U.S. patent number RE41,149 [Application Number 10/859,587] was granted by the patent office on 2010-02-23 for optically active pyridonecarboxylic acid derivatives.
This patent grant is currently assigned to Daiichi Sankyo Company, Limited. Invention is credited to Isao Hayakawa, Youichi Kimura.
United States Patent |
RE41,149 |
Hayakawa , et al. |
February 23, 2010 |
Optically active pyridonecarboxylic acid derivatives
Abstract
N.sub.1-(1,2-cis-2-halogenocyclopropyl)-substituted
pyridonecarboxylic acid derivatives represented by the following
formula (I) the terms of which are defined in the specification and
the salts thereof are disclosed: ##STR00001## These compounds have
patent antibacterial activities against a wide variety of
infectious bacteria and are useful as antibacterial agents by oral
or parenteral administration.
Inventors: |
Hayakawa; Isao (Tokyo,
JP), Kimura; Youichi (Tokyo, JP) |
Assignee: |
Daiichi Sankyo Company, Limited
(Tokyo, JP)
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Family
ID: |
26445063 |
Appl.
No.: |
10/859,587 |
Filed: |
June 3, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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07610916 |
Nov 9, 1990 |
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07343567 |
Apr 27, 1989 |
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Reissue of: |
08142105 |
Oct 28, 1993 |
05587386 |
Dec 24, 1996 |
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Foreign Application Priority Data
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Apr 27, 1988 [JP] |
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63-104625 |
Nov 24, 1988 [JP] |
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63-296984 |
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Current U.S.
Class: |
514/312; 546/156;
546/15; 546/123; 544/363; 544/231; 540/597; 540/575; 540/553;
540/543; 514/278 |
Current CPC
Class: |
C07D
215/56 (20130101); A61P 31/00 (20180101); C07D
401/04 (20130101); A61P 31/04 (20180101) |
Current International
Class: |
C07D
471/04 (20060101); A61K 31/44 (20060101); A61K
31/47 (20060101); A61P 31/04 (20060101); C07D
215/56 (20060101) |
Field of
Search: |
;546/15 ;514/312 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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625414 |
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Nov 1989 |
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AU |
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0195316 |
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Sep 1986 |
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EP |
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341493 |
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Nov 1989 |
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EP |
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0191185 |
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Aug 1996 |
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EP |
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2188317 |
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Sep 1987 |
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GB |
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62-12760 |
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Jan 1987 |
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JP |
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Other References
USPTO Memorandum entitled "Clarification of Treatment of Reissue
Applications That Only Add One or More Narrower Claims", dated Nov.
17, 2007. cited by examiner .
Kimura I synthesis and Antibacterial Activity of
N.sub.1-2-Fluorocyclopropyl-4-Quinolone Derivatives, Research
Institute, Daiichi Seiyaku Co., Ltd. 1987, Japan. cited by other
.
Kimura II Therapeutics in the 21.sup.st Century, The Japanese
United States Congress of Pharmaceutical Sciences, Dec. 2-7, 1987,
Honolulu, Hawaii, Medicinal Chemistry, S156. cited by
other.
|
Primary Examiner: Berch; Mark L.
Attorney, Agent or Firm: Sughrue Mion, PLLC
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATION
This is a Continuation of application Ser. No. 07/610,916 filed on
Nov. 9, 1990, abandoned which is a Continuation-in-Part of
07/343,567 filed Apr. 27, 1989 abandoned.
Claims
What is claimed is:
1. A stereoisomerically pure
N.sub.1-(1,2-cis-2-halogenocyclopropyl)-substituted
pyridonecarboxylic acid derivative represented by the following
formula (I): ##STR00025## wherein R.sub.1 represents a hydrogen
atom, an amino group, a hydroxyl group or a thiol group; R.sub.2
represents a substituent represented by the following formula:
##STR00026## wherein R.sup.23 and R.sup.24 together are
(CH.sub.2)j; where j=2 to 5; A represents C--X.sup.3 or a nitrogen
atom; X.sup.1 and X.sup.2, which may be the same or different, each
represents a halogen atom; and X.sup.3 represents a halogen atom,
an alkyl group of from 1 to 6 carbon atoms, an alkoxyl group from 1
to 6 carbon atoms, a cyano group, a trifluoromethyl group, or a
hydrogen atom; or a pharmaceutically acceptable salt thereof.
2.
7-[7-(S)-Amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[2-(S)--
2-fluoro-1-(R)-cyclopropyl.[.).].
]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a
pharmaceutically acceptable salt thereof.
3. A method for treating bacterial infections which comprises
administering a therapeutically effective amount of
7-[7-(S)-Amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[2-(S)-2-f-
luoro-1-(R)-cyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid or a pharmaceutically acceptable salt thereof.
