U.S. patent application number 10/432043 was filed with the patent office on 2004-04-01 for dehalogeno compounds.
Invention is credited to Hayakawa, Isao, Itoh, Masao, Miyauchi, Rie, Takahashi, Hisashi, Takemura, Makoto.
Application Number | 20040063754 10/432043 |
Document ID | / |
Family ID | 26604261 |
Filed Date | 2004-04-01 |
United States Patent
Application |
20040063754 |
Kind Code |
A1 |
Takahashi, Hisashi ; et
al. |
April 1, 2004 |
Dehalogeno compounds
Abstract
3-(1-Aminocycloalkyl)pyrrolidinyl-substituted-6-dehalodeno(hydrogen-substi-
tuted)quinolon carboxylic acid derivatives having specific
substitunets as represented by the following formula (I), its
salts, and hydrates thereof exhibit a broad and potent
antibacterial activity on gram-negative and gram-positive bacteria,
in particular, resistant bacteria typified by gram-positive cocci,
including MRSA, PRSP and VRE. Thus these compounds are usable as
drugs. 1
Inventors: |
Takahashi, Hisashi;
(Edogawa-ku, JP) ; Miyauchi, Rie; (Edogawa-ku,
JP) ; Itoh, Masao; (Edogawa-ku, JP) ;
Takemura, Makoto; (Edogawa-ku, JP) ; Hayakawa,
Isao; (Edogawa-ku, JP) |
Correspondence
Address: |
SUGHRUE MION, PLLC
2100 PENNSYLVANIA AVENUE, N.W.
SUITE 800
WASHINGTON
DC
20037
US
|
Family ID: |
26604261 |
Appl. No.: |
10/432043 |
Filed: |
May 19, 2003 |
PCT Filed: |
November 19, 2001 |
PCT NO: |
PCT/JP01/10086 |
Current U.S.
Class: |
514/312 ;
514/300; 546/123; 546/156 |
Current CPC
Class: |
C07D 401/04 20130101;
C07D 471/04 20130101; A61P 31/04 20180101; A61P 31/00 20180101 |
Class at
Publication: |
514/312 ;
546/156; 514/300; 546/123 |
International
Class: |
C07D 471/02; C07D 43/02;
A61K 031/4745; A61K 031/4709 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 20, 2000 |
JP |
2000-352269 |
Aug 20, 2001 |
JP |
2001-248822 |
Claims
1. A compound represented by the following general formula (I), its
salts, and hydrates thereof: 41[wherein R.sup.1 represents an alkyl
group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6
carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a
cyclic alkyl group having 3 to 6 carbon atoms, which may have a
substituent, an aryl group, which may have a substituent, a
heteroaryl group, which may have a substituent, an alkoxy group
having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6
carbon atoms; R.sup.2 represents an alkylthio group having 1 to 6
carbon atoms or a hydrogen atom, wherein R.sup.2 and the
abovementioned R.sup.1 may be integrated to form a ring structure
by incorporating a part of the mother skeleton, the thus formed
ring may contain a sulfur atom as a ring-constituent atom, and the
ring may be substituted by an alkyl group having 1 to 6 carbon
atoms, which may have a substituent; R.sup.3 represents a
phenylalkyl group composed of an alkylene group having 1 to 6
carbon atoms and a phenyl group, an alkyl group having 1 to 6
carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, a
hydrogen atom, a phenyl group, an acetoxymethyl group, a
pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group,
a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl
group, a 5-alkyl-2-oxo-1,3-dioxole-4-ylmethyl group, or a
3-acetoxy-2-oxobutyl group; R.sup.4 represents an alkyl group
having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon
atoms, an alkynyl group having 2 to 6 carbon atoms, an alkoxy group
having 1 to 6 carbon atoms, a hydrogen atom, an amino group, a
hydroxyl group, a thiol group, or a halogenomethyl group, and among
the above, the amino group may have one or more substituents
selected from among the group consisting of an alkyl group having 1
to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, and a
formyl group; A represents a nitrogen atom or a partial structure
represented by formula (II): 42 (wherein X represents an alkyl
group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6
carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an
alkoxy group having 1 to 6 carbon atoms, a hydrogen atom, an amino
group, a halogen atom, a cyano group, a halogenomethyl group, or a
halogenomethoxy group, among the above, the amino group may have
one ore more substituents selected from the group consisting of an
alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5
carbon atoms, and a formyl group, wherein X.sup.1 and the
aforementioned R.sup.1 may be integrated to form a ring structure
by incorporating a part of the mother skeleton, the thus formed
ring may contain an oxygen atom, a nitrogen atom, or a sulfur atom
as a ring constituent atom, and this ring may be substituted by an
alkyl group having 1 to 6 carbon atoms, which may have a
substituent); each of R.sup.5 and R.sup.6 independently represents
an alkyl group having 1 to 6 carbon atoms, a hydrogen atom, or a
substituted carboxyl group derived from an amino acid, dipeptide,
or tripeptide, wherein the alkyl group may have one ore more
substituents selected from the group consisting of an alkylthio
group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6
carbon atoms, a hydroxyl group, and a halogen atom; and n
represents an integer 1 or 2].
2. The compound according to claim 1, its salts or hydrates
thereof, wherein the compound of formula (I) is a stereochemically
pure compound.
3. The compound according to claim 1 or 2, its salts or hydrates
thereof, wherein n in the formula (I) is 1.
4. The compound according to any one of claims 1 to 3, its salts or
hydrates thereof, wherein R.sup.3 in the formula (I) is a hydrogen
atom.
5. The compound according to any one of claims 1 to 4, its salts or
hydrates thereof, wherein R.sup.2 in the formula (I) is a hydrogen
atom.
6. The compound according to any one of claims 1 to 5, its salts or
hydrates thereof, wherein R.sup.4 in the formula (I) is a hydrogen
atom.
7. The compound according to any one of claims 1 to 6, its salts or
hydrates thereof, wherein A in the formula (I) is a partial
structure represented by the formula (II).
8. The compound according to claim 7, its salts or hydrates
thereof, wherein X.sup.1 in the formula (II) is a methoxy group, a
methyl group, a difluoromethoxy group, a fluorine atom, or a
chlorine atom.
9. The compound according to claim 7, its salts or hydrates
thereof, wherein X.sup.1 in the formula (II) is a methoxy group or
a methyl group.
10. The compound according to any one of claims 1 to 9, its salts
or hydrates thereof, wherein each of R.sup.5 and R.sup.6 in the
formula (I) is a hydrogen atom.
11. The compound according to any one of claims 1 to 9, its salts
or hydrates thereof, wherein one of either R.sup.5 or R.sup.6 in
the formula (I) is a hydrogen atom and the other is a methyl
group.
12. The compound according to any one of claims 1 to 9, its salts
or hydrates thereof, wherein one of either R.sup.5 or R.sup.6 in
formula (I) is a hydrogen atom and the other is a substituted
carboxyl group derived from an amino acid, a dipeptide, or a
tripeptide.
13. The compound according to any one of claims 1 to 12, its salts
or hydrates thereof, wherein the cyclic alkyl group having 3 to 6
carbon atoms, which may have a substituent, in R.sup.1 is a
halogenocyclopropyl group.
14. The compound according to claim 13, its salts or hydrates
thereof, wherein the halogenocyclopropyl group is a
1,2-cis-2-halogenocyclopropyl group.
15. The compound according to claim 14, its salts or hydrates
thereof, wherein the halogenocyclopropyl group is a
stereochemically pure substituent.
16. The compound according to claim 15, its salts or hydrates
thereof, wherein the halogenocyclopropyl group is a (1R,
2S)-2-halogenocyclopropyl group.
17. The compound according to any one of claims 13 to 16, its salts
or hydrates thereof, wherein the halogen atom of the
halogenocyclopropyl group is a fluorine atom.
18.
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cy-
clopropyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,
its salts or hydrates thereof.
19.
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cy-
clopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salts
or hydrates thereof.
20.
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cy-
clopropyl]-8-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
its salts or hydrates thereof.
21.
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cy-
clopropyl]-8-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
its salts or hydrates thereof.
22.
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cy-
clopropyl]-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic
acid, its salts or hydrates thereof.
23.
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cy-
clopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid,
its salts or hydrates thereof.
24.
7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro--
1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic
acid, its salts or hydrates thereof.
25.
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cy-
clopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid,
its salts or hydrates thereof.
26.
7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro--
1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic
acid, its salts or hydrates thereof.
27.
7-[3-(R)-[1-(ethylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-
-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic
acid, its salts or hydrates thereof.
28.
5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro--
1-(R)-cyclopropyl]-1,4-dihydro-8-fluoro-4-oxoquinoline-3-carboxy
lic acid, its salts or hydrates thereof.
29.
5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro--
1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic
acid, its salts or hydrates thereof.
30.
5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro--
1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic
acid, its salts or hydrates thereof.
31.
5-amino-7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-
-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxyl-
ic acid, its salts or hydrates thereof.
32.
10-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-2,3-dihydro-3-(S)-methy-
l-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid, its
salts or hydrates thereof.
33.
1-(cyclopropyl)-8-methyl-7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolid-
in-1-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salts or
hydrates thereof.
34. A medicament, which comprises the compound described in any one
of claims 1 to 33, its salts or hydrates thereof as an active
ingredient.
35. An antibacterial agent, which comprises the compound described
in any of claims 1 to 33, its salts or hydrates thereof, as an
active ingredient.
36. A therapeutic agent for an infectious disease, which comprises
the compound described in any of claims 1 to 33, its salts or
hydrates thereof, as an active ingredient.
37. A method for treating a disease, which comprises administrating
the compound described in any of claims 1 to 33, its salts or
hydrates thereof, as an active ingredient.
38. A method for treating an infectious disease, which comprises
administrating the compound described in any of claims 1 to 33, its
salts or hydrates thereof, as an active ingredient.
39. A method for producing a medicament, which comprises
formulating the compound described in any of claims 1 to 33, its
salts or hydrates thereof, as an active ingredient.
40. A method for producing an antibacterial agent, which comprises
formulating the compound described in any of claims 1 to 33, its
salts or hydrates thereof, as an active ingredient.
41. A method for producing an infectious disease treating agent,
which comprises formulating the compound described in any of claims
1 to 33, its salts or hydrates thereof, as an active
ingredient.
42. Use of the compound described in any of claims 1 to 33, its
salts or hydrates thereof, for the production of a medicament.
43. Use of the compound described in any of claims 1 to 33, its
salts or hydrates thereof for the production of an antibacterial
agent.
44. Use of the compound described in any of claims 1 to 33, its
salts or hydrates thereof for the production of an infectious
disease treating agent.
Description
TECHNICAL FIELD
[0001] This invention relates to a synthetic quinolone
antibacterial agent which is useful as medicaments, veterinary
drugs, drugs for fishery use, or antibacterial preservatives.
BACKGROUND ART
[0002] Since the discovery of norfloxacin, synthetic quinolone
antibacterial agents have been improved in antibacterial activity
and pharmacokinetics, and many compounds are now used in the
clinical filed as chemotherapeutic agents which are effective for
in almost systemic infectious diseases.
[0003] In recent years, generation of bacteria having low
sensitivity to synthetic quinolone antibacterial agents have been
increasing in clinical situations. For example, like the case of
Staphylococcus aureus (MRSA) and Streptococcus pneumococcus (PRSP)
which are insusceptible to .beta.-lactam antibiotics and
Enterococcus (VRE) which is insusceptible to aminoglycoside
antibacterial agents, a case has been increasing in which a
gram-positive bacteria originally resistant to drugs other than
synthetic quinolone antibacterial agents also became low sensitive
to synthetic quinolone antibacterial agents. In consequence,
synthetic quinolone antibacterial agents having higher efficacy are
thus being demanded in clinical situations.
[0004] With regard to the side effects of synthetic quinolone
antibacterial agents, in addition to the central nervous system
stimulation effect, which has been a problem since priorly, the
induction of convulsion resulting from combined use with
nonsteroidal anti-inflammatory agents, phototoxicity, etc. have
also become known, and the development of synthetic quinolone
antibacterial agents having higher safety is thus also being
demanded.
[0005] It is known that the structure of the substituents at the
7-position and 1-position (or positions corresponding to these
positions; the same shall apply hereinafter) have a large influence
on the antibacterial activity, pharmacokinetics, and safety of
synthetic quinolone antibacterial agents.
[0006] Quinolone derivatives, having a pyrrolidinyl group having an
aminomethyl group at the 3-position, as the substituent at the
7-position of the quinolone mother skeleton, are known to exhibit
strong antibacterial activity against gram-negative and
gram-positive bacteria. For example, there are
7-[3-(1-aminomethyl)pyrrolidin-1-yl]quinolone carboxylic acid
derivatives [Journal of Medicinal Chemistry, vol. 29, p. 445
(1986)].
[0007] Furthermore, known examples of quinolone carboxylic acid
derivatives having a substituent on the carbon atom of the
aminomethyl group of the 3-(1-aminomethyl)pyrrolidin-1-yl group
include 7-[3-(1-aminoethyl)pyrrolidin-1-yl]quinolone carboxylic
acid derivatives [Journal of Medicinal Chemistry, vol. 36, p. 871
(1993)]; 7-[3-(1-amino-1-methylethyl)pyrrolidin-1-yl]quinolone
carboxylic acid derivatives [Journal of Medicinal Chemistry, vol.
37, p. 733 (1994)]; and
7-[3-(1-aminoalkyl)pyrrolidin-1-yl]quinolone carboxylic acid
derivatives [Chemical and Pharmaceutical Bulletin, vol. 42, p. 1442
(1994)], etc.
[0008] However, though the abovementioned quinolone derivatives,
having a 3-(aminomethyl)pyrrolidin-1-yl group, a
3-(1-aminoethyl)pyrrolidin-1-yl group, or a group having a
structure similar to these as a substituent, are compounds which
exhibit strong antibacterial activity, it has been found that due
to the low selective toxicity [see for example, Journal of
Antimicrobial Chemotherapy, vol. 33, p. 685 (1994)], these
compounds act not only on bacteria but also on the cells of
eukaryotic organisms, and they are difficult to use as medical
drugs or as veterinary drugs. Therefore, quinolone compounds having
these substituents have not been put to actual clinical use up
until now.
[0009] Meanwhile, quinolone carboxylic acid derivatives, which have
a 3-(1-aminocycloalkyl)pyrrolidin-1-yl group as a substituent and
are relevant to the present invention, have been described in the
form of abroad concept in PCT/JP96/00208, which provides a
description of compounds with the structure shown in formula A or
formula B. That is, with a quinolone compound of formula A, the
substituent (X.sup.1) at the 6-position is defined as being a
halogen atom or a hydrogen atom. However, only quinolone carboxylic
acids wherein the fluorine atom or other halogen atom is the
substituent at the 6-position are disclosed specifically in the
abovementioned patent application. Therefore, PCT/JP96/00208 does
not provide a specific description concerning quinolone carboxylic
acids wherein hydrogen is substituted at the 6-position.
Furthermore, this publication does not provide any specific
disclosure as embodiments of
3-(1-aminocycloalkyl)pyrrolidinyl-substitute-
d-6-hydrogen-substituted-quinolone carboxylic acids, wherein the
present invention is concerned. 2
[0010] [In the above formula A, X.sup.1 represents a halogen atom
or a hydrogen atom and X.sup.2 represents a halogen atom. (The
definitions of the substituents in the compound shown in formula A
are those given in PCT/JP96/00208 and are irrelevant to the
definitions of substituents of the present invention even when the
same symbols are used.)]
[0011] In the above formula A, R.sup.2 is represented by formula B:
3
[0012] [In the above formula B, p represents an integer from 1 to
3, q represents an integer from 1 to 3, R.sup.9 represents a
hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
R.sup.10 represents a hydrogen atom, an alkyl group having 1 to 6
carbon atoms, an alkyl group having 1 to 6 carbon atoms that has a
hydroxyl group, or an alkyl group having 1 to 6 carbon atoms that
has a halogen atom. (The definitions of the substituents in the
compound shown in formula B are those given in PCT/JP96/00208 and
are irrelevant to the definitions of substituents of the present
invention even when the same symbols are used.)]
[0013] Besides the above, an example of a literature that indicates
a quinolone carboxylic acid derivative, which has a
3-(1-aminocycloalkyl)py- rrolidin-1-yl group and is relevant to the
present invention, is Chemical and Pharmaceutical Bulletin, vol.
42, p. 1442 (1994). However, this literature does not contain any
description whatsoever concerning
3-(1-aminocycloalkyl)pyrrolidinyl-substituted-6-hydrogen-substituted-quin-
olone carboxylic acids, which are compounds of the present
invention.
[0014] Furthermore, for example, PCT/WO99/14214 indicates a
6-hydrogen-substituted-quinolone carboxylic acid derivative, in
which a nitrogen-containing heterocyclic substituent, for example,
the 3-(1-aminoethyl)pyrrolidin-1-yl group, is introduced via a
carbon-nitrogen bond into the 7-position of the quinolone skeleton
and which is relevant to this invention. This application describes
compounds represented by the formulas C and D. However, this
application does not contain any description whatsoever concerning
a 3-(1-aminocycloalkyl)pyrr- olidin-1-yl group, which is relevant
to the present invention, as a substituent at the 7-position of the
quinolone skeleton shown in formula C. Furthermore, this
application does not contain any description whatsoever concerning
3-(1-aminocycloalkyl)pyrrolidinyl-substituted-6-hyd-
rogen-substituted-quinolone carboxylic acids, which are relevant to
the present invention and have the above-mentioned group as a
substituent. 4
[0015] [In the above formula C, R1 represents a cyclic alkyl group
having 3 to 6 carbon atoms, an alkyl group having 1 or 2 carbon
atoms, a straight-chain alkenyl group having 2 to 3 carbon atoms,
or a branched-chain alkyl group or alkenyl group having 3 to 4
carbon atoms, this alkyl group or cyclic alkyl group may be
unsubstituted or the alkyl group or cyclic alkyl group may be
substituted by 1 to 3 fluorine atoms or by a phenyl group which is
unsubstituted or is substituted by 1 to 3 fluorine atoms or is
substituted at the 4-position by a single hydroxyl group, R6
represents a hydrogen atom, a hydroxyl group, an aminocarbonyl
group, a bromine atom, a cyano group, an alkyl group having 1 or 2
carbon atoms, or an alkenyl group or alkynyl group having 2 to 4
carbon atoms, and this alkyl group may be unsubstituted or the
alkyl group may be substituted by a methyl group or an ethyl group
that is unsubstituted or is substituted by 1 to 3 fluorine atoms or
one hydroxyl group or amino group. (The definitions of the
substituents in the compound shown in formula C are those given in
PCT/WO99/14214 and are irrelevant to the definitions of
substituents of the present invention even when the same symbols
are used.)]
[0016] In the above formula, X is represented by formula D: 5
[0017] [In the above formula D, R7 represents an amino group, which
is bonded to a carbon that is not adjacent the nitrogen atom of the
pyrrolidine ring and may be unsubstituted or substituted by one or
two alkyl groups with 1 to 3 carbon atoms, or an aminoalkyl group,
which is bonded to a carbon on the pyrrolidine ring and may be
unsubstituted or substituted by an alkyl group having 1 to 3 carbon
atoms, R9 represents a group selected from among the group
comprised of a hydrogen atom, an alkyl group having 1 to 4 carbon
atoms, an alkenyl group and alkynyl group having 2 to 6 carbon
atoms, and fused and spiroalkyl group having 3 to 6 carbon atoms,
the alkyl group portions of these groups maybe unsubstituted or
substituted by 1 to 3 fluorine atoms, and the abovementioned
substituents R7 and R9 may be integrated to form a fused or Spiro
type ring structure with the pyrrolidine ring, with this fused or
spirocyclic part being formed from 2 to 5 carbon atoms and 0 or 1
nitrogen atom. (The definitions of the substituents in the compound
shown in formula D are those given in PCT/WO99/14214 and are
irrelevant to the definitions of substituents of the present
invention even when the same symbols are used.)]
[0018] Other examples of literature that indicate
6-hydrogen-substituted-q- uinolone carboxylic acid derivatives,
which are relevant to the present invention, include Journal of
Medicinal Chemistry, vol. 39, p. 4952 (1996). However, even this
literature does not contain any description whatsoever concerning
3-(1-aminocycloalkyl)pyrrolidinyl-substituted-6-hyd-
rogen-substituted-quinolone carboxylic acids, which are the
compounds of the present invention.
DISCLOSURE OF THE INVENTION
[0019] The present inventors have conducted intensive studies to
obtain quinolone compounds, which are excellent in antibacterial
activity, high in efficacy, and yet excellent in safety. As a
result, it has been found that
3-(1-aminocycloalkyl)pyrrolidinyl-substituted-6-dehalogeno(hydrogen--
substituted)quinolone carboxylic acid derivatives represented by
formula (I) described below, its salts and hydrates thereof exhibit
potent antibacterial activity upon a broad range of gram-negative
bacteria and gram-positive bacteria and, in particular, exhibit
potent antibacterial activity against drug-resistant bacteria, as
represented by gram-positive cocci, including MRSA, PRSP, and
VRE.
[0020] Furthermore, it has been found that, in addition to
exhibiting such excellent antibacterial activity, the compounds of
this invention are excellent both in terms of safety and
pharmacokinetics and thus enable use in clinical situations, which
could not be achieved with compounds prior to this invention which
have substituents of the same structure at the 7-position of the
quinolone mother skeleton. The present invention has been achieved
based on these findings.
[0021] A comparison of the 6-hydrogen-substituted-quinolone
carboxylic acid derivatives represented by formula (I), its salts
and hydrates thereof according to the present invention with
quinolone compounds wherein the hydrogen at the 6-position of a
compound of this invention is substituted by a fluorine atom shows
that both types of compounds exhibit excellent antibacterial
activity upon a broad range of both gram-negative bacteria and
gram-positive bacteria, including drug-resistant bacteria. However,
it has been found unexpectedly that the 6-hydrogen-substituted-q-
uinolone derivatives, which are the compounds of this invention,
are compounds that, in comparison to the
6-fluorine-substituted-quinolone derivatives, are compounds of
excellent safety that are reduced in acute toxicity and
significantly reduced in micronuclus induction, and also exhibit
good pharmacokinetics, such as improved urinary recovery, etc.
[0022] That is, the present inventors have found that even a
quinolone compound, which has a
3-(1-aminocycloalkyl)pyrrolidin-1-yl group having a cyclic alkyl
group as a substituent on the methyl group of the
3-(aminomethyl)pyrrolidin-1-yl group and which as has been
mentioned above is known to be low in selective toxicity, will
unexpectedly be a compound with excellent selective toxicity and be
a compound of excellent pharmacokinetics as long as it is a
quinolone compound with the structure of the present invention.
[0023] That is, the present invention concerns compounds
represented by the following general formula (I), its salts, and
hydrates thereof: 6
[0024] [wherein R.sup.1 represents an alkyl group having 1 to 6
carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a
halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl
group having 3 to 6 carbon atoms, which may have a substituent, an
aryl group, which may have a substituent, a heteroaryl group, which
may have a substituent, an alkoxy group having 1 to 6 carbon atoms,
or an alkylamino group having 1 to 6 carbon atoms;
[0025] R.sup.2 represents an alkylthio group having 1 to 6 carbon
atoms or a hydrogen atom,
[0026] wherein R.sup.2 and the abovementioned R.sup.1 may be
integrated to form a ring structure by incorporating a part of the
mother skeleton, the thus formed ring may contain a sulfur atom as
a ring-constituent atom, and the ring may be substituted by an
alkyl group having 1 to 6 carbon atoms, which may have a
substituent;
[0027] R.sup.3 represents a phenylalkyl group composed of an
alkylene group having 1 to 6 carbon atoms and a phenyl group, an
alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group
having 2 to 7 carbon atoms, a hydrogen atom, a phenyl group, an
acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl
group, a choline group, a dimethylaminoethyl group, a 5-indanyl
group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxole-4-ylmethyl
group, or a 3-acetoxy-2-oxobutyl group;
[0028] R.sup.4 represents an alkyl group having 1 to 6 carbon
atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl
group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6
carbon atoms, a hydrogen atom, an amino group, a hydroxyl group, a
thiol group, or a halogenomethyl group, and
[0029] among the above, the amino group may have one or more
substituents selected from among the group consisting of an alkyl
group having 1 to 6 carbon atoms, an acyl group having 2 to 5
carbon atoms, and a formyl group;
[0030] A represents a nitrogen atom or a partial structure
represented by formula (II): 7
[0031] (wherein X represents an alkyl group having 1 to 6 carbon
atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl
group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6
carbon atoms, a hydrogen atom, an amino group, a halogen atom, a
cyano group, a halogenomethyl group, or a halogenomethoxy
group,
[0032] among the above, the amino group may have one ore more
substituents selected from the group consisting of an alkyl group
having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbon
atoms, and a formyl group,
[0033] wherein X.sup.1 and the aforementioned R.sup.1 may be
integrated to form a ring structure by incorporating a part of the
mother skeleton, the thus formed ring may contain an oxygen atom, a
nitrogen atom, or a sulfur atom as a ring constituent atom, and
this ring may be substituted by an alkyl group having 1 to 6 carbon
atoms, which may have a substituent);
[0034] each of R.sup.5 and R.sup.6 independently represents an
alkyl group having 1 to 6 carbon atoms, a hydrogen atom, or a
substituted carboxyl group derived from an amino acid, dipeptide,
or tripeptide,
[0035] wherein the alkyl group may have one ore more substituents
selected from the group consisting of an alkylthio group having 1
to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a
hydroxyl group, and a halogen atom; and n represents an integer 1
or 2].
[0036] The present invention also relates to each of the
following:
[0037] a compound of the above formula (I), its salts or hydrates
thereof, wherein the compound of formula (I) is a stereochemically
pure compound;
[0038] a compound of the formula (I), its salts or hydrates
thereof, wherein n in the formula (I) is 1;
[0039] a compound of the formula (I), its salts or hydrates
thereof, wherein R.sup.3 in the formula (I) is a hydrogen atom;
[0040] a compound of the formula (I), its salts or hydrates
thereof, wherein R.sup.2 in the formula (I) is a hydrogen atom;
[0041] a compound of the formula (I), its salts or hydrates
thereof, wherein R.sup.4 in the formula (I) is a hydrogen atom;
[0042] a compound of the formula (I), its salts or hydrates
thereof, wherein A in the formula (I) is a partial structure
represented by the formula (II);
[0043] a compound of the formula (I), its salts or hydrates
thereof, wherein X.sup.1 in the formula (II) is a methoxy group, a
methyl group,
[0044] a difluoromethoxy group, a fluorine atom, or a chlorine
atom;
[0045] a compound of the formula (I), its salts or hydrates
thereof, wherein X.sup.1 in the formula (II) is a methoxy group or
a methyl group;
[0046] a compound of the formula (I), its salts or hydrates
thereof, wherein each of R.sup.5 and R.sup.6 in the formula (I) is
a hydrogen atom;
[0047] a compound of the formula (I), its salts or hydrates
thereof, wherein one of either R.sup.5 or R.sup.6 in the formula
(I) is a hydrogen atom and the other is a methyl group;
[0048] a compound of the formula (I), its salts or hydrates
thereof, wherein one of either R.sup.5 or R.sup.6 in formula (I) is
a hydrogen atom and the other is a substituted carboxyl group
derived from an amino acid, a dipeptide, or a tripeptide;
[0049] a compound of the formula (I), its salts or hydrates
thereof, wherein each of the R.sup.5 and R.sup.6 in formula (I) is
a combination of a hydrogen atom and a methyl group;
[0050] a compound of the formula (I), its salts or hydrates
thereof, wherein R.sup.6 in formula (I) is a substituted carboxyl
group derived from an amino acid, a dipeptide, or a tripeptide;
[0051] a compound of the formula (I), its salts or hydrates
thereof, wherein the cyclic alkyl group having 3 to 6 carbon atoms,
which may have a substituent, in R.sup.1 is a halogenocyclopropyl
group;
[0052] a compound of the formula (I), its salts or hydrates
thereof, wherein the halogenocyclopropyl group is a
1,2-cis-2-halogenocyclopropyl group;
[0053] a compound of the formula (I), its salts or hydrates
thereof, wherein the halogenocyclopropyl group is a
stereochemically pure substituent;
[0054] a compound of the formula (I), its salts or hydrates
thereof, wherein the halogenocyclopropyl group is a (1R,
2S)-2-halogenocyclopropyl group;
[0055] a compound of the formula (I), its salts or hydrates
thereof, wherein the halogen atom of the halogenocyclopropyl group
is a fluorine atom;
[0056]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-
-cyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic
acid, its salts or hydrates thereof;
[0057]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-
-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its
salts or hydrates thereof;
[0058]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-
-cyclopropyl]-8-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic
acid, its salts or hydrates thereof;
[0059]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-
-cyclopropyl]-8-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic
acid, its salts or hydrates thereof;
[0060]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-
-cyclopropyl]-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic
acid, its salts or hydrates thereof;
[0061]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-
-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic
acid, its salts or hydrates thereof;
[0062]
7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluo-
ro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic
acid, its salts or hydrates thereof;
[0063]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-
-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic
acid, its salts or hydrates thereof;
[0064]
7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluo-
ro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic
acid, its salts or hydrates thereof;
[0065]
7-[3-(R)-[1-(ethylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluor-
o-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic
acid, its salts or hydrates thereof;
[0066]
5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluo-
ro-1-(R)-cyclopropyl]-1,4-dihydro-8-fluoro-4-oxoquinoline-3-carboxylic
acid, its salts or hydrates thereof;
[0067]
5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluo-
ro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic
acid, its salts or hydrates thereof;
[0068]
5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluo-
ro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic
acid, its salts or hydrates thereof;
[0069]
5-amino-7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2--
(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carbo-
xylic acid, its salts or hydrates thereof;
[0070]
10-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-2,3-dihydro-3-(S)-me-
thyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid,
its salts or hydrates thereof;
[0071]
1-(cyclopropyl)-8-methyl-7-[3-(R)-[1-(methylamino)cyclopropyl]pyrro-
lidin-1-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salts
or hydrates thereof;
[0072] a medicament, which comprises a compound of formula (I), its
salts or hydrates thereof as an active ingredient;
[0073] an antibacterial agent, which comprises a compound of
formula (I), its salts or hydrates thereof as an active
ingredient;
[0074] a therapeutic agent for an infectious disease, which
comprises a compound of the formula (I), its salts or hydrates
thereof as an active ingredient;
[0075] a method for treating a disease, which comprises
administrating a compound of the formula (I), its salts or hydrates
thereof as an active ingredient;
[0076] a method for treating an infectious disease, which comprises
administrating a compound of the formula (I), its salts or hydrates
thereof as an active ingredient;
[0077] a method for producing a medicament, which comprises
formulating a compound of the formula (I), its salts or hydrates
thereof as an active ingredient;
[0078] a method for producing an antibacterial agent, which
comprises formulating a compound of the formula (I), its salts or
hydrates thereof as an active ingredient;
[0079] a method for producing an infectious disease treating agent,
which comprises formulating a compound of the formula (I), its
salts or hydrates thereof as an active ingredient;
[0080] use of a compound of the formula (I), its salts or hydrates
thereof for the production of a medicament;
[0081] use of a compound of the formula (I), its salts or hydrates
thereof for the production of an antibacterial agent;
[0082] use of a compound of the formula (I), its salts or hydrates
thereof for the production of an infectious disease treating
agent;
[0083] and so on.
