acid on which they are based in preferably re~.cted in excess alcohol in the presence of strong acids, such as sulphuric acid, anhydrous hydrochloric acid, methanesuiphonic acid, p-toluenesulphonic acid or acid ion exchangers 1 at temperatures from about 20" to 200*C, preferably about 600 to 1201t. The water of reaction formed can also be removed by azeotropic distillation with chloroform, carbon tetrachioride, benzene or toluene.

The esters are also advantageously prepared by heating 4. the acid on which they are based~ with dimethylformaxide dialicyl acetal in a s~wilvent, such as dimethylformamide.

The 5-methyl-2-oxo-l,3-dioxol-4-yl-methyI esters used as a prodrug are obtaino4 by reaction cif an alkali metal ailt of tho carboxylic acid on which they are based with 4-bromomethyl- or 4-chloromethyl-5-m4ithyl-l, 3-dioxol-2one~ in a solvent, such as dimethylforzuamide, dimethylacetamide, N-mthylpyrrol idone, dimethyl su lphoxide or *20 tetramethylursa at temperatures of about 00 to 1000C.

preferably 0' to SOT.

The acid addition salts of the compounds according to the invention are prepared in the customary manner, for example by dissolving the betaine in excess aqueous acid and precipitating the salt with a water-niscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. It is also possible to heat equivalent amounts

,W-A-ZLIM

38 of the betaine and acid in water or an alcohol, such as glycol monomethyl ether, and then to evaporate the mixture to dryness or filter off the precipitated salt with suction. Pharmaceutically usable salts are to be understood as, for example, the salts of hydrochloric acid, sulphuric acid, acetic acid, glycolic acid, lactic acid; succinic acid, citric acid, tartaric acid, methanesulphonic acid, 4-toluenesulphonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or 1 aspartic Acid.

"*The alkali metal or alkaline earth metal salts of the carboxylic acids according to the invention are obtained, for example, by dissolving the betaine in excess alkali metal or alkaline earth metal hydroxide solution, filtera" 15 ing from the undissolved betaine and evaporating the filtrate to dryness. Sodium, potassium or calcium salts are pharmaceutically suitable. The corresponding silver salts are obtained by reaction of an alkali metal or alkaline earth metal salt with a suitable silver salt, such as silver nitrate.

The compounds listed by way of example in Table 1 can also be prepared, in addition to thv active compounds mentioned in the examples, it beii< possible for these compounds to be present both as diasteroer mixtures or as the diastereomerically pure or enantiomerically pure compounds.

39 Tabte 1 R I

AA

H F HCH C2HH S 2 H ~jF H

CF

H F H CF H F H C-OCH 3 I

H

Tabte I (continuation) I-

C

2 5

C

2

H

5

F

-CH-CH

2

QQN~

H

Q0N.

H

H

QQN~

H

H

NH

2

H

H

H

CH

CF

CF

CF

CH

(continulation) 4

HO-CH

2

CH

2

CH

3

I

2 IIiI

H

H3r

N

H

CH

3

I

TabLe 1 (continuation)

NC>

H

zc):N:>

H

Hz

OH

H

H

CF

CF

CC'

CH

N

Tabte I (continuation)

H

H

3 C-j2IIcIII

H

F- CH 2

CH

2 TabLej_ (continuation)

H

H

N"

2

CCI

CH

3 0

CH

3

-NH-

N

~ir1r 14

V,

Tabte I (continutilff) ~z2N

R

2

H

H

H

H

H

CH 3 IfI cl1 3

IICH

3 IfCH CH3 zI4~r ii

Z)

xI I I If

H

H

CF

ccI X2f A C-CH,3

CH

I L Lr~9sah-a labte I (contnuation) 3 x i X 2 A F

C

0 F H C H HeHP H C FC D

H

F H C

H

Hz H sF H C I c

H

TabLe 1 (continuation)

C

2 1, HZN kw C11 3 0%- 1

N-

11m 1137

HN

IIz

NH

2

C

2 11 5 Tat I (cniuain R2 R3 2 a.

R

2

AN

CH

3 F *H CF

H

2

N%:

_H F H CF _H [j Fn- H CF

CHN

R* RZ R3 at X2 Ataa H a. a a a.

H a a. a a a aF CH3ONFH

NH

HCH

3 FH.L H CFCH HJ1 H CCJ:

CH

3 -N H CH 3 LJ F HH CF

CH

3

O"H

a sap a. a a a. a. a.

S. a a a. a a a. C a a. a. a Trab~e 1 (continuation)

R$

C ZH ,j 2

H

1

CH

3

X

2 a

C

2

HH

CHS)Q

A

CH

CF

CF

CF

CH

-CZHS

a a a a a. as a a a. a. S.

a a. a a a..

aa a a an a a a aa sa a Tabte I Itcoomtinuatio,.

H CH 3 CO"N( H F

CH

3 H CH3yN F

CH

3 CH aCO-O~<NH-F

CH

3 H 0 K1 ~H3 CH3Oy 7 N- F H O~0~:CH3O)N- F H 0 xiZ3 CH3 O~fsNH

X

2

H

H

H

H

H

A

CH

CF

c'

CH

CF

CCI

H 05 5* Tab~~e 1 (contiuatioN H Hr3iljCH H3Or F j H NC 2

N

HH 3 NaH 2

.CH

3 N F H CF C"3 H CH 2 F H CHI H2(fN 0* 0 000 a S cc a a. *a SO a a a SOS 0 S* S Tabte 1 (continuation)

CH

3 0

H

2

N

CH

3 1

F

F

A

CF

CF

CF

C-CH

3 CH3O:Ny7-

H

2 -NH

CH

3

O

HZH

S a. a a

S

S S S S a S *S 55 Tabte 1,(contir.aat4on) I X2 J A

CH

3 O0-1N-

CH

3 0-COH

CH

3 0f~l OC H -NH

CH

3 0O'' IH-

HO-NH-'

CH3O:j4-

F

F

F

F

F

CF

CF

cc I

CF

CF

S

S 55 55 55

S

S.

S

Tabte I (continuation) Rl R2

R

3 C1 1 1 31 1 11r C"0-ONH

CH

3 O- CON (An jI-

F

F

2F H2

H

H

H

A

cc I CHi CHi

CF

CCI

i Tabte 1 (continuation) -0--fr

~H

3

C

4 A -n

H

C-CH

3 C-CH3 C-CH3 S S .Tz'be I (continuation) I

FQ

F

F

-Q-v

F

H

H

H

C

2

H

5

H

H

H

H

H

CH

2

CH

2 0H

F

F

F

.F

F

H

H

H

F

HH

2 m

CH

CCI

CF

CF

Table 1 (continuation) r

Q~N-

H

N-

H

(Y~QN.

H

a

S

S

Tabte I (continuation)

-KIS

H))4

H

H

H

CC'

NH

2 ~tO

D

i S~ S S S S S S Tat.Ae I (continuation) p

F

F

F

F

F

R

2

QH

H

H

H

H

H

QHN-

H

HN-

H

ff X2

H

N

H

F

NH

2

A

N

CH

CC I

CF

CF

S

S.

a a Tabte 1 (continuation) RQl

H

H

H

H

xi 1

H

H

Q0">

H

H

a. a a OI

P

r

C

as a o ,a ,Iabt* 1 (continuation) I. Q- F -C -F

H

H

XN-

H

oc>--

H

H

H

F

NH

2 Cl

CI

CCI

CF

CF

CH

CP

I

S

Tabto I (continuation)

H'

F

-Q-v

F

-Q-F

F

F

F

R

2

H

H

H

R:'

If x A2 It It

H

F

NH-

2

CF

OfI

CC'

CF

C. C 4*

S

S.

-S C C CC 0 C 0*

C

.4r C CC+ CCa C c* C C C *s cr C C a a. C Tabte I (continuation) 81 82 R3 J- I xl

V

X2A

F.

p.

Fc

H

HN-

CH3 HI

H

CH

3

H

Tabte I (continuat ion)

F

F

p.

p.

V

H

2 Nt~ HZ N wo,' CH3OW H 2

N

cc

I

H"

2 a..

a.

a. a..

a. a a.

a a. a a a. a a a. a. a.

a. a a a a a. a a. a .4 .4 a l~abt I continuation) Q-v p.

P

-Q~F

F

Q-v p.

F

CH

3 ObirN-

C

2

H

H

2 t! Tabte I (continuation)

F

F

CH77H CHac3 gH

CH

3 (NN

H

2

N

CCl

NH

2

N

A2

HJ

H

H

H

F

HZH

-tJ C SHZ3

NZH

-HJCSH 3 F

HZH

NZH

CHO

A--

v

I

IxI CuOL4Wluj~uV))I*fW 3* 34 3 3 300 3 3333 03 33 3 3 33 3 3 303 0 *3 *33 333 3 03 333 3 3 03 3

S

Example of A tablet a-ccording to the inyptntign Each tablet contains: Compound of Example 1 Microcrystalline cellulose Maize starch Insoluble poly-( l-vinyl-2-pyrrolidone) Highly disperse silica Magnesium stearate 583.0 mg 55.0 mg 72.0 mg 30.0 mg 5.0 mg 750.0 mg e.

*0 S

S.

a

S

S.

10 The lacquer shell contains: Poly- (0-hydroxypropyl -0-methyl) cellulose 15 cp Macrogol 4000, recommended INN polyethylene glycols (D)AB, Titanium(IV) oxide 6. 0 Mg 2. 0 mg 10.0 Mg S S *5

S

The compounds according to the invention, while having a low toxicity, exhibit a broad antibacterial spectrum against Gram-positive and Gram-negative germs# in particular against Entorobecteriaceae; above all also against those which are resistant towards various antibiotics, such as, for example, penicillins, cephalosporins, azinoglycos ides, sulphonamides and tetracyclines.

DR A 61Q8 70 e These useful properties enable them to be used as chemotherapeutic active compounds in medicine and as substances for preserving inorganic and organic materials, in particular all types of organic materials, for example polymers, lubricants, paints, fibres, leather, paper and wood, and foodstuffs and water.

The compounds according to the invention are activj against a very broad spectrum of microorganisms. Gramnegative and Gram-positive bacteria and bacteria-like microorganisms can be combated and the diseases caused by these pathogens can be prevented, alleviated and/or cured with the aid of these compounds.

The compounds according to the invention are particularly active against bacteria and bacteria-like microorganisms.

They are therefore particularly suitable in human and veterinary' medicine for the prophylaxis and chemotherapy of local and systemic infections caused by these pathogens.

For example, local and/or systemic diseases caused by the 20 following pathogens or by mixtures of the following pathogens can be treated and/or prevented Gram-positive cocci, for example Staphylococci (Staph.

aureus and Staph. epidermidis) and Streptococci (Strept.

agalactiae, Strept. faecalis, Strept. pneumoniae and Strept. pyogenes); Gram-negative cocci (Neisseria gonorrhoeae) and Gram-negative rod-shaped bacilli, such as Enterobacteriaceae, for example Escherichia coli, Haeso- 71

I

3 philus influenzae, Citrobacter (Citrob. freundli and Citrob. civernis), Salmonella and Shigella; and furthermore Kiebuiella (Kiebs. pneumoniae and Kiebs. oxytoca), Enterobacter (Ent. aerogenes and Ent. agglomerans), Hafnial Serratia. (Serr. marcescens), Proteus (Pr. airabills, Pr. rettgeri and Pr. vulgaris), Providencia and Yersinial and the genus Acinetobacter. The antibacterial spectrum moreover includes the genus Pseudomonas (Ps.

aeruginosa and Ps. maltophilia) as well as strictly anaerobic bacteria, such as, for example, Bacteroides fragilies representatives of the genus Peptococcus, Peptostreptococcus and the genus Clostridium; and furthermore Mycoplasma pneumoniae., M. hominis and X.

3 3urealyticum) and Mycobacteria, for example Mycobacterium tuberculosis.

The above list of pathogens is to be interpreted merely as examples and in no way as limiting. Examples which may be mentioned of diseases which are caused by the pathogene or mixed infections mentioned and can be prevented, alleviated or cured by the compounds according to the invention are* infectious diseases in humans, such as, for example, otitie,# pharyngitis, pneumonia, 7eritonitis, pyelo- ~.nephritis, cystitis, endocarditis, systemic infections, bronchitis (acu1te and chronic), septic infections, diseases of the upper respiratory tract, diffuse panbronchiolitis, pulmonary eaphysema, dysentery, enteritis, liver abscesses, urethritis, prostatitis, epididymitis, gastrointestinal infections bone and joint infections, 72 cystic fibrosis, skin infections, postoperative wound infections, abscesses, phleqmons, wound infections, infected burns, burn wounds, infections in the oral region, infections following dental operations, osteomyelitis, septic arthritis, cholecystitim, peritonitis with appendicitist cholangitis, intraalbdominal abscesses, pancreatitis, sinusitim, mastoiditis, mastitis, tonsillitis, typhoid, meningitis and infections of the nervous system, salpingitis, endometritis, genital infections, pelveoperitonitis and eye infections.

As well as in humans '.4cterial infections can also be treated in other species. Examiples which may be mentioned :are$ X. Pigs colidiarrhoea, enterotoxaemial sepsis, dysenteryo 15 almonellosis, mastitis-metritio-agalactia syndrome and miastitis; Ruminants (cattle, sheep and goats): diarrhoea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis and genital infections; Horses: bronchopneumonias, joint ill, puerperal and postpuerperal infections and salmonellosis; Doga and cats: bronchopneumonial diarrhoa, dernatitis, otitis, urinary tract infections and prostatitis; Poultry (chickens, turkeys'. quaila, pigeons, ornamental birds and others): mycoplassmis, B. coli infections, chronic respiratory tract infections, salsonellosis, pasteurellosis and puittacosis.

Bacterial diseases in the rearing and keeping of stock L A 26 10 73 and ornamental fishes can also be treated, the antibacterial spectrum extending beyond the abovementioned pathogens to further pathogens, such as, for example, Pasteurella, Brucella, Campylobacter, Listeria, Brysipelothrix, Corynebacteria, Borrelia, Treponema, Nocardia, Rickettaia and Yersinia.

The present invention includes pharmaceutical formulations which contain, in addition to non-toxic, inert pharmaceutically suitable excipients, one or more compounds according to the invention or consist of one or more active compounds according to the invention, and processes for the preparation of these formulations.

The present invention also includes pharmaceutical S. formulations in dosage units. This means that the forno..

mulations are present in the form of individual parts, for example tablets, coated tablets, capsules, pills, suppositories and ampoules, the active compound content of which corresponds to a fraction or a multiple of an individuial dose. The dosage units can contain, for 20 examplel, 1, 2, 3 or 4 individual doses or 1/2, 1/3 or 1/4 of an individual dose. An individual dose preferably contains the amount of active compound which is administered in one application and which usually corresponds to a whole, one half, one third or a quarter of a daily dose.

Non-toxic inert pharmaceutically suitable excipients are to be understood as solid, semi-solid or liquid diluents, 74 a fillers and formulation auxiliaries of all types.

Preferred pharmaceutical formulations which may be mentioned are tablets, coated tablets, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, dusting powders and sprays.

Tablets, coated tablets, capsules, pills and granules can contain the active compound or compounds in addition to the customary excipients, such as fillers and 10 extenders, for example starches, lactose, sucrose, glucose, mannitol and silicic acid, binders, for example carboxymethylcellulose, alginates, gelatine and polyvinylpyrrolidone, humectants, for example glycerol, disintegrating agents, for example agar-agar, calcium carbonate and sodium carbonate, solution retarders, for example paraffin, and absorption accelerators, for example quaternary ammonium compounds, wetting agents, for example cetyl alcohol and glycerol monostearate, adsorbents, for example kaolin 20 and bentonite, and lubricants, for example talc, calcium stearate magnesiua stearate and solid polyethylene glycols, or mixtures of the substances listed under to The tablets, coated tablets, capsules, pills and granules can be provided with the customary coatings and shells, optionally containing opacifying agents, and can also be of a composition such that they release the active 75 t compound or compounds only or preferentially in a certain part of the intestinal tract, if appropriate in a delayed manner, examples of embedding compositions which can be used being polymeric substances and waxes.

If appropriate, the active compound or compounds can also be present in microencapsulated form with one or more of the abovementioned excipients.

Suppositories can contain, in addition to the active compound or compounds, the customary water-soluble or 10 water-insoluble excipients, for example polyethylene glycols, fats, for example cacao fat, and higher esters (for example C 1 ,-alcohol with C 1 l-fatty acid) or mixtures of these substances.

Ointments, pastes, creams and gels can contain, in addition to the active compound or compounds, the customary excipients, for example animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures of these 20 substances.