4.
7-[7-(S)-Amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-(1,2-ci-
s-2-fluorocyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
or a pharmaceutically acceptable salt thereof.
5. An antibacterial composition comprising a therapeutically
effective amount of, as an active ingredient,
7-[7-(S)-Amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[2-(S)-2-f-
luoro-1-(R)-cyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid or a pharmaceutically acceptable salt thereof, in combination
with a pharmaceutically acceptable carrier.
6. The .[.stereoisometrically.]. .Iadd.stereoisomerically
.Iaddend.pure N.sub.1-(1,2-cis-2-halogenocyclopropyl)-substituted
pyridonecarboxylic acid derivative of claim 1, wherein R.sup.2
represents a 7-amino-5-azaspiro[2,4]-heptan-5-yl group.
7. The stereoisomerically pure
N.sub.1-(1,2-cis-2-halogenocyclopropyl)-substituted
pyridonecarboxylic acid derivative of claim 6, wherein R.sup.2
represents a 7-(S)-amino-5-azaspiro [.[.2,4.].
.Iadd.2.4.Iaddend.]heptan-5-yl group.
8. The stereoisomerically pure
N.sub.1-(1,2-cis-2-halogenocyclopropyl)-substituted
pyridonecarboxylic acid derivative or a pharmaceutically acceptable
salt thereof of claim 1, wherein R.sup.2 represents
8-amino-6-azaspiro[.[.3,4.]. .Iadd.3.4.Iaddend.]octan-6-yl
group.
9. A method for treating bacterial infections which comprises
administering a therapeutically effective amount of the
stereoisomerically pure
N.sub.1-(1,2-cis-2-halogenocyclopropyl)-substituted
pyridonecarboxylic acid derivative or a pharmaceutically acceptable
salt thereof of claim 1, wherein R.sup.2 represents
8-amino-6-azaspiro[.[.3,4.]. .Iadd.3.4.Iaddend.]octan-6-yl
group.
.Iadd.10. Stereoisomerically pure
7-[(7S)-7-amino-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluoro--
1-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid or a pharmaceutically acceptable salt thereof..Iaddend.
.Iadd.11. A method for treating bacterial infections which
comprises administering a therapeutically effective amount of
stereoisomerically pure
7-[(7S)-7-amino-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fl-
uoro-1-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid or a pharmaceutically acceptable salt thereof..Iaddend.
.Iadd.12. An antibacterial composition comprising a therapeutically
effective amount of, as an active ingredient, stereoisomerically
pure
7-[(7S)-7-amino-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluoro--
1-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid or a pharmaceutically acceptable salt thereof, in combination
with a pharmaceutically acceptable carrier..Iaddend.
Description
FIELD OF THE INVENTION
This invention relates to an antimicrobial compound useful as human
and veterinary medicines, fish medicines, agricultural chemicals,
and antiseptics.
BACKGROUND OF THE INVENTION
Quinolone derivatives having a condensed pyridonecarboxylic acid
skeleton are known as synthetic antimicrobial agents and to provide
potent antimicrobial compounds on substitution of the 1-position
thereof with a cyclopropyl group.
It is further known that the 1-cyclopropylquinolone derivatives
having introduced a fluorine atom to the 2-position of the
cyclopropyl group in a cis-configuration with the
pyridonecarboxylic acid moiety also exhibit potent anti-microbial
activity as disclosed in U.S. Pat. No. 4,871,852 which corresponds
to JP-A-87-12760 (the term "JP-A" as used herein means an
"unexamined published Japanese patent application"). They are
thought to have not only potent antimicrobial activity but improved
safety. One example of the quinolone derivatives having a
cis-fluorocyclopropyl group at the 1-position is shown below.
##STR00002##
Quinolone derivatives having a cis-halogeno-cyclopropyl group,
inclusive of a cis-fluorocyclopropyl group, at the 1-position as
stated above possess excellent properties in antimicrobial activity
and safety. In these compounds, even when they have a substituent
without stereo-isomerism at the 7-position of the
pyridonecarboxylic acid moiety, the halogeno-cyclopropane ring of
itself provides two enantiomers attributed to the .[.static.].
.Iadd.steric .Iaddend.relationship between the pyridonecarboxylic
acid moiety and the halogen atom with respect to the cyclopropane
ring as illustrated below; ##STR00003## wherein R.sup.1, R.sup.2,
A, X.sup.1, and X.sup.2 are hereinafter defined. These quinolone
derivatives are applicable as medicines as long as they are
racemates. On the other hand, when there is stereoisomerism at the
7-positioned substituent of the pyridonecarboxylic acid moiety,
such quinolone derivatives contain four kinds of stereoisomers.
With mixtures of the stereoisomers, it is difficult to specify the
excellent species and to supply them as medicines.
