U.S. patent application number 09/829776 was filed with the patent office on 2001-11-01 for use of 7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-quinolonecarbo- xylic acid and -naphthyridonecarboxylic acid derivatives for the therapy of helicobacter pylori infections and associated gastroduodenal disorders.
Invention is credited to Baasner, Bernd, Bartel, Stephan, Endermann, Rainer, Himmler, Thomas, Jaetsch, Thomas, Labischinski, Harald, Matzke, Michael, Petersen, Uwe, Schaller, Klaus, Schenke, Thomas, Werling, Hans-Otto.
Application Number | 20010036941 09/829776 |
Document ID | / |
Family ID | 7814821 |
Filed Date | 2001-11-01 |
United States Patent
Application |
20010036941 |
Kind Code |
A1 |
Petersen, Uwe ; et
al. |
November 1, 2001 |
Use of
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-quinolonecarbo-
xylic acid and -naphthyridonecarboxylic acid derivatives for the
therapy of Helicobacter pylori infections and associated
gastroduodenal disorders
Abstract
The invention relates to the use of quinolone- and
naphthyridonecarboxylic acid derivatives which are substituted in
position 7 by a 1-aninomethyl-2-oxa-7-azabicyclo[3.3.0]oct-7-yl
radical, and of their salts for the therapy of Helicobacter pylori
infections and associated gastroduodenal disorders.
Inventors: |
Petersen, Uwe; (Leverkusen,
DE) ; Matzke, Michael; (Wuppertal, DE) ;
Jaetsch, Thomas; (Koln, DE) ; Schenke, Thomas;
(Bergisch Gladbach, DE) ; Himmler, Thomas;
(Odenthal, DE) ; Bartel, Stephan; (Kurten, DE)
; Baasner, Bernd; (Bergisch Gladbach, DE) ;
Werling, Hans-Otto; (Wuppertal, DE) ; Schaller,
Klaus; (Wuppertal, DE) ; Labischinski, Harald;
(Wuppertal, DE) ; Endermann, Rainer; (Wuppertal,
DE) |
Correspondence
Address: |
KURT BRISCOE
NORRIS, MCLAUGHLIN & MARCUS, P.A.
220 EAST 42ND STREET, 30TH FLOOR
NEW YORK
NY
10017
US
|
Family ID: |
7814821 |
Appl. No.: |
09/829776 |
Filed: |
April 10, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09829776 |
Apr 10, 2001 |
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09319848 |
Aug 6, 1999 |
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09319848 |
Aug 6, 1999 |
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PCT/EP97/06751 |
Dec 3, 1997 |
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Current U.S.
Class: |
514/210.16 ;
514/259.1; 514/291; 514/312; 514/82 |
Current CPC
Class: |
A61K 31/5395 20130101;
C07F 9/6561 20130101; A61P 31/04 20180101; C07D 491/04 20130101;
A61K 31/4375 20130101; A61K 31/5383 20130101; A61K 31/4709
20130101; A61K 31/4745 20130101; A61P 1/04 20180101 |
Class at
Publication: |
514/210.16 ;
514/258; 514/312; 514/291 |
International
Class: |
A61K 031/519; A61K
031/47 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 16, 1996 |
DE |
196 52 219.6 |
Claims
1. Use of compounds of the formula (I) T--Q (I), in which Q
represents a radical of the formulae 77in which R.sup.1 represents
alkyl having 1 to 4 carbon atoms which is optionally mono- to
trisubstituted by halogen or hydroxyl, alkenyl having 2 to 4 carbon
atoms, cycloalkyl having 3 to 6 carbon atoms which is optionally
substituted by 1 or 2 fluorine atoms, bicyclo[1.1.1 ]pent-1-yl,
1,1-dimethylpropargyl, 3-oxetanyl, methoxy, amino, methylamino,
dimethylamino, phenyl which is optionally mono- or disubstituted by
halogen, amino or hydroxyl, isoxazolyl, thiadiazolyl, R.sup.2
represents hydroxyl, alkoxy having 1 to 4 carbon atoms which is
optionally substituted by hydroxyl, methoxy, amino, dimethylamino
or ethoxycarbonyl, benzyloxy, allyloxy, propargyloxy or
(5-methyl-2-oxo-1,3-dioxol-4-yl)-methyloxy, acetoxymethyloxy,
pivaloyloxymethyloxy, 5-indanyloxy, phthalidinyloxy,
3-acetoxy-2-oxo-butyloxy, nitromethyl or dialkoxycarbonylmethyl
having 1 to 2 carbon atoms in each alkyl moiety, R.sup.3 represents
hydrogen, amino, hydroxyl, methyl or halogen, R.sup.9 represents
hydrogen or optionally methoxy-, hydroxyl- or halogen-substituted
alkyl having 1 to 3 carbon atoms, R.sup.11 represents hydrogen,
CH.sub.3 or CH.sub.2F, A represents N or C--R.sup.7 in which
R.sup.7 represents hydrogen, halogen, CF.sub.3, OCH.sub.3,
OCHF.sub.2, CH.sub.3, CN, CH.dbd.CH.sub.2 or C--CH or else together
with R.sup.1 may form a bridge of the structure
--*O--CH.sub.2--CH--CH.sub.3, --*S--CH.sub.2--CH.sub.2--,
--*S--CH.sub.2--CH--CH.sub.3, --*CH.sub.2--CH.sub.2--CH--CH.sub.3
or --*O--CH.sub.2--N--R.sup.8 where the atom marked with is
attached to the carbon atom of A and in which R.sup.8 represents
hydrogen, methyl or formyl, B represents N, C--H, C--F, C--Cl,
C--NO.sub.2, C--NH.sub.2, D represents N or C--R.sup.10 in which
R.sup.10 represents hydrogen, halogen, CF.sub.3, OCH.sub.3,
OCHF.sub.2 or CH.sub.3 or else together with R.sup.9 may form a
bridge of the structure --O--CH.sub.2--, --*NH--CH.sub.2--,
--N(CH.sub.3)--CH.sub.2--, --*N(C.sub.2H.sub.5)--CH.su- b.2--,
--N(c--C.sub.3H.sub.5)--CH.sub.2-- or --*S--CH.sub.2-- where the
atom marked with * is attached to the carbon atom of D, Y
represents hydrogen or together with R.sup.2 may form a bridge of
the structure --*S--NH-- where the atom marked with * represents Y,
and T represents a radical of the formula 78in which R.sup.4
represents H, CH.sub.3, C.sub.2H.sub.5, optionally
amino-substituted acyl having 1 to 5 carbon atoms, alkoxycarbonyl,
aminocarbonyl, alkylthio-thiocarbonyl and dialkoxyphosphoryl having
1 to 4 carbon atoms in the alkyl moiety, R.sup.5 represents H,
CH.sub.3, C.sub.2H.sub.5 and R.sup.6 represents H, CH.sub.3, and
their pharmaceutically useful hydrates and acid addition salts and
the alkali metal, alkaline earth metal, silver and guanidinium
salts of the parent carboxylic acids for the therapy of
Helicobacter pylori infections and associated gastroduodenal
disorders.
2. Use of compounds of the formula (I) according to claim 1 in
which Q represents a radical of the formula 79in which R.sup.1
represents alkyl having 1 to 4 carbon atoms which is optionally
mono- to trisubstituted by fluorine, represents vinyl, optionally
fluorine-substituted cyclopropyl, bicyclo[1.1.1]pent-1-yl,
1,1-dimethylpropargyl, 3-oxetanyl, methylamino, phenyl which is
optionally mono- or disubstituted by fluorine, amino or hydroxyl,
thiadiazolyl, R.sup.2 represents hydroxyl, optionally
ethoxycarbonyl-substituted alkoxy having 1 to 4 carbon atoms,
benzyloxy, allyloxy, propargyloxy, R.sup.3 represents hydrogen,
amino, hydroxyl, methyl or fluorine, A represents N or C--R.sup.7
in which R.sup.7 represents hydrogen, halogen, CF.sub.3, OCH.sub.3,
OCHF.sub.2, CH.sub.3, CN, CH.dbd.CH.sub.2 or C.dbd.CH or else
together with R.sup.1 may form a bridge of the structure
--*O--CH.sub.2--CH--CH.sub.3 or --*O--CH.sub.2--N--R.sup.8 where
the atom marked with is attached to the carbon atom of A and in
which R.sup.8 is hydrogen or methyl, B represents N, C--H, C--F,
C--Cl, C--NH.sub.2, Y represents hydrogen or together with R.sup.2
may form a bridge of the structure --*S--NH-- where the atom marked
with represents Y, and T represents a radical of the formula 80in
which R.sup.4 represents H, CH.sub.3, C.sub.2H.sub.5, optionally
amino-substituted acyl having 1 to 5 carbon atoms, alkoxycarbonyl,
aminocarbonyl, alkylthio-thiocarbonyl and dialkoxyphosphoryl having
1 to 4 carbon atoms in the alkyl moiety, R.sup.5 represents H,
CH.sub.3, C.sub.2H.sub.5 and R.sup.6 represents H, and their
pharmaceutically useful hydrates and acid addition salts and the
alkali metal, alkaline earth metal, silver and guanidinium salts of
the parent carboxylic acids for the therapy of Helicobacter pylori
infections and associated gastroduodenal disorders.
3. Use of compounds of the formula (I) according to claim 1 in
which Q represents a radical of the formula 81in which R.sup.1
represents alkyl having 1 to 4 carbon atoms which is optionally
mono- or disubstituted by fluorine, optionally fluorine-substituted
cyclopropyl, phenyl which is optionally mono- or disubstituted by
fluorine, R.sup.2 represents hydroxyl, optionally
ethoxycarbonyl-substituted alkoxy having 1 to 4 carbon atoms,
benzyloxy, allyloxy, propargyloxy, R.sup.3 represents hydrogen,
amino, hydroxyl, methyl or fluorine, A represents N or C--R.sup.7
in which R.sup.7 represents hydrogen, chlorine, fluorine,
OCH.sub.3, OCHF.sub.2, CH.sub.3 or CN or else together with R.sup.1
may form a bridge of the structure --*O--CH.sub.2--CH--CH.sub.3, or
--*O--CH.sub.2--N--CH.sub.3 where the atom marked with * is
attached to the carbon atom of A, B represents N, C--H, C--F, Y
represents hydrogen or together with R.sup.2 may form a bridge of
the structure --*S--NH-- where the atom marked with represents Y,
and T represents a radical of the formula 82in which R.sup.4
represents H, CH.sub.3, C.sub.2H.sub.5, optionally
amino-substituted acyl having 1 to 4 carbon atoms or alkoxycarbonyl
having 1 to 4 carbon atoms in the alkyl moiety, R.sup.5 represents
H and R.sup.6 represents H, and their pharmaceutically useful
hydrates and acid addition salts and the alkali metal, alkaline
earth metal, silver and guanidinium salts of the parent carboxylic
acids for the therapy of Helicobacter pylori infections and
associated gastroduodenal disorders.
4. Use of diastereomerically pure and enantiomerically pure
compounds according to claims 1 to 3 for the therapy of
Helicobacter pylori infections and associated gastroduodenal
disorders.
5. Use of
(+)-7-[(1S,5R)-1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl]-
-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-carboxylic
acid for the therapy of Helicobacter pylori infections and
associated gastroduodenal disorders.
6. Diastereomerically pure and enantiomerically pure compounds from
the group consisting of
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)--
1-cyclopropyl-8-difluoromethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarb-
oxylic acid,
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-8-cyano--
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid.
7.
(+)-7-[(1S,5R)-1-Aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl]-8-cyan-
o-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylic
acid.
8. Compounds from the group consisting of
(1R,5R)-1-tert-butoxycarbonylami-
nomethyl-2-oxa-7-azabicyclo[3.3.0]octane,
(1S,5R)-1-aminomethyl-2-oxa-7-az- abicyclo[3.3.0]octane,
(1S,5R)-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]octa- ne
hydrochloride.
9. Use of
(+)-7-[(1S,5R)-1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl]-
-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-carboxylic
acid for preparing medicaments.
10. Medicaments comprising
(+)-7-[(1S,5R)-1-aminomethyl-2-oxa-7-aza-bicycl-
o[3.3.0]oct-7-yl]-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoli-
necarboxylic acid.
Description
[0001] The invention relates to the use of quinolone- and
naphthyridonecarboxylic acid derivatives which are substituted in
position 7 by a 1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]oct-7-yl
radical, and of their salts for the therapy of Helicobacter pylori
infections and associated gastroduodenal disorders.
[0002] In the years following the rediscovery of Helicobacter pylon
(H. pylori; old name Campylo-bacter pylori) by Warren and Marshall
in 1983, the pathophysiological ideas on the genesis of
gastro-duodenal disorders in man were developed further in a
fundamental way.
[0003] H. pylori is considered to be the cause of type B gastritis
and seems to play a causative part in the perpetuation of peptic
ulcers. Epidemiological and pathological investigations likewise
indicate a connection between the long-term colonization of the
mucosa of the stomach by the bacterium and the formation of certain
forms of stomach carcinoma. Because of this, H. pylori was, in
1994, classed as a carcinogen of the first order (most dangerous
cancer-causing category). A rare form of stomach cancer, MALT
lymphoma (mucosa-associated lymphoid tissue) appears likewise
frequently to be caused by the germ. Indeed, in initial
casuistries, after H. pylori eradication, not only the reactive
infiltrates disappeared, but even some of the MALT lymphomas of low
malignancy. A connection with Menetrier's syndrome is also being
discussed. The role of H. pylori in functional gastropathy
(nonulcerous dyspepsia) is still unclear.
[0004] Various epidemiological studies reach the conclusion that
approximately half of the population of the world is infected with
the bacterium. The likelihood of colonization of the stomach by
Helicobacter increases as a function of age. The optimum adaptation
of Helicobacter to the living conditions in the unusual,
low-competition habitat of the stomach seems to be the precondition
for successful establishment of the chronic infection and for the
wide distribution of this pathogenic species.