Dusting powders and sprays can contain, in addition to the active compound or compounds, the customary excipi.

ants, for example lactose, talc, silicic acid, aluminium hydroxide, calcium silicate and polyaaide powder, or mixtures of these substances. Sprays can additionally contain the customary propellarits, for example chloro- 76 fluorohydxocarbons.

Solutions and emulsions can contain, in addition to the active compound or compounds, the customary excipionts, such as solvents, solubilizing agents and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, bonzyl alcohol, benzyl benzoate, propylene glycol, l,3-.butylene glycol# dimethylformamide, oils, in particular cottonseed oil, groundnut oil, maize germ oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydxrofurfuryl ****aloohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also be in a sterile form which is isotonic is with blood.

Suspensions can contain, in adidition to the active compound or compounds, the customary excipients, such an liquid diluents, for example water, ethyl alcohol and 0 4. propylene glycol# and suspending agents, for example ethoxylated isostearyl alcohols, polyoxyothylone sorbitol and aorbitan esters, microcrystalline cellulose, alumin- *ium wetahydxoxide, bentonite, agar-agar and tragacanth, see$*: or mixtures of these substances.

The formulation forms mentioned can also contain colour.

Ing agents, preservatives and additives which Improve the smell and taste, for example peppermint oil and eucalyp- I& A26 10 77 W ft tus oil, and sweeteners, for example saccharin.

The therapeutically active compovnds should preferably be present in the abovementioned pharmaceutical formulations in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.

The abovementioned pharmaceutical formulations -an also contain other pharmaceutical active compounds in addition to the compounds according to the invention.

The abovementioned pharmaceutical formulations are S 10 prepared in the customary manner by known methods, for S. exam le by mixing the active compound or compounds with the excipient o0 excipients.

The formulations mentioned can be used on humans and animals either orally, rectally, parenterally (intra- 15 venously, intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally or locally (dusting powder, ointment, drops) and for the therapy of infections in hollow spaces and body cavities. Possible suitable formulations are injection solutions, solutions and suspensions for oral therapy and gels, infusion formulations, emulsions, ointments or drops. Ophthalmologcal and dermatological formulations, silver salts and other salts, *ardrops, eye ointments, dusting powders or solutions can be used for local therapy. In the case of animals, intake can also be in suitable formulations via the feed or drinking water. Gels, powders, dusting 78 mmpowders, tablets, delayed release tablets, premixes, concentrates, granules, pellets, boli, capsules, aerosols, sprays and inhalants can furthermore be used on humans and animals. The compounds according to the invention can moreover be incorporated into other carrier materials, such as, for example, plastics (chains of plastic for local therapy), collagen or bone cement.

In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound or compounds according to the invention in total amounts .of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results.

An individual dose preferably contains the active corn- 15 pound or compounds according to the invention in amounts of about 1 to about 80, in particular 3 to 30 mg/kg of body weight. However, it may be necessary to deviate from the dosages mentioned, and in particular to do so as a function of the nature and body weight of the object to be treated, the nature and severity of the disease, the nature of the formulation and of the administration of the medicament and the period or interval within which administration takes place.

Thus in some cases it can suffice to manage with less than the abovementioned amount of active compound, whilst in other cases the abovementioned amount of active compound must be exceeded. The particular optimun dosage and mode of administration required for the active 79

I

compounds can easily be determined by any expert on the basis of his expert knowledge.

The new compounds can be administered in the customary concentrations and formulations together with the feed or with feed formulations or with the drinking water.

Infection by Gram-negative or Gram-positive bacteria can in this way be prevented, alleviated and/or cured and promotion of growth and an improvement in feed utilization can in this way be achieved.

10 The minimum inhibitory concentrationS (MIC) were determined by the series dilution method on Iso-Sensitest agar (Oxoid). For each test substance, a series of agar plates which contained concentrations of the active compound *which decreased by a dilution factor of two each time was prepared. The agar plates were inoculated with a multipoint inoculator (Denley). Overnight cultures of the pathogens which had first been diluted so that each e" inoculation point contained about 104 colony-forming particles were used for the inoculation. The inoculated 20 agar plates were incubated at 37°C and the germ growth see was read off after about 20 hours. The MIC value (pg/al) indicates the lowest active compound concentration at which no germ growth was to be detected with the naked eye.

The MIC values of some of the compounds according to the invention are shown in comparison with ciprofloxacin in the following table.

80 i .i *0i PIC vaLues (mg/t) determined by the agar dilution test (Dentey multipoint inoculator; Iso-sensitest agar) Example 1 2 3 4 5 8 9 to Test strain Escherichia coli geumann ProO-euz mirabilis 8223 ProLeus vulgaris 1017 Horganella uorganii 932 ProvidenciastuarLei 12052 Staphylococ- Cus aurmu% FK 422 1756 133 (0.015 (0.015 (0.015 (0.015 (0.015 (0.015 0.25 0.125 0'5 (0,015 0.125 (0,015 0.03 (0.015 0.03 2 (0.015 (0.015 0,5 0.03 0.06 0.06 (0.015 8 16 0.5 1 0.5 32 64 0.06 0.06 0.06 0.125 0.125 0.125 0.06 0.06 0.03 (0.015 (0.015 (0.015 0.125 0.125 0.125 r 25 0,25 0.03 0.03 0.03 0.125 0,125 0,06 0,06 0.06 0.125 0125 0. Enterococcus faecalis 27101 0,125 9790 0.125 0,125 0.06 0,5 0.25 0*06 0.25 2 0,25 2 P IIII~PII PC RIC vatues determined by the agar dilution test (Denley muttipoint inoculator; Iso-sensitest agar) Examptle 14 15 17 18 Ciprotloxacin Test strain Eschorichia 0.06 0.06 (0.015 0.06 0.125 0.03 (0.015 coli Neumann Proteus mirebilis 8223 1 4 0.5 4 8 1 1 Proeous vul- 0.03 0.5 0.03 0.06 0.5 0.06 (0.015 garis 1017 Horganells 00125 0.25 0.03 0.06 0.5 0.06 (0.015 morgani 932 Providencla- 2 4 1 32 8 4 4 stuarti 12052 SLaphylococcuE aureus P 422 0.06 0.25 0.03 0.125 05 0.125 0.25 1756 0.06 0.25 0.03 0.125 0.5 0.125 0.25 133 0.06 0.25 0.03 0.125 0.5 0.125 0.25 En.erococCus faocaIls 27101 0.125 0.25 0.03 0.5 1 0.25 0.05 9790 0.25 0.5 0.5 2 0.5 0.25 c I The following examples illustrate the invention: Preparation of the intermediate products: tert Butyl N-(cis-4-methoxy-pyrrolidin-3-yl)-carbamate a) trans- 1-Benzyl-3-hydroxv-4 -methoxv~vrrolidin 3419 g (0.2 mol) of 3-benzyl-6-oxa-3-azabicyclo(3.1.0J- *6 S hexane Patent 4,254,135) are heated with 3.6 g Get 0(20 mmol) of sodium methylate solution (30% strength) at 10 120"C in 200 ml of absolute methanol in an autoclave for 6000 10 hours. After cooling, the mixture is neutralized with *1.2 g (20 mmol) of acetic acid and the solvent is removed on a rotary evaporator. The residue is taken up in tetrahydrofuran and the sodium acetate is filtered off.

The filtrate is concentrated and the residue is dis- .0 td toes Yield: 0.9 g (91% of theory) Boiling po)int: 112-116'C/0.1 sabar Contents 12% pure 000 20 b) cis-3-Ainino-l-benzvl-4-methoxy-pvrrolidine 5.6 q (25 mmol) of trans- 1-bentyl-3-hydrxy-4 -methoxypyrrolidine and 8.6 g (33 munol) of triphenyiphosphine are initially introduced into 40 al1 of absolute tetrahydro- 83

I

4 furan and a solution of 6 g (34 mmol) of diethyl azodicarboxylate in 40 ml of absolute tetrahydrofuran is added -dropwise at 0*C. 3.9 g (27 mmol) of phthalimide are then added in small portions at 0°C in the course of one hour.

The mixture is stirred at room temperature overnight and concentrated. The residue is dissolved in 80 ml of ethyl acetate and 80 ml of petroleum ether are added. The mixture is left to crystallize out overnight and the crystals (triphenylphosphine oxide and diethyl hydrazinedicarboxylate) are filtered off. The filtrate is concentrated and the residue is heated under reflux with ml of concentrated hydrochloric acid overnight. The undissolved residues are decanted and the solution is concentrated. The residue is taken up in a little water 15 and the solution is rendered alkaline with solid potassium carbonate and extracted five times with 50 ml of chloroform. The extract is dried over potassium carbonate and concentrated and the residue is distilled.

o* Yield: 3.4 g (65.9% of theory) 20 Boiling point: 95C/0.2 mbar *e* c) tert.-Butyl N-(cis- l-Lbnzyl-4-methoxypyrrolidin-3y )-carbamate 3 g (14.5 mmol) of cis-3-amino-l-benzyl-4-methoxy-pyrrolidine and 11 ml of tert.-butanol are added to a solution of 0.65 g of NaOH in 8 ml of water. 3.5 g (16 1aool) of di-tert.-butyl dicarbonate are added dropwise.

The mixture is stirred at room temperature overnight, the Le A 2 108 84 inorganic salts are filtered off with auction and the filtrate is extracted with chloroform. The extract in dfried over potassiumi carbonate and concentrated and the residue is distilled.

Yield: 3.8 g (85.5% of theory) Boiling point: 130-l40 0 CI0.05 mbar d) tert.-Butyl N-(cits-4-methoxypyrrolidin-3-yl)cp rbdImte g (11.4 mmol) of tCert.-butyl N-(cis-l-b>enzyl-4methoxypyrrolidin-3-yl)-carbanate are hydrogenated in 100 ml of methanol on 2 g of palladium-on-active charcoal of Pd) at 100 0 C under 100 bar. The catalyst is filtered off, the filtrate is concentrated and the residue is distilled.

Yield: 1.9 g (81.6% of theory) Boiling point: 84 0 C/0.1 mbar a. ExampleB tert Butyl N- (trans-4-methoxy-py-rrolidin-3-yl carbAmAte a) ~n.~n--ez14mtov~ro dn 27 g (0.41 mol) of sodium azido are dissolved in 50 al of 85 water, and 17.5 g (0.1 mol) of 3-benzyl-6-oxa-3-azabicyclo(3.1.0]hexane in 300 ml of dioxane are added. The mixture is heated under reflux for 72 hours and concentrated, the inorganic salts are dissolved in water and the mixture is extracted with chloroform. The extract is dried over potassium carbonate and concentrated. The residue is dissolved in 50 ml of absolute tetrahydrofuran and the solution is added dropwise to 4 g of sodium hydride (80% strength in paraffin oil) in 200 ml of absolute tetrahydrofuran. The mixture is heated under reflux for one hour and 15 g (0.1 mol) of methyl iodide are then added dropwise. The mixture is subsequently heated under reflux overnight and concentrated, the residue is taken up in water and the mixture is extracted 15 with chloroform. The extract is dried over potassium carbonate and concentrated and the residue is distilled.

13.1 g of a material which is 73% pure according to the gas chromatogram are obtained. 12.7 g of this material in 40 ml of absolute tetrahydrofuran are added dropwise to a suspension of 4 g of lithium aluminium hydride in 150 ml of absolute tetrahydrofuran and the mixture is heated under reflux for 2 hours. Excess lithium aluminium hydride is decomposed by careful dropwise addition of 4 ml portions of water and 15% strength potassium hydroxide S 25 solution and again 4 al of water. The inorganic salts are filtered off with suction and washed several times with chloroform. The organic phases are dried over potassium carbonate and concentrated and the residue is distilled.

Yields 9 g (32.8% of theory) 86 Boiling points 91*C/O.07 mbar The product has a content of 75%, determined by gas chromatography (area method).

b) tort. -Butyl N- (tranh- 1-benzyl-4 -methoxypyrrol idin-3 yl)carbamuts 8.2 g (30 mmol) of tranh 3-amino- 1-benzyl-4 -methoxypyrrolidine and 21 ml of tert.-butanol are added to a .:..solution of 1.3 g of NaCH in 15 sal of water. 7.1 g :(31 mmol) of di-tert.-butyl dicarbonate are added dropwise and the mixture is then stirred at room temperature overnight. Inorganic salts are filtered of f with suction, the filtrate is extracted with chloroform, the extract is dried over potassium carbonate and concentrated and the residue is distilled.

15 Yield: 7.7 g (84.4% of theory) Boiling points 148 0 C/0.l mbar Melting point: 88-90 0

C

c) torte -Butyl N- (trans 4-methoxypyrrol idin- 3-yl) ~S carbAmate 6.7 g (22 mml) of tert.-butyl N- (trans -1-benzyl-4 methoxypyrroidin-3-yl)carbamat* are hydrogenated in 150 al of methanol on 2 g of pal ladium-on-act~t~ve charcoal of Pd) wnder 100 bar at 1000C. The catalyst is filtered off with suction* the filtrate is concentrated 87 and the residue is distilled.

Yield: 2.2 g (46% of theory) Boiling point: 94"C/0.05 mbar trans -3 -Amino-4 -hydroxy-pyrrol idine a) trans -3 -Amino-l1-ben zvl- 4-hvdrox-y-Drrol AdIna 8.9 g (50 mmol) of 3-benzyl-6-oxa-3-azabicyclo3. .0)hex- 10 ane are heated in 75 m.1 of ammonia solution bob* strength) at 120*C in an autoclave for 8 hours. The solution is concentrated and the residue is distilled.

Yield: 6 g (62.4% of theory) Boiling point: 130-140OC/0.l mbar Melting point: 82-84*C trans-3-Amino-4-hydroxy-DRrKOlidin2 5.2 q (27 mo1) of trans -3 -amino-1 -bonzyl 4 -hydroxypyrrolidine are hydrogenated in 40 sl of methanol on 1 g of palladium-on-active charcoal (10% of Pd) at 100OC under 100 bar. The catalyat Ls filtered off with auction, the filtrate is concentrated and the residue is distilled.

Yield: 1 g (36.3% of theory) L§ A 26 1 88 Bkiling point: 110 0 C/0.3 mbar trans-4-Hydroxy-3-(2-hydroxyethylamino)-pyrrolidine a) trans- 1 -Benzyl--hydroxy-3-(2-hydrxethyl amino) DMTrOlidine g (0.22 mol) of 3-benzy1-6-oxa-3-azabicyclo(3.l.0]hexane are heated under reflux with 42 g (0.68 mol) of 2aminoethanol in 450 ml of water overnight. The solution is extracted once with tert.-butyl methyl ether and the aqueous phase is concentrated. The residue is distilled.

Yield: 34.1 g (65.6% of theory) Boiling point: 190 0 C/0.1 mbar b) trane-4-Hvdrox-3-(2-hdrxvethylamino2-DRroKjIji trans-l-Benzyl-4-hydroxy-3-(2-hydroxyethylaino)-pyrrolidine is hydrogenated analogously to Example C b) to give the reaction product as an oil.

9* Le A -ZL-=_E 89 trans-4-Hydroxy-3- (2-hycroxyethyl-methyl-amino) pyrrol idine trans 1 -Ben zyl 4 -hydroxy- 3 (2 -hydzoxyethyl -methyl Amino) -Mrgo1idine *9 .99

S

10 *9

S

17.5 g (0.1 mol) of 3-benzyl-c-oxa-3-azabicyclo[3.1.0]hexane are reacted with 17 g (0.1 mol) of methylaminoethanol in 200 ml of wae analogously to Example D a).

Yield: 18.2 g (73% of theory) Boiling point: 180-.190*C/0.1 mbar b) trans-4 -Hydroxy-3- (2 -hydroxyethyl-methyl-amino) pyrrolidine trans -1-Benzyl-4 -hydroxy-3-(2-hydroxyethyl-methyl-amino) pyrrolidine is hydrogenated analogously to Example C b) to give the reaction product as an oily compound.

15 **99 99 99 9 2-Oxa-5,8-diazabicyclo[4 3.0]nonane dihydrochloride a) 8-Benzyl-2-oxa-5,8-diazabicyclQ(4.3.Ononal.

90 15.6 g (66 mmol) of l-benzyl-4-hydroxy-3-2-hydroxyethyl.

amino) -pyrrolidine are heated under ref lux in a mixture of 60 ml of concentrated sulphuric acid and 20 al of water for 6 hours. The mixture is rendered alkaline with concentrated sodium hydroxide solution, the sodiuxo sulphate which ha. precipitated is filtered of f with auction and the filtrate is extracted with chloroform.

The exti-act in dried over potassium cairbonate and concentrated and the residue is distilled.