[0084] (Mode for Carrying out the Invention)
[0085] The various substituents of the compound of this invention
represented by formula (I): 8
[0086] (R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, n and
A are defined as has been described above) shall now be described.
(For the 6-position of the quinolone mother skeleton or an
equivalent position in the structural formulae indicated in the
present specification, in order to stress that a hydrogen atom is
bonded, the hydrogen atom that is bonded to a carbon, which is
normally not indicated as customary in structural formulae in
organic chemistry, is indicated in some cases (in the form of
"--H"). However, the structural formulae of this specification are
indicated in line with the rules of indication of structural
formulae that are normally practiced in the field of organic
chemistry, and a hydrogen atom that is bonded to a carbon atom will
not always be indicated but will normally be omitted.)
[0087] The substituent R.sup.1 is an alkyl group having 1 to 6
carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a
halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl
group having 3 to 6 carbon atoms, which may have a substituent, an
aryl group, which may have a substituent, a heteroaryl group, which
may have a substituent, an alkoxy group having 1 to 6 carbon atoms,
or an alkylamino group having 1 to 6 carbon atoms.
[0088] Here, an alkyl group having 1 to 6 carbon atoms may be a
straight-chain or branched-chain alkyl group, preferably an alkyl
group having 1 to 4 carbon atoms, more preferably an ethyl group.
As an alkenyl group having 2 to 6 carbon atoms, a vinyl group or a
1-isopropenyl group is preferable. As a halogenoalkyl group having
1 to 6 carbon atoms, a 2-fluoroethyl group is preferable. As a
cyclic alkyl group, a cyclopropyl group is especially preferable.
The cyclic alkyl group may have a substituent, and a halogen atom
is preferable as the substituent. A halogenocyclopropyl group is
preferable as the cyclic alkyl group, which may have a substituent,
and a fluorine atom is especially preferable as the halogen atom in
this group. As a halogenocyclopropyl group, a
monohalogenocyclopropyl group is preferable and a cis-substituted
group is even more preferable.
[0089] Examples of an aryl group, which may have a substituent,
include a phenyl group, etc., which may have 1 to 3 substituents
selected from the group consisting of an alkyl group having 1 to 6
carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen
atom such as fluorine atom, chlorine atom and bromine atom, a
hydroxyl group, an amino group, a nitro group, etc. (in the case
where the aryl group has a plurality of substituents, the
substituents may be of a single type or may be of a plurality of
types). To be more specific, a phenyl group, a2-fluorophenyl group,
a 4-fluorophenyl group, a 2,4-difluorophenyl group, a
2-fluoro-4-hydroxyphenyl group, a 3-amino-4,6-difluorophenyl group,
and a 4,6-difluoro-3-methylaminophenyl group are preferable. By
aryl group, a group that is derived from an aromatic hydrocarbon
compound is referred to. Besides the phenyl group, the aryl group
may also be a naphthyl group or a tricyclic aryl group having more
rings.
[0090] A heteroaryl group is a group that is derived from a
pentacyclic or hexacyclic aromatic heterocyclic compound that
contains one or more hetero atoms selected from among the nitrogen
atom, oxygen atom, and sulfur atom. A pentacyclic or hexacyclic
nitrogen-containing heterocyclic substituent that contains 1 or 2
nitrogen atoms is especially preferable. For example, a pyridyl
group, pyrimidyl group, etc are cired. An alkyl group, a halogen
atom, etc. are preferable as substituents on these rings. A
6-amino-3,5-difluoro-2-pyridyl group is especially preferable.
[0091] As an alkoxy group having 1 to 6 carbon atoms, an alkoxy
group that is derived from an abovementioned alkyl group is
preferable and among these, the methoxy group is preferable. For an
alkylamino group having 1 to 6 carbon atoms, the alkyl portion may
be an abovementioned alkyl group. A methylamino group is preferable
as the alkylamino group.
[0092] As the substituent R.sup.1, a cyclic alkyl group or a
halogenocycloalkyl group is preferable. Among these, a cyclopropyl
group or a 2-halogenocyclopropyl group is preferable. As the
halogen atom in the 2-halogenocyclopropyl group, a fluorine atom is
preferable.
[0093] The substituent R.sup.2 represents an alkylthio group having
1 to 6 carbon atoms or a hydrogen atom, and R.sup.1 and R.sup.2 may
be integrated to form a ring structure comprised of a polymethylene
chain by incorporating a part of the mother skeleton (that is, so
as to contain the nitrogen atom to which R.sup.1 is bonded and the
carbon atom to which R.sup.2 is bonded). The thus formed ring may
contain a sulfur atom as a ring constituent atom, and this ring may
also have an alkyl group or halogenoalkyl group having 1 to 6
carbon atoms as a substituent. The formed ring may be tetracyclic
to hexacyclic in size and this ring may be also saturated or
unsaturated. A methyl group or a fluoromethyl group is preferable
as the substituent on the formed ring. Examples of the fused ring
structure formed in this manner include the following: 9
[0094] (In the above formula, R.sup.7 represents an alkyl group
having 1 to 6 carbon atoms, such as a methyl group, a halogenoalkyl
group having 1 to 6 carbon atoms, such as a fluoromethyl group, or
a hydrogen atom, and R.sup.8 represents a halogen atom, such as a
fluorine atom, or a hydrogen atom.)
[0095] A hydrogen atom is preferable as the substituent R.sup.2 of
the compound of formula (I).
[0096] The substituent R.sup.3 is a phenylalkyl group (aralkyl
group) composed of an alkylene group having 1 to 6 carbon atoms and
a phenyl group, or an alkyl group having 1 to 6 carbon atoms, an
alkoxymethyl group having 2 to 7 carbon atoms, a hydrogen atom, a
phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an
ethoxycarbonyl group, a choline group, a dimethylaminoethyl group,
a 5-indanyl group, a phthalidinyl group, a
5-alkyl-2-oxo-1,3-dioxole-4-ylmethyl group, or a
3-acetoxy-2-oxobutyl group.
[0097] In the case where a compound of this invention is to be used
for antibacterial purposes, it is preferable to use a carboxylic
acid compound wherein R.sup.3 is a hydrogen atom. Meanwhile, a
quinolone derivative wherein the carboxylic acid moiety has been
made an ester is useful as a synthesis intermediate or as a
prodrug. These aspects shall be described in more detail below.
[0098] R.sup.4 represents an alkyl group having 1 to 6 carbon
atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl
group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6
carbon atoms, a hydrogen atom, an amino group, a hydroxyl group, a
thiol group, or an halogenomethyl group, and among the above, the
amino group may have one ore more substituents selected from the
group consisting of an alkyl group having 1 to 6 carbon atoms, an
acyl group having 2 to 5 carbon atoms, and a formyl group. In the
case where there are a plurality of substituent groups, the
substituents may all be of the same type or may be of a plurality
of different types.
[0099] As an alkyl group, which may either be a straight-chain or
branched-chain group having 1 to 6 carbon atoms, a methyl group, an
ethyl group, a normal propyl group, or an isopropyl group is
preferable. As an alkenyl group, which may either be a
straight-chain or branched-chain group having 2 to 6 carbon atoms,
a vinyl group is preferable. As an alkynyl group, which may be a
straight-chain or branched-chain group having 2 to 6 carbon atoms,
an ethynyl group is preferable. As the halogen of a halogenomethyl
group, a fluorine atom is especially preferable and the number
thereof may be 1 to 3. As an alkoxy group, which may have 1 to 6
carbon atoms, a methoxy group is preferable.
[0100] The substituent R.sup.4 is preferably a hydrogen atom, an
alkyl group, or an amino group, and among these, a hydrogen atom, a
methyl group, or unsubstituted amino group (--NH.sub.2) is
especially preferable.
[0101] In the case where R.sup.4 is an amino group, a hydroxyl
group, or a thiol group, it may be protected by a protective group
that is normally used in the relevant fields.
[0102] Examples of such protective groups include (substituted)
alkoxycarbonyl groups, such as tert-butoxycarbonyl group,
2,2,2-trichloroethoxycarbonyl group, etc.; (substituted)
aralkyloxycarbonyl groups, such as benzyloxycarbonyl group,
paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl
group, etc.; (substituted) acyl groups, such as acetyl group,
methoxyacetyl group, trifluoroacetyl group, chloroacetyl group,
pivaloyl group, formyl group, benzoyl group, etc.; (substituted)
alkyl groups or (substituted) aralkyl groups, such as tert-butyl
group, benzyl group, paranitrobenzyl group, paramethoxybenzyl
group, triphenylmethyl group, etc.; (substituted) ethers, such as
methoxymethyl group, tert-butoxymethyl group, tetrahydropyranyl
group, 2,2,2-trichloroethoxymethyl group, etc.; and (alkyl and/or
aralkyl) substituted silyl groups, such as trimethylsilyl group,
isopropyldimethylsilyl group, tert-butyldimethylsilyl group,
tribenzylsilyl group, tert-butyldiphenylsilyl group, etc. (here,
"(substituted)" signifies that a group may have a substituent). A
compound having an amino group, hydroxyl group, or thiol group that
is protected by such a substituent is especially preferable as a
production intermediate.
[0103] A represents a nitrogen atom or a partial structure
expressed by formula (II): 10
[0104] In the case where A is a partial structure of the formula
(II), X.sup.1 represents an alkyl group having 1 to 6 carbon atoms,
an alkenyl group having 2 to 6 carbon atoms, an alkynyl group
having 2 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon
atoms, a hydrogen atom, an amino group, a halogen atom, a cyano
group, a halogenomethyl group, or a halogenomethoxy group, and
among the above, the amino group may have one ore more substituents
selected from the group consisting of an alkyl group having 1 to 6
carbon atoms, an acyl group having 2 to 5 carbon atoms, and a
formyl group.
[0105] As a halogen atom, a fluorine atom, a chlorine atom, and a
bromine atom are preferable and the fluorine atom and chlorine atom
are especially preferable. As an alkyl group, which may be a
straight-chain or branched-chain group having 1 to 6 carbon atoms,
a methyl group, an ethyl group, a normal propyl group, or an
isopropyl group is preferable. As an alkenyl group, which may
either be a straight-chain or branched-chain group having 2 to 6
carbon atoms, a vinyl group is preferable. As an alkynyl group,
which may be a straight-chain or branched-chain group having 2 to 6
carbon atoms, an ethynyl group is preferable. As the halogen of a
halogenomethyl group, a fluorine atom is especially preferable and
the number thereof may be 1 to 3. As an alkoxy group, which may
have 1 to 6 carbon atoms, a methoxy group is preferable. As the
halogen of a halogenomethoxy group, a fluorine atom is especially
preferable and the number thereof may be 1 to 3.
[0106] Among these substituents, an alkyl group or an alkoxy group
is preferable. A methyl group, an ethyl group, a methoxy group, or
a difluoromethoxy group is especially preferable.
[0107] Further, this X.sup.1 and the abovementioned R.sup.1 may be
integrated to form a ring structure comprised of a polymethylene
ring by incorporating a part of the mother skeleton (so as to
contain the carbon atom to which X.sup.1 is bonded and the nitrogen
atom to which R.sup.1 is bonded). The thus formed ring may contain
an oxygen atom, a nitrogen atom, or a sulfur atom as a ring
constituent atom, and this ring may also have as a substituent an
alkyl group having 1 to 6 carbon atoms, which may have a
substituent in turn.
[0108] The formed ring may be pentacyclic to heptacyclic in size
and the ring constituent atoms are not limited to a carbon atom and
may include an oxygen atom, a nitrogen atom, or a sulfur atom.
Further, this ring may be saturated or unsaturated. The thus formed
ring may have an alkyl group having 1 to 6 carbon atoms as a
substituent. This alkyl group may be considered to be the same as
the above-described alkyl group and is preferably a methyl group.
This alkyl group may be substituted by a halogen atom, an alkoxy
group, etc.
[0109] As a partial structure that forms the ring structure formed
by X.sup.1 and R.sup.1, a structure of the following formula:
--O--CH.sub.2--CH(--CH.sub.3)--
[0110] is preferable (the right end of the above is bonded to a
nitrogen atom), and especially, the quinolone skeleton of the
following structure is preferable: 11
[0111] If A is a partial structure of formula (II), preferable
combinations of R.sup.4 and X.sup.1 are those in which R.sup.4 is
an alkyl group having 1 to 6 carbon atoms, an amino group, a
hydrogen atom, or a hydroxyl group and X.sup.1 is an alkyl group
having 1 to 6 carbon atoms, an alkoxy group 1 to 6 carbon atoms, a
halogenomethoxy group, or a hydrogen atom.
[0112] More preferable combinations are those in which R.sup.4 is
an amino group, a hydrogen atom, a hydroxyl group, or a methyl
group and X.sup.1 is a methyl group, a methoxy group, a
difluoromethoxy group, or a hydrogen atom.
[0113] Especially preferable combinations are those in which
R.sup.4 is a hydrogen atom, a hydroxyl group, or a methyl group and
X.sup.1 is a methyl group or a methoxy group.
[0114] Each of substituent R.sup.5 and R.sup.6 independently
represents an alkyl group having 1 to 6 carbon atoms, a hydrogen
atom, or a substituted carboxyl group derived from an amino acid, a
dipeptide, or a tripeptide.
[0115] This alkyl group may have one ore more substituents selected
from the group consisting of an alkylthio group having 1 to 6
carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a
hydroxyl group, and a halogen atom.
[0116] As an alkyl group, which may either be a straight-chain or
branched-chain group having 1 to 6 carbon atoms, a methyl group, an
ethyl group, a normal propyl group, or an isopropyl group is
preferable.
[0117] In the case where the alkyl group has a hydroxyl group as a
substituent, the alkyl group may be a straight-chain or
branched-chain group having 1 to 6 carbon atoms, and the hydroxyl
group is more preferably substituted on the terminal carbon atom of
the alkyl group. As an alkyl group having a hydroxyl group, those
with up to 3 carbon atoms is preferable and a hydroxymethyl group,
a 2-hydroxyethyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl
group, etc. are preferable.
[0118] In the case where the alkyl group has a halogen atom as a
substituent, the alkyl group may be a straight-chain or
branched-chain group having 1 to 6 carbon atoms, and the halogen
atom is preferably a fluorine atom. The number of fluorine atoms
may correspond to a mono-substituted condition to a
perfluoro-substituted condition. Examples thereof include a
monofluoromethyl group, a difluoromethyl group, a trifluoromethyl
group, a 2,2,2-trifluoroethyl group, etc.
[0119] In the case where the alkyl group has an alkylthio group as
a substituent, the alkyl group may be a straight-chain or
branched-chain group having 1 to 6 carbon atoms, and thealkylthio
group may also be a straight-chain or branched-chain group having 1
to 6 carbon atoms. As an alkyl group having an alkylthio group, an
alkylthiomethyl group, an alkylthioethyl group, or an
alkylthiopropyl group is preferable and it is more preferable for
the alkylthio group to be a group having 1 to 3 carbon atoms as
well. More preferable examples thereof include a methylthiomethyl
group, an ethylthioethyl group, and a methylthioethyl group.
[0120] In the case where the alkyl group has an alkoxy group as a
substituent, the alkyl group may be a straight-chain or
branched-chain group having 1 to 6 carbon atoms, and the alkoxy
group may also be straight-chain or branched-chain group having 1
to 6 carbon atoms. As an alkyl group having an alkoxy group, an
alkoxymethyl group, an alkoxyethyl group, or an alkoxypropyl group
is preferable and it is more preferable for the alkoxy group to be
a group having up to 3 carbon atoms as well. More preferable
examples thereof include a methoxymethyl group, an ethoxymethyl
group, and a methoxyethyl group.
[0121] Preferable combinations of R.sup.5 and R.sup.6 are those in
which one is a hydrogen atom and the other is a hydrogen atom, an
alkyl group, or a substituted carboxyl group derived from an amino
acid, a dipeptide, or a tripeptide. Among these, a combination in
which one of either R.sup.5 or R.sup.6 is a hydrogen atom and the
other is a hydrogen atom or an alkyl group is more preferable. As
an alkyl group, a methyl group or an ethyl group is preferable and
a methyl group is especially preferable. Thus, a combination in
which both R.sup.5 and R.sup.6 are hydrogen atoms or a combination
in which one of either R.sup.5 or R.sup.6 is a hydrogen atom and
the other is a methyl group is especially preferable. A compound of
this combination can especially express favorable physiological
activity as an antibacterial agent.
[0122] A quinolone derivative, wherein one of either substituent
R.sup.5 or R.sup.6 is a hydrogen atom and the other is a
substituted carboxyl group derived from an amino acid, a dipeptide,
or a tripeptide is especially useful as a prodrug. Specific
examples regarding this shall be described below.
[0123] A description shall now be given concerning the
halogenocyclopropyl group of R.sup.1.
[0124] The substituent halogen atom is preferably a fluorine atom
or a chlorine atom and a fluorine atom is especially
preferable.
[0125] It is especially preferable for the stereochemical
environment at this moiety that the halogen atom and the quinolone
carboxylic acid moiety have cis-configuration on the cyclopropane
ring. Also, though the cis-configuration substituent in this case
may take the form of a 2-(S)-halogeno-1-(R)-cyclopropyl group or a
2-(R)-halogeno-1-(S)-cyclopro- pyl group, the former is
preferable.
[0126] Though so-called enantiomorphic isomers are present due to
the cis-2-halogenocyclopropyl moiety alone of R.sup.1, all of such
isomers have been found to be strong in antibacterial activity and
high in safety.
[0127] A compound of this invention, exhibits excellent
characteristics when there is a substituent of the structure
represented by the following formula E at the 7-position of a
quinolone mother skeleton, in particular, a
1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoli-
ne-3-carboxylic acid skeleton having a
2-(S)-halogeno-1-(R)-cyclopropyl group. 12
[0128] For this substituent, two optical isomers that are in an
enantiomorphic relationship exist as a result of the asymmetric
carbon atom at the 3-position of the pyrrolidine ring. To be more
specific, these are as follows: 13
[0129] Meanwhile, the correlation of the structural activities of
two types of optically active compounds that are due to the steric
configuration of the substituent at the 7-position (or its
equivalent position) of a
7-[3-(1-aminomethyl)pyrrolidin-1-yl]quinolone carboxylic acid
derivative and the correlation of the structural activities of four
types of optically active substances that are due to the steric
configuration of the substituent at the 7-position of a
7-[3-(1-aminoethyl)pyrrolidin-1-yl]quinolone carboxylic acid
derivative are described in Journal of Medicinal Chemistry, vol.
36, p. 1442 (1994). In this literature, it is indicated that among
these optical isomers, the isomers of the structures shown in the
following formula are highest in antibacterial activity. 14
[0130] From the steric configurations at the 3-position of these
pyrrolidine rings, the present inventors considered that of the two
optical isomers shown in above formula F, the following isomer was
more preferable: 15
[0131] Thus, a more preferable compound of the compounds of this
invention has the structure represented by the following formula:
16
[0132] That is, 3-(1-aminocycloalkyl)pyrrolidinyl
substituted-6-hydrogen-s- ubstituted-quinolone carboxylic acids,
represented by formula (I), its salts, and hydrates thereof
(especially compounds having the structure where the 3-position of
the above pyrrolidine ring is R-configuration, its salts, and
hydrates thereof) exhibit potent antibacterial activity against a
wide range of gram-negative bacteria and gram-positive bacteria,
and in particular, a characteristic of these compounds of this
invention is that they exhibit potent antibacterial activity
against resistant bacteria as represented by gram-positive cocci,
including MRSA, PRSP, and VRE. In addition, the characteristics of
the compounds of this invention are that they exhibit excellent
safety and good pharmacokinetics that enable the compounds to be
used inclinical situations, which could not be achieved with
compounds prior to this invention even if they had substituents of
the same structures.
[0133] Such excellent properties of the compounds of this invention
are exhibited by compounds in which the n in the above-described
substituent is an integer of 1 or 2, and the excellent effects are
seen especially with compounds for which n is an integer 1. That
is, compounds wherein the cyclic part is a tricyclic ring are
preferable compounds.
[0134] In the case where a compound of formula (I) of this
invention has a structure in which diastereomers are present, a
compound comprised of a single diastereomer is preferably
administered when the compound of this invention is administered to
human or animals. The term, "comprised of a single diastereomer" as
used herein means not only a case in which it is completely free
from the other diastereomer but also a case in which it is in a
chemically pure degree. That is, it may be interpreted that the
other diastereomer may be contained as long as there are no
influences on the physical constants and physiological activities
of the compound.
[0135] Also, the term "stereochemically pure" as used herein means
that, in the case where a compound or the like exists in a
plurality of isomer forms due to the bpresence of asymmetric carbon
atoms, the compound is comprised of only one of them. The term
"pure" in this case can also be considered in the same manner as
described above.
[0136] Though the quinolone carboxylic acid derivative of this
invention may be used either in its free form or as an acid
addition salt or a salt of its carboxyl group. Examples of the acid
addition salt include inorganic acid salts, such as hydrochlorides,
sulfates, nitrates, hydrobromides, hydroiodides, phosphates, etc.;
and organic acid salts, such as methanesulfonates,
benzenesulfonates, toluenesulfonates (and other sulfonates),
acetates, citrates, maleates, fumarates, lactates (and other
carboxylates), etc.
[0137] Examples of salts of the carboxyl group include alkali metal
salts, such as lithium salts, sodium salts, potassium salts, etc.;
alkaline earth metal salts, such as magnesium salts, calcium salts,
etc.; ammonium salts, triethylamine salts, N-methylglucamine salts,
tris-(hydroxymethyl)aminomethane salts; etc., and these could
either be inorganic salts or organic salts.
[0138] Also, these free form, acid addition salts and salts of
carboxyl group of the quinolone carboxylic acid derivative may be
present as hydrates.
[0139] Though in the case where a compound of this invention is
used for antibacterial purposes, a carboxylic acid compound wherein
the substituent R.sup.3 is a hydrogen atom is preferably used, a
quinolone derivative whose carboxylic acid moiety is an ester is
useful as a synthesis intermediate or a prodrug. For example, alkyl
esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters, and
phenyl esters are useful as synthesis intermediates.
[0140] Also, the ester to be used as a prodrug is an ester which is
easily hydrolyzed in the living body and form free form of
carboxylic acid, and its examples include oxoalkyl esters, such as
acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyl ester,
choline ester, dimethylaminoethyl ester, 5-indanyl ester,
phthalidinyl ester, 5-alkyl-2-oxo-1,3-dioxole-4-ylmethyl esters,
and 3-acetoxy-2-oxobutyl ester.
[0141] Further, a quinolone derivative, wherein one of either of
the substituents R.sup.5 and R.sup.6 is a hydrogen atom and the
other is a substituted carboxyl group derived from an amino acid, a
dipeptide, or a tripeptide, is useful as a prodrug.
[0142] An amino acid, a dipeptide, or a tripeptide to be used for
obtaining such a prodrug is one wherein the peptide bond, which is
formed by the carboxyl group derived from the amino acid,
dipeptide, or tripeptide and the amino group that exists on the
substituent at the 7-position of the quinolone carboxylic acid
derivative, can be easily hydrolyzed in the living body and form
free form of amine, and its examples include those derived from
glycine, alanine, aspartic acid, and other amino acids,
glycine-glycine, glycine-alanine, alanine-alanine, and other
dipeptides, and glycine-glycine-alanine, glycine-alanine-alanine,
and other tripeptides.
[0143] The compound of this invention represented by the formula
(I) can be produced by various methods, and in a preferred example,
such a compound can be produced for example by reacting a compound
represented by formula (III): 17
[0144] [wherein X.sup.2 represents a substituent which functions as
a leaving group, such as a substituted or unsubstituted
phenylsulfonyl group, a substituted or unsubstituted alkylsulfonyl
group having 1 to 3 carbon atoms, a fluorine atom, a chlorine atom
or a bromine atom;
[0145] R.sup.31 is the R.sup.3 defined in the formula (I) or a
boron-containing group represented by formula (IV):
--B(Y.sup.32)Y.sup.33 (IV)
[0146] (wherein Y.sup.32 and Y.sup.33 may be the same or different
from each other with each being a fluorine atom or an
alkylcarbonyloxy group having 2 to 4 carbon atoms); and
[0147] R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, and A are as
defined in the formula (I)] with a compound of the following
formula (V) or an addtion salt thereof: 18
[0148] [wherein each of R.sup.51 and R.sup.61 independently
represents a hydrogen atom, an alkyl group having 1 to 6 carbon
atoms or a protective group for an amino group, or one of either
R.sup.51 or R.sup.61 represents a hydrogen atom and the other
represents a substituted carboxyl group derived from an amino acid,
a dipeptide, or a tripeptide with an amino group that is
unsubstituted or is protected by a protective group for an amino
group, and
[0149] this alkyl group may have a substituent selected from the
group consisting of an alkylthio group having 1 to 6 carbon atoms,
an alkoxy group having 1 to 6 carbon atoms, a hydroxyl group, and a
halogen atom, and
[0150] n is the same as defined in the formula (I)]
[0151] (in the case where an addition salt is used, the reaction is
carried out under the presence of reagents that cause the addition
salt to become a free form).
[0152] Examples of the acid addition salts include inorganic acid
salts, such as hydrochlorides, sulfates, nitrates, hydrobromides,
hydroiodides, phosphates, etc.; and organic acid salts, such as
methanesulfonates, benzenesulfonates, toluenesulfonates (and other
sulfonates), acetates, citrates, maleates, fumarates, lactates (and
other carboxylates); etc.
[0153] The reaction may be carried out using a solvent or without
using a solvent. A solvent to be used in the reaction may be any
solvent which have no an adverse effect on the reaction, and its
examples include dimethyl sulfoxide, pyridine, acetonitrile,
ethanol, chloroform, dimethylformamide, dimethylacetamide,
N-methylpyrrolidone, tetrahydrofuran, water, 3-methoxybutanol, or a
mixture of thereof.
[0154] The reaction is preferably carried out under the presence of
an acid receptor, such as an inorganic base or an organic base, for
example, an inorganic basic compound, such as a carbonate or
bicarbonate of an alkaline metal or an alkaline earth metal, or an
organic basic compound, such as triethylamine, pyridine,
1,8-diazobicycloundecene, N-methyl piperidene,
N,N-diisopropylethylamine, etc.