[0005] The pathogens are, with their flagella, not only highly
mobile in liquid media but also in the viscous mucous of the mucosa
of the stomach, they adhere to the epithelial cells of the stomach
and they multiply best at an oxygen content of 5%, as is prevalent
in the mucous of the stomach wall. Moreover, the bacteria produce
large amounts of the enzyme urease which cleaves urea into ammonia
and carbon dioxide. The "cloud of ammonia" which is formed possibly
assists the bacteria in neutralizing the acidic medium in the
microenvironment, resulting in protection against the aggressive
stomach acid.
[0006] Peptic Ulcers
[0007] The introduction of the histamine H.sub.2-receptor
antagonists in the 1970s was a milestone in the therapy of peptic
ulcers. World-wide, the frequency of surgical interventions for the
treatment of the ulcer decreased dramatically. This principle of
the acid blockade was improved even more by the development of the
more strongly effective proton pump inhibitors.
[0008] However, the antacid therapy has a causal effect--i.e. by
disinfectant treatment--only on the symptoms of the ulcer, not on
the natural cause of the disease which is characterized by the
occurrence of relapses. This is because virtually all ulcus duodeni
patients and a predominant majority of the patients suffering from
ulcus ventriculi have an H. pylori infection of the stomach and
therefore suffer from infectious diseases. Only ulcerations caused
by nonsteroidal antiphlogistics are not associated with an H.
pylori infection.
[0009] Thus, according to the recommendations of a consensus
conference which was organized by the American National Institute
of Health (NIH) in 1994, all patients suffering from peptic ulcers
should, in the case of a positive germ test, undergo eradication
therapy directed against H. pylori (NIH Consensus Statement 1:
1-23; 1994). The arguments in favour of this came from controlled
therapy studies which showed that, after successful germ
eradication, the ulcer relapse rates decrease dramatically (0% -29%
versus 61% -95%).
[0010] H. pylori Therapy
[0011] In practice, the current eradication of H. pylori is not
particularly simple. There is no simple and nevertheless reliably
effective therapy. The germ is located under the layer of mucous,
where it is well protected and difficult to attack.
[0012] In vitro, H. pylori shows sensitivity towards numerous
antibiotics. However, these antibiotics are, as a monotherapy, not
effective in vivo. They include, inter alia, penicillin,
amoxicillin, tetracycline, erythromycin, ciprofloxacin,
metronidazole and clarithromycin. Likewise, bismuth salts and to a
lesser extent even proton pump inhibitors (omeprazole,
lansoprazole) have antibacterial activity in vitro, but not in
vivo.
[0013] Among all the therapy modalities used hitherto for
eradicating H. pylori, to date only the triple therapies below are
sufficiently effective:
[0014] 1. classic bismuth triple therapy (bismuth salt plus two
antibiotics) and
[0015] 2. modified triple therapy (antacid plus two
antibiotics).
[0016] However, these regimes are complicated eradication methods
with poor compliance which may in up to 35% of all cases be
associated with side effects (stomach aches, sickness, diarrhoea, a
dry mouth, impairment of taste and allergic skin reactions, etc.).
This makes a broader use more difficult. Another great disadvantage
is the large number of medicaments which have to be taken every day
(12-16 tablets/day). This is particularly pronounced in the
quadruple therapy where an acid secretion inhibitor is administered
simultaneously with the classic triple therapy.
[0017] However, the dual therapy (combination of amoxicillin with
omeprazole), which is better tolerated and is propagated in
Germany, has only a low efficacy and even seems to fail
substantially in the case of patients who have been pretreated with
omeprazole and in the case of smokers.
[0018] The antibiotic components which are generally administered
in triple therapies are amoxicillin, nitroimidazole compounds
(metronidazole, tinidazole), tetracycline and, more recently,
macrolides (clarithromycin) [in 3-4 partial doses].
[0019] Throughout the world, eradication rates of 70-90% are
achieved. However, this eradication success can be influenced by a
variety of factors:
[0020] 1. Primarily, mention has to be made of the resistance of
the germ (developing countries: up to 60%, Germany: up to 10%)
towards metronidazole, the antibiotic which is most frequently used
in the triple therapy. In the treatment with Clarithromycin,
reference is likewise made to the disadvantage of a resistance
development of up to 10%.
[0021] 2. Another factor which has to be mentioned is the
abovementioned compliance of the patients.
[0022] Animal Model
[0023] An H. felis mouse model has been described as a suitable
animal model [A. Lee et al., Gastroentrology 99: 1315-1323 (1990)]
and we modified this model in such a way that it is highly suitable
for the screening and the comparative assessment of the
abovementioned compounds.
[0024] In spite of considerable morphological differences, the
corkscrew-like, urease-forming bacterium H. felis is very closely
related to H. pylori. H. felis is a natural inhabitant of the
mucosa of the stomach of dogs and cats. After oral inoculation, the
pathogens also colonize the stomach of mice, in a similar manner to
that in which H. pylori colonizes the stomach of humans. The
established chronic long-term infection leads to active gastritis
in germ-free mice and induces a corresponding immune response.
[0025] The therapeutic efficacy of test samples determined in the
H. felis mouse model is considered to be very predictive for the
corresponding clinical activity.
[0026] In spite of very good in vitro activity of antibiotics (for
example Amoxicillin or erythromycin) against H. pylori, these do
not show any significant clinical therapeutic effect after having
been administered in monotherapy. This fact is also represented by
the H. felis mouse model. Correspondingly, the clinically accepted
eradicative effect of the classic triple therapy could also be
confirmed in the H. felis mouse model.
[0027] Antibacterially effective
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.- 0]oct-7-yl)-quinolone-
and -naphthyridonecarboxylic acid derivatives have already been
disclosed in European Patent Application 589 318 (Bayer). The
surprising activity of such compounds for controlling Helicobacter
spp. has hitherto not been disclosed. Furthermore, European Patent
Application 671 391 (Bayer) discloses that
7-(1-aminomethyl-2-oxa-7-aza-b-
icyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-5-viny-
l-3-quinolonecarboxylic acid is likewise effective against H.
pylori. However, this activity is relatively low. The 5-ethinyl
derivative, which is also described in this application, has been
found to be unstable and therefore unsuitable for therapeutic use.
Japanese Patent Application JP 8048629 (Dainippon) discloses that
compounds such as
8-chloro-1-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-
-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (BAY Y 3118) have
antibacterial activity against H. pylori. It is also known that a
number of highly active quinolones, such as, for example,
ciprofloxacin, lomefloxacin or ofloxacin (Journal of Antimicrobial
Chemotherapy 22, 631-636 [1988], Antimicrobial Agents and
Chemotherapy, 33, 108-109 [1989]), exhibit in vitro activity
against Helicobacter spp. in the animal model (H. felis, mouse),
however, it was found that these clinically used, antibacterially
active quinolones are not capable of eradicating the germ. It is
also not possible to achieve eradication of H. felis in the mouse
model by monotherapeutic treatment with highly active quinolones
which have hitherto not been introduced into the market, such as,
for example, with the abovementioned BAY Y 3118. The use of
trovafloxacin or its derivatives in combination with other
antibiotics, such as amoxicillin or tetracyclines, or proton pump
inhibitors, such as Omeprazole, for the therapy of H. pylori is
described in the Patent Applications EP 676 199 and GB 2 289 674
(Pfizer). It was an object of the present invention to provide
well-tolerated active compounds which are capable of eradicating
this highly specialized bacterium by simple monotherapy.
[0028] It has now been found that the compounds of the formula
(1)
T--Q (I),
[0029] in which
[0030] Q represents a radical of the formulae 1
[0031] in which
[0032] R.sup.1 represents alkyl having 1 to 4 carbon atoms which is
optionally mono- to trisubstituted by halogen or hydroxyl, alkenyl
having 2 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms
which is optionally substituted by 1 or 2 fluorine atoms,
bicyclo[1.1.1]pent-1-yl, 1,1-dimethylpropargyl, 3-oxetanyl,
methoxy, amino, methylamino, dimethylamino, phenyl which is
optionally mono- or disubstituted by halogen, amino or hydroxyl,
isoxazolyl, thiadiazolyl,
[0033] R.sup.2 represents hydroxyl, alkoxy having 1 to 4 carbon
atoms which is optionally substituted by hydroxyl, methoxy, amino,
dimethylamino or ethoxycarbonyl, benzyloxy, allyloxy, propargyloxy
or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyloxy, acetoxymethyloxy,
pivaloyloxymethyloxy, 5-indanyloxy, phthalidinyloxy,
3-acetoxy-2-oxo-butyloxy, nitromethyl or dialkoxycarbonylmethyl
having 1 to 2 carbon atoms in each alkyl moiety,
[0034] R.sup.3 represents hydrogen, amino, hydroxyl, methyl or
halogen,
[0035] R.sup.9 represents hydrogen or optionally methoxy-,
hydroxyl- or halogen-substituted alkyl having 1 to 3 carbon
atoms,
[0036] R.sup.11 represents hydrogen, CH.sub.3 or CH.sub.2F,
[0037] A represents N or C-R.sup.7 in which
[0038] R.sup.7 represents hydrogen, halogen, CF.sub.3, OCH.sub.3,
OCHF.sub.2, CH.sub.3, CN, CH.dbd.CH.sub.2 or C.ident.CH or else
together with R.sup.1 may form a bridge of the structure
--*O--CH.sub.2--CH--CH.su- b.3, --*S--CH.sub.2--CH.sub.2--,
--*S--CH.sub.2--CH--CH.sub.3, --*CH.sub.2--CH.sub.2--CH--CH.sub.3
or --*O-CH.sub.2--N--R.sup.8 where the atom marked with * is
attached to the carbon atom of A and in which
[0039] R.sup.8 represents hydrogen, methyl or formyl, B represents
N, C--H, C--F, C--Cl, C--NO.sub.2, C--NH.sub.2,
[0040] D represents N or C--R.sup.10 in which
[0041] R.sup.10 represents hydrogen, halogen, CF.sub.3, OCH.sub.3,
OCHF.sub.2 or CH.sub.3 or else together with R.sup.9 may form a
bridge of the structure --*O--CH.sub.2--, --*NH--CH.sub.2--,
--*N(CH.sub.3)--CH.sub.2--, --*N(C.sub.2H.sub.5)--CH.sub.2,
--*N(c--C.sub.3H.sub.5)--CH.sub.2-- or --*S--CH.sub.2-- where the
atom marked with is attached to the carbon atom of D,
[0042] Y represents hydrogen or together with R.sup.2 may form a
bridge of the structure --*S--NH-- where the atom marked with
represents Y, and
[0043] T represents a radical of the formula 2
[0044] in which
[0045] R.sup.4 represents H, CH.sub.3, C.sub.2H.sub.5, optionally
amino-substituted acyl having 1 to 5 carbon atoms, alkoxycarbonyl,
amninocarbonyl, alkylthiothiocarbonyl and dialkoxyphosphoryl having
1 to 4 carbon atoms in the alkyl moiety,
[0046] R.sup.5 represents H, CH.sub.3, C.sub.2H.sub.5 and
[0047] R.sup.6 represents H, CH.sub.3,
[0048] and their pharmaceutically useful hydrates and acid addition
salts and the alkali metal, alkaline earth metal, silver and
guanidinium salts of the parent carboxylic acids have high
antibacterial activity against Helicobacter spp. and can be
employed for eradicating this pathogen.
[0049] Preference is given to the compounds of the formula (I)
[0050] in which
[0051] Q represents a radical of the formula 3
[0052] in which
[0053] R.sup.1 represents alkyl having 1 to 4 carbon atoms which is
optionally mono- to trisubstituted by fluorine, represents vinyl,
optionally fluorine-substituted cyclopropyl, bicyclo[1.1.1
]pent-1-yl, 1,1-dimethylpropargyl, 3-oxetanyl, methylamino, phenyl
which is optionally mono- or disubstituted by fluorine, amino or
hydroxyl, thiadiazolyl,
[0054] R.sup.2 represents hydroxyl, optionally
ethoxycarbonyl-substituted alkoxy having 1 to 4 carbon atoms,
benzyloxy, allyloxy, propargyloxy,
[0055] R.sup.3 represents hydrogen, amino, hydroxyl, methyl or
fluorine, p1 A represents N or C--R.sup.7 in which
[0056] R.sup.7 represents hydrogen, halogen, CF.sub.3, OCH.sub.3,
OCHF.sub.2, CH.sub.3, CN, CH.dbd.CH.sub.2 or C.ident.CH or else
together with R.sup.1 may form a bridge of the structure
--*O--CH.sub.2--CH--CH.su- b.3 or --*O--CH.sub.2--N--R.sup.8 where
the atom marked with * is attached to the carbon atom of A and in
which
[0057] R.sup.8 is hydrogen or methyl,
[0058] B represents N, C--H, C--F, C--Cl, C--NH.sub.2,
[0059] Y represents hydrogen or together with R.sup.2 may form a
bridge of the structure --*S--NH-- where the atom marked with *
represents Y, and
[0060] T represents a radical of the formula 4
[0061] in which
[0062] R.sup.4 represents H, CH.sub.3, C.sub.2H.sub.5, optionally
amino-substituted acyl having 1 to 5 carbon atoms, alkoxycarbonyl,
aminocarbonyl, alkylthiothiocarbonyl and dialkoxyphosphoryl having
1 to 4 carbon atoms in the alkyl moiety,
[0063] R.sup.5 represents H, CH.sub.3, C.sub.2H.sub.5 and
[0064] R.sup.6 represents H,
[0065] and their pharmaceutically useful hydrates and acid addition
salts and to the alkali metal, alkaline earth metal, silver and
guanidinium salts of the parent carboxylic acids.