SUMMARY OF THE INVENTION
In the light of the aforesaid situation, the inventors have made
extensive efforts to obtain the single isomers of
1-(1,2-cis-2-fluorocyclopropyl)-substituted quinolone derivatives
within the stereoisomers thereof. And they have succeeded in
obtaining each of the enantiomers of a cis-2-fluorocyclopropylamine
as a pure isomer. As a result of further investigations, they have
also succeeded in synthesizing each of the enantiomers of a
quinolone derivative which are attributed only to the .[.static.].
.Iadd.steric .Iaddend.configuration of the fluorocyclopropane ring
by starting from the above-described amine.
The success of obtaining the enanitomeric quinolone derivatives
useful as an intermediate has made it possible to synthesize an
optically active quinolone derivative comprising one kind of
stereoisomer by reacting with a single isomer of the amine at
introduction of a cyclic amino group to the 7-position. Each of
these stereoisomers was proved more potent in antimicrobial
activity as compared with the corresponding quinolone derivatives
substituted with a mere cyclopropyl group and, in addition, highly
safe with markedly improved selective toxicity. The present
invention has been completed based on these findings.
This invention relates to an
N.sub.1-(1,2-cis-2-halogenocyclopropyl)-substituted
pyridonecarboxylic acid derivative represented by formula (I):
##STR00004## wherein R.sup.1 represents a hydrogen atom, an amino
group, an alkylamino group of from 1 to 3 carbon atoms, a hydroxyl
group or a thiol group;
R.sup.2 represents a cyclic amino group represented by the
following formula: ##STR00005## wherein a, b, c, d, e and f each
independently .[.represent.]. .Iadd.represents .Iaddend.an integer
of 0 or 1, and at least one of a, b, c, d, e, or f is 0; R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10
independently represent hydrogen atoms or alkyl groups of from 1 to
3 carbon atoms, and R.sup.5 may, together with R.sup.6, form a
methylene chain of from 2 to 5 carbon atoms, and R.sup.5 may,
together with R.sup.9, form a methylene chain of from 2 to 4 carbon
atoms; Z represents >CHR.sup.11, >NR.sup.12,
>C.dbd.NOR.sup.13, an oxygen atom or a sulfur atom; wherein
R.sup.11 represents a hydrogen atom, an amino group, a
monoalkylamino group of from 1 to 6 carbon atoms, a dialkylamino
group containing from 1 to 6 carbon atoms per alkyl, a
tert-butoxycarbonylamino group, a benzyloxycarbonylamino group, a
hydroxyl group, an alkoxyl group of from 1 to 6 carbon atoms, a
hydroxyalkyl group of from 1 to 6 carbon atoms or a 2-aminoethyl
group; R.sup.12 represents a hydrogen atom, an alkyl group of from
1 to 6 carbon atoms, a hydroxyalkyl group of from 1 to 6 carbon
atoms, a haloalkyl group of from 1 to 6 carbon atoms, a formyl
group or an alkylcarbonyl group of from 2 to 7 carbon atoms; and
R.sup.13 represents a hydrogen atom .Iadd.or .Iaddend.an alkyl
group of from 1 to 6 carbon atoms; A represents C-X.sup.3 or a
nitrogen atom; X.sup.1 and X.sup.2, which may be the same or
different, each represents a halogen atom; and X.sup.3 represents a
halogen atom, an alkyl group of from 1 to 6 carbon atoms, an alkoxy
group of from 1 to 6 carbon atoms, a cyano group, a trifluoromethyl
group or a hydrogen atom; or a pharmaceutically acceptable salt
thereof.