[0155] The reaction temperature should normally be in the
temperature range of room temperature to 200.degree. C. and
preferably in the range of 25 to 150.degree. C. The reaction time
should be in the range of 30 minutes to 48 hours, and the reaction
is normally completed in approximately 30 minutes to 8 hours.
[0156] The protective group of an amino group may be any protective
group that is generally used in the relevant field, and its
examples include alkoxycarbonyl groups, which may have a
substituent, such as tert-butoxycarbonyl group,
2,2,2-trichloroethoxycarbonyl group, etc.; aralkyloxycarbonyl
groups, which may have a substituent, such as benzyloxycarbonyl
group, para-methoxybenzyloxycarbonyl group,
para-nitrobenzyloxycarbonyl group, etc.; acyl groups, which may
have a substituent, such as acetyl group, methoxyacetyl group,
trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl
group, benzoyl group, etc.; alkyl groups, which may have a
substituent, and aralkyl groups, which may have a substituent, such
as tert-butyl group, benzyl group, para-nitrobenzyl group,
para-methoxybenzyl group, triphenylmethyl group, etc.; ethers,
which may have a substituent, such as methoxymethyl group,
tert-butoxymethyl group, tetrahydropyranyl group,
2,2,2-trichloroethoxyme- thyl group, etc.; and substituted silyl
groups, such as trimethylsilyl group, isopropyldimethylsilyl group,
tert-butyldimethylsilyl group, tribenzylsilyl group,
tert-butyldiphenylsilyl group, etc.
[0157] In the case where each of R.sup.3 and R.sup.31 is an alkyl
group having from 1 to 6 carbon atoms, an alkoxymethyl group having
from 2 to 7 carbon atoms or a phenylalkyl group (aralkyl group)
composed of an alkylene group having 1 to 6 carbon atoms and a
phenyl group, it can be converted into a corresponding carboxylic
acid by treatment under acidic or basic conditions which are
generally used for the hydrolysis of carboxylic acid esters.
[0158] In the case where R.sup.31 has a structure of the formula
(IV), it can be converted into a corresponding carboxylic acid by
subjecting it to hydrolysis under acidic or basic conditions after
allowing the compound (V) to react with the compound (III).
[0159] In the case where deprotection is necessary, the compound of
interest represented by the formula (I) can be obtained by removing
the protective group under appropriate conditions suitable for the
protective group.
[0160] A compound of the formula (V) may be produced by various
methods, and though a method shown in PCT/JP96/00208 maybe given as
an example, the method of production is not limited to thereto.
[0161] A compound of the formula (V) can be produced by removing Q
from a compound represented by the following formula (VI): 19
[0162] [In the above formula (VI), R.sup.512 is the same as the
R.sup.5 defined in the formula (I) or represents a protective group
of an amino group, R.sup.6 and n are the same as defined in the
formula (I), Q is a protective group of an amino group,
[0163] wherein the protective group of an amino group may be
selected from the group consisting of a (substituted)
alkoxycarbonyl group, a (substituted) aralkyloxycarbonyl group, a
(substituted) acyl group, a (substituted) alkyl group, a
(substituted) aralkyl group and a substituted silyl group.]
[0164] An above-described compound may be present in the form of a
salt thereof, a hydrate thereof, or a hydrate of the salt. Examples
of the acid addition salt include inorganic acid salts and organic
acid salts. Specific examples thereof include inorganic acid salts,
such as hydrochlorides, sulfates, hydrobromides, hydroiodides,
phosphates, etc.; and organic acid salts, such as
methanesulfonates, benzenesulfonates, toluenesulfonates (sulfonic
acid salts); acetates, citrates, maleates, fumarates, lactates
(carboxylic acid salts); etc.
[0165] When both R.sup.512 and Q are protective groups of an amino
group, they may be the same or different from each other. However,
it is more favorable for the production of compound (I) that each
is cut off under different reaction conditions.
[0166] Examples of R.sup.512 and Q, which are protective groups of
amino groups, include the following. That is, examples thereof
include a (substituted) alkoxycarbonyl group, a (substituted)
aralkyloxycarbonyl group, a (substituted) acyl group, a
(substituted) alkyl group, a (substituted) aralkyl group, and a
(substituted) silyl group.
[0167] Specific examples thereof include (substituted)
alkoxycarbonyl groups, such as tert-butoxycarbonyl group,
2,2,2-trichloroethoxycarbonyl group, etc.; (substituted)
aralkyloxycarbonyl groups, such as benzyloxycarbonyl group,
para-methoxybenzyloxycarbonyl group, para-nitrobenzyloxycarbonyl
group, etc.; (substituted) acyl groups, such as acetyl group,
methoxyacetyl group, trifluoroacetyl group, chloroacetyl group,
pivaloyl group, formyl group, benzoyl group, etc.; (substituted)
alkyl groups or (substituted) aralkyl groups, such as tert-butyl
group, benzyl group, para-nitrobenzyl group, para-methoxybenzyl
group, triphenylmethyl group, etc.; (substituted) ethers, such as
methoxymethyl group, tert-butoxymethyl group, tetrahydropyranyl
group, 2,2,2-trichloroethoxymethyl group, etc.; and substituted
silyl groups, such as trimethylsilyl group, isopropyldimethylsilyl
group, tert-butyldimethylsilyl group, tribenzylsilyl group,
tert-butyldiphenylsilyl group, etc.
[0168] In producing the compound (I) using an above-mentioned
compound having Q as a protective group, it is necessary to carry
out the reaction by removing the protective group Q. In this case,
its reaction with the compound (III) or (V) may be carried out by a
so-called one-pot reaction or the reaction may be carried out after
once isolating the compound (V) by removing the protective
group.
[0169] As with a compound of the formula (V), a compound of the
formula (VI) can be produced by various methods, and though a
method described in PCT/JP96/00208 may be given as an example, the
production method is not limited thereto.
[0170] Cis-2-fluorocyclopropylamine comprised of a single isomer,
which is desirable for the synthesis of a compound of the formula
(I) comprised of a single isomer, may synthesized for example by
the method described in JP-A-2-231475 (the term "JP-A" as used
herein means an unexamined published Japanese patent appliction").
Synthesis of the compound of formula (I) comprised of a single
isomer using an optically active cis-2-fluorocyclopropylamine
derivative obtained in the manner described above as a raw
material, may be carried out for example in accordance with the
method described for example in JP-A-2-231475.
[0171] Specific examples of compounds of this invention include the
following:
[0172]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-
-cyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid
[shown in the following formula]; 20
[0173]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-
-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid [shown
in the following formula]; 21
[0174]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-
-cyclopropyl]-8-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid
[shown in the following formula]; 22
[0175]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-
-cyclopropyl]-8-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid
[shown in the following formula]; 23
[0176]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-
-cyclopropyl]-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic
acid [shown in the following formula]; 24
[0177]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-
-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic
acid [shown in the following formula]; 25
[0178]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-
-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid
[shown in the following formula]; 26
[0179]
5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluo-
ro-1-(R)-cyclopropyl]-1,4-dihydro-8-fluoro-4-oxoquinoline-3-carboxylic
acid [shown in the following formula]; 27
[0180]
5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluo-
ro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic
acid [shown in the following formula]; 28
[0181]
5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluo-
ro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic
acid [shown in the following formula]; 29
[0182]
10-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-2,3-dihydro-3-(S)-me-
thyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid
[shown in the following formula]; 30
[0183]
7-[3-(R)-(1-aminocyclobutyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)--
cyclopropyl]-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic
acid [shown in the following formula]; 31
[0184]
7-[3-(R)-(1-aminocyclobutyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)--
cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid
[shown in the following formula]; 32
[0185]
7-[3-(R)-(1-aminocyclobutyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)--
cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid
[shown in the following formula]; 33
[0186]
7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluo-
ro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic
acid [shown in the following formula]; 34
[0187]
7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluo-
ro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic
acid [shown in the following formula]; 35
[0188]
7-[3-(R)-[1-(ethylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluor-
o-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic
acid [shown in the following formula]; 36
[0189]
5-amino-7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2--
(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carbox-
ylic acid [shown in the following formula]; 37
[0190]
10-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-2,3-dihydro--
3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic
acid [shown in the following formula]; 38
[0191]
1-(cyclopropyl)-8-methyl-7-[3-(R)-[1-(methylamino)cyclopropyl]pyrro-
lidin-1-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid [shown in
the following formula]; 39
[0192] Since the compound of this invention has potent
antibacterial actions, it can be used as medicaments for use in
human bodies, animals, and fishes or as preservatives of
agricultural chemicals and food.
[0193] In the case where the compound of this invention is used as
a medicament for human bodies, its dose is within the range of from
50 mg to 1 g, preferably from 100 mg to 500 mg, per day per
adult.
[0194] In the case of use as a medical drug for an animal, its dose
varies depending on the purpose of its administration (treatment or
prevention), kind and size of each animal to be treated, kind and
degree of each infected pathogenic bacterium, but is within the
range of generally from 1 mg to 200 mg, preferably from 5 mg to 100
mg, per 1 kg body weight of each animal as a daily dose.
[0195] The daily dose is administered once a day or by dividing it
into two to four doses per day. As occasion demands, the daily dose
may exceed the abovementioned amounts.
[0196] Since the compounds of this invention are active against a
broad range of microorganisms which cause various infectious
diseases, it can treat, prevent or alleviate diseases caused by
such pathogens.
[0197] Examples of bacteria and bacterioid microorganisms on which
the compounds of this invention are effective include the genus
Staphylococcus, Streptococcus pyogenes, hemolytic streptococcus,
enterococcus, pneumococcus, the genus Peptostreptococcus, Neisseria
gonorrhoeae, Escherichia coli, the genera Citrobacter, the genus
Shigella, Klebsiella pneumoniae, the genera Enterobacter, the genus
Serratia, the genus Proteus, Pseudomonas aeruginosa, Haemophilus
influenzae, the genus Acinetobacter, the genus Campylobacter,
Chlamydia trachomatis, and the like.
[0198] Examples of the diseases caused by the above pathogens
include folliculitis, furuncle, carbuncle, erysipelas, phlegmon,
lymphangitis (lymphadenitis), panaritium, subcutaneous abscess,
hidrosadenitis, aggregated acne, infectious atheroma, anal abscess,
mastitis, superficial secondary infections of traumatic wounds,
burn wounds, operative wounds, etc., pharyngolaryngitis, acute
bronchitis, tonsillitis, chronic bronchitis, bronchiectasis,
diffuse panbronchiolitis, secondary infections of chronic
respiratory diseases, pneumonia, pyelonephritis, cystitis,
prostatitis, epididymitis, gonococcal urethritis, non-gonococcal
urethritis, cholecystitis, cholangitis, bacillary dysentery,
enteritis, inflammation of the uterine appendages, intrauterine
infection, bartholinitis, blepharitis, hordeolum, dacryocystitis,
tarsadenitis, corneal ulcer, otitis medea, sinusitis,
periodontitis, pericoronitis, jaw inflammation, peritonitis,
endocarditis, sepsis, meningitis, skin infection, etc.
[0199] Further, examples of acid-fast bacteria on which the
compounds of this invention are effective include tubercle bacilli
[Mycobacterium (abbreviated as "M." hereinafter) tuberculosis, M.
bovis, M. africanum], a typical acid-fast bacteria [M. kansasii, M.
marinum, M. scrofulaceum, M. avium, M. intracellulare, M. xenopi,
M. fortuitum, M. chelonae], etc.
[0200] The acid-fast bacteria infections that are caused by these
pathogens are largely classified according to the causing bacteria
into the three types of tuberculosis, a typical acid-fast bacteria
infection, and leprosy. In addition to the lungs, tubercle bacilli
infections may be seen in the thoracic cavity, trachea/bronchus,
lymph nodes, in a generally disseminated manner, in the bones and
joints, meninges/brain, digestive organs (intestines, liver), skin,
mammary glands, eyes, middle ear/throat, urinary tract, male
genitals, female genitals, etc. The lungs are the main affected
parts of a typical acid-fast bacteria infections (non-tubercle
acid-fast bacteria infections), and other examples of a typical
acid-fast bacteria infections include local lymphadenitis, soft
skin tissue infections, articular infections, general dissemination
type infections, etc.
[0201] The compounds of this invention are also effective against
various microorganisms that cause infections in animals. Examples
of such microorganisms include Escherichia, Salmonella, Pasturella,
Haemophilus, Bordetella, Staphylococcus, Mycoplasma, etc.
[0202] Specific examples of fowl diseases include escherichiosis,
pullorum disease, fowl paratyphoid fever, fowl cholera, infectious
coryza, staphylococcal infection, Mycoplasma infection, etc.,
specific examples of pig diseases include escherichiosis,
salmonellosis, pasturellosis, Haemophilis infection, atrophic
rhinitis, exudative epidermitis, Mycoplasma infection, etc.,
specific examples of cattle diseases include escherichiosis,
salmonellosis, hemorrhagic septicemia, Mycoplasma infection,
contagious bovine pleuropneumonia, mastitis, etc., specific
examples of dog diseases include coliemia, Salmonella infection,
hemorrhagic septicemia, pyometra, cystitis, etc., and specific
examples of cat diseases include exudative pleurisy, cystitis,
chronic rhinitis, Haemophilus infection, kitten diarrhea,
Mycoplasma infection, etc.
[0203] An antibacterial preparation which comprises the compound of
this invention can be prepared by selecting an appropriate
pharmaceutical preparation in accordance to the method of
administration and using any of the generally used methods of
preparing various pharmaceutical preparations. With regard to the
dosage forms of antibacterial preparations having the compound of
this invention as its principle agent, tablets, powders, granules,
capsules, solutions, syrups, elixirs, oily or aqueous suspensions,
etc. can be given as examples of forms of oral pharmaceutical
preparations.
[0204] In the case of injections, a stabilizing agent, an
antiseptic agent, a solubilizing agent, etc. may be used in the
preparation, or a solution which may contain these auxiliary agents
may be contained in a container and thereafter made into a solid
preparation by freeze-drying or the like means to be re-dissloved
when used. Also, a single dose may be contained in a single
container or multiple doses may be contained in the same
container.
[0205] Examples of forms of external-use preparations include
solutions, suspensions, emulsions, ointments, gels, creams,
lotions, sprays, etc.
[0206] A solid preparation may contain pharmaceutically acceptable
additives together with the active compound. For example, fillers,
extenders, binders, disintegrators, solubilization enhancing
agents, moistening agents, lubricating agents, etc. may be selected
and mixed as necessary to form a preparation.
[0207] Examples of forms of liquid preparations include solutions,
suspensions, emulsions, and these may contain suspending agents,
emulsifying agents, etc. as additives.
[0208] Examples of methods of administering the compound of this
invention to an animal include a method of direct oral
administration or oral administration by mixing it with feed, a
method of preparing a solution and then performing oral
administration of the solution directly or upon addition of the
solution to drinking water or feed, a method of injection
administration, etc.
[0209] A pharmaceutical preparation for administering the compound
of this invention to an animal can be prepared optionally as
powders, fine granules, soluble powders, syrups, solutions, or
injections by the techniques generally used in the relevant
field.
[0210] Formulation examples of pharmaceutical preparations are
shown below.
1 Formulation Example 1 (Capsule): Compound of Example 1 100.0 mg
Corn starch 23.0 mg CMC calcium 22.5 mg Hydroxymethyl cellulose 3.0
mg Magnesium stearate 1.5 mg Total 150.0 mg Formulation Example 2
(Solution): Compound of Example 1 1 to 10 g Acetic acid or sodium
hydroxide 0.5 to 2 g Ethyl para-hydroxybenzoate 0.1 g Purified
water 88.9 to 98.4 g Total 100 g Formulation Example 3 (Powder to
be mixed in feed) Compound of Example 1 1 to 10 g Corn starch 98.5
to 89.5 g Light silicic anhydride 0.5 g Total 100 g
BEST MODE OF CARRYING OUT THE INVENTION
[0211] The following describes the invention based on examples and
reference examples, though this invention is not limited to
thereto.
REFERENCE EXAMPLE 1
[0212] Ethyl
2-(2,4-difluoro-3-methylbenzoyl)-3-dimethylaminoacrylate
[0213] 2,4-Difluoro-3-methylbenzoate (4.97 g, 28.9 mmol) was
dissolved in toluene (50 ml), and after adding
N,N-dimethylformamide (0.1 ml) and thionyl chloride (3.16 ml, 43.4
mmol) thereto, it was stirred for 14 hours in an oil bath of
80.degree. C. The reaction solution was then cooled and thereafter
concentrated under a reduced pressure. After adding toluene to the
residue and repeating concentration under a reduced pressure, the
residue obtained was dissolved in tetrahydrofuran (10 ml). This
solution was added dropwise while cooling with ice to a solution in
which ethyl 3-dimethylaminoacrylate (4.97 g, 34.7 mmol) and
triethylamine (5.04 ml, 36.1 mmol) were dissolved in
tetrahydrofuran (20 ml). After completion of dripping, the reaction
solution was heated under reflux for 10 hours. After completion of
the reaction, the reaction solution was filtered, the triethylamine
hydrochloride salt was removed (by diethyl ether washing), and the
filtrate was concentrated under a reduced pressure. The residue
obtained was applied to a short silica gel chromatography and 6.70
g (78%) of the title compound was obtained in the form of a yellow
powder from an n-hexane:ethyl acetate=1:1 eluate.
[0214] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.95 (3H, t,
J=7.08 Hz), 2.18 (3H, t, J=1.95 Hz), 2.92-3.24 (6H, m), 3.99 (2H,
q, J=7.08 Hz), 6.86 (1H, dt, J=1.22, 8.55 Hz), 7.43 (1H, brs), 7.75
(1H, s).
[0215] IR (KBr, disk): 3055, 2985, 2933, 2875, 2814, 1942, 1693,
1630, 1593, 1477, 1431, 1379, 1277, 1255, 1221 cm.sup.-1.
[0216] Melting point: 82 to 84.degree. C.
[0217] Elemental analysis: As C.sub.15H.sub.17F.sub.2NO.sub.3;
Calcd.: C, 60.60; H, 5.76; N, 4.71 Found: C, 60.31; H, 5.73; N,
4.73
REFERENCE EXAMPLE 2
[0218] Ethyl
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-met-
hyl-4-oxoguinoline-3-carboxylate
[0219] Ethyl
2-(2,4-difluoro-3-methylbenzoyl)-3-dimethylaminoacrylate (1.06 g,
3.57 mmol) was dissolved in tetrahydrofuran (15 ml), and after
adding the para-toluenesulfonic acid salt of (1R,
2S)-2-fluorocyclopropyl- amine (970 mg, 3.93 mmol), a solution, in
which triethylamine (552 .mu.l, 3.96 mmol) was dissolved in
tetrahydrofuran (5 ml), was added dropwise under stirring at
-15.degree. C. After stirring the reaction solution for 2 hours at
room temperature, potassium carbonate (740 mg, 5.36 mmol) and
tetrabutylammonium chloride (49.6 mg, 0.179 mmol) were added, and
this reaction suspension was heated under reflux while stirring for
5 days. After cooling the reaction solution, the tetrahydrofuran
was evapolated under a reduced pressure. Dichloromethane (10 ml)
was then added to the residue, and while cooling with ice and
stirring, 2 mol/l hydrochloric acid was added dropwise gradually to
adjust the pH to approximately 3. Then after stirring for 15
minutes at room temperature, extraction with dichloromethane (60
ml.times.3) was performed. After drying over anhydrous sodium
sulfate, filtration was performed, the filtrate was concentrated
under a reduced pressure, and the crude crystals obtained were
stirred and purified in the slurry state in ethyl acetate. 713 mg
(65%) of the title compound was thereby obtained in the form of
colorless crystals.
[0220] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.41 (3H, t,
J=7.08 Hz), 1.56-1.62 (2H, m), 2.66 (3H, d, J=2.69 Hz), 3.85-3.89
(1H, m), 4.39 (2H, q, J=7.08 Hz), 4.78-4.79 and 4.94-4.95 (1H, dm,
J=62.74 Hz), 7.13 (1H, t, J=8.91 Hz), 8.36 (1H, dd, J=6.71, 8.91
Hz), 8.56 (1H, d, J=2.93 Hz).
[0221] IR (KBr, disk): 3438, 3097, 2983, 2939, 2902, 1907, 1720,
1630, 1593, 1566, 1460, 1429, 1387, 1367, 1311, 1250 cm.sup.-1.
[0222] Melting point: 187 to 188.degree. C.
[0223] Elemental analysis: As C.sub.16H.sub.15F.sub.2NO.sub.3;
Calcd.: C, 62.54; H, 4.92; N, 4.56 Found: C, 62.41; H, 4.87; N,
4.53
REFERENCE EXAMPLE 3
[0224]
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4--
oxoguinoline-3-Carboxylic Acid
[0225] Ethyl
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-met-
hyl-4-oxoquinoline-3-carboxylate (1.40 g, 4.56 mmol) was dissolved
in acetic acid (4 ml), and after adding concentrated hydrochloric
acid (4 ml) thereto, it was heated under reflux for 3 hours. After
cooling, the reaction solution was poured into ice water (50 ml)
and the precipitated crystals were filtered out. After washing the
filtered-out crystals with an excess amount of water, washing in
cold ethanol and washing in diethyl ether were performed in that
order, and after drying under a reduced pressure, 1.18 g (93%) of
the title compound was obtained in the form of a white powder.
[0226] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.:1.48-1.72 (2H, m),
2.75 (3H, t, J=2.56 Hz), 4.01 (1H, dd, J=2.81, 5.25 Hz), 4.83-4.84
and 4.98-5.00 (1H, dm, J=62.74 Hz), 7.31 (1H, dd, J=2.20, 8.79 Hz),
8.40-8.44 (1H, m), 8.84 (1H, d, J=2.69 Hz), 14.50 (1H, brs).
[0227] IR (KBr, disk): 3097, 3014, 2956, 2642, 1957, 1728, 1618,
1566, 1508, 1469, 1435, 1389, 1321, 1254, 1200 cm.sup.-1.
[0228] Melting point: 250 to 253.degree. C.
[0229] [.alpha.].sub.D.sup.24.3=-50.00.degree. (c 0.145, 0.1 mol/l
NaOH)
[0230] Elemental analysis: As C.sub.14H.sub.11F.sub.2NO.sub.3;
Calcd.: C, 60.22; H, 3.97; N, 5.02 Found: C, 59.92; H, 3.98; N,
4.92
EXAMPLE 1
[0231]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-
-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-Carboxylic
Acid
[0232] After adding
3-(R)-[1-tert-butoxycarbonylaminocyclopropyl]pyrrolidi- ne (185 mg,
817 .mu.mol) and triethylamine (0.50 ml) to dried dimethyl
sulfoxide (2 ml),
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-
-8-methyl-4-oxoquinoline-3-carboxylic acid (190 mg, 681 .mu.mol)
was added thereto and it was heated under reflux for 17 hours under
a nitrogen atmosphere. After concentrating the reaction solution
under a reduced pressure, the residue was dissolved in chloroform
(50 ml). After washing the organic layer with a 10% aqueous citric
acid solution (25 ml), the organic layer was dried over anhydrous
sodium sulfate. After filtering, the filtrate was concentrated
under a reduced pressure, and after adding dropwise concentrated
hydrochloric acid (5 ml) to the residue while cooling with ice,
stirring at room temperature was performed for 30 minutes. 1 mol/l
Hydrochloric acid (5 ml) was then added to the reaction solution,
and after washing the yellow acidic aqueous solution with
chloroform (20 ml.times.3), the pH was adjusted to 12.0 with an
aqueous sodium hydroxide solution and the insolubles were removed
by filtration. After adjusting the pH of the basic aqueous solution
to 7.4 using 1 mol/l hydrochloric acid, extraction with chloroform
(100 ml.times.4) was performed. After drying over anhydrous sodium
sulfate, the solvent was evapolated under a reduced pressure. The
residue thus obtained was purified by preparative chromatography
(development at the lower layer of a 7:3:1 mixture of
chloroform:methanol:water), recrystallized in ethanol, and dried
under a reduced pressure. 112 mg (43%) of the title compound was
thereby obtained in the form of yellow crystals.
[0233] .sup.1H-NMR (400 MHz, 0.1 mol/l NaOD) .delta.: 0.54 (4H, d,
J=5.61 Hz), 1.19-1.21 (1H, m), 1.58-1.62 (1H, m), 1.66-1.69 (1H,
m), 2.00-2.01 (1H, m), 2.16-2.17 (1H, m), 2.35 (3H, s), 3.16-3.23
(2H, m), 3.37-3.42 (1H, m), 3.54-3.55 (1H, m), 4.04-4.05 (1H, m),
4.94-4.95 and 5.10-5.11 (1H, dm, J=62.16 Hz), 7.01 (1H, d, J=8.78
Hz), 7.95 (1H, d, J=8.78 Hz), 8.43 (1H, s).
[0234] IR (KBr, disk): 3375, 3062, 3006, 2925, 2864, 1728, 1610,
1508, 1475, 1431, 1394, 1348, 1315, 1257 cm.sup.-1.
[0235] Melting point: 228 to 230.degree. C.
[0236] [.alpha.].sub.D.sup.24.7=-235.09.degree. (c 0.285, 0.1 mol/l
NaOH)
[0237] Elemental analysis: As C.sub.21H.sub.24FN.sub.3O.sub.3;
Calcd.: C, 65.44; H, 6.28; N, 10.90 Found: C, 65.10; H, 6.32; N,
10.76
REFERENCE EXAMPLE 4
[0238] Ethyl
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-met-
hoxy-4-oxoguinoline-3-carboxylate
[0239] A mixture of ethyl (2,4-difluoro-3-methoxy)benzoyl acetate
(48.8 g, 189 mmol), synthesized by the method described in
PCT/US98/19138, triethyl orthoformate (78.6 ml, 472 mmol) and
acetic anhydride (250 ml) was stirred while heating for 6 hours in
an oil bath of an external temperature of 120.degree. C. After
letting the reaction solution cool, concentration under a reduced
pressure and solidification by drying were performed. The yellow
extract obtained was then dissolved in toluene (800 ml), the
para-toluenesulfonic acid salt of (1R, 2S)-2-fluorocyclopropylam-
ine (60.1 g, 246 mmol) was added, and while stirring at -15.degree.
C., a solution, in which triethylamine (40.8 ml, 293 mmol) was
dissolved in toluene (200 ml), was added dropwise thereto. After
stirring the reaction solution for 4 hours at room temperature,
water (500 ml) was added, and the organic layer was separated.
After washing the organic layer with saturated saline solution (500
ml.times.2), it was dried over anhydrous sodium sulfate. After
filtering, the filtrate was concentrated under a reduced pressure
and dried. The yellow oily substance obtained was then dissolved in
1,4-dioxane (600 ml), and while cooling with water, 60% oily sodium
hydride (5.94 g, 242 mmol) was added gradually. After stirring the
reaction mixture for 30 minutes at room temperature, concentration
under a reduced pressure was performed until the volume of the
reaction solution became approximately 300 ml. The concentrate thus
obtained was slowly poured into 1 mol/l hydrochloric acid, which
was stirred and cooled with water, and the precipitated crystals
were filtered out. After washing these crystals with excess
purified water, a small amount of ethanol, and excess diethyl
ether, in that order, the crude crystals obtained where slurried in
ethyl acetate and purified. 49.4 g (80.9%) of the title compound
was thereby obtained in the form of colorless crystals.
[0240] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.42 (3H, t,
J=7.08 Hz), 1.55-1.64 (2H, m), 3.88-3.93 (1H, m), 4.04 (3H, d,
J=1.96 Hz), 4.39 (2H, q, J=7.08 Hz), 4.78-4.79 and 4.94-4.95 (1H,
dm, J=62.61 Hz), 7.22 (1H, t, J=8.79 Hz), 8.24 (1H, dd, J=5.86,
8.79 Hz), 8.60 (1H, s).
[0241] Melting point: 190 to 193.degree. C. (decomposed)
REFERENCE EXAMPLE 5
[0242]
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-
-oxoguinoline-3-Carboxylic Acid
[0243] After dissolving ethyl
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]--
1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxy late (34.0 g, 105
mmol) in acetic acid (400 ml) and then adding concentrated
hydrochloric acid (400 ml) thereto, it was heated under reflux for
3 hours. After cooling, the reaction solution was poured into ice
water (1500 ml), and the precipitated crystals were filtered out.
After washing the filtered-out crystals with an excess amount of
water, it was washed with cold ethanol and diethyl ether in that
order, and after drying under a reduced pressure, the crude
crystals obtained were purified by recrystallization from a mixed
solvent of acetonitrile-ethanol and then dried under a reduced
presure. 27.1 g (87.4%) of the title compound was thereby obtained
in the form of a white powder.
[0244] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.45-1.75 (2H,
m), 3.87-3.95 (1H, m), 4.03 (3H, d, J=1.95 Hz), 4.79-4.81 and
4.97-4.99 (1H, dm, J=62.68 Hz), 7.30 (1H, t, J=8.79 Hz), 8.27 (1H,
dd, J=5.86, 8.79 Hz), 8.76 (1H, s).