[0066] Particular preference is given to the compounds of the
formula (I)
[0067] in which
[0068] Q represents a radical of the formula 5
[0069] in which
[0070] R.sup.1 represents alkyl having 1 to 4 carbon atoms which is
optionally mono- or disubstituted by fluorine, optionally
fluorine-substituted cyclopropyl, phenyl which is optionally mono-
or disubstituted by fluorine,
[0071] R.sup.2 represents hydroxyl, optionally
ethoxycarbonyl-substituted alkoxy having 1 to 4 carbon atoms,
benzyloxy, allyloxy, propargyloxy,
[0072] R.sup.3 represents hydrogen, amino, hydroxyl, methyl or
fluorine,
[0073] A represents N or C-R.sup.7 in which
[0074] R.sup.7 represents hydrogen, chlorine, fluorine, OCH.sub.3,
OCHF.sub.2, CH.sub.3 or CN or else together with R.sup.1 may form a
bridge of the structure --*O--CH.sub.2--CH--CH.sub.3, or
--*O--CH.sub.2--N--CH.sub.3 where the atom marked with is attached
to the carbon atom of A,
[0075] B represents N, C--H, C--F,
[0076] Y represents hydrogen or together with R.sup.2 may form a
bridge of the structure --*S--NH-- where the atom marked with
represents Y, and
[0077] T represents a radical of the formula 6
[0078] in which
[0079] R.sup.4 represents H, CH.sub.3, C.sub.2H.sub.5, optionally
amino-substituted acyl having I to 4 carbon atoms or alkoxycarbonyl
having 1 to 4 carbon atoms in the alkyl moiety,
[0080] R.sup.5 represents H and
[0081] R.sup.6 represents H,
[0082] and their pharmaceutically useful hydrates and acid addition
salts and the alkali metal, alkaline earth metal, silver and
guanidinium salts of the parent carboxylic acids.
[0083] Most of the compounds which are suitable for the use
according to the invention have already been disclosed in European
Patent Application 589 318, or they can be prepared by the
processes described therein. Thus, the compounds of the formula (I)
are obtained, for example, by reacting a bicyclic amine T-H with a
quinolone skeleton Q-Hal, where Hal represents, for example, a
halogen atom as leaving group, in accordance with the equation
below: 1 T - H + Q - Hal base --H - Hal T - Q ( I )
[0084] The 7-halogeno-quinolonecarboxylic acid derivatives Q-Hal
used for preparing the compounds of the formula (I) according to
the invention are known, or they can be prepared by known methods.
Thus, the
7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarb-
oxylic acid or ethyl
7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-
-oxo-3-quinolinecarboxylate have been described in European Patent
Application 276 700. The corresponding 7-fluoro derivatives can
also be synthesized, for example, via the reaction sequence below:
7
[0085] An alternative process for preparing the intermediate
2,4-dichloro-3-cyano-5-fluoro-benzoyl chloride (European Patent
Application 276 700), which can be converted into
3-cyano-2,4,5-trifluoro- -benzoyl fluoride, starts with
5-fluoro-1,3-xylene: 5-fluoro-1,3-xylene is dichlorinated at the
ring in the presence of a catalyst under ionic conditions to give
2,4-dichloro-5-fluoro-1,3-dimethylbenzene which is subsequently
chlorinated in the side chains under radical conditions to give
2,4-dichloro-5-fluoro-3 -dichloromethyl-1-trichloromethylbenzene.
This is hydrolysed via the 2,4-dichloro-5
-fluoro-3-dichloromethylbenzoic acid to give
2,4-dichloro-5-fluoro-3-formyl-benzoic acid, which is subsequently
converted into 2,4-dichloro-5-fluoro-3-N-hydroxyiminomethyl--
benzoic acid. Treatment with thionyl chloride gives
2,4-dichloro-3-cyano-5-fluoro-benzoyl chloride which can then be
converted into 3-cyano-2,4,5-trifluoro-benzoyl fluoride by
chlorine-fluorine exchange. 8
[0086] The two five-membered rings in the bicyclic bases T-H
employed are cis-linked. The bases T-H can be employed as racemates
or as enantiomerically pure compounds. Various processes are
suitable for preparing the enantiomerically pure amines T-H:
[0087] 1. The racemic bicyclic amines (T-H) can be reacted with
enantiomerically pure acids, for example carboxylic acids or
sulphonic acids, such as N-acetyl-L-glutamic acid,
N-benzoyl-L-alanine, 3-bromo-campher-9-sulphonic acid,
campher-3-carboxylic acid, cis-campheric acid, campher-10-sulphonic
acid, O,O'-dibenzoyl-tartaric acid, D- or L-tartaric acid, mandelic
acid, methoxy-phenylacetic acid, 1-phenyl-ethanesulphonic acid,
phenyl-succinic acid, to give a mixture of the diastereomeric salts
which can be separated into the diastereomerically pure salts by
fractional crystallization. The enantiomerically pure amines can be
liberated by treating these salts with alkali metal or alkaline
earth metal hydroxides.
[0088] 2. In a similar manner to that described under 1., an
optical resolution of the basic intermediates which are formed
during the preparation of the racemic bicyclic amines can be
carried out using the abovementioned enantiomerically pure
acids.
[0089] 3. Both the racemic amines (T-H) and some of the
intermediates which lead to the bicyclic amines (T-H) can, if
appropriate after acylation, be separated chromatographically on
chiral supports.
[0090] 4. Using chemical linkage with chiral acyl radicals, it is
also possible to convert the racemic amines (T-H) into mixtures of
diastereomers which can be separated by distillation,
crystallization or chromatography into the diastereomerically pure
acyl derivatives from which the enantiomerically pure amines can be
isolated by hydrolysis. Examples of reagents for linkage with
chiral acyl radicals include: methoxy-trifluoromethyl-phenylacetyl
chloride, menthyl isocyanate, D- or L-phenylethyl isocyanate,
menthyl chloroformate, campher-10-sulphonyl chloride.
[0091] 5. During the synthesis of the bicyclic amines (T-H), it is
also possible to introduce chiral instead of achiral protective
groups. In this way, mixtures of diastereomers which can be
separated are obtained. In the intermediate
7-benzyl-2-oxa-7-azabicyclo[3.3.0]octane-1-carbonitri- le, for
example, the benzyl radical can be replaced by a phenylethyl
radical in the R or S configuration.
[0092] Examples of compounds according to the invention are, in
addition to the compounds mentioned in the preparation examples,
the compounds listed in Table 1 below, which can be employed both
in racemic form and as enantiomerically pure or diastereomerically
pure compounds.
1TABLE 1 9 A B R.sup.1 R.sup.2 R.sup.3 C--H C--F 10 OH H C--F C--F
11 OH H C--Cl C--F 12 OH H C--CH.sub.3 C--F 13 OH H C--F C--CN 14
OH H C--F C--F 15 OH F N C--F 16 OH H C--F C--F 17 OH H C--F C--F
18 OC.sub.2H.sub.5 H C--CH.sub.3 C--F 19 OH H C--CH.sub.3 C--F 20
OH NH.sub.2 C--F C--F 21 OH NH.sub.2 N C--F 22 OH CH.sub.3 C--H
C--F 2,4-F.sub.2C.sub.6H.sub.3 OH H
[0093] The compounds according to the invention have strong
antibiotic activity and display a broad antibacterial spectrum
against gram-positive and gram-negative pathogens, but in
particular also against Helicobacter spp., while having low
toxicity.
[0094] These useful properties make it possible to use them as
chemotherapeutic active compounds for the therapy of Helicobacter
pylori infections and associated gastroduodenal disorders which can
be prevented, improved and/or cured by the compounds according to
the invention.
[0095] The compounds according to the invention can be administered
in various pharmaceutical preparations. Preferred pharmaceutical
preparations are tablets, coated tablets, capsules, pills,
granules, solutions, suspensions and emulsions.
[0096] Although the compounds according to the invention are
administered as monotherapeutic agents, they can also be used, if
required, in combination with other therapeutics. Possible
combination partners include: nitroimidazole derivatives, for
example metronidazole; proton pump inhibitors, for example
omeprazole, pantoprazole or lanzoprazole; H.sub.2-receptor
antagonists, such as, for example, cimetidine, ranitidine,
famotidine or nizatidine; bismuth compounds, such as, for example,
bismuth salicylate or CBS (colloidal bismuth subcitrate); other
antibiotics, such as, for example, amoxicillin, azlocillin or
clarithromycin; antacids.
[0097] The minimum inhibitory concentrations of some compounds
according to the invention are shown in an exemplary manner as a
measure for the antibacterial activity in Table 2 below, in
comparison to the structurally similar
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-
-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxyli-
c acid (European Patent Application 671 391) and ciprofloxacin.
[0098] The minimum inhibitory concentrations (MIC) were determined
in the agar dilution test on Columbia agar or basis 2 agar (Oxoid)
using 10% lysed horse blood, either at pH 7 or pH 5, with 1 g of
urea/l. The test substances were tested in replica dishes which
contained concentrations of the active compound which decreased in
each case by a dilution factor of two. For inoculation, fresh
Helicobacter cultures from liquid culture or suspension of the
pathogens from agar plates were used. The inoculated agar plates
were incubated at 37.degree. C. in an atmosphere containing 5-10%
of CO.sub.2 for 48-72 hours. The MIC value (.mu.g/ml) which was
read off is the lowest concentration of active compound at which no
growth was noticeable with the naked eye. The following
Helicobacter isolates were used: H. felis ATCC 49179, H. pylori
NCTC 11637, H. pylori clinic isolate 008.
2TABLE 2 MIC values (mg/l) of some compounds according to the
invention in comparison to a reference compound (Ref.*) (agar
dilution test) MIC (mg/l) Example H. pylori 008 H. pylori 11637 1 B
0.06 0.25 1 BA 0.06 0.06 2 B 0.06 0.5 5 B 0.03 0.03 5 C 0.03 0.03 5
D 1 1 6 C 0.03 0.03 9 B <2 <2 10 B 0.06 0.06 11 B
.ltoreq.0.015 0.03 12 B .ltoreq.0.015 0.03 12 C .ltoreq.0.015 0.03
13 B .ltoreq.0.015 0.03 14 B .ltoreq.0.015 0.125 14 C .ltoreq.0.015
0.03 16 B 0.25 0.125 17 B 0.125 0.25 18 B 0.125 0.125 23 B
.ltoreq.0.015 .ltoreq.0.015 24 B 0.06 0.125 26 B 0.06 0.25 27
.ltoreq.0.015 0.5 29 8 8 30 0.25 0.125 31 <0.5 0.5 34 B 0.125
0.25 Ciprofloxacin 0.125 0.125 Ref.*.sup.) 0.25 0.25 *.sup.) =
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1--
cyclopropyl-6,8-difluror-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic
acid hydrochloride (European Patent Application 671 391)
[0099] As an example of the surprisingly high in vivo activity of
the compounds according to the invention, Table 3 shows the
therapeutic success after a 3-day treatment of infected mice with
rac.
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-di-
fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride
and for
1S,5R-(+)-7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-8-cyano-1--
cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
hydrochloride (Example 5C) in comparison to the treatment with
Ciprofloxacin: whereas the clearance rate with Ciprofloxacin is
only 17%, it is 67% and 100%, respectively, for the compounds
according to the invention. A 14-day treatment of the mice with
3.times.10 mg of rac.
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-di-
fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
hydrochloride/kg even resulted in a total eradication of the
pathogen.
[0100] For studies in the animal model, female Swiss mice (8 to 12
weeks old, SPF breed) were kept with commercial feed and water. For
colonization, a defined H. felis strain (ATCC 49179) was used. The
bacteria were administered as a suspension (0.1 ml with
10.sup.8-10.sup.9 bacteria) 4 times within 7 days using a
pharyngeal tube. Alternatively, stomach homogenates of mice which
had been infected earlier were also used for infection.
[0101] 3-5 days after the infection had established itself, the
treatment with the test preparations was started. As a first
treatment success, the reduction of the germs was determined as
"clearance" 24 hours after the last treatment (for example 3, 7,
10, 14 days; 1-3 times daily). In some cases, pathogen eradication
24 weeks after the end of the treatment was also determined. In
accordance with the "CLO" test used in clinical diagnostics, a
microtitre-based urease test was used. Defined stomach biopsy
specimens were tested for change of colour within a period of 24
hours.
3TABLE 3 Therapeutic success after a 3-day treatment of infected
mice (6 animals per group) Preparation Dose [mg/kg] Clearance %
Substance A 2 .times. 10 4/6 67 Substance B 2 .times. 10 6/6 100
Ciprofloxacin 2 .times. 10 1/6 17
EXAMPLES
[0102] Preparation of the intermediates
Example I 1
[0103] 23
[0104] At 25.degree. C., 4.64 g (20 mmol) of
1-aminomethyl-7-benzyl-2-oxa-- 7-aza-bicyclo[3.3.0]octane are
dissolved in 20 ml of water with 20 ml of 1N HCl. A solution of
1.98 g (22 mmol) of potassium cyanate in 20 ml of water is added
and the -mixture is heated under reflux for 1 hour. The mixture is
concentrated at 60.degree. C./15 mbar, the residue is eluted with
dichloromethane and the eluate is dried with sodium sulphate and
concentrated. This gives an oil (7.3 g) which is purified
chromatographically over silica gel using
dichloromethane/methanol/17% ammonia (150:20:1).
[0105] Yield: 4.0 g (72% of theory) of
7-benzyl-1-ureidomethyl-2-oxa-7-aza- -bicyclo[3.3.0]octane as an
oil,
[0106] .sup.1H-NMR (400 MHz; CDCl.sub.3): 4.9 broad (NH.sub.2), 5.7
ppm broad (NH).
Example I 2
[0107] 24
[0108] In the presence of 2 g of Pd-C, 3.9 g (14 mmol) of
7-benzyl-1-ureidomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane in 70 ml
of ethanol are hydrogenated at 100.degree. C./100 bar, the catalyst
is filtered off, the solution is concentrated and the resulting
product (2.8 g of a viscous oil) is purified by chromatography.