Specifically implicit in the compounds represented by formula (I)
and salts thereof are those wherein R.sup.2 is a cyclic amino group
which may be substituted; those wherein R.sup.2 is a 4- to
7-membered cyclic amino group which may be substituted with a
hydroxyl group, an alkyl group having from 1 to 6 carbon atoms, or
a substituted or unsubstituted amino group; those wherein R.sup.2
is a pyrrolidinyl, piperidinyl, piperazinyl, diazabicycloheptyl or
diazabicyclooctyl group; those wherein R.sup.2 is a cyclic amino
group comprising a single stereoisomer; those wherein R.sup.2 is a
3-aminopyrrolidinyl group; those wherein R.sup.2 is a
7-amino-5-azaspiro[2.4]heptan-5-yl group; and those wherein X.sup.2
is a fluorine atom. More specifically, the compounds according to
the present invention include
7-[3-(S)-amino-1-pyrrolidinyl]-6-fluoro-1-(1,2-cis-2-fluorocyclopropyl)-4-
-oxo-1,4-dihydroquinoline-3-carboxylic acid,
7-[3-(S)-amino-1-pyrrolidinyl]-8-chloro-6-fluoro-1-(1,2-cis-2-fluorocyclo-
propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
7-[7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-(1,2-cis-2-flu-
orocyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
7-[8-amino-6-azaspiro[3.4]octan-6-yl]-8-chloro-6-fluoro-1-(1,2-cis-2-fluo-
rocyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
7-[4-amino-3,3-dimethyl-1-pyrrolidinyl]-8-chloro-6-fluoro-1-(1,2-cis-2-fl-
uorocyclopropyl)-4-oxo-1,4-dihydorquinoline-3-carboxylic acid,
5-amino-7-[3-(S)-amino-1-pyrrolidinyl]-6,8-difluoro-1-(1,2-cis-2-fluorocy-
clopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
7-[4-(S)-amino-2-(S)-methyl-1-pyrrolidinyl]-6-fluoro-1-(1,2-cis-2-fluoroc-
yclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
7-[3-(R)-[1-(S)-aminoethyl]-1-pyrrolidinyl]-8-chloro-6-fluoro-1-(1,2-cis--
2-fluorocyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
7-[3-amino-4-methyl-1-pyrrolidinyl]-6-fluoro-1-(1,2-cis-2-fluorocycloprop-
yl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
7-[4-(S)-amino-2-(S)-methyl-1-pyrrolidinyl]-6-fluoro-1-(1,2-cis-2-fluoroc-
yclopropyl)-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
5-amino-7-[7-amino-5-azaspiro[2.4]heptan-5-yl]-6,8-difluoro-1-(1,2-cis-2--
fluorocyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or
a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
In formula (I), when A represents .[.C-X.sub.3.].
.Iadd.C-X.sup.3.Iaddend., and when X.sup.3 represents a halogen
atom, X.sup.1 and X.sup.3 each preferably represents a fluorine
atom or a chlorine atom; and X.sup.2, preferably represents a
fluorine atom. R.sup.1 represents an alkylamino group of from 1 to
3 carbon atoms, an unsubstituted amino group, a hydroxyl group, a
thiol group, or a hydrogen atom, preferably an unsubstituted amino
group, a methylamino group, or a hydrogen atom.
R.sup.2 represents a cyclic amino group, preferably a 4- to
7-membered, and more preferably 5- to 6-membered cyclic amino
group. The cyclic amino group may further contain oxygen atom(s),
sulfur atom(s) and/or nitrogen atom(s), as in oxazolidinyl,
morpholinyl, thiazolidinyl, thiomorpholinyl, imidazolidinyl,
pyrazolidinyl, and piperazinyl groups. Of these cyclic amino groups
preferred are a pyrrolidinyl group and a piperazinyl group. The
cyclic amino group may have substituents, such as a polar group
(e.g., a substituted or unsubstituted amino group, a substituted or
unsubstituted aminoalkyl group, a
5-substituted-2-oxo-1,3-dioxol-4-ylmethyl group, .Iadd.and
.Iaddend.a hydroxyl group) and a straight chain, branched, or
cyclic alkyl group having up to 6 carbon atoms. Preferred of the
polar groups are an unsubstituted amino group, an aminomethyl
group, a 1-aminoethyl group, and a hydroxyl group. Preferred of the
alkyl group are methyl, ethyl, propyl, gem-dimethyl and gem-diethyl
groups and further, these gem-alkyl groups may preferably form a
cyclopropane or cyclobutane ring which is bonded through a
spiro-union to the cyclic amine skeleton. The cyclic amino group
further includes a bicyclic amino group composed of crosslinking
.[.to.]. .Iadd.two .Iaddend.4- to 7-membered cyclic amino
groups.
Illustrative examples of these cyclic amino groups, particularly
containing the second amino moiety, are shown below; ##STR00006##
wherein R.sup.14, R.sup.15, R.sup.16, R.sup.17, which may be the
same or different, each represents a hydrogen atom or an alkyl
group having from 1 to 6 carbon atoms; R.sup.18, R.sup.19, and
R.sup.20, which may be the same or different, each represents a
hydrogen atom or an alkyl group having from 1 to 6 carbon atoms,
provided that the case wherein R.sup.18, R.sup.19, and R.sup.20
each represents a hydrogen atom and the case wherein R.sup.18 and
R.sup.20 each represents a hydrogen atom and R.sup.19 represents an
alkyl group having from 1 to 6 carbon atoms are excluded; R.sup.21
and R.sup.22, which may be the same or different, each represents a
hydrogen atom or an alkyl group having from 1 to 6 carbon atoms;
R.sup.23 and R.sup.24, which may be the same or different, each
represents a hydrogen atom or an alkyl group having from 1 to 6
carbon atoms, or they may be connected to each other to form a 3-
to 6-membered ring composed of methylene .[.chains.].