[0245] Melting point: 261-263.degree. C. (decomposed)
EXAMPLE 2
[0246]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-
-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-Carboxylic
Acid
[0247] After adding
3-(R)-[1-tert-butoxycarbonylaminocyclopropyl]pyrrolidi- ne (165 mg,
731 .mu.mol) and triethylamine (0.50 ml) to dried dimethyl
sulfoxide (2 ml),
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-
-8-methoxy-4-oxoquinoline-3-carboxylic acid (180 mg, 609 .mu.mol)
was added thereto and it was heated under reflux for 13 hours under
a nitrogen atmosphere. After concentrating the reaction solution
under reduced pressure, the residue was dissolved in chloroform
(100 ml). After washing the organic layer with a 10% aqueous citric
acid solution (50 ml), the organic layer was dried over anhydrous
sodium sulfate. After filtering, the filtrate was concentrated
under a reduced pressure, and after adding dropwise concentrated
hydrochloric acid (5 ml) to the residue while cooling with ice,
stirring was performed at room temperature for 30 minutes. 1 mol/l
Hydrochloric acid (5 ml) was then added to the reaction solution,
and after washing the yellow acidic aqueous solution with
chloroform (50 ml.times.4), the pH was adjusted to 12.0 with an
aqueous sodium hydroxide solution and the insolubles were removed
by filtration. After adjusting the pH of the basic aqueous solution
to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform
(100 ml.times.4) was performed. After drying over anhydrous sodium
sulfate, the solvent was evapolated under a reduced pressure. The
residue thus obtained was purified by preparative chromatography
(development at the lower layer of a 7:3:1 mixture of chloroform
methanol:water), recrystallized in isopropyl alcohol, and dried
under a reduced pressure. 146 mg (60%) of the title compound was
thereby obtained in the form of yellow crystals.
[0248] .sup.1H-NMR (400 MHz, 0.1 mol/l NaOD) .delta.: 0.56 (4H,
brs), 1.31-1.37 (1H, m), 1.50-1.56 (1H, m), 1.77-1.78 (1H, m),
2.02-2.04 (1H, m), 2.19-2.21 (1H, m), 3.31-3.32 (1H, m), 3.49-3.51
(3H, m), 3.50 (3H, s), 4.00-4.02 (1H, m), 4.93-4.94 and 5.09-5.10
(1H, dm, J=62.87 Hz), 7.01 (1H, s), 7.90 (1H, d, J=9.03 Hz), 8.39
(1H, d, J=3.17 Hz)
[0249] IR (KBr, disk): 3373, 3315, 3091, 3003, 2976, 2935, 2856,
1903, 1714, 1618, 1518, 1439, 1371, 1313, 1261, 1219 cm.sup.-1.
[0250] Melting point: 189 to 192.degree. C.
[0251] [.alpha.].sub.D.sup.24.7=-50.83.degree. (c 0.240, 0.1 mol/l
NaOH)
[0252] Elemental analysis: As C.sub.21H.sub.24FN.sub.3O.sub.3;
Calcd.: C, 62.83; H, 6.03; N, 10.47 Found: C, 62.50; H, 6.04; N,
10.26
EXAMPLE 3
[0253]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-cyclopropyl-1,4-dih-
ydro-8-methyl-4-oxoguinoline-3-Carboxylic Acid
[0254] After adding
3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrroli- dine (132
mg, 585 .mu.mol) and triethylamine (245 .mu.l, 1.76 mmol) to dried
dimethyl sulfoxide (1 ml),
1-cyclopropyl-7-fluoro-1,4-dihydro-8-met-
hyl-4-oxoquinoline-3-carboxylic acid BF.sub.2 chelate (181 mg, 585
.mu.mol) was added thereto and it was stirred at room temperature
for 87 hours under a nitrogen atmosphere. After adding cold water
(50 ml) to the reaction solution and filtering out the precipitated
solids, the solids obtained were suspended in a mixed solvent (200
ml) of ethanol/water (9:1), and triethylamine (1 ml) was added
thereto and then heated under reflux for 7 hours. After
concentrating the reaction solution under a reduced pressure, the
residue was dissolved in chloroform (100 ml), and after washing the
organic layer with a 10% aqueous citric acid solution (50 ml), the
organic layer was dried over anhydrous sodium sulfate. After
filtering, the filtrate was concentrated under a reduced pressure,
and after adding dropwise the concentrated hydrochloric acid (2 ml)
to the residue while cooling with ice, it was stirred at room
temperature for 30 minutes. 1 mol/l Hydrochloric acid (2 ml) was
then added to the reaction solution, and after washing the yellow
acidic aqueous solution with chloroform (50 ml.times.3), the pH was
adjusted to 12.0 with an aqueous sodium hydroxide solution. After
adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l
hydrochloric acid, extraction with chloroform (100 ml.times.4) was
performed. After drying over anhydrous sodium sulfate, the solvent
was evapolated under a reduced pressure. The residue thus obtained
was purified by recrystallization in ethanol and then dried under a
reduced pressure. 99.6 mg (46%) of the title compound was thereby
obtained in the form of yellow crystals.
[0255] .sup.1H-NMR (400 MHz, 0.1 mol/l NaOD) .delta.: 0.55-0.57
(4H, m), 0.74-0.76 (1H, m), 0.90-0.92 (1H, m), 1.11-1.13 (1H, m),
1.24-1.26 (1H, m), 1.75-1.77 (1H, m), 2.03-2.05 (1H, m), 2.21-2.24
(1H, m), 2.48 (3H, s), 3.29-3.38 (3H, m), 3.53-3.55 (1H, m),
4.10-4.12 (1H, m), 7.07 (1H, s), 7.96 (1H, s), 8.57 (1H, s).
[0256] Melting point: 230 to 233.degree. C.
[0257] Specific rotation: [.alpha.].sub.D.sup.24.7=-169.35.degree.
(c 0.385, 0.1 mol/l NaOH)
[0258] Elemental analysis: As C.sub.21H.sub.25N.sub.3O.sub.3;
Calcd.: C 68.48%; H 6.86%; N 11.44% Found: C 68.46%; H 6.71%; N
11.38%
REFERENCE EXAMPLE 6
Ethyl 2-(2,6-dichloronicotinoyl)Acetate
[0259] Monoethyl malonate (6.61 g, 50.0 mmol) was dissolved in
anhydrous tetrahydrofuran (100 ml), and after adding magnesium
ethoxide (3.15 g, 28.0 mmol) thereto while cooling with ice, it was
stirred at room temperature for 3 hours. The reaction solution was
then concentrated under a reduced pressure, thereby preparing a
magnesium salt of monoethyl malonate. 2,6-dichloronicotinic acid
(3.84 g, 20.0 mmol) was then dissolved in anhydrous tetrahydrofuran
(80 ml), and after adding 1,1-carbonyldiimidazole (4.87 g. 30.0
mmol) while cooling with ice, it was stirred at room temperature
for 1.5 hours. To this solution, a solution, wherein the previously
prepared magnesium salt of monoethyl malonate was dissolved in
anhydrous tetrahydrofuran (160 ml), was added dropwise over a
period of 10 minutes while cooling with ice. After completion of
dripping, the temperature was gradually brought back to room
temperature and thereafter, stirring was performed for 4 hours.
After adding ethyl acetate (200 ml) to the reaction solution, the
organic layer was washed with a 10% aqueous citric acid solution
(150 ml.times.2), saturated sodium bicarbonate water (150 ml), and
saturated saline solution (150 ml), in that order, and then dried
over anhydrous sodium sulfate. After filtering, the residue
obtained by concentration under a reduced pressure of the filtrate
was applied to a silica gel chromatography, and 4.24 g (81%) of the
title compound was obtained in the form of a pale-pink, oily
substance from an n-hexane:ethyl acetate=3:1 eluate.
[0260] .sup.1H-NMR (400 MHz, CHCl.sub.3) .delta.: 1.12-1.40 (3H,
m), 4.08 (1H, s), 4.15-4.35 (2H, m), 5.72 (0.5H, s), 7.37 (1H, dd,
J=14.5, 8.1 Hz), 9.49 (1H, dd, J=16.4, 8.1 Hz), 12.52 (0.5H,
s).
REFERENCE EXAMPLE 7
[0261] Ethyl
2-(2,6-dichloronicotinoyl)-3-[2-(S)-fluoro-1-(R)-cyclopropyla-
mino]Acrylate
[0262] Ethyl 2-(2,6-dichloronicotinoyl)acetate (7.03 g, 26.8 mmol)
was dissolved in acetic anhydride (30 ml), and after adding
triethyl orthoformate (60 ml) thereto, it was stirred in an oil
bath of 140.degree. C. for 2 hours. After letting the reaction
solution cool, it was concentrated under a reduced pressure, and
after adding toluene (50 ml) to the residue obtained, a
concentration operation under a reduced pressure was performed.
This operation was repeated 3 times, and the residue obtained was
dried under a reduced pressure. 8.42 g of ethyl
2-(2,6-dichloronicotinoyl)-3-ethoxyacrylate was thereby obtained in
the form of a yellow oily substance.
[0263] Next, this crude ethyl
2-(2,6-dichloronicotinoyl)-3-ethoxyacrylate (2.11 g, 6.62 mmol) and
the para-toluenesulfonic acid salt of
2-(S)-fluoro-1-(R)-cyclopropylamine (2.45 g, 9.91 mmol) were
suspended in dichloromethane (30 ml), and triethylamine (2.77 ml,
19.87 mmol) was added dropwise gradually thereto while stirring at
-15.degree. C. After completion of dripping, the reaction solution
was stirred at room temperature for 15 hours. After adding ethyl
acetate (100 ml) to the reaction solution, the organic layer was
washed with a 10% aqueous citric acid solution (80 ml), saturated
sodium bicarbonate water (80 ml), and saturated saline solution (80
ml), in that order, and then dried over anhydrous sodium sulfate.
After filtering, the filtrate was concentrated under a reduced
pressure, and 20.10 g (90%, 2 processes) of the title compound was
thereby obtained as a yellowish-brown, oily substance (E/Z
mixture). This resulting substance was used in the subsequent
reaction without further purification.
[0264] .sup.1H-NMR (400 MHz, CHCl.sub.3) .delta.: 0.85-0.89 (0.7H,
m), 1.00-1.04 (2.3H, m), 1.23-1.38 (2H, m), 3.01 (1H, m), 3.94-4.05
(2H, m), 4.65-4.84 (1H, m), 7.27-7.31 (1H, m), 7.50-7.57 (1H, m),
8.29-8.38 (1H, m), 11.02 (0.8H, brd, J=12.5 Hz).
REFERENCE EXAMPLE 8
[0265] Ethyl
7-chloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxo-
-1,8-naphthylidine-3-carboxylate.
[0266] After dissolving ethyl
2-(2,6-dichloronicotinoyl)-3-[2-(S)-fluoro-1-
-(R)-cyclopropylamino]acrylate (2.07 g, 5.97 mmol) in 1,4-dioxane
(30 ml), 60% oily sodium hydride (287 mg, 7.18 mmol) was added
gradually thereto while stirring at 5.degree. C. The reaction
suspension was then stirred for 1.5 hours at room temperature and
then concentrated under a reduced pressure. After dissolving the
residue in chloroform (100 ml), the organic layer was washed with a
10% aqueous citric acid solution (80 ml), saturated sodium
bicarbonate water (80 ml), and saturated saline solution (80 ml),
in that order, and then dried over anhydrous sodium sulfate. After
filtering, the filtrate was concentrated under a reduced pressure,
diethyl ether was added to the residue thus obtained, and the
precipitated crystals were filtered out, washed with diethyl ether,
and then dried under a reduced pressure at 60.degree. C. for 16
hours. 1.25 g (67%) of the title compound was thereby obtained in
the form of a white powder.
[0267] .sup.1H-NMR (400 MHz, CHCl.sub.3) .delta.: 1.41 (3H, t,
J=7.1 Hz), 1.59-1.72 (2H, m), 3.58-3.63 (1H, m), 4.41 (2H, q, J=7.1
Hz), 4.93-5.12 (1H, m), 7.39-7.41 (1H, m), 8.65-8.68 (2H, m).
[0268] MS (m/z): 310 (M+)
REFERENCE EXAMPLE 9:
[0269]
7-chloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxo-1,8-n-
aphthylidine-3-Carboxylic Acid
[0270] A mixture of ethyl
7-chloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4--
dihydro-4-oxo-1,8-naphthylidine-3-carboxylate (567 mg, 1.83 mmol),
acetic acid (4 ml) and concentrated hydrochloric acid (2 ml) was
heated under reflux for 2.5 hours. After cooling the reaction
solution with ice, ice water (20 ml) was poured into the reaction
solution, the precipitated crystals were filtered out, and after
washing with excess water, a small amount of cold ethanol, and
excess diethyl ether, the crystals were dried under a reduced
pressure at 80.degree. C. for 18 hours. 449 mg (87%) of the title
compound was thereby obtained in the form of white needle
crystals.
[0271] .sup.1H-NMR (400 MHz, CHCl.sub.3) .delta.: 1.70-1.80 (2H,
m), 3.73-3.79 (1H, m), 4.98-5.17 (1H, m), 7.56 (1H, d, J=8.3 Hz),
8.73 (1H, d, J=8.5 Hz), 8.97 (1H, s), 14.11 (1H, brs).
[0272] Melting point: 215 to 220.degree. C.
[0273] Specific rotation: [.alpha.].sub.D.sup.24.5=+26.90.degree.
(c 0.422, 0.1 mol/l NaOH)
[0274] Elemental analysis: As C.sub.12H.sub.8ClFN.sub.2O.sub.3;
Calcd.: C 50.99%; H 2.85%; N 9.91% Found: C 50.90%; H 2.71%; N
9.91%
[0275] MS (m/z): 282 (M.sup.+)
EXAMPLE 4
[0276]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-
-cyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthylidine-3-Carboxylic
Acid
[0277] After adding
3-(R)-[1-[N-(tert-butoxycarbonyl)amino]cyclopropyl]pyr- rolidine
(339 mg, 1.50 mmol) and triethylamine (1.39 ml) to dried
acetonitrile (10 ml),
7-chloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dih-
ydro-4-oxo-1,8-naphthylidine-3-carboxylic acid (283 mg, 1.00 mmol)
was added thereto and the mixture was heated under reflux for 1.5
hours under a nitrogen atmosphere. After concentrating the reaction
solution under a reduced pressure, the residue was dissolved in a
mixed solvent of ethyl acetate (100 ml) and dichloromethane (50
ml), and after washing the organic layer with a 10% aqueous citric
acid solution (50 ml) and saturated saline solution (50 ml) in that
order, the organic layer was dried over anhydrous sodium sulfate.
After filtering, the filtrate was concentrated under a reduced
pressure, and after adding dropwise concentrated hydrochloric acid
(15 ml) to the residue while cooling with ice, it was stirred at
the same temperature for 30 minutes. 1 mol/l Hydrochloric acid (10
ml) was then added to the reaction solution, and after washing the
yellow acidic aqueous solution with chloroform (50 ml.times.4), the
pH was adjusted to 11.0 with an aqueous sodium hydroxide solution.
After adjusting the pH of the basic aqueous solution to 7.4 with 1
mol/l hydrochloric acid, extraction with the lower layer (100
ml.times.2) of a 7:3:1 mixture of chloroform:methanol:water was
performed. The organic layers were then combined, and after drying
the organic layer over anhydrous sodium sulfate, the solvent was
evapolated under a reduced pressure. The residue obtained was
purified by recrystallization in ethanol and then dried under a
reduced pressure. 263 mg (74%) of the title compound was thereby
obtained in the form of white crystals.
[0278] .sup.1H-NMR (400 MHz, 0.1 mol/l NaOD) .delta.: 0.49-0.55
(4H, m), 1.50-1.75 (3H, m), 1.95-2.15 (2H, m), 3.00-3.80 (5H, m),
4.90-5.15 (1H, m), 6.38 (1H, dm, J=9.1 Hz), 8.01 (1H, d, J=9.1 Hz),
8.31 (1H, s).
[0279] IR (KBr, disk) v: 3089, 3008, 2871, 1712, 1624, 1566, 1508,
1446, 1379, 1333, 1257, 1187, 1136, 1095, 1024, 985 cm.sup.-1.
[0280] Melting point: 216 to 218.degree. C.
[0281] Specific rotation: [.alpha.].sub.D.sup.24.5=+63.50.degree.
(c 0.310, 0.1 mol/l NaOH)
[0282] Elemental analysis: As C.sub.19H.sub.21FN.sub.4O.sub.3;
Calcd.: C 61.28%; H 5.68%; N 15.04% Found: C 61.17%; H 5.66%; N
15.04%
[0283] MS (m/z): 373([M+H]).sup.+
REFERENCE EXAMPLE 10
[0284] Ethyl 2,4-difluorobenzoyl Acetate
[0285] Under a nitrogen atmosphere, monoethyl malonate (9.25 g,
70.0 mmol) was dissolved in anhydrous tetrahydrofuran (150 ml), and
after adding magnesium ethoxide (4.17 g, 36.8 mmol) while cooling
with ice, it was stirred at room temperature for 1 hour. The
reaction solution was then concentrated under a reduced pressure,
thereby preparing a magnesium salt of monoethyl malonate.
2,4-difluorobenzoic acid (7.91 g, 50.0 mmol) was then dissolved in
anhydrous tetrahydrofuran (100 ml), and after adding
1,1-carbonyldiimidazole (8.52 g. 52.5 mmol) while cooling with ice,
it was stirred at room temperature for 1 hour. To this solution, a
solution, wherein the previously prepared magnesium salt of
monoethyl malonate was dissolved in anhydrous tetrahydrofuran (60
ml), was added dropwise while cooling with ice. After completion of
dripping, the temperature was gradually brought back to room
temperature and thereafter, stirring was performed for 16 hours.
After adding toluene (100 ml) to the reaction solution, the organic
layer was washed with a 10% aqueous citric acid solution (200 ml),
saturated sodium bicarbonate water (150 ml), and saturated saline
solution (150 ml), in that order, and then dried over anhydrous
sodium sulfate. After filtering, the residue obtained by
concentration under a reduced pressure of the filtrate was applied
to a silica gel chromatography, and 11.0 g (95%) of the title
compound was obtained in the form of a pale-yellow, oily substance
from an n-hexane:ethyl acetate=9:1 eluate.
[0286] .sup.1H-NMR (400 MHz, CHCl.sub.3) .delta.: 1.24-1.36 (3H,
m), 3.95 (2H.times.2/3, d, J=3.66 Hz), 4.20-4.30 (2H, m), 5.80
(1H.times.1/3, s), 6.86-7.02 (2H, m), 7.88-8.04 (1H, m), 12.72
(1H.times.1/3, s).
Reference Example 11
[0287] Ethyl
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxo-
quinoline-3-carboxylate
[0288] A mixture of ethyl 2,4-difluorobenzoyl acetate (5.50 g, 24.1
mmol), triethyl orthoformate (8.00 ml, 48.2 mmol) and acetic
anhydride (6.8 ml) was stirred in an oil bath of 120.degree. C. for
16 hours. After letting the reaction solution cool, it was
concentrated under a reduced pressure, and after adding toluene (30
ml) to the residue obtained, it was concentrated under a reduced
pressure again, and then dried under a reduced pressure. A yellow
oily substance was thereby obtained. This substance was dissolved
in toluene (100 ml), and after adding the para-toluenesulfonic acid
salt of 2-(S)-fluoro-1-(R)-cyclopropylamine (6.46 g, 26.1 mmol),
triethylamine (4.95 ml, 35.6 mmol) was added dropwise gradually
thereto while stirring at -15.degree. C. After completion of
dripping, the reaction solution was stirred at room temperature for
18 hours. After adding water (150 ml) to the reaction solution,
extraction with ethyl acetate (150 ml.times.2) was performed. The
organic layers were combined and washed with saturated saline
solution (150 ml) and then dried over anhydrous sodium sulfate.
After filtering, the filtrate was concentrated under a reduced
pressure, and a brown oily substance was thereby obtained. After
dissolving this substance in dimethylformamide (35 ml), potassium
carbonate (6.55 g, 47.4 mmol) was added thereto and then stirred at
room temperature for 21 hour. Then while cooling with ice and
stirring, 2 mol/l hydrochloric acid (50 ml) was added gradually
thereto and then stirred at room temperature for 6 hours. The
precipitated crystals were filtered out and then washed with excess
water, a small amount of cold ethanol and excess diethyl ether. The
crude crystals obtained were then purified by recrystallization in
ethyl acetate and then dried under a reduced pressure. 5.92 g (84%)
of the title compound was thereby obtained.
[0289] .sup.1H-NMR (400 MHz, CHCl.sub.3) .delta.: 1.41-1.43 (3H,
m), 1.69-1.76 (2H, m), 3.39 (1H, brs), 4.37-4.43 (2H, m), 5.09 (1H,
dm, J=62.46 Hz), 7.16-7.22 (1H, m), 7.41-7.44 (1H, m), 8.49-8.57
(2H, m). Melting point: 227 to 230.degree. C.
Reference Example 12
[0290]
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinol-
ine-3-Carboxylic Acid
[0291] A mixture of ethyl
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4--
dihydro-4-oxoquinoline-3-carboxylate (4.08 g, 13.9 mmol), acetic
acid (9 ml) and concentrated hydrochloric acid (9 ml) was heated
under reflux for 21 hour. After cooling the reaction solution with
ice, ice water (50 ml) was poured into the reaction solution, the
precipitated crystals were filtered out, and after washing with
excess water, a small amount of cold ethanol and excess diethyl
ether, the crystals were dried under a reduced pressure at
80.degree. C. for 16 hours. 3.51 g (95%) of the title compound was
thereby obtained in the form of a white powder.
[0292] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.78-1.84 (2H,
m), 3.52-3.53 (1H, m), 5.13 (1H, dm, J=64.59 Hz), 7.31-7.36 (1H,
m), 7.59 (1H, d, J=9.26 Hz), 8.54-8.53 (1H, m), 14.55 (1H, s).
[0293] Melting point: 302 to 305.degree. C.
[0294] Specific rotation: [a].sub.D.sup.243=+0.38.degree. (c 0.560,
0.1 mol/l NaOH)
EXAMPLE 5
[0295]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-
-cyclopropyl]-1,4-dihydro-4-oxoguinoline-3-Carboxylic Acid
[0296] After adding
3-(R)-[1-[N-(tert-butoxycarbonyl)amino]cyclopropyl]pyr- rolidine
(203 mg, 817 .mu.mol) and triethylamine (0.5 ml) to dried dimethyl
sulfoxide (1 ml), 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,-
4-dihydro-4-oxoquinoline-3-carboxylic acid (197 mg, 743 .mu.mol)
was added thereto and the mixture was heated reflux for 15 hours
under a nitrogen atmosphere. After letting the reaction solution
cool, water (30 ml) was added to the reaction solution while
cooling with ice, and the precipitated crystals were filtered out
and washed well with water. After adding concentrated hydrochloric
acid (5 ml) to the obtained crystals while cooling with ice,
stirring at the same temperature was performed for 30 minutes. 1
mol/l hydrochloric acid (10 ml) was then added to the reaction
solution, and after washing the yellow acidic aqueous solution with
chloroform (50 ml.times.2), the pH was adjusted to 12.0 with an
aqueous sodium hydroxide solution. After adjusting the pH of the
basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid,
extractions into chloroform (100 ml.times.3) and a 95:5 mixture of
chloroform:methanol (100 ml.times.2) were performed. The organic
layers were then combined, and after drying the organic layer over
anhydrous sodium sulfate, the solvent was evapolated under a
reduced pressure. The residue obtained was purified by
recrystallization in ethanol and then dried under a reduced
pressure. 203 mg (74%) of the title compound was thereby obtained
in the form of yellow crystals.
[0297] .sup.1H-NMR (400 MHz, 0.1 mol/l NaOD) .delta.: 0.50-0.54
(4H, m), 1.63-1.68 (3H, m), 2.00-2.12 (2H, m), 2.94-2.97 (1H, m),
3.16-3.36 (4H, m), 5.16 (1H, dm, J=62.40 Hz), 6.43 (1H, s), 6.67
(1H, d, J=9.02 Hz), 7.97 (1H, d, J=9.02 Hz), 8.32 (1H, s).
[0298] IR (KBr, disk) v: 3087, 3008, 2951, 2858, 1699, 1681, 1520,
1471, 1458, 1396, 1363, 1371, 1250 cm.sup.-1.
[0299] Melting point: 251 to 253.degree. C.
[0300] Specific rotation: [.alpha.].sub.D.sup.24.3=+41.90.degree.
(c 0.160, 1 mol/l NaOH)
[0301] Elemental analysis: As C.sub.20H.sub.22FN.sub.3O.sub.3;
Calcd.: C 64.68%; H 5.97%; N 11.31% Found: C 64.69%; H 5.96%; N
11.25%
REFERENCE EXAMPLE 13
[0302]
7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoguinoline--
3-Carboxylic Acid BF.sub.2 Chelate
[0303] While heating and stirring a mixed solution of ethyl
7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carb-
oxylate (2.01 g, 5.00 mmol), acetic acid (5 ml) and acetic
anhydride (5 ml) in an oil bath of 110.degree. C., a boron
trifluoride-tetrahydrofuran complex (0.83 ml, 7.50 mmol) was added
dropwise over a period of 5 minutes. After stirring the reaction
solution at the same temperature for 1.5 hours, excess diethyl
ether was added while cooling with ice, and the precipitated solids
were filtered out (and washed with diethyl ether). After drying
under a reduced pressure at room temperature, 2.06 g (98%) of the
title compound was obtained as a pale gray powder.
[0304] .sup.1H-NMR (400 MHz, d.sub.6-DMSO) .delta.: 1.15-1.30 (4H,
m), 4.43 (1H, m), 7.20 (1H, t, J=71.9 Hz), 8.25 (1H, d, J=8.8 Hz),
8.38 (1H, d, J=8.8 Hz), 9.36 (1H, s).
EXAMPLE 6
[0305]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-cyclopropyl-8-diflu-
oromethoxy-1,4-dihydro-4-oxoguinoline-3-Carboxylic Acid
[0306] After adding
3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrroli- dine (338
mg, 1.50 mmol) and triethylamine (2091 .mu.l, 1.50 mmol) to dried
dimethyl sulfoxide (2 ml),
7-bromo-1-cyclopropyl-8-difluoromethoxy--
1,4-dihydro-4-oxoquinoline-3-carboxylic acid BF.sub.2 chelate (422
mg, 1.00 mmol) was added thereto and stirred at room temperature
for 39 hours under a nitrogen atmosphere. After concentrating the
reaction solution under a reduced pressure, ethanol (20 ml),
triethylamine (4 ml) and water (4 ml) were added to the concentrate
and heated under reflux for 3 hours. After concentrating the
reaction solution under a reduced pressure, the residue was
dissolved in chloroform (100 ml), and after washing the organic
layer in a 10% aqueous citric acid solution (50 ml), the organic
layer was dried over anhydrous sodium sulfate. After filtering, the
filtrate was concentrated under a reduced pressure, and after
adding dropwise concentrated hydrochloric acid (5 ml) to the
residue while cooling with ice, it was stirred at room temperature
for 30 minutes. 3 mol/l Hydrochloric acid (30 ml) was then added to
the reaction solution, and after washing the yellow acidic aqueous
solution with chloroform (50 ml.times.2), the pH was adjusted to
11.0 with an aqueous sodium hydroxide solution. After adjusting the
pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric
acid, extraction with chloroform (50 ml.times.2) was performed.
After drying over anhydrous sodium sulfate, the solvent was
evapolated under a reduced pressure. The residue thus obtained was
purified by recrystallization in a mixed solvent of ethanol/diethyl
ether and then dried under a reduced pressure. 31 mg (8%) of the
title compound was thereby obtained in the form of a yellow
powder.
[0307] .sup.1H-NMR (400 MHz, 0.1 mol/l NaOD) .delta.: 0.57 (4H,
brs), 0.81 (1H, m), 1.03 (1H, m), 1.11 (1H, m), 1.25 (1H, m), 1.78
(1H, m), 2.05 (1H, m), 2.22 (1H, m), 3.35-3.60 (4H, m), 4.08 (1H,
m), 6.45 (1H, dd, J=76.3, 73.8 Hz), 7.07 (1H, d, J=9.3 Hz), 8.00
(1H, d, J=9.3 Hz), 8.46 (1H, s).
[0308] Melting point: 206 to 207.5.degree. C.
[0309] Specific rotation: [.alpha.].sub.D.sup.24.5=-67.70.degree.