[0109] Yield: 1.5 g (58% of theory) of
1-ureidomethyl-2-oxa-7-aza-bicyclo[- 3.3.0]octane as a viscous
oil,
[0110] FAB-MS: m/e 186 [(M+H).sup.+], 371 [(2M+H).sup.+].
Example I 3
[0111] 25
[0112] 7 g (30 mmol) of
1-aminomethyl-7-benzyl-2-oxa-7-aza-bicyclo[3.3.0]o- ctane are
initially charged in 50 ml of dioxane and admixed with 3 g (30
mmol) of triethylamine, and 3 g (30 mmol) of acetic anhydride are
added dropwise with ice-cooling over a period of 10 minutes. The
mixture is stirred at room temperature overnight and concentrated
at 60.degree. C./20 mbar. The resulting residue is purified
chromatographically over silica gel using
dichloromethane/methanol/17% ammonia (150/20(1) as mobile
phase.
[0113] Yield: 8.2 g of
1-acetylaminomethyl-7-benzyl-2-oxa-7-aza-bicyclo[3.- 3.0]octane as
an oil, content (according to GC): 94%.
[0114] Mass spectrum: 274 (M.sup.+), 202, 184, 170, 91 (100%).
Example I 4
[0115] 26
[0116] 7.1 g (25.9 mmol) of
1-acetylaminomethyl-7-benzyl-2-oxa-7-aza-bicyc- lo[3.3.0]octane are
dissolved in 50 ml of tetrahydrofuran, and this solution is added
dropwise to a suspension of 3.1 g (82 mmol) of lithium aluminium
hydride in 60 ml of tetrahydrofuran in such a way that the
temperature is kept at from 31.degree. to 33.degree. C. The mixture
is subsequently heated under reflux for 12 hours and decomposed
with cooling with 1.2 ml of water and 1.2 ml of 15% strength
aqueous sodium hydroxide solution. The precipitate is filtered off
with suction and washed with tetrahydrofuran, and the filtrate is
concentrated. The oil that remains (5.5 g) is purified
chromatographically over silica gel (mobile phase:
dichloromethane/methanol/17% strength ammonia 150:20:1).
[0117] Yield: 4.55 g (67.5% of theory) of
7-benzyl-1-ethylaminomethyl-2-ox- a-7-aza-bicyclo[3.3.0]octane as
an oil.
Example I 5
[0118] 27
[0119] 1.4 g (5.4 mmol) of
7-benzyl-1-ethylaminomethyl-2-oxa-7-aza-bicyclo- [3.3.0]octane are
dissolved in 6 ml of tert-butanol and admixed with a solution of
220 mg (5.5 mmol) of NaOH in 4 nil of water and 1.24 g (5.7 mmol)
of di-tert-butyl dicarbonate. The temperature increases to
27.degree.-31.degree. C. The mixture is stirred overnight and
concentrated and the residue is taken up in approximately 20 ml of
water and extracted with dichloromethane. The extract is dried
using sodium sulphate and concentrated under reduced pressure.
[0120] Yield: 1.58 g (81.5% of theory) of
7-benzyl-1-(N-tert-butoxycarbony-
l-N-ethylaminomethyl)-2-oxa-7-aza-bicyclo[3.3.0]octane as an
oil.
Example I 6
[0121] 28
[0122] In the presence of 0.8 g of Pd-C (10%), 3.5 g (9.7 mmol) of
7-benzyl-1-(N-tert-butoxycarbonyl-N-ethylaminomethyl)-2
-oxa-7-aza-bicyclo[3.3.0]octane in 60 ml of ethanol are
hydrogenated at 70.degree. C./90 bar. The catalyst is filtered off
and washed with ethanol and the filtrate is concentrated. The
residue is purified chromatographically over silica gel (mobile
phase: dichloromethane/methanol 95:5).
[0123] Yield: 2.0 g (76% of theory) of
1-(N-tert-butoxycarbonyl-N-ethylami-
nomethyl)-2-oxa-7-aza-bicyclo[3.3.0]octane as an oil.
Example I 7
[0124] 29
[0125] A: 7-Benzyl-1-cyano-2-oxa-7-azabicyclo[3.3.0] octane
(5-benzyl-hexahydrofuro[2,3-c]pyrrole-6a-carbonitrile) is prepared
according to the procedure of European Patent Application 589 318
and purified chromatographically (silica gel, dichloromethane).
This racemic compound is separated into the enantiomers via a
chromatographic optical resolution (support: Daicel-Chiracell OJ),
and the enantiomers are reacted further via the subsequent steps,
in accordance with the procedures of European Patent Application
589 318.
[0126] B: 1.67 g (7.3 mmol) of
(-)-7-benzyl-1-cyano-2-oxa-7-azabicyclo[3.3- .0]octane in 23 ml of
absolute tetrahydrofuran are reduced under reflux with 362 mg of
lithium aluminium hydride for 15 hours. The suspension is admixed
with aqueous potassium hydroxide solution, inorganic salts are
filtered off with suction and the filtrate is concentrated and
purified by chromatography (silica gel, dichloromethane/methanol
2:1).
[0127] Yield: 1.30 g (76.6% of theory) of
(-)-1-aminomethyl-7-benzyl-2-oxa- -7-azabicyclo[3.3.0]octane as an
oil,
[0128] [.alpha.].sup.0: -6.90 (c=1.3, dichloromethane).
[0129] C: 1.2 g (5.2 mmol) of
(-)-1-aminomethyl-7-benzyl-2-oxa-7-azabicycl- o[3.3.0]octane in 6.5
ml of tert-butanol are admixed with 254 mg of NaOH in 5.1 ml of
water, 1.3 g of di-tert-butyl pyrocarbonate are added and the
mixture is stirred at room temperature for approximately 30
minutes. The mixture is extracted with dichloromethane and the
extract is dried with potassium carbonate and concentrated. The
resulting crude product is purified chromatographically (silica
gel/dichloromethane 10:1).
[0130] Yield: 1.69 g (98% of theory) of
(-)-(1S,5S)-1-tert-butoxycarbonyla-
minomethyl-7-benzyl-2-oxa-7-aza-bicyclo[3.3.0]octane as an oil,
[0131] [.alpha.].sup.0: -11.8.degree. (c=1.16,
dichloromethane).
[0132] D: 1.56 g (4.49 mmol) of
(-)-(1S,5S)-1-tert-butoxycarbonylaminometh-
yl-7-benzyl-2-oxa-7-aza-bicyclo[3.3.0]octane in 50 ml of ethanol
are hydrogenated at 100.degree. C./90 bar in the presence of 0.5 g
of Pd-C (10%). The mixture is filtered, the filtrate is
concentrated and the residue is chromatographed over silica gel
using dichloromethane/methanol- /17% ammonia (150:20:1) as mobile
phase. The concentrated eluate crystallizes through.
[0133] Yield: 790 mg (73% of theory) of
(-)-(1S,5S)-1-tert-butoxycarbonyla-
minomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane,
[0134] Melting point: 104-105.degree. C.,
[0135] [.alpha.].sup.6: -10.2.degree. (0.56, CHCl.sub.3).
Example I 8
[0136] 30
[0137] 5.6 g (16.8 mmol) of
(+)-(1R,5R)-1-tert-butoxycarbonylaminomethyl-7-
-benzyl-2-oxa-7-aza-bicyclo[3.3.0]octane, [.alpha.].sup.0:
+13.1.degree. (c=1.1, dichloromethane), which is prepared
analogously to the procedures in Examples I 7 A to C, are
hydrogenated in 100 ml of ethanol at 70.degree. C./20 bar in the
presence of 1 g of Pd-C (10%). The mixture is filtered, the
filtrate is concentrated and the residue (3.5 g) is chromatographed
over silica gel using dichloromethane/methanol (95:5) as mobile
phase. The concentrated eluate crystallizes through.
[0138] Yield: 2.54 g (63% of theory) of
(+)-(1R,5R)-1-tert-butoxycarbonyla-
minomethyl-2-oxa-7-azabicyclo[3.3.0]octane,
[0139] Melting point: 102-103.degree. C.,
[0140] [.alpha.].sup.6: +7.0.degree. (0.3, CHCl.sub.3).
Example I 9A
[0141] 31
[0142] A solution of 83 g (0.87 mol) of 2-cyano-4,5-dihydrofuran in
2000 ml of absolute ethyl acetate is initially charged at
15.degree. C. At this temperature, first 0.5 ml of trifluoroacetic
acid and then 227 g (0.77 mol, 85% strength) of
N-methoxymethyl-N-[(S)-1-phenylethyl]-N-trime- thylsilylmethylamine
are added dropwise over a period of 10 minutes to this solution.
During the addition, the temperature increases to 45.degree. C. The
reaction mixture is stirred at room temperature overnight and
subsequently washed with 200 ml of saturated sodium bicarbonate
solution. The organic phase is dried over sodium sulphate and
concentrated under reduced pressure. The crude product is purified
by silica gel column chromatography (toluene/ethyl acetate, 99:1),
giving a mixture of diastereomers (56 g, ratio of the diastereomers
A:B=1.6:1). For crystallization, the residue is dissolved in 100 ml
of diethyl ether and slowly cooled to -35.degree. C. The crystals
which have precipitated out are filtered off through a cooled frit
and washed with a little diethyl ether which had been cooled to
60.degree. C.
[0143] Yield: 13.3 g (7.1% of theory) of
(1R,5R)-1-cyano-7-[(S)-1-phenylet-
hyl]-2-oxa-7-azabicyclo[3.3.0]octane (diastereomer A),
[0144] Melting point: 68.degree. C.,
[0145] [.alpha.].sup.5: -34.degree. (c=0.99, methanol). The
absolute configuration was determined by X-ray structure
analysis.
Example I 9B
[0146] 32
[0147] The diastereomer B is obtained as the maleic acid salt by
selective crystallization from the mixture which earlier gave the
diastereomer A. To a solution of the mother liquor from Example I
9A (103.3 g, 0.427 mol; ratio of diastereomers: 31:69, A:B) in 2 l
of ethyl acetate, for example, are added 49.5 g (0.427 mol) of
maleic acid. The mixture is heated under reflux for 2 hours and
cooled to room temperature overnight.
[0148] The crystals are subsequently filtered off with suction and
shaken in ethyl acetate and IN aqueous sodium hydroxide solution
and the organic phase is dried and concentrated. This gives the
diastereomer B in a purity of >96% ee.
[0149] Yield: 32 g (45% of theory) of
(1S,5S)-1-cyano-7-[(S)-1-phenylethyl-
]-2-oxa-7-azabicyclo[3.3.0]octane (diastereomer B).
[0150] The ethyl acetate solution which is enriched with the maleic
acid salt of the diastereomer A is repeatedly extracted with water,
and the aqueous phase is adjusted to pH 8 and extracted with ethyl
acetate. The organic phase is subsequently dried and concentrated,
giving a mixture of isomers which is enriched with diastereomer A.
This isomer mixture can now be used to carry out the selective
crystallization of the diastereomer A from ethyl acetate as
described in Example I 9A.
[0151] In this manner, the mixture of diastereomers can be
separated completely in several steps, so that the yield from
Example I 9A can be increased to approximately 16% of theory or
26%, based on the proportion of diastereomer A.
Example 10A
[0152] 33
[0153] At 30.degree. C., a solution of 16.1 g (0.067 mol) of
(1R,5R)-1-cyano-7-[(S)-1-phenylethyl]-2
-oxa-7-azabicyclo[3.3.0]octane in 70 ml of absolute tetrahydrofuran
is added dropwise to 3.15 g (0.083 mol) of lithium aluminium
hydride in 70 ml of absolute tetrahydrofuran. The reaction mixture
is then heated under reflux for 15 hours and subsequently cooled to
10.degree. C. and admixed successively with 3.5 ml of water, 3.5 ml
of 15% strength potassium hydroxide solution and 3.5 ml of water.
The precipitate is filtered off and washed with tetrahydrofuran and
the filtrate is subsequently concentrated under reduced
pressure.
[0154] Yield: 15.9 g of
(1S,5R)-1-aminomethyl-7-[(S)-1-phenylethyl]-2-oxa--
7-azabicyclo[3.3.0]octane as crude product,
[0155] [.alpha.].sup.5: -38.0.degree. (c=1.21, methanol).
Example I 10B
[0156] 34
[0157] 50 ml of liquid ammonia and 5 g of Raney nickel are added to
a solution of 15 g (0.062 mol) of
(1R,5S)-1-cyano-7-[(S)-1-phenylethyl]-2-o-
xa-7-azabicyclo-[3.3.0]octane in 30 ml of tetrahydrofuran, and the
mixture is then hydrogenated at 80.degree. C. under a hydrogen
pressure of from 110 to 120bar for 5 hours. After the reaction has
gone to completion, the mixture is filtered through Celite and
concentrated.
[0158] Yield: 12.5 g (82% of theory) of
(1R,5S)-1-aminomethyl-7-[(S)-1-phe-
nylethyl]-2-oxa-7-azabicyclo[3.3.0]octane.
Example I 11
[0159] 35
[0160] At 10.degree. C., 6.4 g (0.6 mol) of sodium carbonate and
13.0 g (0.6 mol) of di-tert-butyl dicarbonate are added
successively to a solution of 13.4 g (0.545 mol) of
(1S,5R)-1-aminomethyl-7-[(S)-1-phenylet-
hyl]-2-oxa-7-azabicyclo[3.3.0]octane in 60 ml of dioxane. The
mixture is stirred at room temperature for one hour and
subsequently concentrated under reduced pressure. The residue is
purified by silica gel column chromatography
(dichloromethane/methanol, 95:5).