Yields 4.1 g (28.5% of theory) Boiling points 122-128*C (0.08 mbar) b) 2-Oxa-5.8--iazabicvloS4.3.Q1nonang dihvdrochloridet Ai solution of 4 9 (18.2 mmol) of 8-benzyl-2-oxa-5,8diazabicyclo(4.3.0]nonane in 100 m.1 of methanol and 15 ml of concentrated hydrochloric acid is hydrogenated on 2 g of palladium-on-active charcoal (10q of Pd) at 806C under 100 bar. The catalyst is filtered of f and washed with water. The filtrates concentrated and the product is crystallized by trituratin-n with a little methanol. The crystals are filtered of f with auction, "ashed with acetone and dried in air.

Yields 1.85 g (51% of theory) Mlting points 280*C with decomposition L A 6 10 91 c) 2-9xa-5.Q-diozAbicycjqr4j3.Olnone 7.2 9 (33 mmol) of 8-benzyl-2-oxa-5.,8-diazabicyclo- (4.3.0]nonane arp hydrojenated in 400 ml of methanol with g of palladium-on-active charcoal (10% of Pd) under bar at 1000C. The catalyst is filtered off with suction, the filtrate is concentrated and thei residue is distilled.

Yield- 3.1 g (73.4% of theory) Boiling point: 58 0 C/9.1 mbar.

d x-5 -diazab y 7nnan 3 -b n.y -oa b ylo .1 1hxn d) ras-0a -5,8-daza iycloicyc0)o4.an hih spuife bchromatogray (ilccyclo .)hexne is reacbted ewthy2l enr/ylio -cetanol analoousl to.ai Tehy -amnoyi 4hdoxypyrrolidin ich ris ote anactedanaogol to Example F a) to give 5---,8-dizyl- 3.1-onn, b-izb.cc oiling]ont: wc is bp r.e Lety eA e/ty aceat 1:1:92) 5-Methyl-2-oxa-51 8-diazabicyclo [4 .3 0 1onane dihydrochloride a) B-Benzvl-5-niethyi-2-oxa-5.8-diazabicvclo[4.3.Oloane 18 g (71.9 mruol) of 1-benzyl-4-hydroxy-3-(2-hydroxyethylmethyl -amino) -pyrrol1idine are reacted in 60 ml of concentrated sulphuric acid and 30 ml of water as in Example F a).

*Yield: 10 g (60% of theory) SBoiling point: 1211 0 1C/0.08 mbar b) 5-,ve'thyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane dihydrochloride A solution of 9.4 g (40 minol) of 8-benzyl-5-methyl-2-oxa- 5#8-diazabicyclo[4.3.0]nonane in 150 ml of methanol and 7.4 ml of concentrated hydrochloric acid is hydrogenated on 3 g of palladium-on-active charcoal (10% of Pd) at SO0C under 100 bar. The catalyst in filtered off with suction and the filtrate is concentrated. The residue is triturated with butanol/acetone 1:1 and the crystals are filtered off with suction and dried over P 4 01 0 in 4 desiccator. The product is very hygroscopic.

Yields 8.2 g (95% of theory) Mass spectrums rn/e 142 (XW)i 112 ()(eCMaO) 100 t

.CH

3

N-CH

3 82 (C4H 4 68 (C 4 H6N*) 2-Methyl-3-ox-2 7-diazabicyclo(3.3.O0]octane a) Ethyl N-Cr2. 2-dimethoxytthyl)1-carbarnate 214 q (2 mol) of ethyl chloroformate are added dropwise to 214 g (2 mol) of aminoacetaldehyde Atimethyl acetal in Le A 26 108 93 a a 1 1 of toluene and 90 g of NaOH in 500 ml of water at The mixture is stirred at roam temperature for a furt4',er 2 hours and the aqueous phase is separated off, saturated with sodium chloride and extracted with toluene. The toluene solutions are dried ovar magnesium sulphate and concentrated and the residue is distilled.

Yield: 338 g (95.4% of theory) Boiling point: 60OC/0.03 mbar b) gty rgj-Ally1-M-0.2-dimethoxvethv1 l-carbamate g of sodium hydride (80% strength in paraffin oil) are initially introduced into 500 ml of toluene and 89 g Smol) of ethyl N-(2,^-dim-ethoxyethyl)-earbanate are added edxopwise at 80'C. The mixture is stirred at 80*C for one hour and 73 g (0.6 Mol) of allyl bromide are then added dropwise in the course of three hours, The mixture is stirred at 80 0 C overnight, the salts are dissolved with water and the organic phase is separated off. The aqueous phase is extracted with toluene, the organic phases are dried over potassi=i carbonate and concentrated and the residuj is distilled.

*too 25 Yield: 68 g (62.5% of theory) *too Boiling point: 65OC/0'.09 mnbar 6 ac) Ethyl N-alvi (2-oxoethyl I-carbaiat-e, 68 g (0.313 mol) of ethyl N-allylnN-(2,2-dimethoryethyl)carbamate are heated with 150 ml1 Qf formnic acid at 100OC f ow. one hour.* The mixture is poured onto ice and extracted several times with methylene chloride, the organic phases are washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated and the residue is distillesd.

Yields 46.7 9 (87.2% of theory) Le A 26 108 94, 94 Boiling points 58OC/0.09 mbar d) Ethyl 2-methyl-3-oxa-2,7-diazabicyclo[3.3.0]octane-7carboxylat2 g (0.12 mol) of methyl hydroxyl amino hydrochloride are dissolved in 50 ml of methanol, the solution in cooled in an ice-bath and 22 g (0.12 mol) of 30% strength sodium methylate solution in methanol are added dropwise. The sodium chloride is filtered off with suction and the salt is washed with 80 ml of toluene. The methylhydroxylamine solution is added dropwise in the course of one hour to 20 g (0.117 mol) of ethyl (oxoethyl) -caztaate *got which is heated under reflux in 160 ml of toluene, using a water separator. The mixture is heated under reflux overnight and the product in extracted twice with 80 ml is:~1 of 10% strength hydrochloric acid each time. The hydro-s chloric acid solutions are saturated with potassium carbonate and extracted six times with 200 al of chloroform each time. The extract is dried over X 2 C0 3 and 0 0 a 6concentrated and the residue is distilled.

04 20 Yield: 18.6 g (79.5% of theory) 4 0 Melting points 93*C/0.09 abar e) 2-Methyl-3-oxa-2 r7-diazabicyclo[ 3.3.O0joctane 13 9 (65 wol) of ethyl 2-mothyi-3-oxa-2,7-diazabicyclo- (3.3.0]octans-7-carboxylate are heated under reflux in 300 al of water with 41 9 of B&(OH) 2 .BHa0 overnight.

as 95 as

S

Potassium carbonate is added, the barium carbonate which has precipitated out is filtered off with suction and the filtrate is extracted ten times with 100 ml of chloroform each time. The extract is dried over potassium carbonate and concentrated and the residue is distilled.

Yields 5.4 9 (65% of theory) Boiling point: 80 0 C/10 mnbar -Methyl-octahydropyrrolo(3,4-b]pyrrole (2-taethyl-2,7diazabicyclo[3.3.0]octane) a) l-Benzyl- 3- (2-chloroethyl-methyl -amino) -pyrrolidine- 2. 74.8 g (0.4 mol) of N-benzylmaleimide (Arch. Pharm. ~j 489 (1975)] and 52.0 g (0.4 mol) of 2-chioroethyl-methylamine hydrochloride are initially introduced into 400 ml ofi dioxane and 40.4 g (0.4 mol) of triethylamine are added diropwise at 20*C. The uuixture is then boiled under ref lux for 5 hours. he batch is subsequently poured into 2 1 of ice-water arid extracted. with 3 portions of 400 al of chloroform and the extract is washed with water, dried over sodium sulphate and concentrated on a rotary evaporator. Chroiatography of the residue (101.1 g) on silica gel using ethyl acetates petroleum other (102) gives 56.8 g (51% of theory) of an oil.

96 Rr value: 0.33 (silica gel, ethyl acetate /petroleum ether 1:2) b) 5-Benzyl-4, 6-dioxo-l-methyl-o~ctahydropyrrolo(3,4-b]pvrrole 7.2 g (0.24 mol) of an 80% strength sodium hyd~ride suspension in mineral oil are suspended in 150 ml of absolute dimethylfornamide (dried over calcium hydride), and 62 g (0.22 inol) of 1-benzyl-3-(2-chloroethyl-methylare added dropwise as a solution in 50 ml of absolute dimethylformamide at room temperature. During this, an exothermic reaction takes place with foaming. The mixture is diluted with a further ml of absolute dimethylformamide and subsequently stirred at room temperature for 1 hour and is then poured into ice-water and extracted with methylene chloride. The extract is washed with water, dried with sodium sulphate concentrated on a rotary evaporator. The residue is cbhroxatographed on silica gel using ethyl acetateipetroleum ether and later 16.4 g o~f educt are initially recovered here, and 17.2 g (44% of theory, based on the educt reacted) of an oily product are then ~:'.isolated.

R. value n 0.26 (silica gel, ethyl acetateipetroleum ether 97 c) S-BenzY1-1-methyl,-octahydroovrrlSU .4b oRnrole 1.52 g (40 mmol) of lithium aluminium hydride are initially introduced into 30 ml of anhydrous tetrahydrofuran, and 4.9 g (20 mmol) of 5-benzyl-4,6-dioxo-lmethyl-octahydropyrrolo[3,4-bjpyrrole are added dropwise as a solution in 15 ml of anhydrous tetrahydrofuran. The mixture is then subsequently stirred at the boiling point f or 3 hours. 1. 5 ml of water, 1. 5 ml of 15% strength potassium hydroxide solution and 4.5 ml of water are :0 10 added dropwise in succession to the batch and the precipitate is then filtered off with suction and washed with tetrahydrofuran. The filtrate is concentrated on a sees rotary evaporator and the residue is distilled. 3.1 g (72% of theory) of a colourless distillate of boiling point 80 0 C/0.07 mbar are obtained.

d) 1-Methyl-octahvdropyrroloI 3. 4-blpvrrole 6.49 g (30 mmcl) of [3,4-b]-pyrrole are dissolved in 100 ml of absolute ether, and 5.2 g of hydrogen chloride dried over phosphorus pentoxide are passed in. The hydrochloride suspension formed in concentrated in vacua and the residue is taken up in 100 al of methanol. It is then hydrogenated with 2 g of Pd-on-C strength) at S80C under 50 bar for 4 hours. The catalyst in subsequently filtered off, the filtrate is concentrated and 30 al of 40% strength sodium hydroxide solution and 50 al of ether are added to the residue. The ethereal phase in separated off and the IL A2 6.U 98 a aqueous phase is extracted with 2 x 50 ml of other. The combined organic phases are dried over sodium sulphate and concentrated and the residue is distilled. 1.3 g (34% of theory) of a colourless oil of boiling point 65-66*C/ 12 mbar are obtained.

Purity: >99% Exampl~e j Octahydropyrrolo[314-b]pyrrole (2,7-diazabicyclo[3.3.0J- *octane) 1 -Benzyl- 3- (2-chloroethl amino) -Pyrol 74.8 g (0.4 mol) of N-benzylnialeimide are reacted with 58 g (0.5 mol) of 2-chioroethylamine hydrochloride and 50.5 g (0.5 mol) of triethylatine in accordance with the is: 1 working instructiono of Example Ia. After working up by chromatography, 81.6 g (77% of theory) of an oil with an RF value of 0.24 (on silica gel using ethyl acetate: petroleum ether 1:1) are obtained.

b) 5-Benzyl-4 .6-diogo-2ctahydropvrrlof.4-lvyrrole 17.4 g (0.58 mrnol) -of sodium hydride suspension are reacted with 119 g (0.4S wol) of 1-benzyl-3-(2-chloroethyl amigo) -pyrrol idine -2 j5 -dione 1kn 550 al of absolute dimeth~y1forumamide in accordance with the working instructions of Exppe Ib. After the mixture has been left to L2 A 2610 99 stand overnight, it is worked up under aqueous conditions. On purification by chromatography, impurities are first eluted with ethyl acetate and the product is then eluted with ethyl acetate: methanol value 0.55).

557.7 g of product (56% of theory) are isolated.

c) 5-Benzvl-2ctahydroovrroIor 3.4-i D~yrl 57.7 g (0.25 mol) of crude 5-benzyl-416-dioxo-octahydropyrrolo(314-bjpyrrole are reduced with 21.4 g (0.56 mol) of lithium a luminium hydride by boiling in 700 al of absolute tetrahydrofuran for 10 hours in accordance with the working instructions of Example Ic. Working up by distillation gives 21.0 g (41.1% of theory) of an oil of boiling point 95'C/0.1 mbar.

d) OctahydrOovjrlor3.*4-bj1 vrole 21.0 g (0.104 mol) of (3,4-b]pyrrole are initially introduced into 180 al of ice-cooled methanol, and 17.3 ml (0.208 mol.) of concentrated hydrochloric acid are added. The mixture is then hydrogenated with 2 g of Pd-on-C st:angth) at 900C 0M.20 under 100 bar for 4 hours. The catalyst is filtered off, 37.4 g (0.208 mol) of 30% strength sodium methylate solution are added to the filtrate, the mixture is filtered again and the filtrate is concentrated. The residue is distilled through a small Vigreux column. 5.6 g of a colourless oil (48% of theory) of boiling point 93-95OC/30 uibar, which fumes in air and slowly solidifies Lt A 26 198 100 in the receiver (melting point 40 0 C) are obained.

Octahydropyrrolo[3,4-blpyridine (2,8-diazabicyclo(4.3.0]nonano) a) 6-Bengyl-5 .7-dioxo-ocgtahydro,,vrolor3.4-b1i~yridine 47.6 g (0.2 mol) of pyridine-2,3-dicarboxylic acid Nbenzylimide (British Patent 1,086,637; Chema. Abstr. fil, 95695w) are hydrogenated in 400 ml of glycol monomethyl ether over 15 g of ruthenium-on-active charcoal (54 strength) at 90*C under 100 bar until the calculated .99,,amount of hydrogen has been taken up. The catalyst in then filtered off and the filtrate in concentrated on a rotary evaporator. 44 g of an oily crude product are obtained.

The corresponding hydrogenation with palladium-on-active charcoal strength) gives a quantitative yield of a pure product of melting point 67-69 0

C.

b) 6-Benjyl-gctahydrovyroor 3 .4-bi idine 44 g (about 0.18 sol) of crude or pure 6-benzyl-5,7dioxo-octahydropyrrolo( 3 #4-b]pyridine are reduced with 15.2 9 (0,40 nol) of lithium alainium hydride in 390 al of absolute tetrabydrofuran in the course of 10 hours in tleel 101 101 accordance with the working instructions of Example Ic.

24.4 g of a colourless oil having a bol~qI~g point of 93- 95'C/0.06 mbar are obtained on distillation.

c) -ctahmvdzopvrrgooA3 4bIRnridine 69 9 (0.32 mol) of 6-benzyl-octahydropyrrolo[3,4-b]pyridine are hydrogenated in 450 ml of methanol over 7 g of palladium-on-active charcoal strength) at 90 0 C/90 bar in the course of 3 hours. The c-atalyst is then filtered off, the filtrate is concentrated and the ri 8idue is distilled. 33.8 g (84% of theory) of a colourless solid having a melting paint of 65-67'C and a boiling point of 78 0 *C/9 mbar are obtained.

9X*RF L l-Methyl-octahydropyrrolo(3,4-blpyridine (2-methyl-2,8to:: 15 diazabicyclo[4.3.]onne) 0 4 $seea) 1-h.,lhyl-pyridinium-2, 3-dicarboxylic acid N-benzyliide iodide 190.5 g (0.8 mol) of pyridine-203-dicarboxylic acid Not bensylixide are dissolved in 800 al of nitroaethAane, while heating, and 136 g (0.96 mol) of methyl iodide are added dropvise. The mixture is then boiled for 8 hours while cooling under ref lux (cooling water After cooling, the solid is filtered off with suction and LOAL~ 16 102 102 washed with methylene chloride. 123 g of dark red crystals havinTg a melting point of 162-165 0 C (decomposition) are obtained.

b) 6-Benzyl-1-methyl-5,7-dioxo-octahydropyrrolo(3, 4-b]pyvridine 38 g (0.1 mol) of l-methyl'-pyridinium-2,3-dicarboxylic acid N-benzylimide io(ide are hydrogenated over 1 g of platinum oxide in 450 ml of glycol monomethyl ether at *0,30*C under 70 bar until the uptakce of hydrogen has ended ~10 (51 hours). The catalyst is then filtered off, the filtrate is concentrated, the residue is take~n up in 300 ml of chloroform and the solution is washed 2 x with 300 ml of 10% strength sodium carbonate solutIon each time and with 300 ml of water. After drying over sodiu= sulphate, it is concentrated. 27 g of an oily resiftue 0% remain.