(c 0.295, 0.1 mol/l NaOH)
[0310] Elemental analysis: As
C.sub.21H.sub.23F.sub.2N.sub.3O.sub.4.0.25CH- .sub.3CH.sub.2OH;
Calcd.: C 59.92%; H 5.73%; N 9.75% Found: C 59.85%; H 5.62%; N
9.68%
REFERENCE EXAMPLE 14
[0311] Ethyl
6-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihyd-
ro-8-methyl-5-nitro-4-oxoguinoline-3-carboxylate
[0312] Ethyl
6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-
-methyl-5-nitro-4-oxoquinoline-3-carboxylate (10.04 g, 27.12 mmol)
was dissolved in dimethylformamide (150 ml), and 28% ammonia water
(32.1 ml) was added dropwise thereto while stirring and cooling
with ice. While sealing the reaction solution in a sealed tube, it
was stirred at room temperature for 4 hours. The reaction solution
was then dissolved in methanol (200 ml) and concentrated under a
reduced pressure. The residue obtained was purified by
recrystallization from a mixed solvent of 2-propanol/chloroform/28%
ammonia water, and after drying under a reduced pressure, 7.07 g
(71%) of the title compound was obtained as a yellow powder.
[0313] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.35-1.44 (5H,
m), 2.67 (3H, d, J=3.41 Hz), 3.81-3.87 (1H, m), 4.33-4.41 (3H, m),
4.75-4.78 (0.5H, m), 4.90-4.94 (0.5H, m), 8.47 (1H, d, J=3.41
Hz).
[0314] Elemental analysis: As
C.sub.16H.sub.15F.sub.2N.sub.3O.sub.5; Calcd.: C 52.32%; H 4.12%; N
11.44% Found: C 52.62%; H 4.16%; N 11.12%
REFERENCE EXAMPLE 15
[0315] Ethyl
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-met-
hyl-5-nitro-4-oxoquinoline-3-carboxylate
[0316] Isoamyl nitrite (2.56 ml, 19.1 mmol) was added to
dimethylformamide (40 ml), and while stirring at 65.degree. C., a
solution, wherein ethyl
6-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl--
5-nitro-4-oxoquinoline-3-carboxylate (5.00 g, 13.6 mmol) was
dissolved in dimethylformamide (60 ml), was added dropwise over a
period of 3 hours. After completion of dripping, the reaction
solution was stirred at 65.degree. C. for 4 hours, allowed to cool,
and then poured into water (500 ml). After extraction with
chloroform (200 ml.times.3), the organic layers combined were
washed with 1 mol/l hydrochloric acid (200 ml) and saturated saline
solution (100 ml.times.2) in that order, and then dried over
anhydrous sodium sulfate. After filtering, the filtrate was
concentrated under a reduced pressure, and the residue obtained was
applied to a silica gel chromatography to obtain 2.91 g (61%) of
the title compound in the form of a white powder from a
chloroform:methanol=30:1 eluate.
[0317] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.37 (3H, t,
J=7.08 Hz), 1.40-1.67 (2H, m), 2.70 (3H, d, J=2.93 Hz), 3.89-3.93
(1H, m), 4.34-4.40 (2H, m), 4.79-4.83 (0.5H, m), 4.95-4.98 (0.5H,
m), 8.55 (1H, d, J=2.93 Hz).
REFERENCE EXAMPLE 16
[0318] Ethyl
5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihyd-
ro-8-methyl-4-oxoquinoline-3-carboxylate
[0319] Ethyl
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-met-
hyl-5-nitro-4-oxoquinoline-3-carboxylate (2.50 g, 7.10 mmol) was
dissolved in acetonitrile (20 ml), and after adding a 5% palladium
carbon catalyst (water content: 50%, 1.0 g) thereto, it was stirred
at room temperature for 20 hours under a hydrogen atmosphere at
atmospheric pressure. After removing the catalyst by filtering
(methanol washing), the filtrate was concentrated under a reduced
pressure, and the residue obtained was dissolved in ethyl acetate
(10 ml) and heated under reflux for 30 minutes. n-hexane (10 ml)
was then added, and after performing heated refluxing for 30
minutes, the reaction solution was allowed to stand under room
temperature. The precipitated crystals were then filtered out,
washed with a 1:1 mixed solution of n-hexane:ethyl acetate and
dried under a reduced pressure at 60.degree. C. for 16 hours. 869
mg (38%) of the title compound was thereby obtained as a yellow
powder.
[0320] .sup.1H-NMR (400 MHz, CDCl.sub.3) 6:1.23-1.36 (1H, m), 1.38
(3H, t, J=7.08 Hz), 1.43-1.56 (1H, m), 2.39 (3H, d, J=2.20 Hz),
3.70-3.77 (1H, m), 4.37 (2H, q, J=7.08 Hz), 4.71-4.75 (0.5H, m),
4.87-4.90 (0.5H, m), 6.20 (1H, d, J=11.96 Hz), 8.37 (1H, d, J=3.42
Hz).
REFERENCE EXAMPLE 17
[0321]
5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-m-
ethyl-4-oxoquinoline-3-Carboxylic Acid
[0322] Ethyl
5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihyd-
ro-8-methyl-4-oxoquinoline-3-carboxyl ate (735 mg, 2.28 mmol) was
dissolved in a 1:1 mixed solution (8 ml) of acetic acid:water, and
after adding concentrated sulfuric acid (90 .mu.l) thereto, it was
stirred for 4 hours in an oil bath of 120.degree. C. After cooling
the reaction solution with ice, water (20 ml) was poured therein,
and the mixed reaction solution was stirred at room temperature for
2 hours. The precipitated crystals were filtered out, washed with
excess water, a small amount of cold ethanol and excess diethyl
ether in that order, and then dried under a reduced pressure at
80.degree. C. for 17 hours. 552 mg (82%) of the title compound was
thereby obtained in the form of yellow crystals.
[0323] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 1.23-1.38 (1H,
m), 1.56-1.66 (1H, m), 2.39 (3H, d, J=2.20 Hz), 4.14-4.22 (1H, m),
4.96-5.00 (0.5H, m), 5.12-5.16 (0.5H, m), 6.50 (1H, d, J=12.70 Hz),
8.60 (1H, d, J=3.17 Hz).
[0324] Specific rotation: [.alpha.].sub.D.sup.24.3=-111.00.degree.
(c 0.510, 0.1 mol/l NaOH)
EXAMPLE 7
[0325]
5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluo-
ro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoguinoline-3-Carboxylic
Acid
[0326] After adding
3-(R)-[1-[N-(tert-butoxycarbonyl)amino]cyclopropyl]pyr- rolidine
(643 mg, 2.55 mmol) and triethylamine (0.5 ml) to dried dimethyl
sulfoxide (1 ml),
5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-
-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (250 mg, 850
.mu.mol) was added thereto and stirred at 70.degree. C. for 37
hours while sealing under a nitrogen atmosphere. After letting the
reaction solution cool, the reaction solution was concentrated
under a reduced pressure, the residue obtained was dissolved in
ethyl acetate (100 ml), and washed with a 10% aqueous citric acid
solution (50 ml) and saturated saline solution (30 ml). The organic
layer was then dried over anhydrous sodium sulfate, and after
filtering, the filtrate was concentrated under a reduced pressure.
The residue obtained was then applied to a short silica gel
chromatography and crude crystals were obtained from a
chloroform:methanol=30:1 eluate. After adding dropwise concentrated
hydrochloric acid (5 ml) to the crude crystals while cooling with
ice, it was stirred at the same temperature for 30 minutes. 1 mol/l
Hydrochloric acid (10 ml) was then added to the reaction solution,
and after washing the yellow acidic aqueous solution with
chloroform (50 ml.times.2), the pH was adjusted to 12.0 with an
aqueous sodium hydroxide solution. After adjusting the pH of the
basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid,
extraction with chloroform (100 ml.times.3) was performed. The
organic layers were then combined and dried over anhydrous sodium
sulfate, and then the solvent was evapolated under a reduced
pressure. The residue thus obtained was purified by
recrystallization from ethanol and then dried under a reduced
pressure. 32 mg (9%) of the title compound was thereby obtained in
the form of yellow crystals.
[0327] .sup.1H-NMR (400 MHz, 0.1 mol/l NaOD) .delta.: 0.54-0.57
(1H, m), 0.60-0.67 (1H, m), 1.23-1.55 (3H, m), 1.74-1.85 (1H, m),
1.97-2.17 (2H, m), 2.33 (3H, s), 3.18-3.27 (2H, m), 3.43-3.47 (1H,
m), 3.54-3.63 (1H, m), 3.71-3.78(1H, m), 4.77-4.79(0.5H, m),
4.93-4.96(0.5H, m), 6.00 (1H, s), 8.56 (1H, d, J=3.66 Hz).
[0328] IR (KBr, disk) v: 3402, 3344, 3276, 3097, 2918, 2864, 1724,
1616, 1548, 1506, 1477, 1441, 1408 cm.sup.-1.
[0329] Melting point: 240 to 242.degree. C. (decomposed)
[0330] Specific rotation: [.alpha.].sub.D.sup.23.5=-225.91.degree.
(c 0.525, 0.1 mol/l NaOH)
[0331] Elemental analysis: As C.sub.21H.sub.25FN.sub.4O.sub.3;
Calcd.: C 62.99%; H 6.29%; N 13.99% Found: C 62.86%; H 6.38%; N
13.76%
REFERENCE EXAMPLE 18
[0332] Ethyl
6-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihyd-
ro-8-methoxy-5-nitro-4-oxoguinoline-3-carboxylate
[0333] Ethyl
6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-
-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (13.96 g, 36.14 mmol)
was dissolved in dimethylformamide (180 ml), and 28% ammonia water
(60 ml) was added dropwise in while stirring and cooling with ice.
After stirring the reaction solution at room temperature for 64
hours, water (100 ml) was added to the reaction solution and then
concentrated under a reduced pressure. The water-containing residue
obtained was then subjected to extraction with ethyl acetate (100
ml.times.3), and the organic layers were then combined, washed with
water (150 ml.times.3) and saturated saline solution (200 ml) in
that order, and then dried over anhydrous sodium sulfate. After
filtering, the filtrate was concentrated under a reduced pressure,
the residue obtained was applied to a silica gel chromatography,
and 8.92 g (64%) of the title compound was obtained in the form of
a pale red, oily substance from a chloroform:methanol=30:1
eluate.
[0334] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.37 (3H, t,
J=7.0 Hz), 1.49 (1H, ddd, J=9.5, 6.0, 3.5 Hz), 1.53-1.58 (1H, m),
3.68 (1H, dt, J=8.5, 5.5 Hz), 4.11 (3H, d, J=2.5 Hz), 4.36 (2H, dq,
J=7.0, 1.5 Hz), 4.51 (2H, br), 4.83 (1H, ddt, J=63.3, 5.5, 3.5 Hz),
8.47 (1H, s).
[0335] IR (KBr, disk) v: 3379, 1724, 1608, 1525, 1471, 1323, 1259,
1063 cm.sup.-1.
[0336] HRMS (FAB): As C.sub.16H.sub.16F.sub.2N.sub.3O.sub.6
(M.sup.++1); Calcd.: 384.1007 Found: 384.0974
REFERENCE EXAMPLE 19
[0337] Ethyl
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-met-
hoxy-5-nitro-4-oxoguinoline-3-carboxylate
[0338] Isoamyl nitrite (3.81 g, 32.5 mmol) was added to
dimethylformamide (60 ml), and while stirring at 7.sup.0.degree.
C., a solution, wherein ethyl
6-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-m-
ethoxy-5-nitro-4-oxoquinoline-3-carboxylate (8.90 g, 23.2 mmol) was
dissolved in dimethylformamide (120 ml), was added dropwise thereto
over a period of 3 hours. After completion of dripping, the
reaction solution was stirred at 70.degree. C. for 1 hour, allowed
to cool, and then poured into water (500 ml). After extraction with
ethyl acetate (300 ml.times.3), the organic layers combined were
washed with 1 mol/l hydrochloric acid (300 ml) and saturated saline
solution (200 ml.times.2) in that order, and then dried over
anhydrous sodium sulfate. After filtering, the filtrate was
concentrated under a reduced pressure, and the crude crystals
obtained were recrystallized in ethanol and then dried under a
reduced pressure. 3.81 g (45%) of the title compound was thereby
obtained in the form of yellow crystals.
[0339] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.37 (3H, t,
J=7.0 Hz), 1.55 (1H, ddd, J=9.5, 6.0, 3.5 Hz), 1.59-1.69 (1H, m)
3.93 (1H, dt, J=8.5, 5.5 Hz), 4.11 (3H, t, J=2.5 Hz), 4.37 (2H, dq,
J=7.0, 1.5 Hz), 4.86 (1H, dddd, J=63.0, 6.0, 5.5, 3.5 Hz), 7.20
(1H, d, J=10.0 Hz), 8.55 (1H, d, J=1.5 Hz).
[0340] IR (KBr, disk) v: 3062, 1722, 1639, 1602, 1544, 1425, 1328,
1259, 1057 cm.sup.-1.
[0341] Melting point: 167 to 170.degree. C. (decomposed)
[0342] Elemental analysis: As
C.sub.16H.sub.14F.sub.2N.sub.2O.sub.6; Calcd.: C 52.18%; H 3.89%; N
7.61% Found: C 51.97%; H 3.78%; N 7.56%
REFERENCE EXAMPLE 20
[0343] Ethyl
5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihyd-
ro-8-methoxy-4-oxoguinoline-3-carboxylate
[0344] Ethyl
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-met-
hoxy-5-nitro-4-oxoquinoline-3-carboxylate (3.71 g, 10.1 mmol) was
dissolved in acetonitrile (50 ml), and after adding a 5% palladium
carbon catalyst (water content: 50%, 1.5 g) thereto, it was stirred
at room temperature for 20 hours under a hydrogen atmosphere at
atmospheric pressure. After removing the catalyst by filtering
(methanol washing), the filtrate was concentrated under a reduced
pressure, the residue obtained was applied to a silica gel
chromatography, and 2.68 g (79%) of the title compound was obtained
as a yellow amorphous substance from a chloroform:methanol=30:1
eluate.
[0345] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.38 (3H, t,
J=7.0 Hz), 1.43-1.57 (2H, m), 3.75-3.82 (4H, m), 4.37 (2H, q, J=7.0
Hz), 4.81 (1H, ddt, J=62.5, 6.5, 3.5 Hz), 6.24 (1H, d, J=13.0 Hz),
8.37 (1H, d, J=2.0 Hz).
[0346] HRMS (FAB): As C.sub.16H.sub.17F.sub.2N.sub.2O.sub.4
(M.sup.++1); Calcd.: 339.1156 Found: 339.1150
REFERENCE EXAMPLE 21
[0347]
5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-m-
ethoxy-4-oxoquinoline-3-Carboxylic Acid
[0348] A mixture of ethyl
5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cycloprop-
yl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (2.68 g,
7.92 mmol), acetic acid (20 ml) and concentrated hydrochloric acid
(20 ml) was heated under reflux for 3 hours. After cooling the
reaction solution with ice, water (200 ml) was poured therein and
the precipitated crystals were filtered out. After washing with
excess water, a small amount of cold ethanol and excess diethyl
ether in that order, the crude crystals obtained were purified by
recrystallization in a mixed solvent of chloroform/methanol and
then dried under a reduced pressure. 1.26 g (51%) of the title
compound was thereby obtained in the form of yellow crystals.
[0349] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 1.54-1.64 (2H,
m), 3.76 (3H, s), 4.02-4.07 (1H, m), 4.89-5.10 (1H, m), 6.59 (1H,
d, J=14.0 Hz), 7.73 (2H, br), 8.57 (1H, d, J=1.5 Hz).
[0350] IR (KBr, disk) v: 3432, 3328, 1699, 1576, 1518, 1281, 1236
cm.sup.-1.
[0351] Melting point: 291 to 298.degree. C. (decomposed)
[0352] Specific rotation: [.alpha.].sub.D.sup.25.0=+40.01.degree.
(c 0.305, 0.1 mol/l NaOH)
[0353] Elemental analysis: As
C.sub.14H.sub.12F.sub.2N.sub.2O.sub.4; Calcd.: C 54.20%; H 3.90%; N
9.03% Found: C 54.10%; H 3.86%; N 9.02%
EXAMPLE 8
[0354]
5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluo-
ro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoguinoline-3-Carboxylic
Acid
[0355] After adding
3-(R)-[1-[N-(tert-butoxycarbonyl)amino]cyclopropyl]pyr- rolidine
(788 mg, 3.48 mmol) and triethylamine (2 ml) to dried dimethyl
sulfoxide (1 ml),
5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-
-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (621 mg, 2.00
mol) was added thereto and stirred at 90.degree. C. for 168 hours
while sealing in a sealed tube under a nitrogen atmosphere. After
letting the reaction solution cool and then concentrating the
reaction solution under a reduced pressure, the residue obtained
was dissolved in chloroform (200 ml) and washed with a 10% aqueous
citric acid solution (100 ml). The organic layer was then dried
over anhydrous sodium sulfate, and after filtering, the filtrate
was concentrated under a reduced pressure. After adding dropwise
concentrated hydrochloric acid (10 ml) to the obtained residue
while cooling with ice, it was stirred at the same temperature for
30 minutes. 1 mol/l Hydrochloric acid (20 ml) was then added to the
reaction solution, and after washing the yellow acidic aqueous
solution with chloroform (50 ml.times.3), the pH was adjusted to
12.0 with an aqueous sodium hydroxide solution. After adjusting the
pH of the basic aqueous solution to 7.8 with 1 mol/l hydrochloric
acid, extraction with chloroform (100 ml.times.3) was performed.
The organic layers were then combined and dried over anhydrous
sodium sulfate, and then the solvent was evapolated under a reduced
pressure. The residue thus obtained was purified by
recrystallization from a mixed solvent of ethanol and diethyl
ether, and then dried under a reduced pressure. 74 mg (9%) of the
title compound was thereby obtained in the form of yellow
crystals.
[0356] .sup.1H-NMR (400 MHz, 0.1 mol/l NaOD) .delta.: 0.48-0.53
(4H, m), 1.09-1.21 (1H, m), 1.32-1.43 (1H, m), 1.64-1.75 (1H, m),
1.93-2.01 (1H, m), 2.10-2.23 (1H, m), 3.21-3.23 (1H, m), 3.21-2.27
(1H, m), 3.36-3.43 (6H, m), 3.79-3.84 (1H, m), 4.85-4.84 (1H, m),
4.85-5.04 (1H, m), 6.06 (1H, s), 8.01 (1H, d, J=3.5 Hz).
[0357] IR (KBr, disk) v: 3454, 3410, 1716, 1617, 1577, 1548, 1511,
1232, 1016 cm.sup.-1.
[0358] Melting point: 172 to 178.degree. C. (decomposed)
[0359] Elemental analysis: As
C.sub.21H.sub.25FN.sub.4O.sub.4.0.75H.sub.2O- ; Calcd.: C 58.66%; H
6.21%; N 13.03% Found: C 58.58%; H 6.02%; N 12.76%
REFERENCE EXAMPLE 22
[0360] Ethyl 3-dimethylamino-2-(2,3,4-trifluorobenzoyl)Acrylate
[0361] A mixed solution of 2,3,4-trifluorobenzoic acid (10.3 g,
58.5 mmol), thionyl chloride (6.4 ml, 87.8 mmol) and a catalytic
amount of dimethylformamide was heated under reflux for 30 minutes.
After letting the reaction solution cool, the reaction solution was
concentrated under a reduced pressure, toluene (30 ml) was added to
the residue, and concentration under a reduced pressure was
performed again. The residue obtained was then dissolved in
tetrahydrofuran (20 ml), and the resulting solution was added to a
tetrahydrofuran (40 ml) solution of ethyl
.beta.-dimethylaminoacrylate (9.20 g, 64.3 mmol) and triethylamine
(10.2 ml, 73.1 mmol) while stirring and cooling with ice. The
reaction mixture was then stirred at room temperature for 1.5 hours
and then heated under reflux for 16.5 hours. After letting the
reaction solution cool, the precipitated solids were removed by
filtration and the filtrate was concentrated under a reduced
pressure. The residue was then applied to a silica gel
chromatography, and 15.1 g (86%) of the title compound was obtained
from an n-hexane:ethyl acetate=3:1 eluate.
[0362] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.00 (3H, t,
J=7.1 Hz), 2.88 (3H, brs), 3.33 (3H, brs), 4.01 (2H, q, J=7.1 Hz),
6.95-7.01 (1H, m), 7.34 (1H, brs), 7.80 (1H, s).
REFERENCE EXAMPLE 23
[0363] Ethyl
10-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][-
1,4]benzoxazine-6-Carboxylate
[0364] Ethyl 3-dimethylamino-2-(2,3,4-trifluorobenzoyl)acrylate
(15.0 g, 49.8 mmol) was dissolved in ethanol (30 ml), and to this
solution, an ethanol (10 ml) solution of (S)-2-amino-1-propanol
(4.50 g, 59.8 mmol) was added dropwise while stirring and cooling
with ice. After completion of dripping, the reaction solution was
stirred for 1 hour at room temperature and then concentrated under
a reduced pressure. The residue obtained was dissolved in dimethyl
sulfoxide (50 ml), and after adding spray-dried calcium fluoride
(16 g) thereto, it was stirred at 120.degree. C. for 26 hours.
After letting the reaction suspension cool, the reaction suspension
was concentrated under a reduced pressure, chloroform (200 ml) and
water (200 ml) were added to the residue, and after performing a
separation operation, the water layer was extracted using
chloroform (200 ml). The combined organic layers were then washed
with saturated saline solution (100 ml) and then dried over
anhydrous sodium sulfate. After filtering, the filtrate was
concentrated under a reduced pressure, the residue obtained was
applied to a silica gel chromatography, and 5.60 g (39%) of the
title compound was obtained as a white powder from a
chloroform:methanol=50:1 eluate.
[0365] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.41 (3H, t,
J=7.1 Hz), 1.61 (3H, d, J=7.1 Hz), 4.33-4.44 (5H, m), 7.18 (1H, t,
J=10.0 Hz), 8.06 (1H, dd, J=10.0, 5.4 Hz), 8.39 (1H, s).
REFERENCE EXAMPLE 24
[0366]
10-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]be-
nzoxazine-6-Carboxylic Acid
[0367] A mixture of ethyl
10-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyri-
do[1,2,3-de][1,4]benzoxazine-6-carboxylate (5.60 g, 19.2 mmol),
acetic acid (25 ml) and concentrated hydrochloric acid (25 ml) was
heated under reflux for 4 hours. After cooling the reaction
solution with ice, water (100 ml) was added thereto, and the
precipitated crystals were filtered out and then washed with excess
water, a small amount of cold ethanol and excess diethyl ether in
that order. The crude crystals obtained were then suspended in
ethanol (40 ml) and stirred under room temperature. The crystals
were filtered out, washed with ethanol, and then dried under a
reduced pressure at 80.degree. C. for 17 hours. 4.10 g (81%) of the
title compound was thereby obtained in the form of a white
powder.
[0368] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 1.47 (3H, d,
J=6.8 Hz), 4.44 (1H, d, J=9.6 Hz), 4.62 (1H, d, J=9.6 Hz), 4.99
(1H, q-like, J=6.8 Hz), 7.59 (1H, t, J=9.1 Hz), 7.95 (1H, dd,
J=9.1, 5.4 Hz, 9.07 (1H, s).
[0369] Elemental analysis: As C.sub.13H.sub.10FNO.sub.4; Calcd.: C
59.32%; H 3.83%; N 7.22% Found: C 59.60%; H 3.95%; N 6.99%
EXAMPLE 9
[0370]
10-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-2,3-dihydro-3-(S)-me-
thyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-Carboxylic
Acid
[0371] After adding
3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrroli- dine (252
mg, 1.12 mmol) and triethylamine (0.50 ml) to dried dimethyl
sulfoxide (3 ml),
10-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,-
3-de][1,4]benzoxazine-6-carboxylic acid (244 mg, 928 .mu.mol) was
added thereto and stirred while heating in an oil bath of
100.degree. C. for 18 hours under a nitrogen atmosphere. After
concentrating the reaction solution under a reduce pressure, the
residue was dissolved in chloroform (100 ml). After washing the
organic layer with a 10% aqueous citric acid solution (50 ml) and
saturated saline solution (50 ml), the organic layer was dried over
anhydrous sodium sulfate. After filtering, the filtrate was
concentrated under a reduced pressure, and after adding dropwise
concentrated hydrochloric acid (6 ml) to the residue while cooling
with ice, it was stirred at room temperature for 30 minutes. After
adding 4 ml of water to the reaction solution and washing this
acidic aqueous solution with chloroform (10 ml.times.3), the pH was
adjusted to 12.0 with an aqueous sodium hydroxide solution. After
adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l
hydrochloric acid, extraction with chloroform (100 ml.times.3) was
performed. After drying over anhydrous sodium sulfate, the solvent
was evapolated under a reduced pressure. The residue thus obtained
was purified by recrystallization from ethanol and then dried under
a reduced pressure. 125 mg (36.5%) of the title compound was
thereby obtained in the form of yellow crystals.
[0372] .sup.1H-NMR (400 MHz, 0.1 mol/l NaOD) .delta.: 0.57 (4H, s),
1.54 (3H, d, J=6.80 Hz), 1.66-1.78 (1H, m), 2.01-2.11 (1H, m),
2.19-2.30 (1H, m), 3.38-3.60 (4H, m), 4.25 (1H, d, J=11.0 Hz), 4.47
(1H, d, J=11.0 Hz), 4.55-4.63 (1H, m), 7.11 (1H, d, J=9.03 Hz),
7.81 (1H, d, J=9.03 Hz), 8.32 (1H, s).
[0373] IR (KBr, disk) v: 1634, 1529, 1446, 1429, 1363, 1269, 1227,
798 cm.sup.-1.
[0374] Melting point: 249 to 252.degree. C. (decomposed)
[0375] Elemental analysis: As C.sub.20H.sub.23N.sub.3O.sub.4,
HCl.O.5H.sub.2O; Calcd.: C 57.90%; H 6.07%; N 10.13% Found: C
57.65%; H 5.87%; N 9.97%
EXAMPLE 10
[0376]
1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-7-[3-(R)-[1-(methylamin-
o)cyclopropyl]pyrrolidin-1-yl]-1,4-dihydro-4-oxoquinoline-3-Carboxylic
Acid
[0377] After adding
3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cycl-
opropyl]pyrrolidine (118 mg, 436 .mu.mol) and triethylamine (0.50
ml) to dried dimethyl sulfoxide (1 ml),
7-fluoro-1-[2-(S)-fluoro-1-(R)-cycloprop-
yl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (122 mg,
436 .mu.mol) was added thereto and heated under reflux in an oil
bath of 100.degree. C. for 18 hours under a nitrogen atmosphere.
After concentrating the reaction solution under a reduced pressure,
the residue was dissolved in chloroform (100 ml). After washing the
organic layer with a 10% aqueous citric acid solution (100 ml), the
organic layer was dried over anhydrous sodium sulfate. After
filtering, the filtrate was concentrated under a reduced pressure,
and after adding dropwise concentrated hydrochloric acid (2 ml) to
the residue while cooling with ice, it was stirred at room
temperature for 30 minutes. After adding 1 mol/l hydrochloric acid
(2 ml) to the reaction solution and washing the yellow acidic
aqueous solution with chloroform (50 ml.times.3), the pH was
adjusted to 12.0 with an aqueous sodium hydroxide solution. After
adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l
hydrochloric acid, extraction with chloroform (100 ml.times.3) was
performed. After drying over anhydrous sodium sulfate, the solvent
was evapolated under a reduced pressure. The residue thus obtained
was then purified by a preparative chromatography (developed into
the lower layer of a 7:3:1 mixture of chloroform:methanol:water),
purified further by recrystallization from ethanol, and then dried
under a reduced pressure. 72.8 mg (42%) of the title compound was
thereby obtained in the form of yellow crystals.
[0378] .sup.1H-NMR (400 MHz, 0.1 mol/l NaOD) .delta.: 0.59-0.64
(4H, m), 1.21-1.27 (1H, m), 1.50-1.64 (2H, m), 1.99-2.01 (1H, m),
2.34 (3H, s), 2.42 (3H, s), 2.87-2.89 (1H, m), 3.27-3.29 (3H, m),
3.63-3.65 (1H, m), 4.06-4.07 (1H, m), 5.05 (1H, dm, J=63.72 Hz),
7.09 (1H, m), 8.00 (1H, s), 8.44 (1H, s).
[0379] IR (KBr, disk) v: 3348, 3086, 2939, 2844, 2789, 1711, 1614,
1518, 1435, 1354, 1315, 1257, 1221 cm.sup.-1.
[0380] Melting point: 223 to 224.degree. C.
[0381] Specific rotation: [.alpha.].sub.D.sup.24.7=-119.66.degree.