.Iadd.chain.Iaddend.; and the asterisk indicates an asymmetric
center.
Examples of these cyclic amino groups are 3-aminopyrrolidinyl,
3-methylaminopyrrolidinyl, 3-dimethylaminopyrrolidinyl,
3-ethylaminopyrrolidinyl, 3-propylaminopyrrolidinyl,
3-isopropylaminopyrrolidinyl, 3-amino-4-methylpyrrolidinyl,
3-amino-5-methylpyrrolidinyl, 3-amino-4,5-dimethylpyrrolidinyl,
3-methylamino-4-methylpyrrolidinyl,
3-methylamino-5-methylpyrrolidinyl,
3-methylamino-4,5-dimethylpyrrolidinyl,
3-dimethylamino-4-methylpyrrolidinyl,
3-dimethylamino-5-methylpyrrolidinyl,
3-dimethylamino-4,5-dimethylpyrrolidinyl,
3-dimethylamino-4-methylpyrrolidinyl,
.[.3-dimethylamino-5-methylpyrrolidinyl,
3-dimethylamino-4,5-dimethylpyrrolidinyl, 3-methylpiperazinyl.].
.Iadd.3-methylpiperazinyl.Iaddend., 4-methylpiperazinyl,
3,4-dimethylpiperazinyl, 3,5-dimethylpiperazinyl,
3,4,5-trimethylpiperazinyl, 4-ethyl-3,5-dimethylpiperazinyl,
4-isopropyl-3,5-dimethylpiperazinyl, 3-aminomethylpyrrolidinyl,
3-methylaminomethylpyrrolidinyl, 3-(1-amino)ethylpyrrolidinyl,
3-(1-methylamino)ethylpyrrolidinyl,
3-(1-ethylamino)ethylpyrrolidinyl, 3-(1-amino)propylpyrrolidinyl,
3-(1-methylamino)propylpiperizinyl, 3-aminopyrrolidinyl,
3-amino-4,4-dimethylpyrrolidinyl,
7-amino-5-azaspiro[2.4]heptan-5-yl,
8-amino-6-azaspiro[3.4]-octan-6-yl,
.[.3,4-diazabicyclo[3,2,1]octan-3-yl.].
.Iadd.3,4-diazabicyclo[3.2.1]octan-3-yl.Iaddend.,
9-methyl-3,9-diazabicyclo[3.2.1]octan-3-yl, and
9-ethyl-3,9-diazabicyclo[3.2.1]octan-3-yl.
The structure of the cyclic amino group at the 7-position has a
great influence on antimicrobial activity, toxicity, oral
absorption, and physical properties such as water solubility. For
instance, it is known that quinolones substituted by
3-aminopyrrolidinyl groups have strong antimicrobial spectra
against a broad range of microorganisms covering Gram-positive to
Gram-negative bacteria. Some quinolone derivatives of this type,
however, are susceptible to metabolism or only show low
water-solubility.
3-Aminopyrrolidinyl groups having a spiro ring at the carbon atom
adjacent to the .[.amine.]. .Iadd.amino .Iaddend.group thereof
provide quinolone derivatives .Iadd.which .Iaddend.exhibit improved
oral absorption rate and improved in vivo stability against
metabolism while retaining potent antimicrobial activity. The
compounds of this type have also been proved less causative of
convulsion which is known as a side effect of quinolone type
synthetic antimicrobials.
Further, 3-aminomethylpyrrolidinyl groups in which an amino group
is bonded to a pyrrolidinyl group via a carbon atom provide
quinolone derivatives exhibiting enhanced antimicrobial activity
against Gram-positive bacteria. In particular, the quinolones of
this type in which the carbon atom linking the amino and
pyrrolidinyl groups is substituted with one or two alkyl group(s)
were found to exhibit improved oral absorption rate, safety, and
water solubility over those without such substituent(s).
Additionally preferred as cyclic amino groups are piperazine
groups, such as alkylpiperazine groups and piperazine groups having
a spiro ring.
Examples of cyclic amino groups having substituents other than an
amino group are 3-hydroxypyrrolidinyl, 3-mercaptopyrrolidinyl,
3-hydroxy-4-methylpyrrolidinyl, 3-mercapto-4-methylpyrrolidinyl,
morpholino, thiomorpholino, 2-methylmorpholino,
2-methylthiomorpholino, 2,6-dimethylmorpholino,
2,6-dimethylthiomorpholino, 2,2-dimethylmorpholino, and
2,2-dimethylthiomorpholino groups.
The cyclic amino group is bonded to the 7-position of the
pyridonecarboxylic acid skeleton preferably at the nitrogen atom of
the cyclic amino group. As a matter of course, it may be bonded at
the other atom, i.e., a carbon atom of the cyclic amino group.