19.2 g (0.QT' mol) of crudo~ 6-benzyl-l-methyl-517-dioxooctahydropyrrolo[3t4-b)pyridine are reduced with 6.1 g (0.16 mol) of lithium aluinium hydride in absolute tetrahydrofuran in accordance with the working irvstructions of Example 1c.

Yields 9.5 g (52% of theory), Boiling point: 93-96*C/O.1 Aua.

103 d) 1-MethvL-2ctahYdroovrro. z' b-12Y.riAin2 11.7 g (54 mmol) of 6-benzy8-1nm-methyl-octahydropyrrolo- (3,4-bjpyridine as the dihydrochioride are hydrogenated in 100 ml of methanol over palladium-on-active charcoal in accordance with the working instructions of Example Id. Working up by distillation gives 2.6 g (34% of theory) of a colourless oil of boiling point 83-85*/12 mbar) 10 trans -4 -Methoxy-3-methylamino-pyrrolidine dihydrochioride a) trans-1-Benzyl-3 -benzylimethylamino-4-hydroxypyrj ine 19.4 g '0.1 mol) of 90% strength 3-banzyl-6-oxa-3azabicyclo[3.1.0]hexans are heated under reflux with g (0.12 mol) of benzylxe thylamine in 100 al of dioxana and 200 3l of water overnight. The aixture is extracted with CHC1, the extracts are dried with 20,CO3 and concentrated and the resi'duo is subjcted to incipient distillation up to 160'C (oil bath temperature).

Crude yield: 10*3 g Contents 100% (determined by gas chxovatography) 104 b) trans-l-Benzyl.3-enylmthyamino4-methoxy.

Dvroldine 17.3 g (58 mmol) of crude trans-l1-benzyl- 3-benzylmethyl amino 4-hydroxy-pyrrol id ine in 80 ml of aboolute totrahydrofuran are added dropwise to 2.8 9 (93.3 mmol) of 80% strength sodium hydride in 40 al of absolute tetrahydxofuran and the mixture in heated under ref lux at the same time,~ When .ehe evolution of hydrogen has ended, 8.7 g (6il =mo13 of methyl iodide are added dropwise and the mixture is then heated under ref lux overnight. It is poured into ice-water and extracted with toluene$ the extracts are dried with IaC03 and concentrated and the residue is distilled.

Yields 9.7 g (52% of ti-zeory) Boiling poi.nts l4Q-1150OC/0.1 mbar trana- 4 -Met hoxy- 3-me thyl amIno -prr I i d ine dihydroch1rld 9.3 g (29 mmol) of trans- l-benzyl -3 .benzylmethyl..

amino-4-xiethozy-pyrrolidine ar, dissolved in 100 al of mothanol# 4 *8 al of concentrated hydrochloric acid are aijded and tle mixture is hydrogeniated on g of 10% strength Pd-on-active charcoal at 901C wnder 100 bar. The catalyst is filtered of f with suction# the filtrate is concentrated and the residue is recrystallized fromn isopropanol /methanol.

Yields 3.7 g (62,8% of theory) I&&IA 26 105 Melting point: 157-162*C 2 5-Dimthyl3-oxa-2 ,7-e iazabicyclo 3.3. 0 ]octane a) N-(2-Hethylprop-2-un.,yl)-N-(2,2-dimothoxyethyl)- 89 9 (0.5 mol) o~f N- (212-difnethoxyethyl)-urethane *are added dxopwise to 20 g of sodium hydride strength) in 500 ml of abolute toluene at 90 0 '10, Pa 0i no~ further hydrogen is formed# 54 g (0.6 wol) of goo.

methallyl chloride are added dropwise and the mixture is stirred overnight it 90*C. The sodium chloride which has precipitated out in dissolved with a little water, .,he organic pitass is separato~d ozf, dried over KICOk and concentrated and the residue is distilled.

Yield: 71.3 g (61,7% of theory) Boiling pointi 60'C/0.08 mnbar b) N-f 2-MethvloRoD-2-envl 1-N- I2-oxoothyl 1-urethan2 11.5 g (50 mmol) of X-(2-mothylprop-2'-enyl)-N-(2,2dixethoxyethy1),-urmthane and 1.25 g (5 mmi,4.) of pyridinium p-tolueneaulphate in 100 al of acetone and 10 al of water are heated under ref lux for two days. The mixture in concentra'.,o and the residue is 106 distilled.

Yield: 5.3 g (61.2% of theory) Boiling point: 73 0 0/0.1 mbar c) Ethyl 2,5-dimothy1-3-oxa-2,7-diazabicyclo(3.3.03octane-2-carboxvlate 21.7 g of 30% strength sodium methylate solution are added dropwise to 10 g (0.12 mol) of N-methylhydroxylamine hydrochloride in 26 ml of methanol.

The sodium chloride is filtered off with suction and 1 washed with 8 ml of methanol and 80 ml of toluene.

~:This solultiort is added dropwise to 19.2 g (0.11 mol) of N- (2-methyl-prop-2-enyl (2-oxoethyl )-urethnme, which is heated under ref lux in 160 ml of toluene using a water separator. The mixture is heated under reflux overnight, the product is extracted with 160 ml of 10% strength hydrochloric acid and the hydroch'-ric acid solution is rendered alkaline with potassium carbonate and extracted with six portions of 200 ml of CHCI 3 The extracts are dried over KIC0 3 20 and concentrated and the residue is distilled.

Yield: 13 g (55% of theory) Boiling points 88-95 0 C/0.08 mbar d) 2.5-D2imthyl-3-23a-2.7-diazabicvclof3l.3.Olotans 13 g (60.6 mmol) of ethyl 2,5-dinothyl-3-oza-2,7diazabicyclo[ 13. 3. Oj octane- 7-carboxylat. are heated under reflux with 33 g of Ba(OII) 2

.BH

2 0 in 330 al of 107 water overnight. The BaCO 3 is filtered off with suction, K2CO 3 i5 added to the filtrate, the solid in filtered off with auction again and the filtrate is extracted ten times with 100 ml of CHC1 3 each time.

The extracts are dried over KIC0 3 and concentrated and the residuva is distilled.

Yield: 5.9 g (63.7% of theory) Boilinig point: 64 0 C/5 mbar 2,8-Dimethyl-3-oxa-2,7-diazA-bicyclo(3.3.0]oct-I*ane a IILmto~g--" ebn a)ehd d.imethyproD-2-yl in-30 lefttlunean 32 g (0.8 mol) of NaOH in 300 ml of water. The mixture is stirred at room temperature for a further 2 hours, the organic phase is separated of f, the aqueous phase is extracted with toluene and the :.20 toluene soluti.zons are dried over K 2 COs. The solution in concentratcd and the residue in distilled.

Yield: 132 9 (95% of theory) Boiling points 55*C/O.06 mbar 108 131 g (0.686 mol) of N-(l,1l-dimethoxyprop-2-yl)urethane are added dxopwise to 25 g of sodium hydride (80t strength) in 700 ml of absolute toluenM" at 90 0 C. When the evolution of hydrogen has ended# 61.2 g (0.8 mol) of allyl chloride are added dropwise at 90 0 C and the mixture in r.'tirred overnight at 900C, The sodium chloride which has precipitated out is dissolved with water, the organic phase in 10 separated off, dried over K, 2 C0 3 and concentrated and the residue is distilled.

Yield: 78 g (31.7% of theory) Boiling points 62-69 0 C/O.06 mnbar.

Content: 64.5% pure (determined by gas chromatography) c) N-Kllvl-N-t 1-oxotroo-2-yH -urethane 76.5 g (0.213 mol) of 64.5% pure N-allyl-N-(l,1dimethoxyprop-2-yl) -urethane are heated in 180 31 of formic acid at 100 0 C for one hour. The mixture is poured into ice-water and extracted with CM 2 Cl 2 the extracts are washed neitral with NaHCO 3 solution, dried over XgSO 4 and conccatrated and the residue in distilled.

Yield: 36 g (80.9% of theory) Boiling points 97-102*C/8 mbar Contents 88.*8% pure (determined by gas chromatography) L9_ A. -6 109 109 d) Ethyl 2 18-dimethy-3-oxa-2, 7-diazabicyclo[ 3.3.O]0 octa~ng- cabxlate A methanolic methyihydroxylamine solution in prepared from 16.4 g (0.2 mol) of ?-methylhydroxyl amine hydrochloride in 33 ml of absolute methanol and 36 g (0.2 .01) of 30%~ strength sodium methylate solution, and the solution formed is diluted with 130 ml of toluene and added dxopwise to 354 g 17 mol) of N-allyl-N-(1-oxcdprop-2-yl) -urethane in 250 ml of toluene, which is heated under reflux usning a water separator. The mixture is heated under ref lux overnighto the product is extracted with dilute hydrochloric acid and the hydrochloric acid solution is rendered alkcaline with 42C03 and extracted with CHCl 3 The extract is dried over K 2 C0 3 and concentrated and the residue is distilled.

Yields 18.5 g (50.8% of theory) Boiling points 95-105"C/0.1 mbar e) 2.8-Dimthl-3-oxa-2.7-diaza~bicyclor3.3.Oloctan 9.2 g (42.9 w~)of ethyl 2,8-dimethyl-3-oxa-2,7diazabicyclo(3. 3.0]octane-7-caxboxylate are heated S under ref lux, with 23.5 g of Ba(OH) 2 5 8H 1 0 in 235 al of water overnight. The BaCO 3 is filtered off with suction, K 2 C0 3 is added to the filtrate and the solid is filtered of f with suction again. The filtrate is extracted ten times with 50 al of CHC1 3 eath time.

the extracts are dried over K 3 C0 3 and concentrated Lq A 26 108 110 and the residue in distilled.

Yield: 1.7 g Boiling point: 87-92 0 C/10 mbar The product is a mixture of the possible stereoisomers in a ratio of 3:1 ('H-NMR).

4 g of starting material could to be recovered in the after-runnings.

Examprle P..

2-Methyl-4-oxa-2,8-diazabicyclo(4.3 .lnonane a) Ethyl 4-hydroxymethyl-.3-methylaminopyrrolidile-1carItgjcvlate 9 (50 umo1) of ethyl 2-methyl-3-oxa-2, 4 7-diazabicyclo[3.3.0]octane-7-c'ixboxylate (Exaziple H are hydrogenated in 200 ml of ethanol on 3 g of Pd-onactive charcoal (10% of Pd) at 50'C under 50 bar.

The catalyst is filtered off, the filtrate is concentrated and the residue is distilled.

Yields 8.1 g (80% of theory) Boiling point: 135-140C/0.1 mnbar b) Ethyl 2-methyl-4-oxa-2,8 -diazabicyclo[4 .3 .0]nonane- 8-carbozvlate 10.1 g (50 mol) of ethyl 4-hydroxymethyl-3-methylaiino-pyrrolidine-1-carboxylate and 8 g (0.1 aol) of 111 37% strength formaldehyde solution are dissolved in 100 ml of butanol and the solution is stirred at room temperature overnight. It is then concentrated and the residue in distilled.

Yield: 9.5 g (88.7% of theory) Boiling points 110OC/0.l mbar c) 2-Mothyl- -oxa-2.8-.diazabigccor4.3.0Jnonan2 9 g (42 ouol) of ethyl 2-methyl-4-oxa-.2,8-diazabicyclo[ 4.3.0 3nonanie-8-carboxylate are heated under 10 reflux with 28 g of Ba(OH) 2 .8H.0 in 280 ml of water :overnight. The BaCO 3 is filtered off with suction, the filtrate is concentrated and the residue is boiled up with dioxane. The dioxane solution is concentrated and the residue is distilled.

Yield: 1.3 g (21.8% of theory) Boiling point: 115OC/8 mbar d) 4 ydr onmethy- 3 -Mie &hvIam in ovr ro11 d ine 34 g (0.168 mol) of ethyl 4-hydroxymethyl-3-methylaminopyrrol idin.-l1-carboxylate are heated under reflux with 100 g of Ba(OH)a.SHaO in 400 al of water overnight. The BaCO 3 is filtered off with suction, the Zltrate is concentrated and the reoidue is boiled up ten times with 100 al of dioxane each time. The dioxane solutions are filtered, the filtrate is concentrated and the residue is distilled.

zLg LQ A 112108 112 Yield: 13 g (60.3% of theory) Boiling point: 85-88OC/0.08 mbar e) 2-Methyl-4-oxa-2.8-diazabicvclor4.3.0blnnn 8.1 g (0.1 mol) of 37% strength formaldehyde solution in 20 ml of ai-butanol are added dzopwise to 13 g (0.101 mol) of 4-hydroxymethyl-3-methylanalnopyrrolidine in 100 ml of n-butanol at room temperature. Tht. mixture is stirred at room temperature overnight and concentrated and the residue is distiledo Yield: 8.7 g (61.2% of theory) Boiling point: 84 0 C/6 mbar Examle 3-Oxa-2, 7-diazabicyclo 3.3. 0 ]octane a) Ethyl 2-(tetrahydropyrai-2-yl)-3-oxa-2$7-diazabig I or 3. 1 octang -7-crbyle *18.1 g (0.106 mol) of ethyl N-allyl--N--(2--oxoethylj-o carbamate (Example X are heated under ref lux in 220 al of toluene, and 14.2 g 12 mol) of hydroxypentanal oxine (Acta Chia, Acad. Sci. Hung., 1j, 333 dissolved in 55 al of hot toluene, are added dropwiue. The nixture is heated under re flux overnight and concentrated and the I residue is L2 A 26 iQ8 113 distilled.

Yield: 15.5 g (54% of theory) Boiling point: 160*C/0.01 mbar b) Ethyl 3-oxa-2,7-diazalbicyclo(3.3.0]octane-7carbogyLate_ g (55.54mmol) of ethyl 2-(tetrahydropyran-2-yl)- 3-oxa..217-diazabicyclo( 3.3.0 Joctane-7-carboxylate are heated under ref lux with 8.25 g (56 mmol) of *~.strength perchioric acid in 100 ml of ethanol for minutes. 10.5 g (58 mmol) of 30 strength sodium *9 methylate solution are added, the mixture is concentratedi the residue is taken up in water and the solution is saturated with K, 2 C0 3 and extracted with CHCl 3 The extract is dried over K 2 CO, and concentrated and the residue is distilled.

Yields 7.6 g (73.5% of theory) too, Boiling point: 1,25-130*C/0.1 mbar c) Ethy~l 3-oxca-2 .7-diaz4bicvlo r3.3.0 1octane-7-a y.

::20 8.5 9 (50 =Daol) of ethyl N-(2-oxoethyl)-N-allylcarbamate are heated under retlux with 5.5 g mnmol) of o-trimethyl ailylhydroxyl amino in 100 al of xylene overnight. The mixture is concentrated and the residue is distilled.

Yields 6.8 9 (73% of theory) Boiling points 120-122*C/0.05 mbar 114 d) -di2LZA12Qi1.L 3- Qk1= This substance is obtaied analogously to Example N d) by hydrolysis of ethyl 3-oxa-217-diazabicyclo- 13.3.0]octane-7-carboxylate with Boiling point: W5C/le mbar.

0 9 0gee

S.

9. 9 0*e 09 9 0 0000 6 0 1,0 9* 0 9 0**S ZMaM1L2 3-Methyl-2,7-diazabicyclo C3.3.O0]octane 3-Methyl-2,7-diazabicyclo[ 3.3.0 Joctane 10 analogously to Example 1.

Boiling point: 68t I*C/6 mnbar.

is obtained 2, 3-Dimethyl-2 ,7-diazabicyclo[ 0 ]octane

I

0000 0900 0 0090 2 #3-Dimethyl-2,7-diazabicyclo( 33 -0 ]octane is obtained analogously to Exazple 1.

Boiling pointt 72-74*C110 mbar.

0069 00 0 0 049090 0 1,j 2-Dimethyl-3-oxa-2. 7-diazabicyclo[3. 30 ]octane 115 a) R-Allyl-N- 2-djaethgXvoro~yv1I-acetade 119 g (74 mol) of 2o2-dimethoxypropylacetamide are added dropwise to 29.6 g (0.987 m01) of sodium hydride (80% strength in paraffin oil) in 750 ml of absolute toluene at 80 0 C. The mixture in then stirred for one hour and 100 g (0.83 mol) of allyl bromide are subsequently added dropwise at 800C. The mixture is stirred ove-night at 80OC and cooled and the salts are dissolved with water. The aqueous phase in io separated off &nd extracted twice with 100 ml of toluene each time, The toluene solutions are dried over KIC0 3 and concentrated and the residue is distilled.