(c 0.295, 0.1 mol/l NaOH)
[0382] Elemental analysis: As C.sub.22H.sub.26FN.sub.3O.sub.3;
Calcd.: C 66.15%; H 6.56%; N 10.52% Found: C 65.92%; H 6.52%; N
10.40%
EXAMPLE 11
[0383]
1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-7-[3-(R)-[1-(methylami-
no)cyclopropyl]pyrrolidin-1-yl]-1,4-dihydro-4-oxoguinoline-3-Carboxylic
Acid
[0384] After adding
3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cycl-
opropyl]pyrrolidine (102 mg, 379 .mu.mol) and triethylamine (0.50
ml) to dried dimethyl sulfoxide (1 ml),
7-fluoro-1-[2-(S)-fluoro-1-(R)-cycloprop-
yl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (112 mg,
379 .mu.mol) was added thereto and stirred while heating in an oil
bath of 100.degree. C. for 15 hours under a nitrogen atmosphere.
After concentrating the reaction solution under a reduced pressure,
the residue was dissolved in chloroform (100 ml). After washing the
organic layer with a 10% aqueous citric acid solution (100 ml), the
organic layer was dried over anhydrous sodium sulfate. After
filtering, the filtrate was concentrated under a reduced pressure,
and after adding dropwise concentrated hydrochloric acid (2 ml) to
the residue while cooling with ice, it was stirred at room
temperature for 30 minutes. After adding 1 mol/l hydrochloric acid
(2 ml) to the reaction solution and washing the yellow acidic
aqueous solution with chloroform (50 ml.times.4), the pH was
adjusted to 12.0 with an aqueous sodium hydroxide solution. After
adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l
hydrochloric acid, extraction with chloroform (100 ml.times.3) was
performed. After drying over anhydrous sodium sulfate, the solvent
was evapolated under a reduced pressure. The residue thus obtained
was then purified by a preparative chromatography (developed into
the lower layer of a 7:3:1 mixture of chloroform:methanol:water),
purified further by recrystallization from ethanol, and then dried
under a reduced pressure. 78.3 mg (50%) of the title compound was
thereby obtained in the form of yellow crystals.
[0385] .sup.1H-NMR (400 MHz, 0.1 mol/l NaOD) .delta.: 0.57-0.61
(4H, m), 1.33-1.40 (1H, m), 1.56-1.58 (2H, m), 1.99-2.01 (1H, m),
2.34 (3H, s), 2.87-2.89 (1H, m), 3.15-3.17 (1H, m), 3.52-3.54 (3H,
m), 3.53 (3H, s), 4.00-4.02 (1H, m), 5.02 (1H, dm, J=64.45 Hz),
7.03 (1H, s), 7.92 (1H, d, J=7.03 Hz), 8.39 (1H, s).
[0386] IR (KBr, disk) v: 3352, 3095, 3051, 2939, 2837, 2787, 1716,
1699, 1616, 1520, 1439, 1358, 1319, 1259, 1221 cm.sup.-1.
[0387] Melting point: 213 to 215.degree. C.
[0388] Specific rotation: [.alpha.].sub.D.sup.24.7=-38.46.degree.
(c 0.195, 0.1 mol/l NaOH)
[0389] Elemental analysis: As C.sub.22H.sub.26FN.sub.3O.sub.4;
Calcd.: C 63.60%; H 6.31%; N 10.11% Found: C 63.36%; H 6.31%; N
9.97%
EXAMPLE 12
[0390]
5-amino-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-7-[3-(R)-[1-(me-
thylamino)cyclopropyl]pyrrolidin-1-yl]-1,4-dihydro-4-oxoguinoline-3-Carbox-
ylic Acid
[0391] After adding
3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cycl-
opropyl]pyrrolidine (690 mg, 2.25 mmol) and triethylamine (0.50 ml)
to dried dimethyl sulfoxide (4 ml),
5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-c-
yclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid
(250 mg, 850 .mu.mol) was added thereto and heated under reflux in
an oil bath of 70.degree. C. for 24 hours under a nitrogen
atmosphere. After concentrating the reaction solution under a
reduced pressure, the residue was dissolved in chloroform (100 ml).
After washing the organic layer with a 10% aqueous citric acid
solution (100 ml) and saturated saline solution (100 ml), the
organic layer was dried over anhydrous sodium sulfate. After
filtering, the filtrate was concentrated under a reduced pressure,
and after adding dropwise concentrated hydrochloric acid (5 ml) to
the residue while cooling with ice, it was stirred at room
temperature for 30 minutes. After adding 1 mol/l hydrochloric acid
(2 ml) to the reaction solution and washing the yellow acidic
aqueous solution with chloroform (50 ml.times.3), the pH was
adjusted to 12.0 with an aqueous sodium hydroxide solution. After
adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l
hydrochloric acid, extraction with chloroform (100 ml.times.3) was
performed. After drying over anhydrous sodium sulfate, the solvent
was evapolated under a reduced pressure. The residue thus obtained
was then purified by preparative chromatography (developed into the
lower layer of a 7:3:1 mixture of chloroform:methanol:water),
purified further by recrystallization from ethanol, and then dried
under a reduced pressure. 70.0 mg (20%) of the title compound was
thereby obtained in the form of yellow crystals.
[0392] .sup.1H-NMR (400 MHz, 0.1 mol/l NaOD) .delta.: 0.56-0.64(4H,
m), 1.21-1.61 (3H, m), 1.92-1.96 (1H, m), 2.22 (3H, s), 2.45 (3H,
s), 2.68-2.73 (1H, m), 3.19-3.31 (3H, m), 3.59-3.66 (1H, m),
3.72-3.77 (1H, m), 4.76-4.78 (0.5H, m), 4.98-5.01 (0.5H, m), 5.97
(1H, s), 8.55 (1H, d, J=3.66 Hz).
[0393] IR (KBr, disk) v: 3440, 3329, 3082, 3005, 2964, 2937, 2877,
1716, 1620, 1549, 1506, 1437, 1404 cm.sup.-1.
[0394] Melting point: 129 to 131.degree. C.
[0395] Specific rotation: [.alpha.].sub.D.sup.22.6=-291.90.degree.
(c 0.285, 0.1 mol/l NaOH)
[0396] Elemental analysis: As
C.sub.21H.sub.25FN.sub.4O.sub.3.0.25H.sub.2O- ; Calcd.: C 63.07%; H
6.62%; N 13.37% Found: C 62.89%; H 6.42%; N 13.27%
EXAMPLE 13
[0397]
2,3-dihydro-3-(S)-methyl-10-[3-(R)-[1-(methylamino)cyclopropyl]pyrr-
olidin-1-yl]-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-Carboxylic
Acid
[0398] After adding
3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cycl-
opropyl]pyrrolidine (125 mg, 521 .mu.mol) and triethylamine (0.50
ml) to dried dimethyl sulfoxide (1 ml),
10-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-
-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (132 mg, 500
.mu.mol) was added thereto and stirred while heating in an oil bath
of 100.degree. C. for 20 hours under a nitrogen atmosphere. After
concentrating the reaction solution under a reduced pressure, the
residue was dissolved in chloroform (100 ml). After washing the
organic layer with a 10% aqueous citric acid solution (50 ml) and
saturated saline solution (50 ml), the organic layer was dried over
anhydrous sodium sulfate. After filtering, the filtrate was
concentrated under a reduced pressure, and after adding
concentrated hydrochloric acid (3 ml) to the residue while cooling
with ice, it was stirred at room temperature for 30 minutes. After
adding water (3 ml) to the reaction solution and washing the yellow
acidic aqueous solution with chloroform (50 ml.times.3), the pH was
adjusted to 12.0 with an aqueous sodium hydroxide solution. After
adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l
hydrochloric acid, extraction with chloroform (100 ml.times.3) was
performed. After drying over anhydrous sodium sulfate, the solvent
was evapolated under a reduced pressure. The residue thus obtained
was then purified by recrystallization from ethanol-ammonia water
and then dried under a reduced pressure. 135 mg (70%) of the title
compound was thereby obtained in the form of yellow crystals.
[0399] .sup.1H-NMR (400 MHz, 0.1 mol/l NaOD) .delta.: 0.56-0.60
(4H, m), 1.45-1.50 (1H, m), 1.52 (3H, d, J=6.59 Hz), 1.99-2.01 (1H,
m), 2.32 (3H, s), 2.86-2.88 (1H, m), 3.21-3.55 (4H, m), 4.22, 4.45
(each 1H, ABq, J=11.36 Hz), 4.57-4.59 (1H, m), 7.04-7.08 (1H, m),
7.80 (1H, d, J=9.03 Hz), 8.32 (1H, s).
[0400] Melting point: 227 to 229.degree. C.
[0401] Specific rotation: [.alpha.].sub.D.sup.247=-131.00.degree.
(c 0.200, 0.1 mol/l NaOH)
[0402] Elemental analysis: As C.sub.21H.sub.25N.sub.3O.sub.4;
Calcd.: C 65.78%; H 6.57%; N 10.96% Found: C 65.49%; H 6.55%; N
10.82%
EXAMPLE 14
[0403]
7-[3-(R)-[1-(ethylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluor-
o-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-Carboxylic
Acid
[0404] After adding
3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(ethyl)amino]cyclo-
propyl]pyrrolidine (2.16 g, 8.40 mmol) and triethylamine (4 ml) to
dried dimethyl sulfoxide (10 ml),
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-
-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.95 g, 7.00
mmol) was added thereto and heated under reflux in an oil bath of
100.degree. C. for 51 hour under a nitrogen atmosphere. After
concentrating the reaction solution under a reduced pressure, the
residue was dissolved in chloroform (150 ml). After washing the
organic layer with a 10% aqueous citric acid solution (100 ml) and
saturated saline solution (100 ml), the organic layer was dried
over anhydrous sodium sulfate. After filtering, the filtrate was
concentrated under a reduced pressure, and after adding dropwise
concentrated hydrochloric acid (10 ml) to the residue while cooling
with ice, it was stirred at room temperature for 30 minutes. After
adding 1 mol/l hydrochloric acid (20 ml) to the reaction solution
and washing the yellow acidic aqueous solution with chloroform (100
ml.times.5), the pH was adjusted to 12.0 with an aqueous sodium
hydroxide solution. After adjusting the pH of the basic aqueous
solution to 7.4 with 1 mol/l hydrochloric acid, extraction with
chloroform (150 ml.times.4) was performed. After drying over
anhydrous sodium sulfate, the solvent was evapolated under a
reduced pressure. The residue thus obtained was purified by
recrystallization from ethanol and then dried under a reduced
pressure. 1.61 g (55%) of the title compound was thereby obtained
in the form of yellow crystals.
[0405] .sup.1H-NMR (400 MHz, 0.1 mol/l NaOD) .delta.: 0.57-0.63
(4H, m), 1.04 (3H, t, J=6.95 Hz), 1.19-1.25 (1H, m), 1.47-1.64 (2H,
m), 1.97-1.98 (1H, m), 2.40 (3H, s), 2.70-2.73 (2H, m), 2.86-2.87
(1H, m), 3.26-3.28 (3H, m), 3.61-3.63 (1H, m), 4.02-4.05 (1H, m),
5.03 (1H, dm, J=64.11 Hz), 7.07 (1H, d, J=9.26 Hz), 7.98 (1H, d,
J=9.26 Hz), 8.43 (1H, d, J=3.41 Hz).
[0406] IR (KBr, disk) v: 3294, 2964, 2848, 1699, 1612, 1508, 1473,
1431, 1396, 1389, 1350, 1308, 1261 cm.sup.-1.
[0407] Melting point: 191 to 194.degree. C.
[0408] Specific rotation: [.alpha.].sub.D.sup.24.3=-236.55.degree.
(c 0.145, 0.1 mol/l NaOH)
[0409] Elemental analysis: As C.sub.23H.sub.28FN.sub.3O.sub.3;
Calcd.:. C 66.81%; H 6.83%; N 10.16% Found: C 66.52%; H 6.86%; N
10.03%
EXAMPLE 15
[0410]
1-(cyclopropyl)-8-methyl-7-[3-(R)-[1-(methylamino)cyclopropyl]pyrro-
lidin-1-yl]-1,4-dihydro-4-oxoguinoline-3-Carboxylic Acid
[0411] After adding
3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cycl-
opropyl]pyrrolidine (880 mg, 3.25 mmol) and triethylamine (11.0 ml)
to dried dimethyl sulfoxide (5 ml),
1-cyclopropyl-7-fluoro-8-methyl-1,4-dihy-
dro-4-oxoquinoline-3-carboxylic acid (425 mg, 1.63 mmol) was added
thereto and heated under reflux in an oil bath of 70.degree. C. for
38 hours under a nitrogen atmosphere. After concentrating the
reaction solution under a reduced pressure, the residue was
dissolved in ethyl acetate (200 ml). After washing the organic
layer with a 10% aqueous citric acid solution (100 ml), the organic
layer was dried over anhydrous sodium sulfate. After filtering, the
filtrate was concentrated under a reduced pressure, and after
adding dropwise concentrated hydrochloric acid (6 ml) to the
residue while cooling with ice, it was stirred at room temperature
for 30 minutes. After adding 1 mol/l hydrochloric acid (12 ml) to
the reaction solution and washing the yellow acidic aqueous
solution with chloroform (50 ml.times.3), the pH was adjusted to
12.0 with an aqueous sodium hydroxide solution. After adjusting the
pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric
acid, extraction with chloroform (100 ml.times.3) was performed.
After drying over anhydrous sodium sulfate, the solvent was
evapolated under a reduced pressure. The residue thus obtained was
then purified by recrystallization from a mixed solvent of
methanol/2-propanol, and then dried under a reduced pressure. 331
mg (53%) of the title compound was thereby obtained in the form of
yellow crystals.
[0412] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.57-0.65 (1H,
m), 0.87-0.92 (1H, m), 0.97-1.04 (1H, m), 1.11-1.18 (1H, m),
1.28-1.34 (1H, m), 1.64-1.71 (1H, m), 1.99-2.021H, m), 2.45 (3H,
s), 2.50 (3H, s), 2.71-2.76 (1H, m), 3.32-3.36 (3H, m), 3.64-3.70
(1H, m), 4.01-4.05 (1H, m), 6.99 (1H, d, J=9.06 Hz), 8.131H, d,
J=9.06 Hz), 8.85 (1H, s).
[0413] Melting point: 190 to 192.degree. C.
[0414] Elemental analysis: As C.sub.22H.sub.27N.sub.3O.sub.3;
Calcd.: C 69.27%; H 7.13%; N 11.02% Found: C 69.00%; H 7.16%; N
10.96%
REFERENCE EXAMPLE 25
[0415] Ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate
[0416] Ethyl 1-acetylcyclopropanecarboxylate (200 g, 1.28 mol) was
dissolved in ethanol (1000 ml), and bromine (72.7 ml, 1.41 mol) was
added dropwise while stirring and cooling with ice. After
completion of dripping, the temperature of the reaction solution
was raised to 30.degree. C. and stirring was performed for 2 hours.
After adding water (1000 ml) to the reaction solution while cooling
with ice, it was concentrated under a reduced pressure was
performed. After extracting the concentrate into ethyl acetate (750
ml.times.2), it was washed with a 10% aqueous sodium thiosulfate
solution (500 ml.times.2) and saturated sodium bicarbonate water
(500 ml.times.2) in that order and then dried over anhydrous sodium
sulfate. After filtering and concentrating the filtrate under a
reduced pressure, 291 g (97%) of the title compound was obtained as
a yellow, oily substance.
[0417] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.30 (3H, t,
J=7.1 Hz), 1.60-1.63 (4H, m), 4.22 (2H, q, J=7.1 Hz), 4.49 (2H,
s).
[0418] TLC: Rf=0.7 (n-hexane:ethyl acetate=3:1)
REFERENCE EXAMPLE 26
Diethylphosphonoacetic Acid
[0419] Ethyl diethylphosphonoacetate (10 g, 446 mmol) was dissolved
in ethanol (275 ml), and after adding dropwise a 2 mol/l aqueous
sodium hydroxide solution (275 ml, 550 mmol) while stirring and
cooling with ice, it was stirred at room temperature for 1 hour.
The reaction solution was then concentrated under a reduced
pressure, and the concentrate was made acidic by concentrated
hydrochloric acid while cooling with ice. Extractions into ethyl
acetate (200 ml.times.4), chloroform (100 ml.times.2) and 5%
methanol/chloroform (250 ml.times.2) were then performed. The
combined organic layers were then dried over anhydrous sodium
sulfate, and after filtering, the filtrate was concentrated under a
reduced pressure. 89 g (quantitative) of the title compound was
thereby obtained as a colorless, oily substance.
[0420] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.35 (6H, t,
J=6.8 Hz), 2.98 (2H, d, J=21.7 Hz), 4.19 (4H, q, J=6.8 Hz).
[0421] TLC: Rf=0.1 (chloroform:methanol=9:1)
REFERENCE EXAMPLE 27
[0422] Ethyl
1-[2-[N-[1-(S)-phenylethyl]amino]acetyl]cyclopropanecarboxyla-
te
[0423] 1-(S)-phenylethylamine (12.1 g, 100 mmol) was dissolved in
acetonitrile (120 ml), and an acetonitrile (50 ml) solution of
triethylamine (15.3 ml, 110 mmol) and ethyl 1-(2-bromoacetyl)
cyclopropanecarboxylate (23.5 g, 100 mmol) was added dropwise in
while stirring and cooling with ice. After completion of dripping,
the reaction solution was stirred while cooling with ice for 1.5
hours. The reaction solution was then poured into water (75 ml) and
concentrated under a reduced pressure. The concentrate was
subjected to extraction with diisopropyl ether (75 ml.times.2) and
then washed with water (75 ml). After extracting the organic layer
into 1 mol/l hydrochloric acid (100 ml.times.2), the acidic aqueous
solution was washed with ethyl acetate (100 ml). After adding a 1
mol/l aqueous sodium hydroxide solution (100 ml) to this acidic
aqueous solution and then further adding saturated sodium
bicarbonate water (100 ml), extraction with ethyl acetate (100 ml)
was performed. The organic layer was then washed with water (100
ml) and saturated saline solution (100 ml) in that order, and then
dried over anhydrous sodium sulfate. After filtering and then
concentrating the filtrate under a reduced pressure, 18.6 g (68%)
of the title compound was obtained as a pale-yellow, oily
substance.
[0424] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.17 (3H, t,
J=7.1 Hz), 1.38 (3H, d, J=6.6 Hz), 1.48 (4H, s), 3.71 (1H, q, J=6.6
Hz), 3.86 (2H, d, J=2.0 Hz), 4.10 (2H, q, J=7.1 Hz).
[0425] TLC: Rf=0.6 (n-hexane:ethyl acetate=1:1)
REFERENCE EXAMPLE 28
[0426] Ethyl
1-[2-[N-(diethylphosphonoacetyl)-N-[1-(S)-phenylethyl]amino]a-
cetyl]cyclopropanecarboxylate
[0427] Method A:
[0428] Diethylphosphonoacetic acid (15.1 g, 76.8 mmol) was
dissolved in anhydrous tetrahydrofuran (120 ml), and after adding
1,1'-carbonyldiimidazole (13.7 g, 84.5 mmol) while cooling with
ice, it was stirred at room temperature for 1 hour. After adding an
anhydrous tetrahydrofuran (30 ml) solution of ethyl
1-[2-[N-[1-(S)-phenylethyl]amin- o]acetyl]cyclopropanecarboxylate
(17.6 g, 64.0 mmol) to the reaction solution while cooling with
ice, it was stirred at room temperature for 1 hour. After adding 1
mol/l hydrochloric acid (100 ml) and ethyl acetate (100 ml) to the
reaction solution and performing an extraction operation, the
organic layer was separated. The aqueous layer was then subjected
to extraction with ethyl acetate (100 ml) and the combined organic
layer was washed with saturated sodium bicarbonate water (100 ml)
and saturated saline solution (100 ml) in that order, and then
dried over anhydrous sodium sulfate. After filtering and then
concentrating the filtrate under a reduced pressure, 28.7 g (99%)
of the title compound was obtained as a yellow syrup.
[0429] Method B
[0430] Diethylphosphonoacetic acid (32.8 g, 166 mmol) was dissolved
in anhydrous benzene (700 ml), and after adding
N,N'-dimethylformamide (1 ml), thionyl chloride (18.2 ml, 250 mmol)
was added thereto and heated under reflux for 1.5 hours. After
letting the reaction solution cool, it was concentrated under a
reduced pressure, and after adding dried toluene (100 ml) thereto,
its concentration under a reduced pressure was performed again.
After repeating this operation 3 times, the concentrate was
dissolved in anhydrous tetrahydrofuran (300 ml) and after adding
dropwise an anhydrous tetrahydrofuran (300 ml) solution of ethyl
1-[2-[N-[1-(S)-phenylethyl]amino]acetyl]cyclopropanecarboxylate
(45.7 g, 166 mmol) and triethylamine (25.1 ml, 183 mmol) while
stirring and cooling with ice, it was stirred while cooling with
ice for 1.5 hours and then stirred at room temperature for 2 hours.
After adding 1 mol/l hydrochloric acid (300 ml) and ethyl acetate
(300 ml) to the reaction solution and performing an extraction
operation, the organic layer was separated. The aqueous layer was
then subjected to extraction with ethyl acetate (300 ml) and the
combined organic layer was washed with saturated sodium bicarbonate
water (300 ml) and saturated saline solution (300 ml) in that
order, and then dried over anhydrous sodium sulfate. After
filtering and then concentrating the filtrate under a reduced
pressure, 43.6 g (70%) of the title compound was obtained as a
yellow syrup.
[0431] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.14, 1.20 (3H,
t, J=7.1 Hz), 1.29-1.68 (13H, m), 2.85, 4.69 (2H, dd, J=9.5, 20.7
Hz), 3.18, 4.55 (2H, d, J=22.2 Hz), 4.06-4.22 (6H, m), 5.42, 6.05
(1H, q, J=7.1 Hz), 7.26-7.37 (5H, m).
[0432] MS (m/z): 454 ([M+H]).sup.+
[0433] TLC: Rf=0.1 (n-hexane:ethyl acetate=1:1)
REFERENCE EXAMPLE 29
[0434]
4-(1-ethoxycarbonylcyclopropyl)-1-[1-(S)-phenylethyl]-3-pyrrolin-2--
one
[0435] After dissolving ethyl
1-[2-[N-(diethylphosphonoacetyl)-N-[1-(S)-ph-
enylethyl]amino]acetyl]cyclopropanecarboxylate (25.0 g, 55.2 mmol)
in toluene (250 ml), tert-butoxypotassium (7.40 g, 66.2 mmol) was
added gradually while stirring and cooling with ice. After stirring
the reaction solution for 15 minutes at room temperature, a 10%
aqueous citric acid solution (250 ml) and ethyl acetate (250 ml)
were added thereto, and after performing an extraction operation,
the organic layer was separated. The aqueous layer was then subject
to extraction with ethyl acetate (250 ml), and after washing the
combined organic layer with saturated sodium bicarbonate water (250
ml) and saturated saline solution (250 ml) in that order, the
organic layer was dried over anhydrous sodium sulfate. After
filtering, the filtrate was concentrated under a reduced pressure,
the concentrate was applied to a silica gel chromatography, and
12.1 g (73%) of the title compound was obtained as a orange syrup
from an n-hexane:ethyl acetate=2:1 to 1:2 eluate. The instrumental
analysis data for this resulting compound agreed with the data
indicated in PCT/JP96/00208.
[0436] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.18, (3H, t,
J=7.2 Hz), 1.60-1.63 (7H, m), 3.80 (1H, dd, J=1.5, 9.0 Hz),
4.07-4.11 (2H, m), 4.13 (1H, d, J=9.0 Hz), 5.55 (1H, q, J=7.1 Hz),
5.84 (1H, t, J=1.5 Hz), 7.24-7.36 (5H, m).
[0437] MS (m/z): 300 ([M+H]).sup.+
[0438] TLC: Rf=0.5 (n-hexane:ethyl acetate=1:1)
REFERENCE EXAMPLE 30
[0439]
4-(S)-(1-ethoxycarbonylcyclopropyl)-1-[1-(S)-phenylethyl]pyrrolidin-
-2-one
[0440]
4-(1-ethoxycarbonylcyclopropyl)-1-[1-(S)-phenylethyl]-3-pyrrolin-2--
one (12.1 g, 40.5 mmol) was dissolved in ethyl acetate (120 ml), a
5% platinum carbon catalyst (water content: 50%, 2.4 g) was added
thereto, and it was stirred at room temperature for 17 hours under
a hydrogen atmosphere at atmospheric pressure. The reaction
solution was then filtered through cellite (washed with ethyl
acetate) and the filtrate was then concentrated under a reduced
pressure. The concentrate was applied to a silica gel
chromatography, and 9.00 g (74%) of the compound of the title were
obtained as a pale-yellow syrup from an n-hexane:ethyl acetate=3:2
eluate. Further, 2.60 g (21%) of the diastereomer (4-(R)-isomer) of
the title compound was obtained as a pale-yellow syrup. The
instrumental analysis data for this resulting compound agreed with
the data indicated in PCT/JP96/00208.
[0441] 4-(S)-isomer:
[0442] .sup.1H-NMR (400 MHz, CDCl.sub.3) 6:0.63-0.65 (2H, m), 1.13
(3H, t, J=7.1 Hz), 1.12-1.19 (2H, m), 1.52 (3H, d, J=7.3 Hz), 2.17
(1H, dd, J=9.0, 16.8 Hz), 2.46 (1H, dd, J=9.3, 16.3 Hz), 2.67-2.76
(2H, m), 3.47 (1H, t, J=8.3 Hz), 3.96-4.11 (2H, m), 5.51 (1H, q,
J=7.3 Hz), 7.26-7.35 (5H, m).
[0443] TLC: Rf=0.45 (n-hexane:ethyl acetate=1:1)
[0444] 4-(R)-isomer:
[0445] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.72-0.76 (2H,
m), 1.18-1.24 (2H, m) 1.21 (3H, t, J=7.1 Hz), 1.52 (3H, d, J=7.1
Hz), 2.27-2.32 (1H, m), 2.44-2.52 (2H, m), 3.14 (2H, d, J=8.0 Hz),
4.10 (2H, q, J=7.1 Hz), 5.50 (1H, q, J=7.1 Hz), 7.26-7.35 (5H,
m).
[0446] TLC: Rf=0.5 (n-hexane:ethyl acetate=1:1)
REFERENCE EXAMPLE 31
[0447]
1-[1-[1-(S)-phenylethyl]-2-one-4-(S)-pyrrolidin-4-yl]-1-Cyclopropan-
ecarboxylic Acid
[0448]
4-(S)-(1-ethoxycarbonylcyclopropyl)-1-[1-(S)-phenylethyl]pyrrolidin-
-2-one (10.5 g, 34.9 mmol) was dissolved in 70 ml of ethanol, and
after adding a 1 mol/l aqueous sodium hydroxide solution (70 ml)
while cooling with ice, the reaction solution was stirred at room
temperature for 15.5 hours and then at 40.degree. C. for 3 hours.
After concentrating the reaction solution under a reduced pressure,
the remaining aqueous layer was washed with ethyl acetate (70 ml).
The aqueous layer was then made acidic by concentrated hydrochloric
acid while cooling with ice and then subjected to extraction with
chloroform (70 ml.times.3). The organic layer was then dried over
anhydrous sodium sulfate, and after filtering, the filtrate was
concentrated under a reduced pressure. 9.40 g (99%) of the title
compound was thereby obtained as white solids.
[0449] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.72-0.74 (2H,
m), 1.21-1.23 (2H, m), 1.52 (3H, d, J=7.3 Hz), 2.17 (1H, dd, J=8.8,
16.8 Hz), 2.48 (1H, dd, J=9.5, 16.8 Hz), 2.66-2.78 (2H, m), 3.50
(1H, t, J=9.3 Hz), 5.51 (1H, q, J=7.3 Hz), 7.25-7.34 (5H, m).
REFERENCE EXAMPLE 32
[0450]
4-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-1-[1-(S)-phenylethy-
l]pyrrolidin-2-one
[0451] A toluene (15 ml) solution of triethylamine (9.6 ml, 69
mmol) and diphenylphosphoric acid azide (DPPA; 10.4 g, 37.9 mmol)
was added to a toluene (80 ml) suspension of
1-[1-[1-(S)-phenylethyl]-2-one-4-(S)-pyrrol-
idin-4-yl]-1-cyclopropanecarboxylic acid (9.4 g, 34.4 mmol), and
after stirring at room temperature for 1 hour under a nitrogen
atmosphere, it was heated under reflux for 1.5 hours. After cooling
the reaction solution to room temperature, tert-butyl alcohol (95
ml) was added thereto and heated under reflux for 15 hours. After
letting the reaction solution cool, the reaction solution was
concentrated under a reduced pressure and ethyl acetate (95 ml) and
water (95 ml) were added to the concentrate. After performing an
extraction operation, the organic layer was separated and the
aqueous layer was subjected to extraction with ethyl acetate (95
ml). The combined organic layer was then washed with saturated
saline solution (95 ml) and then dried over anhydrous sodium
sulfate. After filtering and concentrating the filtrate under a
reduced pressure, the concentrate was applied to a silica gel
chromatography and 10.7 g (90%) of the title compound was obtained
as a colorless, amorphous substance from a chlorine:methanol=50:1
eluate.