[0161] Yield: 18.9 g (quantitative) of
(1S,5R)-1-tert-butoxycarbonylaminom-
ethyl-7-[(S)-1-phenylethyl]-2-oxa-7-azabicyclo[3.3.0]octane,
[0162] [.alpha.].sup.5: -19.0.degree. (c=1.5 in methanol).
Example I 12
[0163] 36
[0164] 18.0 g (0.052 mol) of
(1S,5R)-1-tert-butoxycarbonylaminomethyl-7-[(-
S)-1-phenylethyl]-2-oxa-7-azabicyclo[3.3.0]octane are dissolved in
150 ml of absolute methanol and, after addition of 2.5 g of 10%
palladium-activated carbon, hydrogenated at 70.degree. C. and 20
bar for 9 h. The catalyst is filtered off and the filtrate is
concentrated under reduced pressure.
[0165] Yield: 12.5 g (99% of theory) of
(1R,5R)-1-tert-butoxycarbonylamino-
methyl-2-oxa-7-azabicyclo[3.3.0]octane,
[0166] [.alpha.].sup.6: +11.9.degree. (c=0.7, methanol).
[0167] Treatment of
(1R,5R)-1-tert-butoxycarbonylaminomethyl-2-oxa-7-azabi-
cyclo-[3.3.0]octane with concentrated hydrochloric acid at room
temperature gives
(1S,5R)-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]octane
hydrochloride.
Example I 13
[0168] Ethyl
8-cyano-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinol-
ine-carboxylate 37
[0169] A. Methyl 3-bromo-2,4,5-trifluoro-benzoate: with
ice-cooling, 772 g of 3-bromo-2,4,5-trifluoro-benzoyl fluoride are
added dropwise to a mixture of 1460 ml of methanol and 340 g of
triethylamine. The mixture is stirred at room temperature for 1
hour. The reaction mixture is concentrated, the residue is taken up
in water and methylene chloride and the aqueous phase is extracted
with methylene chloride. The organic phase is dried over sodium
sulphate and then concentrated, and the residue is distilled under
reduced pressure. This gives 752.4 g of methyl
3-bromo-2,4,5-trifluoro-benzoate of boiling point 122.degree. C./20
mbar.
[0170] B. Methyl 3-cyano-2,4,5-trifluoro-benzoate: 269 g of methyl
3-bromo-2,4,5-trifluoro-benzoate and 108 g of copper cyanide in 400
ml of dimethylformamide are heated at reflux for 5 hours. All
volatile components of the reaction mixture are subsequently
distilled off under reduced pressure. The distillate is then
fractionated over a column. This gives 133 g of methyl
3-cyano-2,4,5-trifluoro-benzoate of boiling point 88-89.degree.
C./0.01 mbar.
[0171] C. 3-Cyano-2,4,5-trifluoro-benzoic acid: a solution of 156 g
of methyl 3-cyano-2,4,5-trifluoro-benzoate in 960 ml of glacial
acetic acid, 140 ml of water and 69 ml of concentrated sulphuric
acid is heated at reflux for 8 hours. Most of the acetic acid is
subsequently distilled off under reduced pressure and the residue
is admixed with water. The precipitated solid is filtered off with
suction, washed with water and dried. This gives 118.6 g of
3-cyano-2,4,5-trifluoro-benzoic acid as a white solid of melting
point 187-190.degree. C.
[0172] D. 3-Cyano-2,4,5-trifluoro-benzoyl chloride: 111 g of
3-cyano-2,4,5-trifluoro-benzoic acid and 84 g of oxalyl chloride in
930 ml of dry methylene chloride are, with addition of a few drops
of dimethylformamide, stirred at room temperature for 5 hours. The
methylene chloride is subsequently stripped off and the residue is
distilled under reduced pressure. This gives 117.6 g of
3-cyano-2,4,5-trifluoro-benzoyl chloride as a yellow oil.
[0173] E. Ethyl
2-(3-cyano-2,4,5-trifluoro-benzoyl)-3-dimethylamino-acryla- te: a
solution of 55 g of 3-cyano-2,4,5-trifluoro-benzoyl chloride in 50
ml of toluene is added dropwise to a solution of 36.5 g of ethyl
3-dimethylamino-acrylate and 26.5 g of triethylamine in 140 ml of
toluene in such a way that the temperature remains between 50 and
55.degree. C. The mixture is then stirred at 50.degree. C. for
another 2 hours. The reaction mixture is concentrated under reduced
pressure and used for the next step without further work-up.
[0174] F. Ethyl
2-(3-cyano-2,4,5-trifluoro-benzoyl)-3-cyclopropylamino-acr- ylate:
at 20.degree. C., 30 g of glacial acetic acid are added dropwise to
the reaction product from step E. A solution of 15.75 g of
cyclopropylamine in 30 ml of toluene is subsequently added
dropwise. The mixture is stirred at 30.degree. C. for 1 hour. 200
ml of water are then added, the mixture is stirred for 15 minutes
and the organic phase is separated off and once more shaken with
100 ml of water. The organic phase is then dried over sodium
sulphate and concentrated under reduced pressure. The resulting
crude product is used for the next step without further
work-up.
[0175] G. Ethyl
8-cyano-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-qui-
noline-carboxylate: the reaction product from step F and 27.6 g of
potassium carbonate in 80 l of dimethylformamide are stirred at
room temperature for 16 hours. The reaction mixture is then added
to 750 ml of ice-water and the solid is filtered off with suction
and washed with 80 ml of cold methanol. Drying gives 47 g of ethyl
8-cyano-1-cyclopropyl-6,7-
-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate of melting point
209-211.degree. C.
Example I 14
[0176] 2,4-Dichloro-5-fluoro-1,3-dimethylbenzene 38
[0177] a) Solvent-Free
[0178] 1 g of anhydrous iron(m) chloride is initially charged in
124 g of 3,5-dimethyl-fluorobenzene and chlorine is introduced
(approximately 4 h) at the rate of its consumption. The reaction is
initially slightly exothermic (temperature increase from 24 to
32.degree. C.) and the temperature is kept below 30.degree. C. by
cooling. After the introduction of 120 g of chlorine, the mixture
solidifies. According to GC analysis, 33.4% of monochloro compound,
58.4% of the desired product and 5% of more highly chorinated
compounds have been formed. The hydrogen chloride is removed and
the reaction mixture is subsequently distilled over a column under
water pump vacuum:
[0179] The initial fraction gives, at 72-74.degree. C./22 mbar, 49
g of 2-chloro-5-fluoro-1,3-dimethylbenzene. After an intermediate
fraction of 5 g, 75 g of 2,4-dichloro-5-fluoro-1, 3-dimethylbenzene
are distilled over at 105.degree. C./22 mbar; melting range:
64-65.degree. C.
[0180] b) in 1.2-dichloroethane
[0181] 1 kg of 3,5-dimethyl-fluorobenzene and 15 g of anhydrous
iron(E) chloride are initially charged in 1 l of 1,2-dichloroetane
and chlorine is introduced at the rate of its consumption
(approximately 4 h). Initially, the reaction is exothermic
(temperature increase from 24 to 32.degree. C.), and the
temperature is kept below 30.degree. C. by cooling. After the
introduction of 1200 g of chlorine, GC analysis shows that 4% of
the monochloro compound, 81.1% of the desired product and 13.3% of
more highly chlorinated compounds have been formed. Solvent and
hydrogen chloride are distilled off and the residue is then
distilled over a column under water pump vacuum:
[0182] The initial fraction gives 40 g of
2-chloro-5-fluoro-1,3-dimethylbe- nzene. After a small intermediate
fraction, 1115 g of 2,4-dichloro-5-fluoro-1,3-dimethylbenzene are
distilled over at 127-128.degree. C./50 mbar.
Example I 15
[0183]
2,4-Dichloro-5-fluoro-3-dichloromethyl-1-trichloromethylbenzene
39
[0184] In a photochlorination apparatus fitted with a chlorine
inlet and an outlet for the hydrogen chloride to a washer and a
light source in the vicinity of the chlorine inlet tube, 1890 g of
2,4-dichloro-5-fluoro-1,3-- dimethylbenzene are initially charged,
and chlorine is metered in at from 140 to 150.degree. C. Over a
period of 30 h, 3850 g of chlorine are introduced. According to GC
analysis, the content of desired product is 71.1%; the proportion
of underchlorinated compounds is 27.7%.
[0185] Distillation over a 60 cm column with Wilson spirals gives
an initial fraction of 1142 g which can be recycled into the
chlorination. The main fraction at 160-168.degree. C./0.2 mbar
gives 2200 g of
2,4-dichloro-5-fluoro-3-dichloromethyl-1-trichloromethylbenzene of
a melting range of 74-76.degree. C. After recrystallization of a
sample from methanol, the melting point is 81-82.degree. C.
Example I 16
[0186] 2,4-Dichloro-5-fluoro-3-formyl-benzoic acid 40
[0187] In a stirred apparatus with gas outlet, 2500 ml of 95%
strength sulphuric acid are initially charged at 70.degree. C., and
500 g of molten
2,4-dichloro-5-fluoro-3-dichloromethyl-1-trichloromethylbenzene are
added dropwise with stirring. Evolution of hydrogen chloride starts
after a short while. Metered addition is continued for 2 h and the
mixture is stirred until the evolution of gas ceases. After cooling
to 20.degree. C., the mixture is discharged under 4 kg of ice and
the precipitated solid is filtered off with suction. The product is
washed with water and dried.
[0188] Yield: 310 g,
[0189] Melting range: 172-174.degree. C.
Example I 17
[0190] 2,4-Dichloro-5-fluoro-3-N-hydroxyiminomethyl-benzoic acid
41
[0191] In a stirred apparatus, 80 g of hydroxylammonium chloride
are initially charged in 500 ml of ethanol, 200 ml of 45% strength
aqueous sodium hydroxide solution are added dropwise and, at
4045.degree. C., 200 g of 2,4-dichloro-5-fluoro-3-formyl-benzoic
acid are subsequently introduced. The reaction is slightly
exothermic, and stirring is continued at 60.degree. C. for 5 h.
After cooling to room temperature, the pH is adjusted to <3 by
dropwise addition of hydrochloric acid, the product is taken up in
tert-butyl methyl ether, the organic phase is separated off and the
solvent is distilled off. 185 g of
2,4-dichloro-5-fluoro-3-N-hydroxyiminomethyl-benzoic acid are
obtained as residue; melting range: 190-194.degree. C.
Example I 18
[0192] 2,4-Dichloro-3-cyano-5-fluoro-benzoyl chloride 42
[0193] In a stirred apparatus fitted with a metering device and a
gas outlet via a reflux condenser to a washer, 600 ml of thionyl
chloride are initially charged and, at 20.degree. C., 210 g of
2,4-dichloro-5-fluoro-3- -N-hydroxyiminomethyl-benzoic acid are
introduced at the rate at which hydrogen chloride and sulphur
dioxide are formed. After the addition, the mixture is heated under
reflux until evolution of gas has ceased. The mixture is
subsequently distilled, giving, in a boiling range of
142-145.degree. C./10 mbar, 149 g of
2,4-dichloro-3-cyano-5-fluoro-benzoy- l chloride (content according
to GC: 98.1%); melting range: 73-75.degree. C.
Example I 19
[0194] 3-Cyano-2,4,5-trifluoro-benzoyl fluoride 43
[0195] 50 g of potassium fluoride are suspended in 120 ml of
tetramethylene sulphone and, at 15 mbar, subjected to incipient
distillation (approximately 20 ml) for drying. 50.4 g of
2,4-dichloro-3-cyano-5-fluoro-benzoyl chloride are subsequently
added and the mixture is stirred with exclusion of moisture at an
internal temperature of 180.degree. C. for 12 hours. Vacuum
distillation gives 32.9 g of 3-cyano-2,4,5-trifluoro-benzoyl
fluoride with a boiling range of 98-100IC/12 mbar.
Example I 20
[0196] 3-Cyano-2,4,5-trifluoro-benzoyl chloride 44
[0197] 76.6 g of 3-cyano-2,4,5-trifluoro-benzoyl fluoride, together
with 1 g of anhydrous aluminium chloride, are initially charged at
60-65.degree. C., and 25 g of silicon tetrachloride are then added
dropwise at the rate at which gas is given off. After the evolution
of gas has ceased at 65.degree. C., the mixture is distilled under
reduced pressure. In the boiling range of 120-122.degree. C./14
mbar, 73.2 g of 3-cyano-2,4,5-trifluoro-benzoyl chloride distil
over.
Example I 21
[0198] 45
[0199] 0.5 g (2.07 mmol) of
(1R,5R)-1-tert-butoxycarbonylaminomethyl-2-oxa-
-7-azabicyclo[3.3.0]octane in 30 ml of ethanol are admixed with 13
ml of approximately 3.5 N hydrochloric acid, and the mixture is
stirred at room temperature for 4 hours. The mixture is
concentrated and the salt is isolated.
[0200] Yield: 0.3 g (67.5% of theory) of
(1S,5R)-1-aminomethyl-2-oxa-7-aza- bicyclo[3.3.0]octane
dihydrochloride,
[0201] Melting point: 284.degree. C.,
[0202] [.alpha.].sup.4: +16.5.degree. (c=1, methanol).
[0203] (1R,5S)-1-Aminomethyl-2-oxa-7-azabicyclo[3.3.0]octane
dihydrochloride and
(1SR,5RS)-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]octa- ne
dihydrochloride are also obtained correspondingly.
[0204] Preparation of the Active Compounds
Example 1
[0205] 46
[0206] A. R=(CH.sub.3).sub.3C--O--CO
[0207] B. R=H.times.HCl
[0208] A: A mixture of 332 mg (1 mmol) of
1-cyclopropyl-8-difluoromethoxy--
6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 4 ml
of acetonitrile and 2 ml of dimethylformamide with 112 mg (1 mmol)
of 1,4-diazabicyclo[2.2.2]octane and 267 mg (1.1 mmol) of
1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane
is heated under reflux for 1 hour. The suspension is concentrated
at 70.degree. C./15 mbar and the residue is admixed with a little
water and treated in an ultrasonic bath for 30 minutes. The
undissolved precipitate is filtered off with suction, washed with
water and dried at 90.degree. C. under high vacuum.