The steroisomerism of the cyclic amine moiety at the 7-position is
explained below. In cases where a cyclic amine has isomers, if it
is reacted in the form of an isomeric mixture with a
1-(1,2-cis-halogenocyclopropyl)quinolone derivative, the resulting
quinolone derivative should be a mixture of diasteromers based on
the steric relation with the 1,2-cis-2-halogenocyclopropyl group at
the 1-position. In this cases, therefore, it is necessary that only
one of the isomers of the starting amine should be reacted.
The functional group of the cyclic amino group at the 7-position
such as amino, hydroxy and thiol groups may be protected by a
conventional protective group prior to the substitution with the
quinolone skeleton. The examples of such protective groups include
alkoxycarbonyl groups such as t-butoxycarbonyl group,
2,2,2-trichloroethoxycarbonyl group and the like;
aralkyloxycarbonyl groups such as benzyloxycarbonyl group,
p-methoxybenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group
and the like; acyl groups such as acetyl group, methoxyacetyl
group, trifluoroacetyl group, chloroacetyl group, pivaloyl group,
formyl group, benzoyl group and the like; alkyl or aralkyl groups
such as t-butyl group, benzyl group, p-nitrobenzyl group,
p-methoxybenzyl group, triphenylmethyl group and the like; ethers
such a methoxymethyl group, t-butoxymethyl group,
2,2,2-trichloroethoxymethyl group, tetrahydrofuran-2-yl group and
the like; silyl groups such as trimethylsilyl group,
isopropyldimethylsilyl group, t-butyldimethylsilyl group,
t-butyldiphenylsilyl group, tribenzylsilyl group and the like.
The 1,2-cis-2-halogenocyclopropyl group at the N.sub.1-position is
described below. Introduction of a halogen atom to the cyclopropyl
group, particularly a fluorine atom, brings about an effect to
reduce lipophilicity of the whole molecule. It is known that drugs
are more likely to be distributed to the central nervous system as
lipophilicity thereof increases. In this connection, introduction
of the 1,2-cis-2-halogeno-cyclopropyl group yields quinolones
having reduced toxicity while retaining excellent antimicrobial
activity as compared with the corresponding
1-cyclopropyl-quinolones. The halogen atom to be introduced
includes fluorine and chlorine atoms, with a fluorine atom being
preferred.
It is particularly preferable that the halogen atom and the
pyridonecarboxylic acid moiety are cis with respect to the
cyclopropane ring. Irrespective of whether the 7-cyclic amino group
has stereoisomers or not, the quinolone derivatives of formula (I)
have enantiometric pairs ascribed to the
.[.cis-2-halogenocyclo-propyl.]. .Iadd.cis-2-halogenocyclopropyl
.Iaddend.moiety at the 1-position as illustrated below. Potent
activity and high safety were observed in either of these
enantiomers.
More precisely, a pyridonecarboxylic acid derivative having a
2-(S)-halogeno-1-(R)-cyclopropyl group shows more .[.patent.].
.Iadd.potent .Iaddend.antibacterial activity than that having a
2-(R)-halogen-1-(S)-cycloproplyl group. ##STR00007##
The pyridonecarboxylic acid derivatives according to the present
invention include the respective free acids, acid-addition salts
thereof, and the salts of the carboxyl group thereof. The
acid-addition salts include inorganic acid salts, e.g.,
hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides,
and phosphates; and organic acid salts, e.g., acetates,
methanesulfonates, benzenesulfonates, toluenesulfonates, citrates,
maleates, fumarates, and lactates.
The salts of the carboxyl group may be organic or inorganic and
include alkali metal salts, e.g., lithium salts, sodium salts, and
potassium .[.salts,.]. .Iadd.salts; .Iaddend.alkaline earth metal
salts, e.g., magnesium salts and calcium salts; ammonium salts,
triethylamine salts, N-methylglucamates, and
tris(hydroxymethyl)aminomethane salts.
Some of these free acids and salts may exist as a hydrate.
Esterification of the carboxylic acid moiety of the
pyridonecarboxylic acid derivatives of formula (I) gives compounds
useful as synthesis intermediates or pro-drugs. For example, alkyl
esters, benzyl esters, alkoxyalkyl esters, phenylaklyl esters and
phenyl esters are useful as synthesis intermediates. Esters which
are easily severed in the body to form free carboxylic acids are
useful as pro-drugs. Examples of such esters are acetoxymethyl
esters, pivaloyloxymethyl esters, ethoxycarbonyloxy esters,
chlorine esters, dimethylaminoethyl esters, 5-indanyl esters,
phthalidinyl esters, and oxoalkyl esters (e.g.,
5-substituted-2-oxo-1,3-dioxol-4-ylmethyl esters and
3-acetoxy-2-oxobutyl esters).