[0452] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.56-0.85 (4H,
m), 1.37 (9H, s), 1.51 (3H, d, J=7.3 Hz), 2.32-2.44 (3H, m), 2.79
(1H, dd, J=7.3, 10.0 Hz), 3.36 (1H, m), 4.66 (1H, brs), 5.50 (1H,
q, J=7.3 Hz), 7.26-7.34 (5H, m)
[0453] TLC: Rf=0.15 (n-hexane:ethyl acetate=1:1)
REFERENCE EXAMPLE 33
[0454]
3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-1-[1-(S)-phenylethy-
l]Pyrrolidine
[0455]
4-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-1-[1-(S)-phenylethy-
l]pyrrolidin-2-one (10.4 g, 30.2 mmol) was dissolved in anhydrous
tetrahydrofuran (100 ml) and a 1.0M borane-tetrahydrofuran
complex/tetrahydrofuran solution (90.7 ml, 90.7 mmol) was added
dropwise gradually thereto under a nitrogen atmosphere while
cooling with ice. After completion of dripping, it was stirred for
16 hours under the condition of from ice-cooling to room
temperature. After slowly adding an aqueous solution (100 ml) of
potassium carbonate (25.0 g, 181 mmol) to the reaction solution
while cooling with ice, it was heated under reflux was for 1.5
hours. After letting the reaction solution cool, it was extracted
with ethyl acetate (100 ml.times.2) and then washed with saturated
saline solution (100 ml) The organic layer was then dried over
anhydrous sodium sulfate, and after filtering, the filtrate was
concentrated under a reduced pressure. The concentrate was applied
to a silica gel chromatography and 8.20 g (82%) of the title
compound was obtained in the form of colorless crystals from a
chloroform:methanol=100- :1 to 30:1 eluate.
[0456] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.62 (2H, brs),
0.75-0.88 (2H, m), 1.35 (3H, d, J=6.6 Hz), 1.41 (9H, s), 1.63 (2H,
m), 1.88-1.92 (1H, m), 2.14-2.17 (1H, m), 2.27-2.34 (2H, m), 2.63
(1H, brs), 3.15 (1H, t-like, J=6.6 Hz), 5.10 (1H, brs), 7.23-7.33
(5H, m).
[0457] MS (m/z): 331 ([M+H]).sup.+
[0458] TLC: Rf=0.4 (chloroform:methanol=9:1)
REFERENCE EXAMPLE 34
[0459]
3-(R)-[1-(tert-butoxycarbonylamino)Cyclopropyl]Pyrrolidine
[0460]
3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-1-[1-(S)-phenylethy-
l]pyrrolidine (270 mg, 0.817 mmol) was dissolved in ethanol (15
ml), and after adding a 10% palladium carbon catalyst (water
content: 52.0%; 270 mg), it was stirred at 40.degree. C. for 3
hours under a hydrogen atmosphere at atmospheric pressure. After
removing the catalyst by filtering (ethanol washing), the filtrate
was concentrated under a reduced pressure, and as a result, 185 mg
(quantitative) of the title compound was obtained in the form of a
colorless syrup.
[0461] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.69 (2H, brs),
0.79 (2H, brs), 1.42 (9H, s), 1.43-1.50 (1H, m), 1.86-1.88 (1H, m),
2.15-2.19 (1H, m), 2.68-2.72 (1H, m), 2.90-3.07 (3H, m), 4.92 (1H,
brs).
REFERENCE EXAMPLE 35
[0462]
1-benzyloxycarbonyl-3-(R)-[1-(tert-butoxycarbonylamino)Cyclopropyl]-
Pyrrolidine
[0463]
3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-1-[1-(S)-phenylethy-
l]pyrrolidine (1.70 g, 5.15 mmol) was dissolved in dichloromethane
(34 ml), and benzylchloroformate (1.10 ml, 7.73 mmol) was added
dropwise while stirring and cooling with ice. The reaction solution
was then stirred at room temperature for 2.5 hours and then stirred
at 40.degree. C. for 1.5 hours. After letting the reaction solution
cool, the reaction solution was concentrated under a reduced
pressure, the concentrate was applied to a silica gel
chromatography, and 1.40 g (75%) of the title compound was obtained
in the form of a colorless syrup from an n-hexane:ethyl acetate=2:1
eluate. The instrumental analysis data for this resulting compound
agreed with the data indicated in PCT/JP96/00208.
[0464] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.70 (2H, brs),
0.80 (2H, brs), 1.41 (9H, s), 1.63 (1H, m), 1.92 (1H, m), 2.25 (1H,
m), 3.07-3.12 (1H, m), 3.29-3.31 (1H, m), 3.56 (2H, m), 4.85 (1H,
brs), 5.12 (2H, s), 7.33-7.36 (5H, m).
[0465] TLC: Rf=0.4 (n-hexane:ethyl acetate=1:1)
REFERENCE EXAMPLE 36
[0466]
1-benzyloxycarbonyl-3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)Ami-
no]Cyclopropyl]Pyrrolidine
[0467]
1-benzyloxycarbonyl-3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-
pyrrolidine (1.40 g, 3.89 mmol), N,N'-dimethylformamide (7 ml),
silver oxide (9.0 g, 39 mmol) and methyl iodide (24 ml, 389 mmol)
were placed in a shaded and sealed tube, and this mixture was
stirred for 13 hours in an oil bath of 80.degree. C. The reaction
solution was then filtered through cellite (ethyl acetate washing)
and the filtrate was then diluted with ethyl acetate (100 ml). The
organic layer was then washed with water (50 ml.times.3) and
saturated saline solution (50 ml) in that order, and dried over
anhydrous sodium sulfate. After filtering, the filtrate was
concentrated under a reduced pressure, the concentrate was applied
to a silica gel chromatography, and 1.31 g (89%) of the title
compound was obtained in the form of a pale-yellow syrup an
n-hexane:ethyl acetate=2:1 eluate. The instrumental analysis data
for this resulting compound agreed with the data indicated in
PCT/JP96/00208.
[0468] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.83 (4H, brs),
1.42 (9H, s), 1.55 (1H, m), 1.88 (1H, m), 2.28-2.43 (1H, m), 2.83
(3H, s), 3.02-3.04 (1H, m), 3.25-3.33 (1H, m), 3.55 (2H, m), 5.12
(2H, s), 7.32-7.35 (5H, m).
[0469] MS (m/Z): 374 ([M+H]).sup.+
[0470] TLC: Rf=0.4 (n-hexane:ethyl acetate=1:1)
REFERENCE EXAMPLE 37
[0471]
3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)Amino]Cyclopropyl]Pyrro-
lidine
[0472]
1-benzyloxycarbonyl-3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)ami-
no]cyclopropyl]pyrrolidine (1.31 g, 3.48 mmol) was dissolved in
ethanol (13 ml), and after adding a 10% palladium carbon catalyst
(water content: 50%; 0.65 g) thereto, it was stirred at room
temperature for 5 hours under a hydrogen atmosphere at atmospheric
pressure. After performing filtration through cellite (ethanol
washing), the filtrate was concentrated under a reduced pressure.
As a result, 0.92 g (quantitative) of the title compound was
obtained in the form of a colorless syrup.
[0473] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.80 (4H, brs),
1.46 (9H, s), 1.81 (1H, m), 2.04 (1H, brs), 2.28-2.42 (1H, m), 2.54
(1H, brs), 2.84 (3H, s), 2.88-2.96 (3H, m).
[0474] TLC: Rf=0.1 (chloroform:methanol=9:1)
REFERENCE EXAMPLE 38
[0475]
3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)Amino]Cyclopropyl]-1-[1-
-(S)-phenylethyl]Pyrrolidin-2-one
[0476]
4-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-1-[1-(S)-phenylethy-
l]pyrrolidin-2-one (7.87 g, 22.8 mmol) was dissolved in
dimethylformamide (100 ml), and while cooling with ice, 60% oily
sodium hydride (10.10 g, 27.4 mmol) was added and stirred for 5
minutes. Then, methyl iodide (7.11 ml, 114 mmol) was added dropwise
thereto while stirring at room temperature. After completion of
dripping, the reaction suspension was stirred at room temperature
for 14 hours. After adding 60% oily sodium hydride (296 mg, 7.40
mmol) and methyl iodide (1.00 ml, 16.1 mmol), it was stirred at
40.degree. C. for 24 hours. After adding a saturated aqueous
ammonium chloride solution (100 ml) and water (150 ml) to the
reaction suspension while stirring and cooling with ice, extraction
with ethyl acetate (300 ml.times.2) was performed. The combined
organic layer was then washed with water (100 ml.times.2) and
saturated saline solution (100 ml.times.2) in that order, and then
dried over anhydrous sodium sulfate. After filtering, the filtrate
was concentrated under a reduced pressure, the residue obtained was
applied to a silica gel chromatography, and 7.53 g (92%) of the
title compound was obtained in the form of a colorless oily
substance from a chloroform:methanol=50 to 30:1 eluate.
[0477] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.83 (4H, m),
1.32 (6H, s), 1.38 (3H, s), 1.51 (3H, d, J=7.1 Hz), 1.61 (3H, d,
J=16.6 Hz), 2.43 (1H, m), 2.68-2.81 (3H, m), 3.21 (1H, m),
5.48-5.50 (1H, m), 7.26-7.36 (5H, m).
REFERENCE EXAMPLE 39
[0478]
3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)Amino]Cyclopropyl]-1-[1-
-(S)-phenylethyl]Pyrrolidine
[0479]
3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]-1-[1-
-(S)-phenylethyl]pyrrolidin-2-one (7.53 g, 21.0 mmol) was dissolved
in anhydrous tetrahydrofuran (70 ml) and a 1.0M
borane-tetrahydrofuran complex/tetrahydrofuran solution (63.0 ml,
63.0 mmol) was added dropwise gradually thereto while stirring and
cooling with ice. After completion of dripping, it was stirred at
room temperature for 20 hours. After slowly adding an aqueous
solution (72 ml) of potassium carbonate (7.22 g) while cooling with
ice, it was heated under reflux for 1.5 hours. After letting the
reaction solution cool to room temperature, water (150 ml) was
added, extraction with ethyl acetate (200 ml.times.2) was
performed, and then the combined organic layer was washed with
saturated saline solution (200 ml) and then dried over anhydrous
sodium sulfate. After filtering, the filtrate was concentrated
under a reduced pressure, the concentrate was applied to a silica
gel chromatography, and 7.19 g (99%) of the title compound was
obtained in the form of a colorless syrup from a
chloroform:methanol=50:1 eluate.
[0480] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.73 (4H, m),
1.35. (9H, s), 1.36 (3H, s), 1.61 (1H, m), 1.85 (1H, m), 1.97 (1H,
m), 2.27 (1H, m), 2.50-2.58 (2H, m), 2.79 (3H, s), 2.99 (1H, m),
3.14-3.19 (1H, m), 7.27-7.30 (5H, m).
REFERENCE EXAMPLE 40
[0481]
3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)Amino]Cyclopropyl]Pyrro-
lidine
[0482]
3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]-1-[1-
-(S)-phenylethyl]pyrrolidine (7.19 g, 20.9 mmol) was dissolved in
ethanol (78 ml), and after adding a 10% palladium carbon catalyst
(water content: 50%; 3.9 g), it was stirred at 40.degree. C. for 4
hours under a hydrogen atmosphere at atmospheric pressure. After
performing filtration through cellite (ethanol washing), the
filtrate was concentrated under a reduced pressure. As a result,
4.38 g (quantitative) of the title compound was obtained in the
form of a colorless syrup. The .sup.1H-NMR data and the TLC Rf
value of this resulting compound agreed with the data indicated
previously.
[0483] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.80 (4H, brs),
1.46 (9H, s), 1.81 (1H, m), 2.04 (1H, brs), 2.28-2.42 (1H, m), 2.54
(1H, brs), 2.84 (3H, s), 2.88-2.96 (3H, m).
[0484] TLC: Rf=0.1 (chloroform:methanol=9:1)
REFERENCE EXAMPLE 41
[0485]
4-(R)-[1-[N-(tert-butoxycarbonyl)-N-(ethyl)Amino]Cyclopropyl]-1-[1--
(S)-phenylethyl]Pyrrolidin-2-one
[0486]
4-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-1-[1-(S)-phenylethy-
l]pyrrolidin-2-one (4.16 g, 12.1 mmol) was dissolved in
dimethylformamide (50 ml). Under a nitrogen atmosphere and at room
temperature, 60% oily sodium hydride (580 mg, 14.5 mmol) was added
thereto and stirred for 10 minutes, and then ethyl iodide (4.87 ml,
60.5 mmol) was added dropwise. After completion of dripping, the
reaction suspension was stirred at room temperature for 15 hours.
After adding a saturated aqueous ammonium chloride solution (150
ml) to the reaction suspension while stirring and cooling with ice,
extraction with ethyl acetate (150 ml.times.2) was performed. The
combined organic layer was then washed with water (150 ml.times.2)
and saturated saline solution (150 ml) in that order, and then
dried over anhydrous sodium sulfate. After filtering, the filtrate
was concentrated under a reduced pressure, the residue obtained was
applied to a silica gel chromatography, and 4.56 g (quantitative)
of the title compound was obtained in the form of a colorless oily
substance from an n-hexane:ethyl acetate=1:2 eluate.
[0487] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.49-0.80 (4H,
m), 1.02-1.04 (3H, m), 1.37 (9H, s), 1.49-1.51 (3H, m), 1.92-1.94
(1H, m), 2.04-2.06 (1H, m), 2.36-2.38 (1H, m), 2.67-2.70 (2H, m),
3.20-4.23 (2H, m), 5.48-5.50 (1H, m), 7.26-7.52 (5H, m).
REFERENCE EXAMPLE 42
[0488]
3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(ethyl)Amino]Cyclopropyl]-1-[1--
(S)-phenylethyl]Pyrrolidine
[0489]
4-(R)-[1-[N-(tert-butoxycarbonyl)-N-(ethyl)amino]cyclopropyl]-1-[1--
(S)-phenylethyl]pyrrolidin-2-one (4.56 g, 12.1 mmol) was dissolved
in anhydrous tetrahydrofuran (80 ml)., and a 1.0M
borane-tetrahydrofuran complex/tetrahydrofuran solution (48.0 ml,
48.0 mmol) was added dropwise in while stirring and cooling with
ice. After completion of dripping, the reaction solution was
stirred for 16 hours under the condition of from ice cooling to
room temperature. After concentrating the reaction solution under a
reduced pressure, a 9:1 mixed solution (100 ml) of ethanol and
water was added thereto, and after adding triethylamine (5 ml), it
was heated under reflux for 4 hours. After cooling the reaction
solution to room temperature, concentration was performed under a
reduced pressure, saturated sodium bicarbonate water (100 ml) was
added to the residue, extraction with chloroform (100 ml.times.2)
was performed, and then the combined organic layer was washed with
saturated saline solution (100 ml) and then dried over anhydrous
sodium sulfate. After filtering, the filtrate was concentrated
under a reduced pressure, the concentrate was applied to a silica
gel chromatography, and 4.26 g (99%) of the title compound was
obtained in the form of a colorless syrup from a
chloroform:methanol=100:1 to 95:5 eluate.
[0490] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.54-0.78 (4H,
m), 1.09-1.11 (3H, m), 1.33-1.43 (13H, m), 1.84-1.97 (2H, m),
2.26-2.28 (2H, m), 2.56-2.57 (2H, m), 2.86-2.96 (1H, m), 3.13-3.18
(2H, m), 7.21-7.30 (5H, m).
REFERENCE EXAMPLE 43
[0491]
3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(ethyl)Amino]Cyclopropyl]Pyrrol-
idine
[0492]
3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(ethyl)amino]cyclopropyl]-1-[1--
(S)-phenylethyl]pyrrolidine (3.01 g, 8.40 mmol) was dissolved in
ethanol (120 ml), and after adding a 10% palladium carbon catalyst
(water content: 50%; 3.0 g), it was stirred at 40.degree. C. for 5
hours under a hydrogen atmosphere at atmospheric pressure. After
performing filtration through cellite (ethanol washing), the
filtrate was concentrated under a reduced pressure. As a result,
2.16 g (quantitative) of the title compound was obtained in the
form of a colorless syrup.
[0493] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.83-0.85 (4H,
m), 1.46 (9H, s), 1.74-1.82 (1H, m), 2.16-2.18 (2H, m), 2.43-2.52
(2H, m), 2.90-2.99 (2H, m), 3.21-3.24 (2H, m).
REFERENCE EXAMPLE 44
[0494] 2,3,4-trichlorobenzoic Acid
[0495] Sodium hydroxide (45.42 g, 1.090 mol) was dissolved in water
(220 ml), and while cooling with ice, bromine (16.85 ml, 0.327 mol)
was dripped therein over a period of 5 minutes. After stirring the
reaction solution at 0.degree. C. for 15 minutes, a dioxane (220
ml) solution of 2',3',4'-trichloroacetophenone (24.40 g, 0.109 mol)
was dripped therein at 0.degree. C. over a period of 30 minutes.
After stirring at room temperature for 14 hours, water (350 ml) was
added and then washed with dichloromethane (350 ml). The aqueous
layer obtained was gradually made acidic with concentrated
hydrochloric acid while cooling with ice and the resulting crystals
were filtered out. After washing the filtered-out crystals with
water, the water was removed by azeotropic distillation with
toluene. 22.33 g (91%) of the title compound was thereby obtained
as a pale yellow powder.
[0496] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.58 (1H, d,
J=8.3 Hz), 7.70 (1H, d, J=8.6 Hz)
REFERENCE EXAMPLE 45
[0497] Ethyl (2,3,4-trichlorobenzoyl)Acetate
[0498] 2,3,4-trichlorobenzoic acid (4.51 g, 20.0 mmol) was
dissolved in tetrahydrofuran (80 ml), carbonyldiimidazole (3.89 g,
24.0 mmol) was added thereto while cooling with ice, and then
stirred at room temperature for 3 hours (solution A). Meanwhile,
malonic acid monoethyl ester monopotassium salt (6.81 g, 40.0 mmol)
was suspended in ethyl acetate, and while cooling with ice,
triethylamine (13.9 ml, 100.0 mmol) and magnesium chloride (5.71 g,
60.0 mmol) were added thereto. After stirring at room temperature
for 3 hours, the reaction solution was cooled with ice and the
above-described solution A was dripped into this reaction solution
over a period of 10 minutes. After then washing solution A into the
reaction solution using tetrahydrofuran (10 ml), it was stirred at
room temperature for 14 hours, and then the reaction solution was
poured into a 10% aqueous citric acid solution (200 ml). This was
then extracted with ethyl acetate (200 ml), washed with saturated
saline solution (200 ml), and then dried over anhydrous sodium
sulfate. After then removing the drying agent by filtration, the
solvent was evapotated under a reduced pressure, and the crude
product obtained was subject to silica gel chromatography, thereby
obtaining 2.681 g (45%) of the title compound as a pale-red oil
from an n-hexane:ethyl acetate=5:1 eluate.
[0499] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.25 (1.5H, t,
J=7.2 Hz), 1.34 (1.5H, t, J=7.0 Hz), 3.99 (1H, s), 4.19 (1H, q,
J=7.2 Hz), 4.28 (1H, q, J=7.0 Hz), 5.47 (0.5H, s), 7.37-7.49 (2H,
m), 12.45 (0.5H, m)
REFERENCE EXAMPLE 46
[0500] Ethyl
7,8-dichloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-
-oxoquinoline-3-carboxylate
[0501] A mixture of ethyl (2,3,4-trichlobenzoyl)acetate (2.681 g,
9.07 mmol), acetic anhydride (10 ml) and triethyl orthoformate (20
ml) was heated under reflux for 2.5 hours in an oil bath at
140.degree. C. After evaporationg the solvent under a reduced
pressure, azeotropic distillation was carried out using toluene (3
times) to obtain 3.272 g of a crude ethyl
3-ethoxy-2-(2,3,4-trichlorobenzoyl)acrylate as a pale-red oil.
[0502] The above-obtained crude ethyl
3-ethoxy-2-(2,3,4-trichlorobenzoyl)a- crylate product (3.272 g) was
dissolved in dichloromethane (50 ml),
2-(S)-fluoro-1-(R)-cyclopropylamine tosylate (2.467 g, 9.98 mmol)
and triethylamine (1.64 ml, 11.79 mmol) were added thereto in that
order while cooling with salted ice, and stirred at room
temperature for 19.5 hours. Ethyl acetate (200 ml) was added to the
reaction solution, and after washing with 10% aqueous citric acid
solution (80 ml.times.2), saturated aqueous sodium bicarbonate
solution (80 ml) and saturated saline solution (80 ml), it was
dried over anhydrous sodium sulfate. After then removing the drying
agent by filtration, the solvent was evapotated under a reduced
pressure to obtain a crude ethyl
3-[2-(S)-fluoro-1-(R)-cyclopropyl]amino-2-(2,3,4-trichlorobenzoyl)acrylat-
e (3.59 g) as a pale-orange, gum-like substance.
[0503] The above-obtained crude ethyl
3-[2-(S)-fluoro-1-(R)-cyclopropyl]am-
ino-2-(2,3,4-trichlorobenzoyl)acrylate (3.57 g) was dissolved in
dried dioxane (45 ml), and after adding sodium hydride (60%
content, 433 mg, 10.82 mmol) while cooling with ice, it was stirred
for 14 hours while heating in an oil bath at 50.degree. C. After
evaporationg the solvent under a reduced pressure, the residue was
dissolved in chloroform (150 ml), and after washing with 10%
aqueous citric acid solution (50 ml) and saturated saline solution
(50 ml), it was dried over anhydrous sodium sulfate. After then
removing the drying agent by filtration, the solvent was evaporated
under a reduced pressued pressure, and the crude product obtained
was subject to silica gel chromatography, thereby obtaining 1.475 g
(48%) of the title compound as a pale-yellow powder from a
chloroform:ethyl acetate=1:2 eluate.
[0504] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.35-1.50 (1H,
m), 1.41 (3H, t, J=7.1 Hz), 1.55-1.75 (1H, m), 4.08-4.13 (1H, m),
4.39 (2H, q, J=7.1 Hz), 4.80-4.98 (1H, m), 7.53 (1H, d, J=8.5 Hz),
8.34 (1H, d, J=6.8 Hz), 8.57 (1H, d, J=2.7 Hz).
[0505] MS (m/z): 344 (M.sup.+).
REFERENCE EXAMPLE 47
[0506]
7,8-dichloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoqu-
inoline-3-Carboxylic Acid
[0507] A mixture of ethyl
7,8-dichloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]--
1,4-dihydro-4-oxoquinoline-3-carboxylate (1.114 g, 3.237 mmol),
acetic acid (8 ml) and concentrated hydrochloric acid (4 ml) was
heated under reflux for 2 hours in an oil bath at 130.degree. C.
After then adding water (40 ml) and cooling with ice, the crystals
formed were filtered out and washed with water (5 ml.times.2), 5%
aqueous ethanol solution (5 ml.times.2), and diethyl ether (5
ml.times.2), thereby obtaining 909 mg (89%) of the title compound
as a pale-yellow powder.
[0508] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.40-1.80 (2H,
m), 4.23-4.28 (1H, m), 4.83-5.02 (1H, m), 7.67 (1H, d, J=8.8 Hz),
8.38 (1H, d, J=8.6 Hz), 8.86 (1H, d, J=2.7 Hz)
[0509] Melting point: 198 to 201.degree. C.
[0510] Specific rotation:
[.alpha.].sub.D.sup.24.5=-24.0.degree.
[0511] Elemental analysis: As C.sub.13H.sub.8Cl.sub.2FNO.sub.3;
Calcd.: C 49.39%; H 2.55%; N 4.43% Found: C 49.14%; H 2.40%; N
4.33%
[0512] MS (m/z): 315 (M.sup.+), 354 [(M+K).sup.+]
EXAMPLE 16
[0513]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-8-chloro-1-[2-(S)-flu-
oro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-Carboxylic
Acid
[0514] A mixture of 7,8-dichloro-1-[2-(S)-fluoro-1-(R)-140.degree.
C. cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (253
mg, 0.80 mmol),
3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (272 mg,
1.20 mmol), N-methyl piperidine (0.195 ml, 1.60 mmol) and dimethyl
sulfoxide (3 ml) was stirred for 55 hours while heating in an oil
bath at 80.degree. C. and under a nitrogen-replaced atmosphere.
After evaporating the solvent, the residue was partitioned in ethyl
acetate (50 ml) and 10% aqueous citric acid solution (30 ml), and
after separating the organic layer, the organic layer was washed
with saturated saline solution (30 ml). The organic layer thus
obtained was dried over anhydrous sodium sulfate, and after
removing the drying agent by filtration, the solvent was evaporated
under a reduced pressure. The residue was subject to silica gel
chromatography and a crude 7-{3-(R)-[1-(tert-butoxycarbonylami-
no)cyclopropyl]pyrrolidin-1-yl}-8-chloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl-
]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained from a
chloroform:methanol=10:1 eluate.
[0515] The above-obtained crude
7-{3-(R)-[1-(tert-butoxycarbonylamino)cycl-
opropyl]pyrrolidin-1-yl}-8-chloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-d-
ihydro-4-oxoquinoline-3-carboxylic acid was dissolved in
concentrated hydrochloric acid (5 ml) while cooling with ice, and
after stirring at room temperature for 20 minutes, the solution was
transferred into a separation funnel and washed with chloroform (10
ml.times.10 times or more). Saturated aqueous sodium hydroxide
solution was then added while cooling with ice to the aqueous layer
after washing, thereby adjusting the pH to >11, and thereafter,
the pH was adjusted to 7.7 by adding concentrated hydrochloric acid
and 1 mol/l hydrochloric acid. The aqueous layer obtained was then
subject to extraction into chloroform (100 ml) and
chloroform:methanol=9:1 (100 ml.times.2), and the combined organic
layer was dried over anhydrous sodium sulfate. After removing the
drying agent by filtration, the solvent was evaporated under a
reduced pressure. The residue was then purified by a preparative
chromatography (developed into the lower layer of a 7:3:1 mixture
of chloroform:methanol:water), slurry-purified using
ethanol-diethyl ether, and then dried under a reduced pressure to
obtain 96 mg (30%) of the title compound as a pale-yellow
powder.
[0516] .sup.1H-NMR (400 MHz, 0.1 mol/l NaOD/D.sub.2O) .delta.:
0.45-0.65 (4H, m), 1.15-1.30 (1H, m), 1.50-1.75 (2H, m), 2.00-2.10
(1H, m), 2.10-2.25 (1H, m), 3.25-3.40 (2H, m), 3.55-3.75 (2H, m),
4.10-4.15 (1H, m), 4.90-5.15 (1H, m), 7.05 (1H, d, J=9.0 Hz), 7.99
(1H, d, J=9.3 Hz), 8.39 (1H, d, J=3.7 Hz).
[0517] Melting point: 128 to 130.degree. C.
[0518] Specific rotation:
[.alpha.].sub.D.sup.24.5=-193.0.degree.
[0519] Elemental analysis: As C.sub.20H.sub.21ClFN.sub.3O.sub.3
.1.5H.sub.2O: Calcd.: C 55.49%; H 5.59%; N 9.71% Found: C 55.74%; H
5.45%; N 9.57%
[0520] MS (m/z): 406[(M+H).sup.+]
REFERENCE EXAMPLE 48
[0521] Ethyl
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-hydroxy-8-methy-
l-1,4-dihydro-4-oxoguinoline-3-carboxylate
[0522] Ethyl
5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl--
1,4-dihydro-4-oxoquinoline-3-carboxylate (1.414 g, 4.39 mmol) was
suspended in 35% aqueous sulfuric acid solution (15 ml), and while
cooling with ice, an aqueous sodium nitrite solution (394 mg, 5.70
mmol/4.5 ml) was dripped therein over a period of 5 minutes. After
then stirring at 0.degree. C. for 30 minutes, a small amount of
urea was added, and at the same temperature, an aqueous copper (II)
nitrate trihydrate solution (17.00, 70.2 mmol/155 ml) was dripped
therein over a period of 10 minutes. After stirring at 0.degree. C.
for 5 minutes, copper (I) oxide (565 mg, 3.95 mmol) was added while
stirring the reaction solution violently. After then stirring at
room temperature for 20 minutes, extraction into chloroform (200
ml.times.2) was performed, and after making the aqueous layer
slightly basic with sodium bicarbonate, the aqueous layer was
extracted with chloroform (150 ml.times.3). The combined organic
layer was then dried over anhydrous sodium sulfate, and after
removing the drying agent bt the filtration, the solvent was
evaporated under a reduced pressure. The crude product obtained was
then subject to a silica gel chromatography, thereby obtaining 297
mg (21%) of the title compound as a yellow powder from a
chloroform:methanol=10:1 eluate.