[0209] Yield: 487 mg (88% of theory) of
7-(1-tert-butoxycarbonylaminomethy-
l-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-8-difluoromethoxy-6-fl-
uoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
[0210] Melting point: 215-217.degree. C. (decomposition).
[0211] B. 476 mg (0.86 mmol) of
7-(1-tert-butoxycarbonylaminomethyl-2-oxa--
7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-8-difluoromethoxy-6-fluoro-1,4-
-dihydro-4-oxo-3-quinolinecarboxylic acid are dissolved in 5 ml of
hot, half-concentrated hydrochloric acid, and the solution is
filtered and concentrated at 60.degree. C./15 mbar. The residue is
admixed with a little ethanol and reconcentrated, and the salt is
isolated and dried at 90.degree. C. under high vacuum.
[0212] Yield: 385 mg (91% of theory) of
7-(1-aminomethyl-2-oxa-7-aza-bicyc-
lo[3.3.0]oct-7-yl)-1-cyclopropyl-8
difuoromethoxy-6-fluoro-1,4dihydro-4-ox- o-3-guinolinecarboxylic
acid hydrochloride,
[0213] Melting point: 182-185.degree. C. (decomposition).
[0214] AA. By the method of step A,
(+)-(1R,5R)-1-tert-butoxycarbonylamino-
methyl-2-oxa-7-aza-bicyclo[3.3.0]octane is converted into
(+)-(1R,5R)-7-(1-tert-butoxycarbonylaminomethyl-2
-oxa-7-aza-bicyclo[3.3.-
0]oct-7-yl)-1-cyclopropyl-8-difluoromethoxy-6
-fluoro-1,4-dihydro-4-oxo-3-- quinolinecarboxylic acid.
[0215] Melting point: 166-167.degree. C. (decomposition),
[0216] [.alpha.].sup.5: +26.degree. (c=0.25, DMF).
[0217] BA. By the method of step B, the product from step AA is
converted into
(-)-(1S,5R)-7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-c-
yclopropyl-8-difluoromethoxy-6
-fluoro-1,4-dihydro-4-oxo-3quinolinecarboxy- lic acid
hydrochloride.
[0218] Melting point: 194-197.degree. C. (decomposition),
[0219] [.alpha.].sup.5: -21.degree. (c=0.5, DMF).
[0220] AB. By the method of step A,
(-)-(1S,5S)-1-tert-butoxycarbonylamino-
methyl-2-oxa-7-aza-bicyclo[3.3.0]octane is converted into
(-)-(1S,5S)-7-(1-tert-butoxycarbonylaminomethyl-2
-oxa-7-aza-bicyclo[3.3.-
0]oct-7-yl)-1-cyclopropyl-8-difluoromethoxy-6-fluoro-1,4-dihydro-4-oxo-3-q-
uinolinecarboxylic acid.
[0221] Melting point: 166-167.degree. C. (decomposition),
[0222] [.alpha.].sup.5: -27.degree. (c=0.125, DMF).
[0223] BB. By the method of step B, the product from step AB is
converted into
(+)-(1R,5S)-7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-c-
yclopropyl-8-difluoromethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxy-
lic acid hydrochloride.
[0224] Melting point: 194-197.degree. C. (decomposition),
[0225] [.alpha.].sup.5: +19.degree. (c=0.5, DMF).
Example 2
[0226] 47
[0227] A. R=(CH.sub.3).sub.3C--O--CO
[0228] B. R=H.times.HCl
[0229] C. R=H
[0230] A: By the method of Example 1A,
5-amino-1-cyclopropyl-6,7-difluoro--
1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid are
converted into
5-amino-7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-
-7-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarbo-
xylic acid (77% of theory) of melting point 219-221.degree. C.
(decomposition) (after chromatographic purification over silica gel
using dichloromethane/methanol/17% aqueous ammonia 150/20/1 as
mobile phase).
[0231] B: By method of Example 1 B, 405 mg (0.76 mmol) of the
product from step A are reacted with 7 ml of half-concentrated
hydrochloric acid.
[0232] Yield: 244 mg (69% of theory) of
5-amino-7-(1-aminomethyl-2-oxa-7-a-
za-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4--
oxo-3-quinolinecarboxylic acid hydrochloride,
[0233] Melting point: 242-244.degree. C. (decomposition).
[0234] FAB-MS: m/e 433 [(M+H).sup.+].
[0235] C: 235 mg (0.44 mmol) of the product from step A are
dissolved at room temperature in 20 ml of dichloromethane and
admixed with 1.4 ml of trifluoroacetic acid. The mixture is stirred
at room temperature for 3 hours and then concentrated, and the
residue is evaporated twice with ethanol. This gives 148 mg of
5-amino-7-(1-aminomethyl-2-oxa-7-aza-bicycl-
o[3.3.0]oct-7-yl)-1-cyclopropylfluoro-1,4dihydro-8-methoxy-4-oxo-3-quinoli-
necarboxylic acid trifluoroacetate as crude product which is
purified over 40 g of silica gel using dichloromethane/methanol/17%
aqueous ammonia (150/20/1) as mobile phase, giving the betain.
[0236] Yield: 69 mg (36% of theory) of
5-amino-7-(1-aminomethyl-2-oxa-7-az-
a-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-o-
xo-3-quinolinecarboxylic acid,
[0237] Melting point: 209-211.degree. C. (decomposition).
Example 3
[0238] 48
[0239] A. R=(CH.sub.3).sub.3C--O--CO
[0240] B. R=H.times.HCl
[0241] A: By the method of Example 1A,
1-cyclopropyl-6,7-difluoro-1,4-dihy-
dro-5-methyl-4-oxo-3-quinolinecarboxylic acid are converted into
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-
-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic
acid (76% of theory).
[0242] B: By the method of Example 1B, the product from step A is
reacted with half-concentrated hydrochloric acid to give
7-(1-aminomethyl-2-oxa-7-
-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6fluoro-1,4
dihydro-5-methyl-4-oxo-3quinolinecarboxylic acid hydrochloride of
melting point 251-253.degree. C. (decomposition).
Example 4
[0243] 49
[0244] A. R=(CH.sub.3).sub.3C--O--CO
[0245] B. R=H.times.HCl
[0246] A: By the method of Example 1A,
6,7,8-trifluoro-1,4-dihydro-1-methy-
lamino-4-oxo-3-quinolinecarboxylic acid are converted into
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-6-
,8 difluoro-1,4dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic
acid (68% of theory) of melting point 225-227.degree. C.
(decomposition).
[0247] B: By the method of Example 1B, the product from step A is
reacted with half-concentrated hydrochloric acid to give, in a
yield of 65%,
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-6,8-difluoro-1,4-dih-
ydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid hydrochloride
of melting point 177-179.degree. C. (decomposition).
[0248] FAB-MS: m/e: 395 [(M+H).sup.+], 366.
Example 5
[0249] 50
[0250] A. R=(CH.sub.3).sub.3C--O--CO
[0251] B. R=H.times.HCl
[0252] A: By the method of Example 1A,
7-chloro-8-cyano-1-cyclopropyl-6-fl-
uoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (European Patent
276 700) is converted into
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bi-
cyclo[3.3.0]oct-7-yl)-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-q-
uinolinecarboxylic acid.
[0253] B: By the method of Example 1B, the product from step A is
reacted with half-concentrated hydrochloric acid to give
7-(1-aminomethyl-2-oxa-7-
-aza-bicyclo[3.3.0]oct-7-yl)-8cyano-1-cyclopropyl-6fluoro-1,4-dihydro-4-ox-
o-3-quinolinecarboxylic acid hydrochloride of melting point
241.degree. C. (decomposition).
[0254] C. By the method of the reactions in steps A and B,
(+)-1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane
gives
(+)-7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-8-cyano-1--
cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
hydrochloride,
[0255] Melting point: 293.degree. C. (decomposition),
[0256] [.alpha.].sup.4: +50.60 (c=0.7, methanol).
[0257] D. By the method of the reactions in steps A and B,
(-)-1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane
gives
(-)-7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-8-cyano-1--
cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
hydrochloride,
[0258] Melting point: 292.degree. C. (decomposition),
[0259] [.alpha.].sup.4: -49.degree. (c=1, methanol).
[0260] E: A solution of 5.4 g (0.224 mmol) of
(1R,5R)-1-tert-butoxycarbony-
laminomethyl-2-oxa-7-azabicyclo[3.3.0]octane, 6.5 g (0.204 mol) of
ethyl
8-cyano-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyla-
te and 4.6 g (0.459 mol) of triethylamine and 300 ml of absolute
acetonitrile is stirred at room temperature overnight. The mixture
is subsequently concentrated under reduced pressure and the residue
is chromatographed over silica gel (dichloromethane/methanol,
99:195:5). This gives 9.2 g (83.6% of theory) of ethyl
(+)-7-[(1R,5R)-1-tert-butoxyc-
arbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl]-8-cyano-1-cycloprop-
yl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylate,
[0261] [.alpha.].sup.4: +81.10 (c=1.5, dichloromethane).
[0262] 9.1 g (0.169 mol) of ethyl
(+)-7-[(1R,5R)-1-tert-butoxycarbonylamin-
omethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl]-8-cyano-1-cyclopropyl-6fluoro--
1,4-dihydro-4-oxo-quinolinecarboxylate are admixed with 150 ml of
10% strength hydrochloric acid. The mixture is heated under reflux
for 1 hour and subsequently cooled to room temperature. The
colourless crystals are filtered off and washed with a little
absolute isopropanol.
[0263] Yield: 6.9 g (91% of theory) of
(+)-7-[(1S,5R)-1-aminomethyl-2-oxa--
7-azabicyclo[3.3.0]oct-7-yl]-8-cyano-1-cyclopropyl-6-fluoro-1,4dihydro-4ox-
o-quinolinecarboxylic acid hydrochloride,
[0264] Melting point: 293.degree. C.,
[0265] [.alpha.].sup.4: +50.6.degree. (c=0.8 in methanol).
Example 6
[0266] 51
[0267] A. B. R=(CH.sub.3).sub.3C--O--CO
[0268] C. R=H.times.CF.sub.3COOH
[0269] A: 172 mg (0.5 mmol) of
1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-me-
thoxy-4-oxo-3-quinolinecarboxylic acid-BF.sub.2-chelate in 5 ml of
acetonitrile/dimethylformamide (1:1) are admixed with 150 mg (0.62
mmol) of
1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicylco[3.3.0]octane
and 40 mg (0.38 mmol) of 1,4-diazabicyclo[2.2.2]octane and heated
at 40.degree. C. for 12 hours. The mixture is concentrated and can
be used as crude product in step B. However, it can also be
purified chromatographically over silica gel (mobile phase:
dichloromethane/methanol 95:5) to characterize the intermediate
step. This gives 128 mg of
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicy-
clo[3.3.0]oct-7-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-q-
uinolinecarboxylic acid-BF.sub.2-chelate as a yellow solid; FAB-MS:
m/e 566 [(M+H).sup.+], 546 [(M-F).sup.+].
[0270] B: The evaporation residue obtained from step A is taken up
in 20 ml of dichloromethane/methanol (1:1) and, after addition of
2.6 ml of triethylamine, heated under reflux for 10 hours. The
mixture is concentrated and the residue is taken up in 4 ml of
water and admixed with 3 ml of 2N HCl. The precipitate is filtered
off with suction, washed with 20 ml of water and dried at
80.degree. C. under high vacuum. This gives 210 mg of
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3-
.3.0]oct-7-yl)-1-cyclopropyl-6fluoro-1,4dihydro-8-methoxy-4-oxo-3-quinolin-
e-carboxylic acid;
[0271] .sup.1H-NMR (400 MHz; DMSO): .delta. 3.63 ppm s
(OCH.sub.3).
[0272] C: 206 mg (0.4 mmol) of the product from step B are
dissolved in 13 ml of dichloromethane and admixed with 3.4 ml of
trifluoroacetic acid. The solution is stirred at 25.degree. C. for
30 minutes and then concentrated under reduced pressure. The
residue is stirred repeatedly with absolute ethanol and the
precipitate is filtered off with suction, washed well with ethanol
and dried at 80.degree. C. under high vacuum.
[0273] Yield: 114 mg (54% of theory) of
7-(1-aminomethyl-2-oxa-7-aza-bicyc-
lo[3.3.0]oct-7-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-qu-
inolinecarboxylic acid trifluoroacetate,
[0274] Melting point: 215-216.degree. C. (decomposition).
Example 7
[0275] 52
[0276] A. R=(CH.sub.3).sub.3C--O--CO
[0277] B. R=H.times.CF.sub.3COOH
[0278] A: 313 mg (1 mmol) of
7,8-dichloro-1-cyclopropyl-1,4-dihydro-5-meth-
yl-4-oxo-1,6-naphthyridine-3-carboxylic acid in 5 ml of
acetonitrile are admixed with 168 mg (1.5 mmol) of
1,4-diazabicyclo[2.2.2]octane and 266 mg (1.1 mmol) of
1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3- .0]octane
and stirred at 50.degree. C. for 2 hours. The mixture is
concentrated, the residue is treated with water, and the
precipitate is filtered off with suction, washed with water and
dried at 90.degree. C. under high vacuum.
[0279] Yield: 272 mg (52.5% of theory) of
7-(1-tert-butoxycarbonylaminomet-
hyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-8-chloro-1-cyclopropyl-1,4-dihydro-
-5-methyl-4-oxo-1,6-naphthyridine-3-carboxylic acid,
[0280] Melting point: 209-210.degree. C. (decomposition).