Yields 112 g (75.6% of theory) Boiling points 70*C/0.08 mbar, b) N--lvl-N- I2-oxo~rooyl I-acetamide 85.5 g (0.425 mol) of N-allyl-IN-(212-dimethoxypropyl)-acetamide are heated under ref lux with 212 ml of formic acid for one hour. The mixture is poured onto 500 9 of ice and extracted several times with methylene chloride,, the organic phases are washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated and the residue is distilled.

Yields 50 g (75.0% of theoryi) Boiling points 79'C/0.25 mbar.

L 2 A 6 198- 116 c) 7-Acetyl-1 ,2-dimethyl-3-oxa-2,7-diazabicyclo(3.3.0]- 15.5 q (0.1 mol) of N-ally1-N- (2-oxoproyl I-acetamide are dissolved in 100 ml of dkoxane, and 9 g ot anhydrous sodium acetate and 9 g (0.108 mol) of Nmethyi hydroxyl amino hydrochloride in 10 ml of water are added. The mixture is heated under ref lux iovernight and cooled and the salts are filtered off with auction Ad washed with dioxane. The filtrate is concentrated, the residue is taken up in 100 ml of water and K 2 C0 3 in added. The mixture is extracted with CHC1 3 the extract is dried over K 2 C0 3 and concentrated and tha residue is distilled.

Yields 15.9 g (86.3% of theory) Boiling points 75OC/0.1 mbar.

d) 1.2-Okmethvl- -oxa-2,7-diatabicyclor3.3.Oloctane 11.8 g (64 mmol) of 7-acetyl-1,2-dimethyl-3-ora-2,7diazabicyclo[3.3.0]octane are heated under ref lux with 12 g of NaOU in 36 ml of water overn~ight. The 20 mixture is saturated with K,2C0 3 and extracted several times with CHC130 the extract is dried over KIC0 3 and concentrated and the residue is distilled.

Yield: 4.7 g (51.6% of theory) Boiling points 40*C/0.2 abar.

117 2, 4-Dimethyl-3-oxa-2, 7-diazabicyc!a( 3 3..0 ]octane a) Ethyl N- (but-2-enyl) 2-dimethoxyethyl) -carbaiuat 89 g (0.5 mol) of ethyl N-(2,2-dimethoxyethyl)carbamate are a~dded dropwise to 17.5 g (0.58 mol) of Na2H (80% strength in paraffin oil) in 500 ml of 0684 absolute toluene at 800C. The mixture is then stirred 10 for one hour and 80 g (0.59 mol) of 1-bromo-2-butene are subsequently added dxopwise at 80*C. The mixture is stirred at 80 0 C overnight and coaled, the salts *are dissolved with water and the aqueous phase is separated off and extracted with toluene. The toluene solutions are dried over K2C0 3 and concentra- #foe ted and the residue is distilled.

of 0 Yield: 90 g (77.0% of theory) Boiling point: 650C/0.1 mabar.

4 0 0 0b) Ethyl N-(but-j-enyl) -t2-oXo!ethv11-rarbamat2 20 90 g (0.39 mel) of ethyl N-(but-2-onyl)-N--(2,2dinthoxythyl)-carbawute are heated under ref lux with 200 al of forluic acid for one hour. The mixture in poured onto 500 9 of ice and extracted with methylene chloride, the organic phases are washed with sodium bicarbonate solution, dried over mag- -o 118 of neuium sulphate and concentrato'd and the residue is distilled.

Yields 33.6 q (46.5% of theory) Doiling points 65"C/0-1 mbar.

c) Ethyl 2,4-dimethy"'-3-oxa-2 1 7-diazabicyclo(3.3.0]- 2.,tane-7-garboxyl ate 18.4 g (0,1 mol) of ethyl N- (but-2-enyl) (2-.oxoethyl) -carbamate are dih solved inl 100 a2l of dioxane, and 9 g of anhydrour sodium acetate and 9 qg0, 10A8 10 mol) of N-methylhy'Jroxylamine hydrochlorlde in 10 ml of water are added. The mi'xture is heated under ref lux overnight and cooled and the salts are filtered off with suction and washed with dioxane.

The filtrate is concentrated, the residue is tAken up in 100 ml of water and K 2 C0 3 is added. The mixture is extracted with CHC1 3 1 the extract in dried over KIC0 3 and concentrated and the residue is distilled.

Yield: 15.0 g (70% of theory) Boiling point: 74-87 0 C/0.l mbar, 20 d) 2.-imethyl!-3-oxsa-2s2-diazAbicyglor3.31..'QJW 13.2 g (61.6 nzol) of ethyl 2,4-dimethyl-3-oxa-207diazabicyclo 3. 3. 0 octane.-7 -caxboxylato are heated under reflux with 39, g of Ba(OH) 2 8H20 in 200 al of water overnight. K 3

CQ)

3 in addod, the DaCO 3 is f iltered off with suct~ion and the filtrate is extracted several times with CHC1 3 The extract is diid over 119 K.C0 3 and concentrated and the residue is distilled.

Yield: 4.86 g (54,8% of theory) Boiling point: 74 0 C/8 mbar.

Eth ,Yl 2,7-diazabicyclot3,3.0]octaflO-2-carboxylatO 7.Benzyl-2,7-diaz~bicyclOj3.3. 0]octaneO (Example Jc) is reacted with ethyl chioroformate analt.4ouuly to Example Oik) to give ethyl 7-benzyl-2,7-diazabicycloE3.3. 0 ]octane- 10 2-carboxylate, and this is then dobenzyJlated hydrogetolytically analogously Example Jd). A colourless oil og bollur, point 90' 0 /O1 mbar is obtained.

2-I'henyl-2, 7-diazabicyclo 3. 0 octane The preparation Is carried out analogo~iuly to &;tample 1, Boiling point: 103*C/0.08 abar.

2Joe- 2~ 120 4-Oxa-218-diazabicyclo[4 a) Ethyl 3-amino-4-hyd-roxymethyl-pyrrolidifle-1carboxyla&2 Ethyl 3 -oxa-2 ,7 -diazabicyclo C3. 3. 0] octal-7 -carboxylate (Example Qc) is hydrogenated analogously to Example Pa).

Boiling point: 163-168'C/0-8 Ybar b) 3~~iDOA-hvdVoxvs~ethXI 2YrQidilG *Ethyl 3 -amuino- 4 -hydroxymethyl-pyrrol idine-l1-carboxylate is hydrolyzed analogously to Example Pd).

Boiling point: 78 0 C/0.06 mbar.

c) 4-Oxa-2 -dz~bcVg1Q 4.3 0 1 noflafl 3 -Amino -4 -hydxoxymethyl -pyrrol id',.ne in reacted with formaldehyde solution analogously to Example Pe).

Boiling pointi 5O-60*C/0.07 mabar 121 Ixample trans-3-Ethylamino-4-methylthio-pyrrolidine a) i-Senzoyl-trans-3-ethylamino-4-methylthio- ProTidine_ 8.65 g (50 mmol) of 1-benzoyl-2,5-dihydropyrrole [Chem. Ber. 22, 2521 (1889)] are initially introduced into 30 ml of methylene chloride, and 4.94 g mmol) of methaneaulphonyl chloride in 20 ml of methylene chloride are added dropwise at 0°C. The mixture is subsequently stirred at 20-25*C for 16 hours and concentrated under 8 mbar and the residue is dissolved in 50 ml of tetrahydrofuran. 18 g (0.2 mol) of 50% strength aqueous ethylamine solu- 15 tion are then added. The batch is boiled for 18 hours, while cooling under reflux, poured into water and extracted with methylene chloride. On concentrating, 11.1 g of crude product are obtained, and the crude product is chromatographed with ethyl acetate/ethanol 51 on sillca ,0 (RF value 0.34).

Yields 7.4 g (56% of theory).

b) trans- 3-Ethyl ami o-4-methyl thio-DvrrOl dine g (22 mol) of l-benzoyl-trans-3-ethylaxino-4methylthio-pyrrolidine are stirred vigorously with 22 al of 5N NaOH at 100'C for 24 hours, until the 122 conversion is homogeneous. The mixture is then extracted with 3 x 80 ml of ether and the Axtract is dried over sodium sulphate and concentrated on a ~rotary evaporator. The crude product is distile through a micro-puncture column.

Yield: 1.56 g (44% of theory) of colourless liquid, Boiling point: 52 0 C/0. 1 mbar Example Z t ran s 3-anino-4 -methylthio-pyrrol idine 1 -Benz oyl 5-dihydropyr role is reacted with methylsulfenyl chloride analogously to Example Y to give l-benzyl-3- *.chloro-4-methylthiopyrrolidine which is reacted as a crude product with amm~onia to give 3-amino-l-benzoyl-4-methylthio-pyrrolidine and the benzoyl radical is removed with sodium hydroxide solution.

Yield over 3 stages: 47 of theory Boiling point: 108-110*C/ll mbar.

Example ZA 4=M2thyl-21 8-dia abicyclo N .3.01 nonane a) 5-Met-hyl-i, 4-dihydropyridine-2, 3-dicarboxylic acid N-ben zvlimide 33 g (0.29 mol) of 2-niethyl-2-propenal-dinethylhydrazone and 55 g (0.29 mol) of N-benzylnmaleinimide are stirred in 225 ml of acetonitrile for 3 ho~urs at Le A 26 108-13- 123 Then the solvent is removed in a rotary evaporator, the residue is taken up in 600 ml of toluene and, after adding 150 g of silica gel, the mixture is boiled for 1 hour under reflux.

Then the mixture is filtered while hot and the silica gel is boiled out several times with ethanol. The combined organic phases are concentrated in a rotary evaporator.

17.5 g (24 of theory) of red crystals of a melting point of 184-186'C are obtained.

b) 5-Methyl'-hexahydropyridine-2,3-dicarboxylic acid N-benzylimide 17.5 g (70 mmol) of 5-methyl-1,4-dihydropyridine-2,3o dicarboxylic acid N-benzylimide are hydrogenated in 150 ml of tetrahydrofuran at 70'C and under 100 bar over palladium on active charcoal. Then the catalyst is filtered off and the filtrate is concentrated by evaporation. The solid oily residue (13.0 g) is used as a crude product in the next stage.

c) 8-Benzvl-4-methyl-2, 8-diazabicyclo [4.3.01 nonane 13.0 g of crude 5-methyl-hexahydropyridine-2,3-dicarboxylic acid N-benzylimide are added in the form of a solution in 50 ml of absolute tetrahydrofuran to 4.6 g (0.12 mol) of lithium aluminium hydride in 100 ml of absolute tetrahydrofuran, already present in the vessel. Then the mixture is boiled for 17 hours under reflux. 4.6 g of water in 14 ml of tetrahydrofuran, 4.6 g of 10 strength sodium hydroxide solution and 13.8 g of water are added dropwise one after the other. The salts are filtered off, the filtrate is concentrated by evaporation and the residue is distilled.

Le 26 13 124 Yield: 8.7 g (54 %1 based on 5-rethyl-l,4-dihydropyridine-2,3-dicarboxyl.c acid N-benzylimide); boiling point: 95-98*C/0.l mbar.

d) 4-Methyl-2, 8-diazabicyclo 14.3.01 nonane g (35 mmol) of 8-benzyl-4-methyl-2,8-diazabicyclo[4.3.Olnonane are dissolved in 60 ml of methanol and hydrogenated over palladium on acitive charcoal at 100*C and under 100 bar. Then the catalyst is filtered off, the filtrate is concentrated by evaporation and the residue is distilled.

*Yield: 3.3 g (G'7 of theory) is boiling point: 88-89'C/lrbar.

The IH-NMR spectrum shows the compound to be a mixture *of two stereoisomers in a ratio of 7:2.

Exam~le AA 61718 -Te t ra flu oro 1- 2 4-d if 1u orophe nyl-114 -d ihydre,- 4-oxo-3-quinolinecarboxylic acid S525 Ethyl 3,4,5, 6-pentafluorobenzoyl)-3-(2 14difloroo2henviaminol -acrvtl 2 44.3 g of 2,4-difluoroaniline are added dropwise to a solution of 115 g of ethyl 3-ethoxy'-2-(2,3,4,5,6pentafluorobenzoyl)-aczylate in 380 ml of ethanol, while cooling with ice and stirring. The mixture is stirred at room temperature for 1 hour, 380 al of 13S water are added, while cooling with ice, and the precipitate is filtered off with suction, washed with ethanol/H 2 0 and dried. 135.4 9 of the title compound of nelting point 97-990C are obtained.

Le A 26 108 125 b) Ethyl 516,718 -tetra fluoro-l-(2 ,4-dif luorophenyl) 1A--jhyO-4 -oxo- 3_r~inoj inecarb-.Klate A mixture of 135.4 g of ethyl 2-(2,314,5,6pentaf luorobenzoyl) 4-dif luorophenyl amino) acrylate, 20.6 g of sodium fluoride and 300 ml of anhydrous dimethylformamide in heated at 140-150 0

C

for 3 hours. The suspension in poured hot onto 2 kg of ice and the precipitate is filtered off with suction, washed with water and dried. 122 g of the title compound of melting point 160-162*C are .::obtained.

C) 5,6,7,8-Tetrafluoro-l-(2,4-difluorophenyl)-"Li4dihydro-4-oxo-3-- inolinecarboxylic acid so :6.640.1 g of ethyl 516,7,8-tetrafluoro-l-(2,4-difluorophenyl) -114 -dihydro- 4-oxo- 3 -uinol inec arboxyl ate are added to a mixture of 28.5 m! of concentrated sulphuric acid, 250 ml of glacial acetic acid and 200 ml of water and the mixture is heated under reflux, for 2 hours. The hot solution is poured onto ice and the precipitate is filtered off with suction, washed with water and dried. 34.5 g of the title compound of melting point 250-252'C are obtained.

MM26A 7-Dichloro-l-cyclopropyl-6-fluoro-1, 4-dibycdro-4-oxo-3cruinolinecarhoxvlir. acid a) Ethyl (2.4-dighloro-3,6-difgurobenzov1)-Agetate Le A 26 108 126 2.1 g of magnesium filings are suspended in 5 ml of anhydrous ethanol. 0.5 ml of carbon tetrachloride is added and, when the reaction has started, a mixture of 14 g of ethyl malonate, 10 ml of absolute ethanol and 41 ml of toluene is added dropwise. The mixture is then heated at 70°C for a further 1.5 hours and cooled to -5°C to -10°C with acetone/dry ice, and a solution of 21.5 g of 2,4-dichloro-3,6-difluorobenzoyl chloride in 30 ml of toluene is slowly added dropwise at this temperature. The mixture is stirred at 0 C for 1 hour and allowed to come to room temperature overnight, and a mixture of 35 ml of ice-water and 5 ml of concentrated sulphuric acid is allowed to run in, while cooling with ice. The phases are 15 separated and subsequent extraction is carried out twice with toluene. The combined toluene solutions are washed once with saturated sodium chloride solution and dried with Na 2 SO and the solvent is stripped off in vacuo. 34.7 g of diethyl (2,4- 20 dichloro-3,6-difluorobenzoyl)-malonate are obtained as a crude product.

0.04 g of p-toluenetoluenesulphonic acid is added to an emulsion of 34.7 g of crude diethyl (2,4-dichloro-3,6-difluorobenzoyl)-malonate in 40 al of 25 water. The mixture is heated at the boiling point for 3 hours, while stirring thoroughly, the cooled emuls.on is extracted several times with methylene chloride, the combined CHCI1, solutions are washed once with saturated sodium chloride solution and 127 dried with Na 2

SO

4 and the solvent is distilled off in vacuo. Fractionation of the residue (33.9 g) in vacuo gives 13.9 g of ethyl (214-dichloro-3,6dif luorobenzoyl) -acetate of boiling point llO-115 0

C/

0.5 mbrs 0.5zban 1,5241.

b) Ethyl 2 4-dichloro-3,6-dif luorobenzoyl) -3-ethoxyac ryl ate 13.7 9 of ethyl (2,4-dichloro-.3,6-difluorobenzoyl)acetate are heated under ref lux with 10.25 g of triethyl orthoformate and 11.8 g of acetic anhydride :for 2 hours. The mixture is then concentrated in vacuo up to a bath temperature of 140 0 C and 15.7 of ethyl 2-(2,4-dichloro-3,6.-difluorobenzoyl)-3- I. ethoxy-acrylatc are obtained as an oil, n 0 D 1,5302, c) Ethyl 2-(2,4-dichloro-3,6-difluorobenzoy1)-3-cyclo- 400 propyl amino- acrylate 15.6 g of ethyl (2,4-dichloro-3 1 6-difluorobenzoyl)- 3-ohoxyacryateare dissolved in 50 ml of eth-anol, 664 20 while cool.ing. The mixture In stirred at room temperature for 1 hour, 50 .1 of water are added, while cooling with ice, and the precipitate is filtered off with suction, rinsed with athanol/H 2 0 and dried. 14.1 9 of ethyl 2-(2.4-dichloro.