[0523] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.36-1.47 (1H,
m), 1.40 (3H, t, J=7.1 Hz), 1.53-1.63 (1H, m), 2.51 (3H, t, J=2.4
Hz), 3.85-3.90 (1H, m), 4.39 (2H, q, J=7.2 Hz), 4.77-4.96 (1H, m),
6.58 (1H, d, J=11.5 Hz), 8.52 (1H, d, J=3.2 Hz).
[0524] MS (m/z): 324 [(M+H).sup.+]
REFERENCE EXAMPLE 49
[0525]
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-hydroxy-8-methyl-1,4--
dihydro-4-oxoquinoline-3-Carboxylic Acid
[0526] A mixture of ethyl
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-hy-
droxy-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (325 mg,
1.005 mmol), acetic acid (3 ml) and concentrated hydrochloric acid
(1.5 ml) was heated under reflux for 2 hours in an oil bath at
120.degree. C. After then adding water (30 ml) and cooling with
ice, the crystals formed were filtered out and then washed with
water, 5% aqueous ethanol solution, and diethyl ether to obtain 267
mg (90%) of the title compound as a pale-yellow powder.
[0527] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.40-1.75 (2H,
m), 2.58 (3H, t, J=2.5 Hz), 3.99-4.04 (1H, m), 4.80-5.05 (1H, m),
6.70 (1H, d, J=11.3 Hz), 8.76 (1H, d, J=3.2 Hz), 13.17 (0.7H, d,
J=1.0 Hz), 13.34 (0.7H, brs).
[0528] Melting point: 209 to 213.degree. C.
[0529] Specific rotation:
[.alpha.].sub.D.sup.24.7=-111.6.degree.
[0530] Elemental analysis: As C.sub.14H.sub.11F.sub.2NO.sub.4:
Calcd.: C 56.95%; H 3.76%; N 4.74% Found: C 56.90%; H 3.74%; N
4.68%
[0531] MS (m/z): 296[(M+H).sup.+]
EXAMPLE 17
[0532]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-
-cyclopropyl]-5-hydroxy-8-methyl-1,4-dihydro-4-oxoquinoline-3-Carboxylic
Acid
[0533] A mixture of
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-hydroxy--
8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (205 mg,
0.694 mmol),
3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (314 mg,
1.388 mmol), N-methyl piperidine (0.243 ml, 1.388 mmol), and
dimethyl sulfoxide (1.5 ml) was stirred for 66 hours while heating
in an oil bath at 80.degree. C. under a nitrogen-replaced
atmosphere. After evaporating the solvent, the residue was
partitioned in chloroform (50 ml) and 10% aqueous citric acid
solution (30 ml), and after separating the organic layer, the
aqueous layer was further subject to extraction into chloroform (30
ml). The combined organic layer was then dried over anhydrous
sodium sulfate, and after removing the drying agent by filtration,
the solvent was evaporated under a reduced pressure to thereby
obtain a crude 7-{3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-
pyrrolidin-1-yl}-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-hydroxy-8-methyl-1,4-
-dihydro-4-oxoquinoline-3-carboxylic acid.
[0534] The above obtained crude
7-{3-(R)-[1-(tert-butoxycarbonylamino)cycl-
opropyl]pyrrolidin-1-yl}-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-hydroxy-8-me-
thyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was dissolved in
concentrated hydrochloric acid (20 ml) while cooling with ice, and
after stirring at room temperature for 20 minutes, the solution was
transferred into a separation funnel and washed with chloroform (20
ml.times.5 times). Saturated aqueous sodium hydroxide solution was
then added while cooling with ice to the aqueous layer after
washing, thereby adjusting the pH to >11, and thereafter, the pH
was adjusted to 7.5 to 7.8 by adding concentrated hydrochloric acid
and 1 mol/l hydrochloric acid. The aqueous layer obtained was then
subject to extraction into chloroform (100 ml),
chloroform:methanol=9:1 (100 ml.times.2), and the lower layer of
chloroform:methanol:water=7:3:1 (100 ml), and the combined organic
layer was dried over anhydrous sodium sulfate. After removing the
drying agent by filtration, the solvent was evaporated under a
reduced pressure. The residue was then purified by a preparative
chromatography (developed into the lower layer of a 7:3:1 mixture
of chloroform:methanol:water), slurry-purified using diethyl ether,
and then dried under a reduced pressure to obtain 119 mg (43%) of
the title compound as a yellow powder.
[0535] .sup.1H-NMR (400 MHz, 0.1 mol/l NaOD/D.sub.2O) .delta.:
0.45-0.55 (4H, m), 1.05-1.20 (1H, m), 1.45-1.70 (2H, m), 1.90-2.00
(1H, m), 2.05-2.20 (1H, m), 2.16 (3H, s), 3.05-3.20 (2H, m),
3.25-3.35 (1H, m), 3.40-3.50 (1H, m), 3.90-3.95 (1H, m), 4.90-5.10
(1H, m), 6.16 (1H, s), 8.33 (1H, d, J=3.4 Hz).
[0536] Melting point: 203-206.degree. C.
[0537] Specific rotation:
[.alpha.].sub.D.sup.25.1=-274.4.degree.
[0538] Elemental analysis: As
C.sub.21H.sub.24FN.sub.3O.sub.4.1.5H.sub.2O: Calcd: C 58.87%; H
6.35%; N 9.81% Found: C 59.23%; H 6.20%; N 9.48%
[0539] MS (m/z): 402[(M+H).sup.+]
EXAMPLE 18
[0540]
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-8-cyano-1-[2-(S)-fluo-
ro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-Carboxylic
Acid
[0541] A mixture of ethyl
8-cyano-7-fluoro-1-[2-(S)-fluoro-1-(R)-cycloprop-
yl]-1,4-dihydro-4-oxoquinoline-3-carboxylate (250 mg, 0.785 mmol),
3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (267 mg,
1.18 mmol), 1,4-diazabicyclo[2.2.2]octane (132 mg, 1.18 mmol), and
dimethyl sulfoxide (13 ml) was stirred for 2 hours at room
temperature under a nitrogen-replaced atmosphere. After evaporating
the solvent, the residue was partitioned in chloroform (30 ml) and
10% aqueous citric acid solution (30 ml), and the organic layer was
separated. The organic layer obtained was dried over anhydrous
sodium sulfate, and after removing the drying agent by filtration,
the solvent was evaporated under a reduced pressure. The residue
was dissolved in concentrated hydrochloric acid (4 ml) and glacial
acetic acid (4 ml) at room temperature and then stirred for 12
hours while heating in an oil bath at 110.degree. C. After
evaporating the solvent, concentrated hydrochloric acid (2 ml) and
water (20 ml) were added, and the solution was transferred into a
separation funnel and then washed with chloroform (50 ml). 10 mol/l
Aqueous sodium hydroxide solution was then added to the aqueous
layer after washing, thereby adjusting the pH to >12. Then after
washing with chloroform (50 ml), the pH was adjusted to 8.3 by
adding concentrated hydrochloric acid and 1 mol/l hydrochloric
acid. The aqueous layer obtained was then concentrated to 5 ml
under a reduced pressure, subject to extraction into
chloroform:methanol=10:1 (50 ml.times.3), and the combined organic
layer was dried over anhydrous sodium sulfate. After removing the
drying agent by filtration, the solvent was evaporated under a
reduced pressure. The yellow solids thus obtained were
recrystallized in ethanol and then dried under a reduced pressure
to obtain 124 mg (40%) of the title compound as a yellow
powder.
[0542] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.48-0.51 (4H,
m), 1.66-1.90 (3H, m), 1.99-2.03 (1H, m), 2.03-2.09 (1H, m),
3.57-3.70 (3H, m), 3.79-3.83 (1H, m), 4.03-4.08 (1H, m), 5.18-5.35
(1H, m), 7.14 (1H, d, J=9.3 Hz), 8.16 (1H, d, J=9.3 Hz), 8.61 (1H,
d, J=3.9 Hz).
[0543] Melting point: 138 to 140.degree. C.
[0544] Specific rotation:
[.alpha.].sub.D.sup.24.5=+19.16.degree.
[0545] Elemental analysis: As
C.sub.21H.sub.21FN.sub.4O.sub.3.1.25H.sub.2O- : Calcd: C 60.21%; H
5.65%; N 13.07% Found: C 60.42%; H 5.62%; N 12.72%
[0546] MS (m/z): 397[(M+H).sup.+]
EXAMPLE 19
[0547]
7-[3-(R)-(1-aminocyclobutyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)--
cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-Carboxylic
Acid
[0548] A mixture of
7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy--
1,4-dihydro-4-oxoquinoline-3-carboxylic acid (290 mg, 0.98 mmol),
3-(R)-[1-(tert-butoxycarbonylamino)cyclobutyl]pyrrolidine (283 mg,
1.18 mmol), triethylamine (0.409 ml, 2.94 mmol), and dimethyl
sulfoxide (5 ml) was stirred for 112 hours while heating in an oil
bath at 80.degree. C. under an argon-replaced atmosphere. After
evapotating the solvent, the residue was partitioned in chloroform
(50 ml) and 10% aqueous citric acid solution (30 ml), and after
separating the organic layer, the organic layer was washed with
saturated saline solution (30 ml). The organic layer obtained was
then dried over anhydrous sodium sulfate, and after removing the
drying agent by filtration, the solvent was evaporated under a
reduced pressure. The residue was subject to a silica gel
chromatography and a crude
7-{3-(R)-[1-(tert-butoxycarbonylamino)cyclobut-
yl]pyrrolidin-1-yl}-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihyd-
ro-4-oxoquinoline-3-carboxylic acid was thereby obtained from a
chloroform:methanol=20:1 eluate.
[0549] The above obtained crude
7-{3-(R)-[1-(tert-butoxycarbonylamino)cycl-
obutyl]pyrrolidin-1-yl}-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-d-
ihydro-4-oxoquinoline-3-carboxylic acid was dissolved in
concentrated hydrochloric acid (5 ml) while cooling with ice, and
after stirring for 5 minutes in an ice-water bath, the solution was
transferred into a separation funnel and washed with chloroform (10
ml.times.3 times). 10 mol/l Aqueous sodium hydroxide solution was
then added while cooling with ice to the aqueous layer after
washing, thereby adjusting the pH to >12, and thereafter, the pH
was adjusted to 7.4 by adding concentrated hydrochloric acid and 1
mol/l hydrochloric acid. The aqueous layer obtained was then
subject to extraction into chloroform (100 ml.times.3) and the
combined organic layer was dried over anhydrous sodium sulfate.
After removing the drying agent by filtration, the solvent was
evapotaed under a reduced pressure. The residue was then
recrystallized in ethyl acetate-hexane and dried under a reduced
pressure 99 mg (24%) of the title compound as a yellow powder.
[0550] .sup.1H-NMR (400 MHz, d.sub.6-DMSO) .delta.: 1.30-1.45 (1H,
m), 1.45-1.60 (1H, m), 1.60-1.70 (1H, m), 1.70-2.50 (8H, m),
3.30-3.40 (1H, m), 3.40-3.50 (1H, m), 3.50 (3H, s), 3.56-3.60 (2H,
m), 4.03-4.09 (1H, m), 5.00-5.22 (1H, m), 7.09 (1H, d, J=9.1 Hz),
7.92 (1H, d, J=9.1 Hz), 8.57 (1H, d, J=3.4 Hz).
[0551] Melting point: 174.degree. C.
[0552] Elemental analysis: As
C.sub.22H.sub.26FN.sub.3O.sub.4.0.25H.sub.2O- : Calcd: C 62.92%; H
6.36%; N 10.01% Found: C 63.20%; H 6.22%; N 10.10%
[0553] MS (m/z): 416[(M+H).sup.+]
REFERENCE EXAMPLE 50
[0554] 3-cyano-2,4-Difluorobenzoic Acid
[0555] After dissolving diisopropylamine (56.0 ml, 395 mmol) in
anhydrous tetrahydrofuran (400 ml), the solution was stirred at
-15.degree. C. under a nitrogen atmosphere. After dripping therein
a hexane solution of n-butyllithium (1.52M, 260 ml, 395 mmol), the
solution was stirred while cooling with ice for 1 hour. After
cooling this solution to -78.degree. C., a solution, in which
2,6-difluorobenzonitrile (25.0 g, 180 mmol) was dissolved in
anhydrous tetrahydrofuran (100 ml), was dripped therein over a
period of 1 hour. After completion of dripping, the reaction
solution was stirred at -78.degree. C. for 1 hour and then dried
carbon dioxide was bubbled into this reaction solution for 30
minutes. Thereafter, the reaction solution was stirred at
-78.degree. C. for 1 hour, then raised gradually in temperature,
and then stirred at room temperature for 12 hours. 100 ml of 1
mol/l Hydrochloric acid was then added to the reaction solution
while cooling with ice and extraction into diethyl ether (500
ml.times.2) was performed. The combined organic layer was washed
with saturated saline solution (500 ml) and then dried over
anhydrous sodium sulfate. After filtration, the filtrate was
concentrated under a reduced pressure, thereby obtaining 29.7 g
(90%) of the yellow, amorphous compound of the title. This product
was used in the subsequent reaction without further
purification.
[0556] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.10 (1H, m),
8.32 (1H, m)
REFERENCE EXAMPLE 51
[0557] Ethyl
8-cyano-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihyd-
ro-4-oxoguinoline 3-carboxylate
[0558] 3-cyano-2,4-difluorobenzoic acid (29.6 g, 162 mmol) was
dissolved in dried toluene (250 ml), and after adding a catalytic
amount of N,N-dimethylformamide, thionyl chloride (17.7 ml, 243
mmol) was dripped in while stirring at room temperature. Upon
completion of dripping, the reaction solution was stirred for 1
hour in an oil bath at 80.degree. C. Then after letting the
reaction solution cool, the reaction solution was concentrated
under a reduced pressure, toluene (100 ml) was added to the
residue, and vacuum concentration was performed again. This
operation was repeated 3 times. The concentrate thus obtained was
dissolved in anhydrous tetrahydrofuran (200 ml), and this solution
was dripped, while stirring and cooling with ice, into a solution,
in which triethylamine (30 ml) and ethyl 3-dimethylaminoacrylate
(24.3 g, 170 mmol) were dissolved in anhydrous tetrahydrofuran (100
ml). After completion of dripping, the reaction solution was heated
under reflux for 12 hours. After then filtering the reaction
solution through cellite (washing with diethyl ether), the filtrate
was concentrated under reduced pressure and the residue obtained
was subject to a short silica gel chromatography. A brown, oily
substance was then obtained by vacuum concentration of a
chloroform:methanol=100:1 to 100:3 eluate.
[0559] This substance was then dissolved in anhydrous
tetrahydrofuran (300 ml), 2-(S)-fluoro-1-(R)-cyclopropylamine
paratoluenesulfonate (28.2 g, 114 mmol) was added thereto, and
while stirring at -15.degree. C., a solution, in which
triethylamine (23 ml, 165 mmol) was dissolved in anhydrous
tetrahydrofuran (50 ml), was dripped therein gradually. After
completion of dripping, the reaction solution was stirred while
cooling with ice for 2 hours and then stirred at room temperature
for 12 hours. Water (300 ml) was then added to the reaction
solution, and vacuum concentration was performed to evaporate the
tetrahydrofuran. Water (300 ml) was further added, and then
extraction into ethyl acetate (400 ml.times.3) was performed. After
washing the combined organic layer with saturated saline solution
(500 ml), it was dried over anhydrous sodium sulfate. After
filtration, the filtrate was concentrated under reduced pressure. A
yellowish-brown, oily substance was thus obtained.
[0560] This substance was dissolved in a dried 1,4-dioxane (400
ml), and while stirring and cooling with ice, 60% oily sodium
hydride (4.35 g) was added gradually. This reaction suspension was
then stirred at room temperature for 1 hour. After then
concentrating the reaction solution to approximately 1/3rd the
original volume under a reduced pressure, 0.5 mol/l hydrochloric
acid (50 ml) was poured in gradually while cooling with ice. The
precipitated solids were filtered out, washed with water, and then
washed with small amounts of cold ethanol and diethyl ether, in
that order. The crude crystals obtained were purified by
recrystallization in isopropanol, and dried under a reduced
pressure to obtain 10.6 g (49%) of the title compound as
yellowish-white crystals.
[0561] Melting point: 172 to 177.degree. C. (decomposed)
[0562] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.23-1.30 (1H,
m), 1.41 (3H, t, J=7.1 Hz), 1.61-1.99 (1H, m), 4.00 (1H, m), 4.40
(2H, q, J=7.1 Hz), 5.10 (1H, dm, J=63.5 Hz), 7.31 (1H, m), 8.52
(1H, d, J=2.6 Hz), 8.77 (1H, m)
TEST EXAMPLE 1
[0563] Antibacterial activities of the compounds of this invention
were measured in accordance to the standard method designated by
the Japan Society of Chemotherapy, with the results shown as MIC
values (microgram/ml) units in the following table. For comparison
with the MIC values of the compounds of this invention, MIC values
of levofloxacin (LVFX), ciprofloxacin (CPFX) and
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin--
1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-o-
xoquinoline-3-carboxylic acid (Reference drug 1), which is
described in PCT/JP96/00208, are also shown in the table.
2TABLE 1 Example Example Example Example Example 1 2 3 10 11 E.
coli, .ltoreq.0.003 .ltoreq.0.003 .ltoreq.0.003 .ltoreq.0.003 0.006
NIHJ S. flexneri, 0.006 0.012 .ltoreq.0.003 0.006 0.012 2A 5503 Pr.
vulgalis, .ltoreq.0.003 0.012 .ltoreq.0.003 0.006 0.012 08601 K.
0.025 0.05 0.012 0.025 0.1 pneumoniae, Type 1 Ser. 0.025 0.1 0.025
0.05 0.2 marcescens, 10100 Ps. 0.05 0.2 0.05 0.1 0.2 aeruginosa,
32104 Ps. 0.025 0.05 0.025 0.025 0.1 aeruginosa, 32121 Ps. 0.2 0.2
0.05 0.1 0.2 maltophilia, IID-1275 S. aureus, .ltoreq.0.003
.ltoreq.0.003 .ltoreq.0.003 .ltoreq.0.003 .ltoreq.0.003 209P S.
.ltoreq.0.003 0.012 0.003 0.006 0.012 epidermidis, 56500 Str.
.ltoreq.0.003 0.006 0.003 .ltoreq.0.003 0.012 pyogenes, G-36 Str.
faecalis, 0.012 0.025 0.012 0.012 0.05 ATCC 19433 S. aureus, 0.05
0.05 0.025 0.025 0.05 870307 Str. .ltoreq.0.003 0.006 .ltoreq.0.003
.ltoreq.0.003 0.006 pneumoniae J24 Example Example Reference 14 15
drug 1 LVFX CPFX E. coli, .ltoreq.0.003 .ltoreq.0.003 .ltoreq.0.003
0.012 .ltoreq.0.003 NIHJ S. flexneri, 0.006 0.006 .ltoreq.0.003
0.025 0.006 2A 5503 Pr. vulgalis, 0.012 0.012 .ltoreq.0.003 0.012
.ltoreq.0.003 08601 K. 0.05 0.025 0.006 0.1 0.025 pneumoniae, Type
1 Ser. 0.1 0.1 0.012 0.1 0.025 marcescens, 10100 Ps. 0.1 0.1 0.025
0.2 0.005 aeruginosa, 32104 Ps. 0.05 0.05 0.012 0.1 0.025
aeruginosa, 32121 Ps. 0.2 0.2 .ltoreq.0.003 0.39 0.78 maltophilia,
IID-1275 S. aureus, .ltoreq.0.003 .ltoreq.0.003 .ltoreq.0.003 0.2
0.1 209P S. 0.006 0.006 .ltoreq.0.003 0.39 0.2 epidermidis, 56500
Str. .ltoreq.0.003 .ltoreq.0.003 .ltoreq.0.003 0.2 1.56 pyogenes,
G-36 Str. faecalis, 0.025 0.025 0.006 0.78 0.78 ATCC 19433 S.
aureus, 0.012 0.025 0.012 .ltoreq.6.25 3.13 870307 Str.
.ltoreq.0.003 .ltoreq.0.003 .ltoreq.0.003 0.78 0.1 pneumoniae
J24
TEST EXAMPLE 2
[0564] For the compound described as Example 1 of this invention,
the micronucleus test in bone marrow of mice was performed by the
following method.
[0565] Mice groups, each consisting of five, six-week-old, Slc:ddY
male mice, were used. The compound of this invnetion described as
Example 1 and
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluor-
o-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic
acid (Reference drug 1) described in PCT/JP96/00208 were dissolved
in and diluted with 0.1 mol/l NaOH/saline solution. The 0.1 mol/l
NaOH/saline solvent was used as a control, and as a positive
Reference drug, a drug solution, prepared by dissolving and
diluting cyclophosphamide (CP) in saline solution, was used. All
drug solutions were disinfected by filtration through Mylex GS 0.22
.mu.m filters. With each drug solution, a single intravenous dose
of 10 ml/kg was administered at an administration rate of 0.2
ml/min. 24 hours after administration, myeloma cells were collected
from the femur bone, the smear preparations were prepared, and
these were dyed with acrylic orange. Using a fluorescence
microscope, 1000 polychromatic erythrocytes were observed for each
individual mouse, and the frequency of occurrence of micronucleated
polychromatic erythrocytes and the ratio of orthochromatic
erythrocytes and polychromatic erythrocytes among 1000 erythrocytes
were calculated.
[0566] As a result, a significant difference in the micronucleus
induction rate was not seen between the control and any of the 25,
50, and 100 mg/kg administration groups for the compound described
as Example land the judgment result was thus negative. That is, the
compound described as Example 1 was found to be extremely weak in
micronucleus induction and high in safety.
[0567] In contrast, with the comparison compound,
7-[3-(R)-(1-aminocyclopr-
opyl)pyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-
-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Reference drug 1)
described in PCT/JP96/00208, micronucleus induction in comparison
to the control was clearly seen with the 50 and 100 mg/kg
administration groups.
[0568] These results show that the compound described as Example 1
of this invention, wherein a fluorine atom of the 6-position of the
comparison compound,
7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-6-fluoro-1-[2-(S)-
-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxyli-
c acid described in PCT/JP96/00208 is replaced by a hydrogen atom,
exhibits a potent antibacterial action upon a broad range of both
gram-negative bacteria and gram-positive bacteria, including
resistant bacteria, and yet is high in safety.
TEST EXAMPLE 3
[0569] For the compound of this invention described as Example 1,
the blood concentration and organ concentration after oral
administration were determined by the following methods.
Measurements were also made by the same methods for Reference drug
1.
[0570] Method 1: Animal Tests
[0571] An administration solution was prepared by dissolving a
tested compound to a concentration of 2 mg/ml (as free compound) in
distilled water, and using a 2.5 ml disposable syringe or a metal
oral probe, the solution was orally administered at a dose of 20
mg/kg to fasting rats (Crj: CD IGS; male; 7-week-old; Charles River
Japan, Inc.).
[0572] The absorption test groups (4 rats per group; total of 6
groups) were killed by exsanguination while under ether
anesthetization 0.25, 0.5, 1, 2, 4, or 6 hours after drug
administration, and the blood, liver, kidneys, and lungs were
sampled. With the blood, serum was sampled by centrifugation (3000
rpm.times.15 minutes, 4.degree. C.) after coagulation. Tissues were
homogenized after adding 3 to 5 ml of 0.1M phosphate buffer
solution (pH 7.0) and the centrifugation supernatants (3000
rmpm.times.15 minutes, 4.degree. C.) were collected.
[0573] The excretion test groups (4 rats per group) were put in a
metabolic cage after drug administration, and collected urine
samples for 0 to 4 hours and 4 to 24 hours were sampled while
cooling with ice, and at the time of sampling, the interior of the
cage was washed with approximately 15 ml of 0.1 mol/l phosphate
buffer solution (pH 7.0) to recover the urine attached to the
interior of the cage. Also in order to examine glucuronide and
other conjugated compounds, a part of the sample was separated,
hydrolyzed with an equivalent amount of 1 mol/l aqueous sodium
hydroxide solution, and thereafter neutralized with 0.5 mol/l
hydrochloric acid, and concentration measurements were made on
samples prepared in this manner.
[0574] Method 2: Drug Concentration Measurements
[0575] Determination of drug concentrations in liquid samples were
quantified by an agar well method bioassay using the B. subtilis
ATCC6051 strain as the test organism. A test medium was prepared by
inoculating a suspension containing 5.times.10.sup.7CFU/ml of
spores of the test bacteria at a proportion of 1% into an nutrient
agar (Eiken Kagaku) that was sterilized at 121.degree. C. for 15
minutes and then cooled to approximately 50.degree. C. After
placing 10 ml each of this medium in a sterilized Petri dish and
solidifying horizontally, four holes of 8 mm diameter were made to
prepare a test plate medium. The Bioassay System TDA-1 (Dainippon
Seiki) was used for preparation of the test plate media. For the
measurements, the test samples (diluted with serum or phosphate
buffer solution as necessary), serial dilutions of the drug
solutions for calibration (two-fold serial dilutions prepared so
that the inhibition ring diameter will be approximately 10 to 30
mm), and a reference drug solution (a drug solution of given
concentration for correction of the error among plates; normally, a
concentration of forming an inhibition ring of approximately 20 mm
is used) were prepared, and 50 .mu.L of the test sample (or the
drug solution for calibration) were placed in each of two of the
four holes of each plate and 50 .mu.L of the reference solution was
placed in each of the other two holes. After addition of the
sample, the plate medium was set still for 1 hour at 4.degree. C.
to perform preliminary dispersion and then culturing at 37.degree.
C. was performed for approximately 18 hours, and the inhibition
ring diameters were measured using CA-400 (Dainippon Seiki). The
concentrations of the test samples were measured using a
calibration curve determined by second-order regression from the
logarithmic values of the drug concentration of the calibration
curve serial dilutions and the inhibition ring diameters.
[0576] For the tissue concentration (.mu.g/ml), the concentration
(.mu.g/ml) in the homogenate supernatant was determined from the
tissue weight (g) and the added phosphate buffer amount (ml) and
using the following equation:
[Tissue concentration]=[Homogenate concentration].times.([Tissue
weight]+[Buffer solution amount])/[Tissue weight]
[0577] The urinary excretion rate (%) was determined from the
amount (.mu.g) of drug administered, amount (ml) of urine (or
washing solution), and concentration (.mu.g/ml) in urine (or
washing solution):
[Urinary excretion rate]=100.times.([Amount of
urine].times.[Concentration in urine])/[Amount of drug
administered]
[0578] Method 3: Calculation of Pharmacokinetic Parameters
[0579] For each drug, the pharmacokinetic parameters in rats were
calculated based on mean concentration, by non-compartmental
analysis, and using the pharmacodynamics analysis software, PSAG-CP
(Asmedica).
[0580] The serum concentration and the organ concentration for
liver, kidneys, and lungs of the compound of Example 1 and
Reference drug 1, determined by the above methods, are shown in
Table 2.
3TABLE 2 Compound of Compound Example 1 (addition (1 HCl, 0.25 IPA,
Reference Drug product) 0.25 H.sub.20) (1 MsOH, 1 H.sub.20) Serum
C.sub.max(.mu.g/ml) 1.7 1.6 t.sub.1/2 (h) 1.2 1.0 AUC.sub.0-4 h 3.1
2.3 (.mu.g .multidot. h/ml) Tissue Liver 27.4 11.6
C.sub.max(.mu.g/g) Kidney 14.2 5.0 Lung 3.8 3.0 Liver 34.5 (11.0)
10.4 (4.6) AUC.sub.0-4 h Kidney 29.0 (9.2) 7.1 (3.1) (tissue/serum
Lung 10.0 (3.2) 5.3 (2.3) ratio) Urinary 0-24 h 8.1 1.8 recovery
after addition 8.7 2.3 ratio of (per conjugated dose) compounds
[0581] As is apparent from Table 2, the compound of this invention
was found to be distributed at higher concentrations, for both
serum and tissue, in comparison to Reference drug 1. It is thus
apparent that the compound of this invention is excellent in oral
absorption. It is also apparent that the compound of this invention
is excellent in tissue penetration.
[0582] The structures of the compounds that were compared in
activities are as follows. 40
INDUSTRIAL APPLICABILITY
[0583] Compounds of this invention exhibit excellent antibacterial
action upon a broad range of both gram-negative and gram-positive
bacteria and, in particular, exhibit potent antibacterial activity
even against resistant gram-positive bacteria, such as
methicillin-resistant Staphylococcus aureus (MRSA),
penicillin-resistant Streptococcus pneumoniae (PRSP),
vancomycin-resistant Enterococcus (VRE), etc., and
quinolone-resistant bacteria, and yet are excellent in safety
characteristics, such as being negative in micronucleus tests, and
excellent in pharmacokinetics, such as being improved in urinary
recovery rates and being excellent in oral absorption and tissue
penetration, etc. The compounds of this invention are thus useful
as antibacterial compounds to be used in chemotherapy against
microbial infections.
* * * * *