[0281] B: 150 mg (0.29 mmol) of the product from step A in 2 ml of
dichloromethane are admixed with 1.5 ml of trifluoroacetic acid and
stirred at 25.degree. C. for 45 minutes. The solution is
concentrated and the residue is repeatedly admixed with
dichloromethane and reconcentrated. The resulting salt is isolated
and dried at 70.degree. C. under high vacuum.
[0282] Yield: 68 mg (45% of theory) of
7-(1-aminomethyl-2-oxa-7-aza-bicycl-
o[3.3.0]oct-7-yl)-8-chloro-1-cyclopropyl-1,4dihydro-5-methyl-4-oxo-1,6-nap-
hthyridine-3-carboxylic acid trifluoroacetate,
[0283] Melting point: 125-128.degree. C. (decomposition).
[0284] Mass spectrum (ESI): m/e 419 [(M+H).sup.+].
Example 8
[0285] 53
[0286] A. R=(CH.sub.3).sub.3C--O--CO C.
[0287] B. R=H.times.CF.sub.3COOH
[0288] A: By the method of Example 7A, ethyl
7-chloro-1-cyclopropyl-8-fluo-
ro-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylate are converted,
in a yield of 20%, into ethyl
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza--
bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-1,6-napht-
hyridine-3-carboxylate of melting point 146-148.degree. C.
(decomposition).
[0289] B: By the method of Example 7B, the product from step A is
reacted with trifluoroacetic acid to give ethyl
7-(1-aminomethyl-2-oxa-7-aza-bicy-
clo[3.3.0]oct-7-yl)-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-1,6-naphthyri-
dine-3-carboxylate trifluoroacetate of melting point
199-200.degree. C. (decomposition).
[0290] C: 136 mg (0.25 mmol) of the product from step B are admixed
with 10 ml of half-concentrated hydrochloric acid and heated under
reflux for approximately 30 minutes. The mixture is concentrated
and the residue is treated with ethanol. The solid is filtered off
with suction and dried at 80.degree. C. under high vacuum.
[0291] Yield: 97 mg (91% of theory) of
7-(1-aminomethyl-2-oxa-7-aza-bicycl-
o[3.3.0]oct-7-yl)-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-1,6-naphthyridi-
ne-3-carboxylic acid hydrochloride,
[0292] Melting point: 301-304.degree. C. (decomposition).
Example 9
[0293] 54
[0294] A. R=(CH.sub.3).sub.3C--O--CO
[0295] B. R=H.times.CF.sub.3COOH
[0296] A: By the method of Example 1A, ethyl
1-cyclopropyl-6,7,8-trifluoro-
-1,4-dihydro-4-oxo-3-quinolinecarboxylate is converted into ethyl
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-
-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate.
[0297] B: 1.2 g of the product from step A in 10 ml of
trifluoroacetic acid are stirred at 25.degree. C. for 5 minutes and
then concentrated, and the residue is stirred with ether. The
resulting solid is purified chromatographically in
dichloromethane/methanol (95:5) over a little silica gel.
[0298] Yield: 215 mg (17% of theory) of ethyl
7-(1-aminomethyl-2-oxa-7-aza-
-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-qu-
inolinecarboxylate trifluoroacetate,
[0299] Melting point: 139-141.degree. C.
Example 10
[0300] 55
[0301] A. R=(CH.sub.3).sub.3C--O--CO
[0302] B. R=H.times.HCl
[0303] A: 4.96 g (10 mmol) of
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7--
aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-
-quinolinecarboxylic acid are suspended in 200 ml of
tetrahydrofuran/water (1:1) at 25.degree. C., admixed with 2.3 g (7
mmol) of caesium carbonate and treated in an ultrasonic bath for
approximately 10 minutes, resulting in a clear solution. At
30.degree. C./15 mbar, most of the mixture is evaporated and the
remaining solution is lyophilized. This gives 7.4 g of a colourless
residue which mainly comprises the caesium salt of
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-
-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid which is contaminated by some inorganic salt. 637 mg of this
caesium salt are dissolved in 5 ml of dimethylformamide at
25.degree. C. and admixed with 213 mg (1.5 mmol) of methyl iodide.
The suspension is stirred at 25.degree. C. overnight and then
concentrated on a rotary evaporator and the residue is treated with
light naphtha and dried at 80.degree. C. under high vacuum.
[0304] Yield: 360 mg of methyl
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-
-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo--
3-quinolinecarboxylate,
[0305] Melting point: 141-144.degree. C. (decomposition).
[0306] B: The product obtained from step A is dissolved in 25 ml of
dichloromethane, admixed with 1.5 ml of trifluoroacetic acid and
stirred at room temperature for 2 hours. The solution is
concentrated under reduced pressure and the residue is purified
chromatographically over silica gel using
dichloromethane/methanol/17% ammonia =150:20:1. The resulting
product is initially charged in 2 ml of water and dissolved with
0.76 ml of 1N HCl. The mixture is concentrated at 60.degree. C./15
mbar and the salt is dried at 50.degree. C. under high vacuum.
[0307] Yield: 226 mg of methyl
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]-
oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyl-
ate hydrochloride,
[0308] Melting point: 109-111.degree. C.
Example 11
[0309] A: By the method of Example 10A, 1-bromobutane gives 1-butyl
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-
-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate
of melting point 146-148.degree. C.
[0310] B: By the method of Example 10B, the protecting group is
cleaved off with trifluoroacetic acid and the resulting
trifluoroacetate is purified chromatographically using the
ammoniacal mobile phase. 1-Butyl
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-di-
fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate of melting point
117-119.degree. C. (decomposition) is isolated.
Example 12
[0311] A: By the method of Example 10A, allyl bromide gives allyl
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-
-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate
of melting point 143-145.degree. C.
[0312] B: By the method of Example 10B, the protecting group is
cleaved off with trifluoroacetic acid and the resulting
trifluoroacetate is purified chromatographically using the
ammoniacal mobile phase. Allyl
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-di-
fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate of melting point
133-135.degree. C. (decomposition) is isolated.
[0313] C: By the method of Example 10B, the protecting group is
cleaved off with trifluoroacetic acid and the resulting crude
trifluoroacetate is treated with ethanol and ether and isolated as
a solid: allyl
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-di-
fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate trifluoroacetate of
melting point 118-119.degree. C. (decomposition).
Example 13
[0314] A: By the method of Example 10A, propargyl bromide gives
propargyl
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-
-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate
of melting point 159-1600C.
[0315] B: By the method of Example 10B, the protecting group is
cleaved off with trifluoroacetic acid and the resulting
trifluoroacetate is purified chromatographically using the
ammoniacal mobile phase. Propargyl
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-di-
fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate of melting point
127-129.degree. C. (decomposition) is isolated.
Example 14
[0316] A: By the method of Example 10A, benzyl bromide gives benzyl
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-
-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate
of melting point 148-149.degree. C.
[0317] B: By the method of Example 10B, the protecting group is
cleaved off with trifluoroacetic acid and the resulting
trifluoroacetate is purified chromatographically -using the
ammoniacal mobile phase. Benzyl
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-di-
fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate of melting point
118-119.degree. C. (decomposition) is isolated.
[0318] C: By the method of Example 10B, the protecting group is
cleaved off with trifluoroacetic acid and the resulting crude
trifluoroacetate is treated with ethanol and ether and isolated as
a solid: benzyl
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-di-
fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate trifluoroacetate of
melting point 119-120.degree. C. (decomposition).
Example 15
[0319] A: By the method of Example 10A, ethyl bromoacetate gives
ethoxycarbonylmethyl
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicy-
clo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoli-
necarboxylate of melting point 150-152.degree. C.
[0320] B: By the method of Example 10B, the protecting group is
cleaved off with trifluoroacetic acid and the resulting
trifluoroacetate is purified chromatographically using the
ammoniacal mobile phase. Ethoxycarbonylmethyl
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-
-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate
of melting point 144-146.degree. C. (decomposition) is
isolated.
Example 16
[0321] 56
[0322] A. R=(CH.sub.3).sub.3C--O--CO
[0323] B. R=H.times.HCl
[0324] A: By the method of Example 1A,
1-(cis-2-fluoro-cyclopropyl)-6,7-di-
fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is converted
into
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-
-(cis-2-fluoro-cyclopropyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyl-
ic acid (74% of theory) of melting point 202-206.degree. C.
(decomposition).
[0325] B: By the method of Example 1B, the product from step A is
reacted with half-concentrated hydrochloric acid to give
7-(1-aminomethyl-2-oxa-7-
-aza-bicyclo[3.3.0]oct-7-yl)-1-(cis-2-fluoro-cyclopropyl-6-fluoro-1,4-dihy-
dro-4-oxo-3-quinolinecarboxylic acid hydrochloride of melting point
257-259.degree. C. (decomposition).
Example 17
[0326] 57
[0327] A. R=(CH.sub.3).sub.3C--O--CO
[0328] B. R=H
[0329] A: By the method of Example 1A,
1-tert-butyl-6,7-difluoro-1,4-dihyd- ro-4-oxo-3-quinolinecarboxylic
acid is converted into
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-
-tert-butyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
(84% of theory) of melting point 131-133.degree. C.
(decomposition).
[0330] B: By the method of Example 1B, the product from step A is
deblocked with half-concentrated hydrochloric acid for 15 minutes
and the resulting crude product is purified chromatographically
over silica gel using an ammoniacal mobile phase
(dichloromethane/methanol/17% ammonia 30:8:1). In addition to
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7--
yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (melting
point: >330.degree. C.), this gives
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.-
0]oct-7-yl)-1-tert-butyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid of melting point 217-218.degree. C. (decomposition).
Example 18
[0331] 58
[0332] A. R=(CH.sub.3).sub.3C--O--CO
[0333] B. R=H.times.CF.sub.3COOH
[0334] A: By the method of Example 1A,
1-(fluoro-tert-butyl)-6,7-difluoro--
1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is converted into
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-
-(fluoro-tert-butyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid (81% of theory) of melting point 161-162.degree. C.
(decomposition).
[0335] B: By the method of Example 1B, the product from step A is
deblocked with trifluoroacetic acid and the crude product which is
obtained after concentration is crystallized by treatment with
ethanol. This gives
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-(fluoro-
-tert-butyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
trifluoroacetate of melting point 197-198.degree. C.
(decomposition).
Example 19
[0336] 59
[0337] A. R=(CH.sub.3).sub.3C--O--CO
[0338] B. R=H.times.CF.sub.3COOH
[0339] A: By the method of Example 1A,
1-(difluoro-tert-butyl)-6,7-difluor-
o-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is converted into
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-
-(difluoro-tert-butyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid (59% of theory).
[0340] B: By the method of Example 6C, the product from step A is
deblocked with trifluoroacetic acid in dichloromethane, the crude
product which is obtained after concentration is taken up in water
and washed with dichloromethane and the aqueous phase is
lyophilized. This gives, in a yield of 12%,
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-(d-
ifluoro-tert-butyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid trifluoroacetate of melting point 154-160.degree. C.
(decomposition).
Example 20
[0341] 60
[0342] A. R=(CH.sub.3).sub.3C--O--CO
[0343] B. R=H.times.HCl
[0344] A: By the method of Example 1A,
1-(trifluoro-tert-butyl)-6,7-difluo-
ro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is converted into
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-
-(trifluoro-tert-butyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid (73% of theory) of melting point 131.degree. C.
[0345] B: By the method of Example 1B, the product from step A is
deblocked with hydrochloric acid. This gives, in a yield of 41%,
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-(trifluoro-tert-bu-
tyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
hydrochloride of melting point 228.degree. C. (decomposition).
Example 21
[0346] 61
[0347] A. R=(CH.sub.3).sub.3C--O--CO
[0348] B. R=H.times.HCl
[0349] A: By the method of Example 1A,
1-cyclopropyl-6,7-difluoro-5-hydrox-
y-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is converted into
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-
-cyclopropyl-6-fluoro-5-hydroxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid (63% of theory).
[0350] B: By the method of Example 1B, the product from step A is
reacted with half-concentrated hydrochloric acid to give
7-(1-aminomethyl-2-oxa-7-
-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6-fluoro-5-hydroxy-1,4-dihydro--
4-oxo-3-quinolinecarboxylic acid hydrochloride of melting point
225.degree. C. (decomposition).
Example 22
[0351] 62
[0352] A. R=(CH.sub.3).sub.3C--O--CO
[0353] B. R=H.times.HCl
[0354] A: By the method of Example 1A,
7-chloro-6-fluoro-1,4-dihydro-4-oxo-
-1-(1,2,5-thiadiazol-3-yl)-1,8-naphthyridine-3-carboxylic acid is
converted into
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.-
3.0]oct-7-yl)-6-fluoro-1,4-dihydro-4-oxo-1-(1,2,5-thiadiazol-3-yl)-1,8-nap-
hthyridine-3-carboxylic acid (66% of theory).
[0355] B: By the method of Example 1B, the product from step A is
reacted with half-concentrated hydrochloric acid to give
7-(1-aminomethyl-2-oxa-7-
-aza-bicyclo[3.3.0]oct-7-yl)-6-fluoro-1,4-dihydro-4-oxo-1-(1,2,5-thiadiazo-
l-3-yl)-1,8-naphthyridine-3-carboxylic acid hydrochloride of
melting point 207.degree. C. (decomposition).
Example 23
[0356] 63
[0357] A. R=(CH.sub.3).sub.3C--O--CO; (+)-enantiomer
[0358] B. R=H.times.HCl; (+)-enantiomer
[0359] A: A mixture of 481 mg (1.7 mmol) of
1-cyclopropyl-6,7,8-trifluoro--
1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 5 ml of
acetonitrile and 2.5 ml of dimethylformamide with 217 mg (1.9 mmol)
of 1,4-diazabicyclo[2.2.2]octane and 467 mg (1.9 mmol) of
(+)-(1R,5R)-1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oc-
tane is heated under reflux for 5 hours, and the solution is
filtered hot. The reaction product crystallizes out and is filtered
off with suction and washed with a little acetonitrile. The
precipitate is subsequently stirred well with approximately 40 ml
of water, filtered off with suction and dried at 80.degree. C.
under high vacuum.