A process for synthesizing the pyridonecarboxylic acid derivatives
of formula (I) is illustrated below, taking the compound wherein
A=C-H; R.sup.1=H; .[.X.sup.1-x.sup.2=F.].
.Iadd.X.sup.1=X.sup.2=F.Iaddend.; and R.sup.3=Et (ethyl group,
hereinafter the same) for instance. ##STR00008## wherein R.sup.2'
has the same meaning as R.sup.2 or a cyclic amino group having the
same structure as R.sup.2 but being protected.
An optically active
1-(1,2-cis-2-fluorocyclopropyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-
-carboxylic acid ethyl ester (6a) or .[.6b).]. .Iadd.(6b)
.Iaddend.is hydrolyzed under acidic or alkaline conditions to give
a free carboxylic acid derivative (7a) or (7b). The free acid (7a)
or (7b) is reacted with a cyclic amine R.sup.2'-H to obtain a
desired compound (IIIa) or (IIIb). If necessary, a protective group
is removed from the resulting compound under proper conditions
selected according to the protective group to obtain a desired
compound (IVa) or (IVb).
The substitution reaction with the cyclic amine can be carried out
in a solvent such as dimethyl sulfoxide, pyridine, acetonitrile and
3-methoxybutanol, at a temperature of from room temperature to
150.degree. C., preferably from 40.degree. to 120.degree. C., for
0.5 to 5 hours, usually from 0.5 to 2 hours.
Alternatively, the compound (6a) or (6b) is reacted with a cyclic
amine under the same conditions as recited above, and the resulting
compound (IIa) or (IIb) as is produced is then hydrolyzed under
acidic or alkaline conditions and, if necessary, a protective group
is removed, to obtain a desired compound (IIIa) or (IIIb) or (IVa)
or (IVb).
The optically active cis-2-fluorocyclopropylamine can be
synthesized as follows. 2-Fluorocyclopropanecarboxylic acid is
reacted with (R)-(+)-.alpha.-methylbenzylamine to yield
N-[1-(R)-phenylethyl]-1,2-cis-fluorocyclopropanecarboxamide. The
reaction can be carried out in tetrahydrofuran in the presence of
N,N-carbonyldiimidazole. The reaction may also be effected in
accordance with a mixed anhydride procedure, in which the
carboxylic acid is dissolved in an aprotic solvent and reacted with
a halogenoformic ester in the presence of a base at low
temperatures and then reacted with the benzylamine to obtain the
carboxamide. The resulting carboxamide can be separated into each
isomer by chromatographic techniques.
The aprotic solvent to be used in the mixed anhydride procedure is
not particularly limited and includes ethers, e.g., diethyl ether,
diisopropyl ether, tetrahydrofuran, 1,4-dioxane, and
.[.1,2-dimethoxyethyane.]. .Iadd.1,2-dimethoxyethane.Iaddend.;
halogenated hydrocarbons, e.g., dichloromethane, chloroform,
1,2-dichloroethane, and 1,1,2,2-tetrachloroethane; aromatic
hydrocarbons, e.g., benzene, toluene, and xylene; and aliphatic
hydrocarbons, e.g., pentane, hexane, heptane, and cyclohexane.
Commonly employed of them is tetrahydrofuran or chloroform. The
water contained in the solvent to be used is usually removed
beforehand.
The halogen atom in the halogenoformic ester is normally a chlorine
atom. The halogenoformic ester includes methyl, ethyl,
2,2,2-trichloroethyl, phenyl, p-nitrophenyl and benzyl esters.
The base to be used may be either an organic or an inorganic. The
inorganic base includes alkali metal hydroxides, carbonates and
hydrogencarbonates, e.g., lithium hydroxide, sodium hydroxide,
potassium hydroxide, lithium carbonate, sodium carbonate, potassium
carbonate, sodium hydrogencarbonate, and potassium
hydrogencarbonate. The organic base includes trialkylamines, e.g.,
triethylamine, tripropylamine, tributylamine,
N,N-diisopropylethylamine; dialkylanilines, e.g., diethylaniline
and dimethylaniline; and heterocyclic compounds, e.g.,
N-methylmorpholine, pyridine, and N,N-dimethylaminopyridine.
Separation of the carboxamide into optical isomers can be effected
by known techniques, such as silica gel column chromatography under
normal pressure or under pressure, preparative thin layer
chromatography, and high performance liquid chromatography (HPLC).
Separation into optical isomers can also be performed by other
separation techniques generally employed, such as recrystallization
and reprecipitation.