3 g 6-dif luorobenzoyl) -3-cyc lopropylanino-acrylate of melting point 106-1070C are obtained.

128 d) Ethyl 5,7-dichloro-l-cyclopropyl-6-fluoro-1,4dlihydro-4-oxg- 3--aulnol inecarboxylatsa_ 6 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)- 3-cyclopropylanino-acrylate axe heated in 100 al of dimethylformaiide at 150 0 C with 2.75 g of potassium carbonate for 2.5 hours. The mixture is poured into 600 ml of ice-water and the precipitate is filtered off with suction, washed with water and dried.

5.2 g of ethyl 5,7-dichloro-l-cyclopropyl-6-fluoro- 14 4-dihydro- 4-oxo- 3-qu inol inecarboxyl ate of melting e)point 227-229 0 C ar07 ob*taine-.

e) 5.7-Dichloro-l-cyclopropyl-6-fluoro-1,4-dihydro-4xo-3-cniinoinecarboxylic acid 5.2 g of ethyl 5,7-dichloro-l-cyclopropyl-6-fluoro- 1, 4-dihydro-4-oxo-3-quinolinecarboxylate are heated under reflux in a mixture of 38 ml of acetic acid, :30 ml of water and 4.3 ml of concentrated sulphuric acid for 2.5 hours. After cooling, the mixture is poured into 250 ml of ice-water and the precipitate in filtered off with suction, washed with water and dried. 4.8 g of 5,7-dichloro-l-cyclopropyl-6-fluoro- 4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 277-2780C are obtained..

L L~ A 22 6 .0 129 7 -Dichloro-6-f uoro-l-(2,4dif uoropheny.1,4..dihydo- 4-oxo-3-quinolinecarboxylic acid a) Ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-(2,4difluoro~,henylamino1 -acrylate, 35.3 g of ethyl 2-(2,4-dichloro-316-difluorobenzoyl)-3-ethoxyacrylate are dissolved in 120 ml of ethanol, and 12.9 g of 2,4-difluoroaniline are added 10 dropwisel while cooling with ice. The mixture is fee a stirred at room temperature for 1.5 hours, 120 ml of water are adde~d, while cooling, and the precipitate 90:041* is filtered off with~ suction, rinsod with ethanol/-

H,

2 0 and dried. 40.5 g of ethyl 2-(2,4-dichloro- 3, 6-di fluorobenzeyl) (2,4 -di luorophenyl amno) 6:04 acrylato are obtained, melting point: 84-8611C.

b) Ethyl 5,7-dichloro-6-fluoro-l-(2,4-difluorophenyl).

a 0 01 .4-dihvdro-4-oxo-3-aUinolinecarboxvl-at, 43.6 g of ethyl 2- 4-dichloro-3 j6-dif luoro.

20 benzoyl)-3-(2,4-difluorophenylamino)-acrylate are *Vs* heated in 260 al of dimothylformamide at 1500C with 15.2 9 of potassium carbonate for 2.5 hours. The mixture is pourad into 1 litre of ice-water and the precipitate is filtered off with auction, washed with water and dried. 38.6 g of ethyl 517-dichloro- 13o I L IL~._I 6-fluoro-l-(2,4-difluorophenyl)-l,4-dihydro-4-oxo- 3-quinolinecarboxylate are obtained.

c) 5,7-Dichloro-6-fluoro-l-(2,4-difluorophonyl)-1,4dihdro-4-oxo-3. quinolinecarboxylic acid 41.6 9 of ethyl 5,7 dichloro-6-fluoro-l-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate are heated under reflux with 250 ml of acetic acid$ 200 ml of water and 28.5 ml of concentrated sulphuric acid for 3 hours. After cooling 1 1the mixture is poured into 2 litres of ice-water and the precipitate is filtered off with suction, washed with water and dried. 35.5 g of 5,7-dichloro-6fluoro-1-(2,4-difuorophnyl)-,4-dihydro- 4-oxo-3quinolinecarboxylic acid are obtained, nelting point: 244-246%., Exams1ej. 0

COOH

X HC1 SA~. 855 ug (3 inmol) of 1-cyclopropyl-6,7#8-trifluoro- 1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated undar ref lux in a mixture of 9 al of acetonitrile and 4. al kit dimethylformamide in the presence of 330 mg (3.3 mmol) of Il 4-diazabicyclo[ 2.2.2 ]octane and 750 mg of ~Lh 26 131 3 trans-3-tert. -butoxycarbonyl-amino-4 -rethoxy-pyrrolidine for 1 hour6 The mixture is evaporated, the residue in stirred with water and the mixture is dried.

Yield: 1.3 g (90.5% of theory) of 7-(trans-3-tert.butoxycarbonylamino-4-methoxy--pyrrolidinyl )-1-cyclopropyl-6,8-difluoro-114-dihydro-4-oxo-3-quinolinecarboxylic acid.

Melting point: 222-224*C (with decomposition) (from glycol monomethyl ether).

B. 1.2 g (3.5 nunol) of the product from stage A are ~*:introduced into 10 ml of 3N hydrochloric acid, the mixture is stirred until a solution is obtained and the solution is concentrated. The residue is triturated with ethanol, filtered off with suction and dried at 60* under 1s a high vacuum.

Yield: 0.73 g (70% of theory) of 7-(trans-3-amino-4methoxy-l-pyrrolidinyl).-l-cyclopropyl-6, 8-difluoro-4-oxo- 3-.quinolinecarboxylic acid hydrochloride.

Melting point: 279*C (with decomposition) I& A26 198 132 z&aMWAA-

HC

l-Cyclopropyl-61 7-dif luoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted analogously to Example 1 to g ive s owe A. 7- (trans-3 -tort.-Butoxycarbonylamino-4-methoxy-1pyrrolidinyl)-l-cyclopropyl-6-fluoro-1 4-dihydro-4-oxo- 3-quinolinecarboxylic acid# melting points 247-2490C (with decomposition).

B. 7-(trans 3-Amino 4 -methoxy- 1-pyrroLidinyl)-l-cyc lopropyl- -fluoro-4-oxo-3-quinolinecarb.>oxylic acid hydrochloride, melting points from 293C (with decomposition).

ExW212~ 3 0 a...H I Ch x HCI ~S A reaction isa carri..)d out analgouly to Example I withl Id& 2. 1033 *133 I- cis -3-tert. -butoxycarbonyl amino- 4-methoxy-pyrrol idine to give: 7-(cia-3..tert.-Butoxycarbpnylamino-4-methoxy-lpyrrolidinyl) -l-cyclopropyl-6,8-difluoro-1,4-dihydro-4oxo-3-quinolinecarboxylic acid, melting points 230-231 0

C

(with nposition).

B. 7-(cis-3-Amino-4-methoxy-l-pyrrolidinyl)-i-cyclopropyl-6,8-difluoro-4-oxo-3-quinolinec.tboxylic acid hydrochloride, melting point 201-203'C (with decomposi- Exampile -4 'P COOK H2N:%r x CF 3

COOH

9 (5 mmol) of 8-chloro-l-cyclopropyl-6#7-difluoro-l,4-dihy'dxo-4-oxo-3-quinolinecarboxylic acid are hpated under ref lux in a mixture of 10 a~l of acetonitrile and 5 =l of cdizuthyformamide with 550 mg (5 mmol) of 1, 4-diazabk~fclo[2.2.2 ]octane and 1.2 g (5.6 mmol) of cis- 3-tert -butoxycarbonylamiuio-4 -mothoxy-pyrrol idins for 2 houirs. The mixture is allowed to cool and the precipitat. which has s4parated out is filtered off with suction, rinsed thoroughly with water and dried at 1000C In vacuc.

134 Yields 2.0 g of 7-(cis-3-tert.-butoxycarbonylamino-4-methory-l-pyrrolidinyl) -8-chloro-l-cyclopropyl- 6-f luor6-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 222-225 0 C (with decomposition).

B. 1.9 g (3.8 mmol) of the product from stage A are stired in 10 ml of trifluoroacetic acid at room temperature for 20 minutes, the solution is concentrated, the oil which remains is evaporated twice with methylene chloride and the residue is stirred with ether. The precipitate which has separated out is filtered off with uction, washed with ether and dried at 60 0 C in vacuo.

Yield: 1.9 g (97% of theory) of 7-(cis-3-amino-4 -methoxy- 1-pyrrolidinyl) -8 -ch1oro-I-cycIopropy1-6-fIuoro-1 dihydro-4-oxo-3-quinoliriecarboxylic acid trifluoroacetate, melting point: 235-239C (with decomposition).

ij"Examle *900

-COOH

9**9I CHx cis3-tt Butoxycarbonylamino- 4-methoxy-pyrrol idine is reacted with 1-cyclopropyl-6 7-difluoro-1 4-dihydro-4oxo-3-quinolincarboxylic acid analogously to Example 1 to give: 135 A. 7- (cL a-3-tert. -But oxycarbonyl amino -4-methoxy-..

Pyrrolidinyl)--cyclopropyl-6fluoro-1,4dLhydro.4oxo 3-quinolinecarboxcylic acid, melting point 232-233 0 C (with decomposition), B. 7-(cis-3-Amin"o-4-methoxy-l-pyrrolidinyl)-l-cyclo.

propyl-6-fluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride, mi~elting point 252-256 0 C (with decomponition) (uintering beforeh~ind).

ExamTyle 6 10 8XMCl CH3~A cis-3-tert. -Butoxycarbonylamino-4-methoxypyrrolidine is reacted with 7-chioro- l-cyc lopropyl-6 -f luoro-l1, 4 -dihydro- 4-oxo-1, 8-naphthyridine-3-carboxylic acid analogously to Example 1 to give: A. 7 -(cis -tert. -Butoxycarbonylaino 4-methoxy- 1 pyrrolidinyl) -l-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxylic acid, melting point 214- 2160C (with d~composition).

7- (cis -3 -Amino- 4-mthoxy- -pyrrol idinyl -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-18-naphthyridine-3.

Le2 Q A 136 10 136 carboxylic acid hydrochloride, melting point 205-2101 (with decomposition).

Maase t_--trum: m/e 362 330 (le-32), 318 (M'-CO 2 286, 2601 41 (C 3

H

5 36 (HCl).

0

COOK

HO"-

1. 1 g (10 mmol) of 1, 4-diazabcyclof 2.2.2 ]octan and 0.55 g (5.4 mmol) of trans -amino- 4 -hydroxy-pyrolc ine are added to 1. 33 g (5 mmnol) of 1-cyclopropyl-6, 7-difluoro-1,4 4-dihydro-4-oxo-3-quinolinecarboxylicc acid in a :i mixture of 30 ml of acetonirile and 5 ml of dimethyl- :::':formamide and the mixture in heated under reflux for 1 hour. The suspension is concentrated, _,ater is added to :i the residue and the undissolved product is filtered off with auction and recrystallized from dimethyylformamide.

ieldi 1.2 g (73% of theory)) of 7-(tranS-3-amino-4 .:.ihydroxy-l-pyrrolidinnyl)-l-ycloproylp-floro1,4 dihydro-4-oxo-3-quinolinecara9Boxylic acid, Meltinrg poilnti 274-2780C0 (with decouposition).

137

H

850 mg (3 mmol) of 1-cyc).opropyl-6,7,8-trifluoro-1,4dihydxto-4 -oxo-3-cpuinolinecarboxylic acid are heated under reflux in 9 ml of pyridine with 630 mg (3.1 mmol) of 2oxa-5,8-diazabicyclo(4 .3.Ojnonane dihydxochloride and ~:500 mg (4.5 mmol) of 114-diazabicyclo(2.2.2)octane for 1 hour. The mixture is concentrated, the residue is stirred with water and the precipitate in filtered of f with suction, washed with water, dried and recrystallized from glycol monomethyl ether.

Yield: 840 mg (72% of theory) of 1-cyclopropyl-6,8dif luoro-1 4-dihydro-7- (2-oxa-5 j8-diazabicyclo 4. 3. 0]non- 8-yl) -4-oxo-3-quinolinecarboxylic acid, Melting point: 289-291 0 C (with decomposition); Mass spectrum: mis 391 (K,347 (M*-CO 2 331, 306, 294, 262, 234, 98, 41 (CAS).

-138 F 01 The reaction is carried ou. .inalogously to Examnple 8 with 5-methyl-2-oxa-5,8-diazabicyclo(4 .3 .0]nonane dihydrochloride to gives 1-cyclopropyl-6,8B-dif luoro-1, 4-dihydro- 7-(5-methyl-2-oxa-5,8-diazabicyclo4.3.0]lon-8-yl)-4-oxo- 3-quinolinecarboxylic acid, melting points from 270"C (with decomposition); Mass zpectrum: m/e 405 361 (MW-CO 2 )t 331t 112, (100%).

Example

COOH

3.

0795 mg (3 o1) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4 -oxo-3-quinolinecarboxylic acid arit heated under reflux in a mixture of 9 al of acetonitrile and 4.5 al of dimethylfoniaulde with 890 mg (4.1 mmol) of 5-methyl-2- 8-diaitabicyclo[4 .3.0]nonane dihydrochiorid. and 139 860 mg (7.8 mnmol) of l,4-diazabicyclo[2.2.2 ]octane for 2 hours. The mixture is evaporated, the residue is stirred with water and the undissolved product in filtered off with suction, washed with water, dried and recrystallized from dimethylfonnamide.

Yieldt 0.8 g (69% of theory) of l-cyclopropyl-6-fluorel, 4-dihydro-7- (5-methyl-2-oxa-5j-diazabicyclo(4.3.0]non- 8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point 340 0 C (with decomposition) (on heating up, the substance already becomes dark from about 3000).

M as spectrum: m/e 343 (K t -C0 2 313, 244, 112 (100%).

Example 11

COOH

C,

The reaction is carried out analogously to Example with 8-chloro-l-cyclopropyl-6 7-dif luoro-l, 4-dihydx'o-4oxo-3-quinolinecarboxylic acid to give 8-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro-7-(5-methyl-2-oxa-5, 8-diazabicyclo4[ 0]non-8-yl) -4-oxo-3-quinolinecarboxylic acid, melting point 258-2620C (with decompoition) (recrystallized from dinethylformamide).

14(0 I I F C 2

HS

H 3 The reaction is carried out analogously to Example with 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid to give l-ethyl-618-difluoro-l,4- *Goo dihydro-7-(5-methyl-2-oxa-5,8-diazabicyclo(4.3.O]non-8yl)-4-oxo-3-guinolinecarboxylic acid, melting paint 279- 281"C (with decomposition).

Examvle 130

COOH

00:0 0.84 q (3 mmol) of 1-cycloprop l-6,7l8-trifluoro-1,4dihydro-4-oxo-3-quinolinecarboxylic acid are heated under reflux in a mixture of 6 al of acetonitril. and 3 al of dimethylformaside with 0.66 9 (6 sinai) of 1,4-diazabicyclo[2.2.2 ]octane and 0.49 g (3.5 mmol) of 2-methyi-2,8diazabicyclo(4.3.0]nonans for 2 hours. The suspension is concentrated, the residue Is stirred with 20 al of water, L~e A 26 108 141 the mixture is brought to pH 7 with 2N hydrochloric acid and the precipitate is filtered off with auction, washed with water, dried and recrystallized from glycol monomethyl ether.

Yield: 0.7 g (58% of theory) of l-cyclopropyl-6o8-difluoro-l,4-dihydro-7-(2-methyl-2,8-diazabicyclo(4.3.]non-8-yl) -4-oxo-3-quinolinecarboxylic acid, melting point 204-207 0

C.

6 60Exainole 14

COOH

C

C I* Analogously to Example 13, 1-cyclopropyl-6-fluoro-1,4dihydro-7-(2-methyl-28-diazabicyclo(4.3.]non-8-yl)4oxo-3-quinolinecarboxcylic acid, melting point 234-2360, is obtained with 1-cyclopropyl-6, 7-cifluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid.

142 C H:

FB

A. l-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3quinolinecarboxylic acid is reacted with 2,8-diazabicyclo(4.3.0]nonane analogously to Example 13 to give 1cyclopropyl-7-(2,8-diazabicyclo[4.3 0]non-b-yl)-6,8difluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acido melting point 265- 67* (with decomposition) (recrystallized from dimethylformamide).

S. If the reaction of Example 15 A) is carriid out in a mixture of ace tonitrile/l-methyl-2-pyrrolidinone and the crude product is recrystallized from dimothylformamide, 1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0 noni- 8-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline- 15 carboxylic of melting point 269-271*C (with decomposition) is obtained. According to a comparison by chromatography and spectroscopy, the product is identical to the product *too prepared according to process A).