[0360] Yield: 748 mg (87% of theory) of
(+)-(1R,5R)-7-(1-tert-butoxycarbon-
ylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluo-
ro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, -Melting point:
202-203.degree. C. (decomposition).
[0361] [.alpha.].sup.3: +94.degree. (c=0.46, CHCl.sub.3).
[0362] B: 701 mg (1.39 mmol) of
(+)-(1R,5R)-7-(1-tert-butoxycarbonylaminom-
ethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-d-
ihydro-4-oxo-3-quinolinecarboxylic acid are dissolved in 16 ml of
hot, half-concentrated hydrochloric acid and the solution is
filtered and concentrated at 60.degree. C./15 mbar. The residue is
admixed with some ethanol and reconcentrated, and the salt is
isolated and dried at 80.degree. C. under high vacuum.
[0363] Yield: 537 mg (88% of theory) of
(+)-(1S,5R)-7-(aminomethyl-2-oxa-7-
-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo--
3-quinolinecarboxylic acid hydrochloride,
[0364] Melting point: 214-216.degree. C. (decomposition).
[0365] [.alpha.].sup.3: +490 (c=0.45, DMF).
[0366] ee>99.8% (determined by capillary electrophoresis).
Example 24
[0367] 64
[0368] A. R=(CH.sub.3).sub.3C--O--CO; (-)-enantiomer
[0369] B. R=H.times.HCl; (-)-enantiomer
[0370] A: By the method of Example 23 A,
(-)-(1S,5S)-1-tert-butoxycarbonyl-
aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane gives, in a yield of
67%,
(-)-(1S,5S)-7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0-
]-oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline-carbo-
xylic acid,
[0371] Melting point: 209-210.degree. C. (decomposition).
[0372] [.alpha.].sup.3: -96.degree. (c=0.43, CHCl.sub.3).
[0373] B: By the method of Example 23 B, the product from step A is
deblocked by reaction with hydrochloric acid to give
(-)-(1RS,5S)-7-(aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopr-
opyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
hydrochloride,
[0374] Melting point: 214-216.degree. C. (decomposition).
[0375] [.alpha.].sup.3: -49.degree. (c=0.33, DMF).
[0376] ee>99.8% (determined by capillary electrophoresis).
Example 25
[0377] 65
[0378] A. R=(CH.sub.3).sub.3C--O--CO
[0379] B. R=H.times.CF.sub.3COOH
[0380] A: 250 mg (0.85 mmol) of
9-cyclopropyl-6,7-difluoro-2,3,4,9-tetrahy-
droisothiazolo[5,4-b]quinoline-3,4-dione in 101 ml of absolute
pyridine and 247 mg (1.02 mmol) of
1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bi- cyclo[3.3.0]octane
are heated under reflux overnight. After cooling, the mixture is
admixed with 40 ml of water and the precipitate is filtered off
with suction, washed with water and dried under reduced pressure.
This gives 190 mg of
7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicy-
clo[3.3.0]oct-7-yl)-9-cyclopropyl-6-fluoro-2,3,4,9-tetrahydroisothiazolo[5-
,4-b]quinoline-3,4-dione.
[0381] B: The product from step A is, by the method of Example 6C,
deblocked with trifluoroacetic acid in dichloromethane, the
solution is concentrated and evaporated repeatedly with a little
toluene, the residue is taken up in 5 ml of methanol and the salt
is precipitated out using 20 ml of isopropanol.
[0382] Yield: 163 mg of
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-y-
l)-9-cyclopropyl-6-fluoro-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,-
4-dione trifluoroacetate,
[0383] Melting point: 215.degree. C. (decomposition).
Example 26
[0384] 66
[0385] A. R=(CH.sub.3).sub.3C--O--CO
[0386] B. R=H.times.HCl
[0387] A: 0.72 g (2.72 mmol) of
9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7-
H-pyrido[1,2,3-de][1,3,4]-benzoxadiazine-6-carboxylic acid in 36 ml
of acetonitrile is admixed with 0.4 g (2.8 mmol) of
1-tert-butoxycarbonylami- nomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane
and 0.6 g of 1,4-diazabicyclo[2.2.2]octane and the mixture is
heated under reflux for 16 hours. The mixture is concentrated and
the residue is taken up in water and extracted with
dichloromethane. The extract is then dried with sodium sulphate and
concentrated, the residue is stirred with methanol and the
resulting solid is isolated and dried under reduced pressure. This
gives 0.6 g of
10-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicy-
clo[3.3.0]oct-7-yl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de-
][1,3,4]-benzoxadiazine-6-carboxylic acid of melting point
176.degree. C.
[0388] B: 0.6 g (1.9 mmol) of the product from step A is dissolved
in 105 ml of 4N hydrochloric acid/dioxane (1:1) and heated at
60.degree. C. for 2 hours. The solution is concentrated and stirred
with some ethanol and the precipitate is filtered off with suction
and dried.
[0389] Yield: 110 mg of
10-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7--
yl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,3,4]-benzoxa-
diazine-6-carboxylic acid hydrochloride,
[0390] Melting point: 233.degree. C.
Example 27
[0391] 67
[0392] A mixture of 283 mg (1 mmol) of
1-cyclopropyl-6,7,8-trifluoro-1,4-d-
ihydro-4-oxo-3-quinolinecarboxylic acid in 4 ml of acetonitrile and
2 ml of dimethylformamide and 112 mg (1 mmol) of
1,4-diazabicyclo[2.2.2]octane and 234 mg (1.3 mmol) of
1-ureidomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane is heated under
reflux for 2 hours. The mixture is concentrated and the residue is
admixed with some water and treated in an ultrasonic bath. The
undissolved precipitate is filtered off with suction, washed with
water and dried at 100.degree. C. under high vacuum.
[0393] Yield: 237 mg (53% of theory) of
1-cyclopropyl-6,8-difluoro-1,4-dih-
ydro-4-oxo-7-(1-ureidomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-3-quinoli-
necarboxylic acid,
[0394] Melting point: 185-187.degree. C. (decomposition).
Example 28
[0395] 68
[0396] By the method of Example 27,
8-chloro-1-cyclopropyl-6-fluoro-1,4-di-
hydro-4-oxo-7-(1-ureidomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-3-quinol-
inecarboxylic acid is obtained,
[0397] Melting point: 232-234.degree. C. (decomposition).
Example 29
[0398] 69
[0399] By the method of Example 27,
1-cyclopropyl-8-difluoromethoxy-6-fluo-
ro-1,4-dihydro-4-oxo-7-(1-ureidomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-
-3-quinolinecarboxylic acid is obtained,
[0400] Melting point: 232-234.degree. C. (decomposition).
Example 30
[0401] 70
[0402] By the method of Example 27,
8-chloro-6-fluoro-1-[(1R,2S)-2-fluoro--
cyclopropyl]-1,4-dihydro-4-oxo-7-(1-ureidomethyl-2-oxa-7-aza-bicyclo[3.3.0-
]oct-7-yl)-3-quinolinecarboxylic acid is obtained,
[0403] Melting point: 208-210.degree. C. (decomposition).
Example 31
[0404] 71
[0405] 310 mg (1 mmol) of
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-
-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid in 2.3 ml of dimethylformamide is heated under reflux with 2.3
ml of formic acid for 8 hours. The mixture is concentrated under
reduced pressure, the residue is stirred with 8 ml of water and the
precipitate is filtered off with suction, dried and chromatographed
over silica gel using dichloromethane/methanol (95:5) as mobile
phase.
[0406] Yield: 173 mg (40% of theory) of
1-cyclopropyl-6,8-difluoro-7-(1-fo-
rmylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1,4-dihydro-4-oxo-3-qu-
inolinecarboxylic acid,
[0407] Melting point: 208-209.degree. C. (decomposition),
Example 32
[0408] 72
[0409] 730 mg (2 mmol) of
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-
-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid are initially charged at room temperature in a mixture of 1.3
ml of water and 1 ml of 4N aqueous sodium hydroxide solution, and
the mixture is cooled with ice and admixed with 0.24 ml of carbon
disulphide. The mixture is stirred at 5.degree. C. for 1 hour and
subsequently at room temperature for another 15 hours. The
suspension is admixed with 50 ml of acetone and cooled, and the
precipitate is filtered off with suction, washed with acetone and
dried at 80.degree. C. under high vacuum. This gives 657 mg of the
sodium salt of the dithiourethane. 409 mg of this sodium salt are
initially charged in 5 ml of dimethylformamide and admixed with 123
mg of 1-bromopropane in 1 ml of dimethylformamide, and the mixture
is stirred at room temperature overnight. The mixture is
concentrated at 70.degree. C./12 mbar, the residue is stirred with
ethanol, the precipitate is filtered off with suction and dried and
the resulting crude product (225 mg) is purified by chromatography
over silica gel using dichloromethane/methanol/17% ammonia
(150:4:1).
[0410] Yield: 56 mg of
7-(1-propylthio-thiocarbonylaminomethyl-2-oxa-7-aza- -bicyclo
[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-q-
uinolinecarboxylic acid,
[0411] Melting point: 162-166.degree. C. (decomposition).
Example 33
[0412] 73
[0413] 395 mg (1 mmol) of
7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-
-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid in 15 ml of dichloromethane are admixed with 406 mg (2 mmol)
of bis(trimethylsilyl)acetamide and stirred at 25.degree. C. for 3
hours. The mixture is subsequently admixed with 173 mg (1 mol) of
diethylphosphoryl chloride and stirred at room temperature for 24
hours. Unreacted starting material is filtered off with suction,
the mother liquor is concentrated and the residue is
chromatographed over silica gel (mobile phase:
dichloromethane/methanol 95:5).
[0414] Yield: 73 mg (1.5%) of
7-(1-diethoxyphosphoryl-aminomethyl-2-oxa-7--
aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-
-quinolinecarboxylic acid,
[0415] FAB-MS: m/e 542 [(M+H).sup.+], 524.
Example 34
[0416] 74
[0417] A. R=(CH.sub.3).sub.3C--O--CO
[0418] B. R=H.times.HCl
[0419] A: A mixture of 283 mg (1 mmol) of
1-cyclopropyl-6,7,8-trifluoro-1,-
4-dihydro-4-oxo-3-quinolinecarboxylic acid in 3 ml of acetonitrile
and 1.5 ml of dimethylformamide and 120 mg (1.07 mmol) of
1,4-diazabicyclo[2.2.2]- octane and 400 mg of (1.5 mmol) of
1-(N-tert-butoxycarbonyl-N-ethyl-aminom-
ethyl)-2-oxa-7-aza-bicyclo[3.3.0]octane is heated under reflux for
6 hours, the solution is concentrated, and the residue is admixed
with 20 ml of water and treated in an ultrasonic bath. The
undissolved precipitate is filtered off with suction, washed with
water and dried at 80.degree. C. under high vacuum.
[0420] Yield: 460 mg (86% of theory) of
7-[1-(N-tert-butoxycarbonyl-N-ethy-
laminomethyl)-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl]-1-cyclopropyl-6,8-difluo-
ro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
[0421] Melting point: 166-168.degree. C. (decomposition).
[0422] B: 430 mg (0.8 mmol) of the product from step A are
dissolved in 15 ml of hot, half-concentrated hydrochloric acid, and
the solution is filtered and concentrated at 60.degree. C./15 mbar.
The residue is admixed with some ethanol and reconcentrated, and
the salt is isolated and dried at 80.degree. C. under high
vacuum.
[0423] Yield: 272 mg (72% of theory) of
7-(ethylaminomethyl-2-oxa-7-aza-bi-
cyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quino-
linecarboxylic acid hydrochloride,
[0424] Melting point: 280-281.degree. C. (decomposition).
Example 35
[0425] 75
[0426] A. R=(CH.sub.3).sub.3C--O--CO
[0427] B. R=H.times.HCl
[0428] A: By the method of Example 1A,
9,10-difluoro-3(S)-methyl-7-oxo-2,3-
-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid is
converted into
10-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3-
.3.0]oct-7-yl)-9-fluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][-
1,4]benzoxazine-6-carboxylic acid of melting point 157-158.degree.
C. (decomposition).
[0429] B: By the method of Example 1B, the product from step A is
reacted with half-concentrated hydrochloric acid to give
10-(1-aminomethyl-2-oxa-- 7-aza-bicyclo[3.3.0]oct-7-yl)-9-fluoro-3
(S)-methyl-7-oxo-2,3-dihydro-7H-p-
yrido[1,2,3-de]-[1,4]benzoxazine-6-carboxylic acid hydrochloride of
melting point 191-193.degree. C. (decomposition).
Example 36
[0430] 76
[0431] 350 mg, (1.21 mmol) of ethyl
8-cyano-1-cyclopropyl-6,7-difluoro-1,4-
-dihydro-4-oxo-quinolinecarboxylate and 260 mg (1.2 mmol) of
(1SR,5RS)-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]octane
dihydrochloride in 30 ml of absolute acetonitrile are admixed with
470 mg (4.64 mmol) of triethylamine and stirred at room temperature
overnight. The mixture is concentrated and the residue is purified
chromatographically (silica gel; dichloromethane/methanol 9:1). 450
mg (86% of theory) of ethyl
7-([1SR,5RS]-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]oct-7-yl)-8-cyano-1-c-
yclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylate are
isolated, melting point: 193.degree. C.
[0432] Ethyl
7-([1R,5S]-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]oct-7-yl)-8-
-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxyl
ate and 7-([1S,5R]-1-aminomethyl-2-oxa-7-azabicyclo
[3.3.0]oct-7-yl)-8-cyano-1-cy-
clopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylate are also
prepared in a corresponding manner.
* * * * *