C. 65 g (167 mmol) of the betaine (stage A) are dissolved in 330 ai of half-concentrated hydrochloric acid by heating, the st'lution is concentrated and the residue in stirred with 300 ml of ethanol. The undissolved 143 _r _1I~I~ICI_ precipitate is filtered off with suction, washed with ethanol and dried at OOOC in vacuo.

Yield: 66,3 g (93% of theory) of l-cyclopropyl-7-(2 8diazabicylo[ 4,39 ]non-8-yl) -6 ,8-difluoro-1, 4-dihyd ro-4oxo-3-quinolinecarboxylic acid hydrochloride, melting point: 303-305 0 C (with decomposition).

gxamipre 16 0 C OOH $fee 9 0 9 Analogously to ExampleQ 13, 1-cyclopropyla7-2 #7-diaz~abii 10 cyclo3.3.0]ct-7-yl)6-fluor-14-dihyd ro4oo3 quinolnecaroxylicc aci, melting pointt 260282* (with decomposiion) is obtained with 1-cycelopropyl 7-di fluoro-114-4 dihyd.-o-4-oxo-3 -quinoli necarboxylici ac id. and 2 ,7-dizabicyclo(3.3. 0 ]octane.

HMass spectrum: m/e/ 357 313 (100%, W-COI), 269, 257t 2441 82, 28.

949 9I 144 IsamRie 11 CH3 too 0.*4 Analogously to Example 13j 1-cyclopropyl-6-fluoro-114dihydro-7-(2-mothyl-2#7-diazabicyclo(3.3.0)oct-7-yl)-4oxo-3-quinolinecarboxylic acid, melting pointt 206-2080C (with decomposition), is obtained with 1-cyclopropyl-607dif luoro-114-dihydro-4-oxo-3-quinolinecarboxylic acid and 2-met'hyl-2,7-diazabicyclo[3.3,O]octans.

CH3 'be 4 0" Analogously to Example 13, 1-cyclopropyl-6,8-difluoro- 1#4-dihydro-7-(2-mothyl-2l7-diazabit-yclo(3.3#0)oct-7-yl)- 4-oxo-3-quinolinecarboxylic acid; melting point 198- 200'C (with decomposition), is obtained with 2-methyl-2#7diaxabicycloI3.3.01c>ctane.

14S -a 131 Zxamplet 1 0

COOK

H 3C"-,N- A mixture of 2.83 g (10 mmol) of 1-cyclopropyl-6,, 8- 9trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.1 g (10 mmol) of 1,4-diazabicjyc-loC,.1.2.&2,2 ano and 1.4 g (11 mmol) of 2-methyl-3-oa-217-diazabcyclo(3.3.

0Ooctano in 20 ml of acetonitrile and 10 ml of 1-methyl- 0S.2-pyrrolidinone is heated under reflux for 1 hour, It is concentrated in vacuo, the residue is stirred with water (pH 7) and the precipitate is filtered off with auction, washed with water and dried at 60* in vacuo. The crude *66:0 product (3.7 g) is recrystallized from dimethylformamide.

Yields 1.9 g (49% of theory) of 1-cyclopropyl-6,8-difluoro-1 4-dihydro-7-( 2-mthyl-3-oxa-2,7-diazabicyclo- 13.3.Ojoct7-yl)-4-oxo-3-quinolinecarboxylic acid, melting point 221-223*C (with decomposition).

9*9**9 146 0

H

3 C

COO

N CO

CH

3 The reaction is carried out analogously to Examplb 19 with 2,5-dimothyl-3-oxa-2,7-diazabicyclo[ 3.3. 0]octane to give 1ccorp69dfur~,-iyr--25 dimethyl-3-oxa-2,7-diazabicyclo[3.3.0oct-7-y)-4-oxo.3quinolinecarboxylic acid of melting point 237-238*C (with decomposition).

0

COON

N

The reaction is carried out analogously to Example 19 with 218-dimethyl..3-oxa-2 #7-diazabicyclol 3.3.O0]octane to give 1-ylpoy-*-ilor-,-iyr--28 d3.methyl-3-oxa-2,7-diazabicyclo[3.3.O)oct..7-yl)-4-oxo-3quinolinecarboxylic acid of melting point 1974199*C.

I& A.-ILU- 147

!OOH

A. 3 g 110 mmol) of 8-chloro-1-cyclopropyl-6,7-disf luoro-11 4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated under ref lux in a mixture of 30 ml of acetonitrile and 15 ml of 1-meohyl -a-pyrrol.d-rnone with 1.4 g (11 '0400, mmol) of 2,8-diazabicyclo[4.3.O]nonane and 1.65 g mmol) of 1 4-diabicyclof 2.2.2 ]octane for 1 hour. After cooling, the suspension is stirred with about 150 ml of water and the undimsolved precipitate in filtered off with suction, washed with water and ethanol and drie. at 80 0 C/12m bar. The crude product is recrystallized from ml of glycol monomethyl ether.

Yield: 2.3 g (57% of theory) of 8-chloro-l-cyclopropyl- 7-(2,8-diaza bicyc10E4.3. 03non--yl)- fuoro-1 4-dhydro- 4-oxo-3-quinolinecarboxylic acid, melting point: 224- 2260C (with decomposition).

00 13. The crude btaine is prepared analogously to Example 22 A. and in suspended in 50 al of water and dissolved by addition of 17 ml of 1N hydrochloric acid and heating.

After cooling in an ice-bath, the precipitate which has separated out is filtered off with suction, washed with 6thanol and dried at 100*C in vacuo.

LiA 2fi -48 1483 I Yield: 2.7 g (61% of theory) of 8-chloro-l-cyclopropyl- 7-(218-diazabicyclo(4.3.]nn-8-yl)-6-floo14dhdo 4-oxo-3-c.-uinolinecarboxylic acid hydrochloride, melting point: from 225*C decomposition.

Exanglne 22 cot.

HN

Hj The reaction is carried out analogously to Example 22 with 9, 10-dif luoro-2, 3-dihydro-3-methyl-7-oxo-7H-pyrido- (1,2,3-de](1,4]benzoxazine-6-carboxylic acid and the reaction product obtained is purified by chromatography on silica gel using methylene chloride/methanol/17% strength aqueous amonia solution (308:1) as the mobile phase. 10-(2,8-Diazabicyclo[4.3.0]non-8-yl-9-fluoro-2,3dihydro-3-methyl-7-oxo-7H-pyrido[l,2,3-deJ11,4]benzoxazine-6-carboxylic acid of melting point 291-2920C (with decomposition) is obtained.

LgK2I- 149 149 P 0 6 g (20 mmol) of 1-cyclopropyl-5l,6l7,-totrafluoro-1,4dihydxo-4-oxo-3-quilolinecarboxylic acid are heated under reflux in 30 ml of 1-methyl-2-pytrolidinone and 60 *1 of acetonitrile with 2.2 g (20 nmmol) of 1,4-diazabicyclo- [2.2.2]octane and 2.7 g (21.4 mmol) of 2,8-diazabicyclo- (4.3.03 nonane for 1 hour. The mixture is concentrated to a substantial degree in vacuo, the residue is stirred with 200 ml of water and the undisolved crystals are filtered off with suction, washed with water and dried.

Yield: 6.3 g (77.4% of theory) of 1-cyclopropyl-7-(2,8diazabicycl(4 3.0]non-8-yl]-5,618-trifluoro-14-dihydro- 4-oxo-3-quinolinecarboxylic acid Melting point: 266-269 0 C (with decomposition); after recrystallization from dimethylformamide: melting point: 272-2730C (with dicomposition).

I&Q A 26 10 -150

NH

2 0 Y COOH ml of saturated ethanolic ammonia solution are added ~to 4.1 g (10 mmol) of the product from Example 24 in ml of pyridine, and the mixture is heated at 120°C in an autoclave for 12 hours. The suspension is evaporated, the residue is stirred with water and the pH is brought to 7 with 2N hydrochloric acid. The precipitate which has separated out is filtered off with suction and recrystallized from glycol monomethyl ether.

Yield: 0.7 g (17% of theory) of 5-amino-l-cyclopropyl-7- (2,8-diaabicyclo [4.3.0]non-8yl)-6,8-difluoro-1,4dihydro-4-oxo-3-quinolinecarboxylic acid, melting points 275-277°C (with decomposition).

Mass spectrums m/e 404 384 290, 249, 96 (100%).

*ooJ Le A 26 108 151 A. Analogously to Example 13, 1-cyclopropyl-7-(2,7diazabicyclo[3.3.0]oct-7-yl)-6,8-difluoro-l,4-dihydro-4oxo-3-quinolinecarboxylic acid, melting point: 277-2800 (with decomposition), is obtained with 2,7-diazabicyclo- O~octane.

B. 370 mg of the betaine are dissolved in 13 ml of half-concentrated hydrochloric acid, the solution is concentrated and the residue is treated with 10 ml of ethanol. The undissolved product is filtered off with suction, waLhed with ethanol and dried.

Yield: 290 mg of l-cyclopropyl-7-(2,7-diazabicyclo- 0:.0 3.3,0]oct-7-yl)-68-d ifuoro-1,4-dihydro-4-oxo-3-quino- 1 linecarboxylic acid hydrochloride, melting point: 269- 271 0 C (with decomposition).

L2A i 26 10 152 L4 O ExaMD12l 27 0

COOH

CH

3 -NH- F The reaction is carried out analogously to Example 8 with trans-4-methoxy-3-methylamino-pyrrolidine dihydrochloride. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7- (trans-4-methoxy-3-methylamino-l-pyrolidinyl)-4-oxo-3quinolinecarboxylic acid, melting point: 268-270 0 C (with decomposition) is obtained.

Exampjlg 28

COOC

2

H

xCF 3

COOH

A. 1.4 g (2.9 mmol) of the product from Example 3 A) and 1.98 ml (1.7 g, 12 mmol) of dimethylformamide diethyl acetal are heated at 120*C in 15 ml of absolute diawthylformamide for 2 hour. The mixture is then is concentrated in vacuo. The residue which remains is stirred with acetonitrile. Th. precipitate in filtered 153 4 4- i. 1off with suction, washed with a little acetonitrile and dried.

Yield: 0.8 g (54.4% of theory) of ethyl 7 -(cis-3-tert.butoxycarbnylamino- 4 -methoxy- 1-pyrro1 dinyl) -I-cyclopropyl-6 8 -difluoro-1,4-dihydro-4-oxo- 3-quino inscarboxylate, melting point: 151-152*C.

S. 0.3 g (0.6 numol) of the product from Example 28 A) are stirred in 10 ml of trifluoroacetic acid at 20 0 C for 10 minutes. The trifluoroacetic acid is then removed in vacuo. The residue solidifies on addition of diethyl ether. The solid is isolated, washed with diethyl ether and dried.

Yield: 0.25 g (80.61 of theory) of ethyl 7-(cia-3-amino- 4-methxy--pyrrolidny)--cyclopropyl-6, -difluoro-1..4.

dihydro-4 -oxo-3-quinolinecarboxyl ate trifluoroacetate Melting point: 124-126C.

gxamle 29 *1I 0 Anlogouly to Example 13# -cyc lopropyl i6,8 -diffluoro- 1, 4-dihyro-7- (2-mothylf-4-za-2 8-dizbcyl(.. nn 8-y)-4-oxo-3-quinolinecarboxylicli acid# melting point 134 258-260'C (with decomposition),1 in obtained with 2-mothyl- 4-oxo-218-diazabicyclo(4

S

G~

*5 5 5 SeS S

S.

S

S

S

*5@S

S.

S S

S

S

S

5 Analogously to Example 19, 1-cyclopropyl-6#8-difluoro- 1, 4-dihydro-7- 3-oxa-2 ,7-diazabicyclo[ 3.3. 0 ]octan-7-yl) 4-oxo-3-quinolinecarboxylic acid is obtained with 3-oxa- 2,7-diazabicyclo(3 Examp..-, 0 0i XHC1

CAH

A. 1.1 g (10 mmol) of 1,4-diazabicyclo[2.2.2 ]octane and 1.4 g (11 mmol) of 2.8-diazabicyclo(4.3.Ojnonane are added to 2.53 g (10 mmol) of 1-ethyI-6,7-difluoro-1,4dihydro-4-ozo-3-quinolinecarboxylic &cid in 30 al of is acetonitrile and 15 al of dinothylformamid. and the mixture is heated under reflux f or 1 hour. The nixture i3 L2&LQ A 265 10 155 concentrated, the residue in stirred with water and the precipitate is filtered of f with suction, washed with water and dried.

Yields 3.1 g (86% of theory) of 7-(2.8-diazabicyclo- [4.3.0]non-8-yl)-l-ethyl-6-fluoro-4-oxo-3-quinolinecarboxylic acid, melting point: 259-2610C (with decompos ition) B. 2.9 g (8 mmol) of the betaine from stage A are dissolved in 20 ml of half -concentrated hydrochloric acid under the influence of heat, the solution is filtered hot ~and the hydrochloride is precipitated from the filtrate by addition of ethanol. This hydrochloride is filtered :2 off with suction, washed with ethanol and dried at 120 0

C/

12 mnbar.

is Yield: 1.8 g (57% of theory) of 7-(2,8-diazabicyclo- [4.3.0]non-B-yl)-l-ethyl-6-fluoro-4-oxo-3-quilolinecarboxyiic acid hydrochloride,, melting point, with decompositions 299*C (dark coloration already starting from about 215 0 C) so 9 9.'.N Reaction analogously to Example 31 with 1-cyclopropyl- 15ij 6 7-diflUOro-1 4 -dihydro-4 -oxo-3-quinaol inec~rbacid givesI A. 1-Cyclopropyl-7-(,8-diazabicyclo 4. 30nonr8.yl) 6-fluoro-4-oxo-3-quinolinecarboxylic acid, melting point: 249-257 0 C (with decomposition) B. l-Cyclopropyl-7-(2,8-diazabicyclo(4.3.0]non-8-yl) o-fluoro-4-oxo-3-quinolinecarboxylic acid hydrochloride, melting point with decomposition: 320 0 C (dark coloration already starting from about 288 0

C).

EXAM-Rle 33 0 e0g

COON

1.1 g (3 nunol) of 1-cyclopropyl-7-(28-diazabicycloron-8-yl) -6,8-difluoro-l 4-dihydaro-4-xo-3-quinolinecavboxylic acid are heated under reflux in 10 al of 15 dimethylformamide and i al of formic acid for 4 hour.

The mixture is evaporated, the residue is stirred with 4 ml of water and the precipitate is filtered off with suction, dried (crude yields I g. content: 99.5%) and recrystallzed from dizmethylfornazuide.

Yields 0.8 g (64% of theory) of 1-cyclopropyl-6,8 -difluoro-7-(2-formyl-28-diazabicyclo[4.3.0]no..8 yl)-1,4.

LM A. 2fi 108 157 I I _L_ dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 276-278 0

C.

0

SCOOH

5 1.1 g (3 mmol) of 1-cyclopropyl-7-(2,8-diazabicyclo- [4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are dissolved in a mixture of 8 ml of dioxane and a solution of 120 mg of sodium hydroxide in 1 ml of water, and at the same time 3 ml of IN sodium hydroxide solution and 260 mg of acetyl chloride are added, while cooling with ice. The mixture is subsequently stirred at room temperature for 2 hours and diluted with 30 ml of water and the precipitate which has separated out is filtered off with suction. The crude product is recrystallized from glycol monomethyl ether.

Yield: 0.6 g (46% of theory) of 7-(2-acetyl-2,8-diazabicyclo 4.3.0 ]non-8-yl)-l-cyclopropyl-6,8-difluoro-1,4dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 261-2630C (with decomposition) 158 A. Analogously to Example 13, 8-chloro-1-cyclopropyl- :6O 6-fluoro-l14-dihydro-7-(2-methyl-2,7-diazabicyclo(3.3.0]- S oct-7-yi -oxo-3'-quinol ineearboxyii'e acid, MaItifig points 222-227'C (with decomposition), in obtained with 8-chloro-l-cyclopropyl-6,7-difluoro-1, 4-dihydro-4-oxo-3quinol.Lnecarboxylic acid and 2-methyl-2,7-diazabic-yclo- 3. 0]octane.

B. 2.3 g (5,V mmol) of the betaine from stage A are "to:%dissolved in 15 ml of 1N hydrochloric acid under the s0 influence of heat, the solution in evaporated and the 6 :0 9residue in treated with ethanol. The precipitate is filtere4, off with suction, washed with water and dried.

Yield: 2.2 g (87.7% of theory) of 8-chloro-l-cyclopropyl- 6-fluoxro-,4-dihydro-7-(2-mthyl-2,7-diazabicyclo[3.3.O]oct-7-yl) -4-oxo-3-quinolinecarboxylic acid hydrochloride,, melting points 303-305'C (with decomposition).

5

COOH

cH 3 Analogously to Example 13, l-cyclopropyl-6#8-difluoro- 1,4-dihydxro-7-(3-methyl-2,7-diazabicyclo(3,3.O]oct-7-y1)s: 4-amo-3"q12inolinecarboxylic acid is obtained with 3methyl-2,7-diazabicyclo(3,3.O'octane, and is converted into l-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-methyl- 2, 7-diazabicyclo( 3.3. Qjoct-7-yl )-4-oxo-3-quinolinecarboxylic acid hydrochloride, melting point: 216-2210C (with decomposition), analogously to Example 15 C. with halfconcentrated hydrochloric acid.

3 S.,0

SSH

S t o o 5.553 A. Amxue f14 ml f -ylpopl67e is trfurS0-iyr--x--unlncroyi cd xo5o..#-ixbcyl,222 otn n A.7 A (5.,5r of145(5uol) of 2#3-et ylopropazbyl-67,- M [3.3.0]octane in 15 ml of acetonitrile and 7.5 ml of dimethylformamide 13i heated under reflux for 1 hour.

After cooling, the precipitite is filtered off with suction, washed with water and recrystallized from glycol monomethyl ether.

Yields 1 g (47% of theory) of 1-cyclopropyl-7-(2,3dimethyl-2,7-diazabicyclo[2.2.2]oct-7-yl)-6,8-difluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting points 208-2090C (with decomposition).

B. 0.7 g (1.7 mnol) of the betaine from stage A are dissolved in 6 ml of hot half-concentrated hydrochloric acid and the solution is filtered and concentrated to a s bstantial degree in vacuo. About 15 ml of ethanol are added, the mixture is cooled in an ice-bath and the salt is filtered off with suction, washed with ethanol and dried at 100'C/1 mbar.

Yield: 0.64 g (84% of theory) of l-cyclopropyl-7-(2,3dimethyl-2,7-diazabicyclo[2.2.2]oct-7-yl)-6,8-difluoro- 1 ,4-dihydro-4 -oxo-3-quinolinecarboxylic acid hydrochloride, melting points 233-236 0 C (with decomposition).

L 26 I08 4 COOK H 3 C NxHC 1

CH

3 Analogously to Example 37 A. and 8-chloro-l-cyclopropyl-7-(2,3-dimethyl-2,7-diazabicyclo(2.2.2joct-7-yl)- 6-f luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid .:::hydrochloride, melting points 240-241*C (with decomposition), is obtained with B-chloro-l-cyclopropyl-6,7difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

0

COOK

H

3 CH ~N 2:

F

too.

The reaction is carried out analogouzly to 9xainple 19 '08:90with 1,2-dimethyl-3-oxa-2,7-diazabicyclo(3. 3.0]octan* to 8:010:give 1-cyclopropyl-6,8-difluoto-14-dihydro-7-( 1,2dimethyl-3-oxa-2,7-diazabicyclo(3. a .0]oct-7-yl)-4-oxo-3quinolinecarboxylic acid of melting point 269-2710C (with decomposition).

DeILQ A 26? 10 152 0

-COOH

xHCI

H

1.45 g (13 =oL) of 1,4-4,-iazabicyco(2.2.2]coctane and 1.23 g (9.6 mmol) of 2-oxa-5,8-diazabicyclo[4.3.O]nofane 5 are added to 2.6 g (8.7 mmol) of 8-chloro-l-cyclopropyl- 6,7-difluoro1,4 -dihydr-4-oxo-3-uin,1inecarboxylic acid in a mixture of 25 ml of acetonitrile and 12.5 ml of dizmethyformamide and the mixture is heated under refluz for 1 hour. It is concentrated, the residue is stirred with water and the undissolved precipitate is filtered off with suction and washed with water. This crde 1cyclopropyl-8-chloro-6-fluoro-14-dihydro-7-(2-oxa-5,8too I diazabicyclo(4. 3. 0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid is introduced into 85 ml of 1N hydrochloric acid, 15 and 6 ml of concentrated hydrochloric acid are added. The hydrochloride which has precipitated out is filtered off with suction, washed with ethanol and dried.

0 a Yield: 3.0 g (77.7% of theory) of B-chloro-1-cyclopropyl- 6&Vso 6-f luoro- 1,4-dihyd-7-(2-oxa-I'4iaabicYcloo4.3. 0 Ionto 8-yl -4-oxo-3-quinolinecarboxylic acid hydrochloride, malting points from 290*C decomposition.

163 Analogously to Example 13, 8-chloro-i-cyclopropyl-6f 1-oro-7 -methyl-4 -oxa-2, 8-diazabicyclo 3. 0 )non-8yl)-4-oxo-3-quinoliflecarboxylic acid, melting point: 202- 203 0 C (with decomposition), is obtained with tl-chloroo-1- 0cyclopropyvl-6,7-dif luoro-I I4-dihydro-4-oxo3-aifloline- *GOP* carboxylic acid and 2-methyl-4-oxa-2,8-diaz ,,,,yrlo- 3. 0 ]nonane.

FAB mass spectrums rn/s 422 4 )i 404 (422-H 2 0).

0

COOH

"*C0 2 C 2

H

A. The reaction is carried out analogously to Example 13 with ethyl 2 j7-Gdiazabicy 10oE3. .3.O0 )octane 2-carboxylate to give 1-cyclopropyl-7- (2-.thoxycarbonyl1-2,7-diaizabi- CYCloE3.3.O]oc-7-yl)-6,8-difluoro14dihydro-4-ox(3Go quinolinecarboxylic acid of mlting point 191-1920C.

164 B. 1.8 g (4 mmol) of the product from Example 42A are heated in 30 ml of concentratqd hydrochloric acid under gentle reflux for 15 hours. The solution is concentrated, the residue is stirred with ethanol and the precipitate is filtered off with suction, washed with ethanol and dried at 120°C/12 mbar.

Yield: 1.1 g (67% of theory) of 1-cyclopropyl-7-(2,7diazabicyclo[3.3.0]oct-7-yl)-6,8-difluoro-1,4-dihydro-4oxo-3-quinoiolinecarboxylic acid hydrochloride, melting point: 273-275 0 C (with decomposition). The product is identical to the compound obtained according to Example 26B.

Example 43 A. 7.8 g (20 mmol) of l-cyclopropyl-7-(2,8-diazabicycl[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3quinolinecarboxylic acid are introduced into 175 ml of ethanol, and 2.4 g (25 mmol) of methanesulphonic acid are added at about 70 0 C. The betaine dissolves, and on cool.

ing the salt precipitates out, this being filtered off with sucjlon, washed with ethanol and dried at 120 0 C/12 mbar. It is readily soluble in water.

Yield: 8.6 g (88.6% of theory) of 1-cyclopropyl-7-(2,8diazabicyclo[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-4oxo-3-quinolinecarboxylic acid mesylate, melting points 262-265"C (with decomposition).

The following compounds ar obtained analogouslys Le A 26 108 1.55 B. 1-Cyclopropyl-7-(2, 8-diazabicyclo4.3.0]non-S-yl)- 6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid tosylate, melting point: 248-250 0 C (with decomposition).

C. 1-Cyclopropyl-7-(2,8-diazabicyclo4.3.0]non-8-yl 6, 8-difluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid lactate, melting pointt 205C-215*C, after sintering beforehand.

Examrnle 44 3.9 g (10 mmnol) of l-cyclopropyl-7-(2,8-diazabicyclo- [4.3O9non-8-yl)-6,-difluoro-l,4-dihydro-4-.oxo--quinolinecarboxylic acid are suspended in 50 ml of water, and ml of 1N sodium hydroxide solution are added at room temperature, whereupon the product largely dissolves. A slight turbidity is removed by filtration through a membrane filter, the filtrate is concentrated under a high vacuum and the residue is stirred with ether, filtered off with suction and dried.

Yieldt 3.4 g (82.7% of theory) of sodium 1-cyclopropyl- 7-(2,8-diazabicyclo[4.3.O]non-8-yl)-6,8-difiuoro-1,4-dihydro- 4 -oxo- 3 -qu inol inec arboxyl ate; the salt decomposes slowly above 210C without molting.

6*t e* Le A 26 106 166 I L I

I

F

A mixture of 3.9 g (10 miol) of l-cyclopropyl-7-(2,8diazabicyclo[4.3.0]non-8-yl)-6,8-difluoro-l,4-dihydro-4oxo-3-quinolinecarboxylic acid in 100 ml of dimethylformamide is heated at BO-100 0 C with 4.2 g of triethylamine and 2.8 g of 2-bromoethanol for 20 hours. The solution is then concentrated in vacuo and the residue obtained is purified by chromatography on 200 g of silica gel (mobile phase: CHa2Cl2/CH 3 HO/17% strength NH 3 30:8:1).

The eluate is concentrated and the residue is stirred with ethanol, filtered off with suction and dried.

Yield: 1.8 g (41.6% of theory) of 1-cyclopropyl-6,8difluoro-14-dihydro-7-(2-(2-hydroxyethyl)-2,8-diazabicyclo[4.3.0]non-8-ylJ-4-oxo-3-quinolinecarboxylic acid, melting pointt 200-206*C (with decomposition).

Mass spectrum: Wle 433 402 -CHaOH), 140, 110 96 1S7 L_ I_ 0

COOH

CH

3

S

1 LJ F The reaction is carried out analogously to Example 13 with trans-3-ethylamino-4 -methylthio-pyrrol idine to give *04s 5 l-cyclopropyl-7-(trans-3-ethylamino-4-methylthio)-6,8 difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 215-216 0 C (with decomposition).

.4..7 0

*COOK

r The reaction is carried out analogously to Example 13 with 2-phenyl-2,7-diazabicyclo[ 3. 3 ]octane to give 1cyclopropyl-6,8-difluoro- 4-dihydro-4-oxo-7- (2-phenyl- 2,7-diazabicyclo([3.340]oct-7-yl)-3-quinolinecarboxylic acid, melting point: 259-260*C (with decomposition).

Le A 2-108 1 C

("H

3

F

Analogously to Example 13, 5,6,8-trifluoro-1-(2,4-difluorophonyl )-l14-dihydro-7- (2-methyl-2, 8-diazabicyclo- 5 [4.3.O]non-8-yl)-4-oxo-3-quinolinecarboxylic acid is obtained with 5 j6 #7 ,8-tetraf luoro-1- (214-dif luorophenyl) 1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid.

0S40 N N

I

too

C

*:to H

F

t An~logously to Example 24, 7-(2,8-diazabicyclo[4 .3.O]non- *Veo:8-yi) 8-trifluoro-1-( 2 4-difluorophonyl)-l, 4-dihydro- 4-oxo-3-quinolinecarboxylic acid is obtained with 5,6,7,8-tetrafluoro-l-(2,4-difluorophenyl)-1,4-dihydxo- 4-oxo-3-quinolinecarboxylic acid.

I& A 6 108- 169 Analogously to Example 25, 5 -amino- 7 8-dia zabicyc lc- [4 O]non-8-yl)-6,B-difluoro-l-(24-difluorophenyl)-1,4dihydro-4-oxo-3-quinolinecarboxylic acid is obtained with 7-(218-diazabicyclo(4.3.0]non-8-yl)-5,6,8-trifluoro-l- *000 .(2,4-difluorophenyl)-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

N ICOOH Analogously to Example 15 A# 5-chloro-1..cyclopropyl-7- 8-diazabicyclo 403.0]non-8-yl luoro-l, 4-dihydro- 4-oxo-3-quinolinecarboxylic acid, melting point: 2700C (decmposition), is obtained with 5,7-dichaloro-1..cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (ref 1wx for 5 hours).

Le iA i 108 170

I

HOO

Analogously to Example 8, 5-chloro-l-cyclopropyl-6fluoro-l, 4-dihydro-7- (2-oxa-5, 8-diazabicyclo( 4.3. 0]non- 8-yl)-4-oxo-3-quinolinecarboxylic acid is obtained with 5,7-dichloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-3see a quinolinecarboxylic acid (reflux for 5 hours).

0 see.

C1 0 F

COOX

too* Qa** a* 1. Anlgul toEape1 ,I-hlr--28daai cycl(4..0]on-8yl)6-fuor--24d&Ioohnl 1*-iyr--x--unlncroyi acid isotie wih 57dcl.o6fur..(#-ilorpoy)14 diydo--xo3-unoincrbxyicaid(rfuxfoH is hor) Lg A 26 108 171

M

COOH

N

Analogously to Example 8f 5-chloro-6-fluoro-l-(2,4difluorophenyl -dihydro-7- (2-oxa-5, 8-diazabicyclo- (4.3.0]non-B-yl)-4-oxo-3-quinolinecarboxylic acid is :::obtained with 5,7-dichloro-6-fluoro-1-(2,4-difluorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (reflux for 5 hours).

0I*0

CH

3

S

The. ri o iscarie utaalgusy oExmle1 quThe rnctaon is caraied tot gina-lool to Exampl1 7-(trans-3-ethylamino-4-mthylthio-1-pyrrolidinyl).6.

f luoro-I 4-dihydro-4-oxo-3-quinolineci~xboxylic acid, melting pointi 217-216*C (with decomposition),, 26LQ 1982 172

C

Exa:Mple 56 0 C00FH

I

qN

H

2 N N F x HC1

CH

3

S

7- (trans-3-kxino-4-rethylthio-l-pyrrolidinyl) -1-cyclopropyJ.-6, 8-dif luoro-l 4-dihydro,-4-oxo-3-q-uinolinecarboxylic, melting point: 208-211'C (with decomposition) and 7-(trans- 3-amino-4 -methylthio-1-pyrrolidinyl) -1-cyclopropyl-61 8-difluoro-l,4-dihydro-4-oxo-3-q-uinolinecarboxycaidhro li ci ydo chloride, rnelt$.ng point: 255-257'C (with decor-sition), are obtained with trans- 3-anino- 4 -methylthio-pyrtolidine analogously to Examples 13 and Example 57 0 F COOH Cl- 3 I-Cyclopropyl-6, 8-difluoro-1, 4-dihyOz&o-7- (4-methyl-2, 8diazabicyclo(4.3.Q1inon-8-yl) 4 -oxo-3-quinolinecarboxylic acid, melting point: 213-215*C (with decomposition) (reCrystallised from glycol monomethyl ether), and 1-cyclopropyl-6, 8-difluoro-1, 4-dihydro-7- (4-methyl-21 8-diazabicyclo 14,3 iQ 1non- 8-yl) 4-oxo- 3-quinolinecarboxyl ic acid hydrochloride, melting point: 204-212*C (with decompe- Le A 26 108 13- 173 tion) axe obtained with 4-methy1-2,8-diazabicyclo,/4.3.O? nonane analogously to Examples 13 and The product consists of a mixture of 2 stereoisoners.

C.

C

Le A 26 108 17 174

Claims (2)

1. 2-oxa-5 ,8-diazabicycic- .3 .0]rionanle d ihydroctiloride, tran s-2-oxa-5, 8-di azabicyclo[(4.3. 0] non ane,
2. 5-methyl-2-oxa-5 ,8-diazabicyclo[4. 3, 0]nonane dihydrochioride, 2, 8-diazabicyclo[4 .3 .0)nonane, 4-methvl-2, 8-diazabicyclo(4. 2 -metlhyl-2,8-diazabicyclo[4 .3 .0]nona-ne, 2-methiyl-2 ,7-diaz~abicyclo[3.3 .0]octane, 3-oxa-2 ,7-diazabicyclo[3.3.O]octane, 2 -methyl-3-oxa-2 ,7-diatzabicyclo(3 Oloctane, 2 ,5-dimetliyl-3-oxa-2 ,7-diazabicyclo[3 .3 .0]octine, 2, 8-di methyl-3-oxa-2 ,7-diaza.,bicyclo[3 Oloctane, 2-methyl-4-oxa-2, 8-diazabicyclo[4 Ojnonanwe, 3-methvl-2,7-diazab"cyclo[3 2, 3-diniethiyl-2, 7-diazabicyclo[3 Ojoctane, 20 etnyl 2 ,7-d iazabicycl[3 O]octane-2-carboxyl ate, 2-pheny1-2 ,7-diazabicyclo[3 ,3.Ojjoctanc, 4-oxa-2, 8-diazibicyclo[4.3 .,lnonane.. DATED this 27th day of February, 1996. LIAYTR AKTIENGESELLJSCHAFT' o By its Patent Attorneys DAVIES COLLISON CAVE AL A The invention relates to new intermediate compounds for use in the synthesis of 7-(1-pyrrolidinyl)-3-quinolone- and -napSthyridone carboxylic acid derivatives. S S 54 0 000 0 S 4* 'SOS 005* 5* S