The thus separated optionally active carboxamide can be led to an
optically active cis-2-fluorocyclopropanecarboxylic acid by
hydrolysis. The reaction can be carried out by dissolving the
carboxamide in, for example, concentrated hydrochloric acid,
followed by heating. The hydrochloric acid may be replaced with
sulfuric acid or nitric acid. A solvent, such as acetic acid and a
lower alcohol, may be used.
The resulting carboxylic acid can be converted at once by Curtius
reaction in the presence of a t-butanol to a protected
cis-1-(t-butoxycarbonylamino)-2-fluorocyclopropane. The reaction
can be carried out conveniently by use of diphenylphosphorylazide,
but the synthesis of the intermediate azide compound is not limited
thereto, and general methods of synthesis can be applied.
The resulting optically active cis-2-fluorocyclopropylamine
derivative can be made use of in obtaining a quinolone derivative
having a cis-fluorocyclopropyl group at the 1-position as a single
isomer. The quinolone derivative according to the present invention
can then be obtained by reacting this isomer with the cyclic amine
as described above.
The pyridonecarboxylic acid derivatives according to the present
invention exhibit potent antimicrobial activity and thus can be
used as human and veterinary medicines, fish medicines,
agricultural chemicals, and food preservatives.
The dose of the pyridoncarboxylic acid derivatives for use as human
medicines ranges from 50 mg to 1 g, preferably from 100 mg to 300
mg, per day for adult. The dose for use as veterinary medicines
generally ranges from 1 mg to 200 mg, preferably from 5 mg to 100
mg, per kg of body weight per day, though more or less
.[.verying.]. .Iadd.varying .Iaddend.depending on the purpose of
administration (therapeutic use or preventive use, etc.), the kind
and size of the animal, the kind of .[.pothogenic.].
.Iadd.pathogenic .Iaddend.organisms, and the symptoms. The daily
dose recited above may be divided into 2 to 4 doses per day. If
necessary, the daily dose may be sometimes deviated from the
above-recited range.
The pyridonecarboxylic acid derivatives of this invention are
active against a wide variety of microorganisms causing various
infectious diseases and capable of curing or alleviating and/or
preventing the diseases caused by such .[.phthogenes.].
.Iadd.pathogens.Iaddend..
Illustrative examples of bacteria or bacterium-like microorganisms
on which the pyridonecarboxylic acid derivatives of the invention
are effective are Staphylococcus sp., Streptococcus pyogenes,
Streptococcus Haemolyticus, enterococci, Streptococcus pneumoniae,
Peptostreptococcus sp., Neisseria gonorrhoeae, Escherichia coli,
Citrobacter sp., Shiqella sp., Klebsiella pneumoniae, Enterobacter
sp., Serratia sp., Proteus sp., Pseudomonas aeruginosa, Haemophilus
influenzae, Acinetobacter sp., Campylobacter sp., and
Chlamidiae.
Examples of diseases caused by these pathogenes include
folliculitis, furuncle, carbuncle, erysipelas, phlegmon,
lymphangitis/lymphadenitis, felon, subcutaneous abscess,
spiradenitis, acne conglobata, infectious atheroma, perianal
abscess, mastadenitis, superficial secondary infections after
trauma, burn or surgery trauma, pharyngolaryngitis, acute
bronchitis, tonsillitis, chronic bronchitis, bonchiectasis, diffuse
panbronchiolitis, secondary infections of chronic respiratory
diseases, pneumonia, pyelonephritis, cystitis, prostatitis,
epididymitis, gonococcal urethritis, non-gonococcal urethritis,
cholecystitis, cholangitis, bacillary dysentery, enteriris,
adnexitis, intrauterine infections, Bartholinitis, blepharitis,
hordeolum, dacryocystitis, tarsadenitis, keratohelcosis, otitis
media, sinusitis, paradentitis, pericoronitis circumcoronitis,
gnathitis, peritonitis, endocarditis, septicemia, meningitis, and
skin infectious.
Examples of susceptible microorganisms causing veterinary
infectious diseases include those of fowl, such as Escherichia sp.,
Salmonella sp., Pasteurella sp., Haemophilus sp., Bordetella sp.,
Staphylococcus sp., and Mycoplasma sp. Specific examples of
veterinary diseases caused by these microorganisms include
colibacillosis, pulloium disease, avian paratyphosis, fowl chlera,
infectious coryza, staphylococcal infections, and mycoplasmal
diseases; those of swin, such as colibacillosis, malmonelosis,
pasteurellosis, haemophylus infection, atrophic rhintis,
exduadative epidermitis, and mycoplasmal diseases; those for
cattle, such as colibacillosis, salmonellosis, hemorrhagic
septicemia, mycoplasmal diseases, bovine contageous
pleurponeumonia, and bovine mastesis; those of dogs, such as
coliform sepsis, salmonelosis, hemorrhagic septicemia, pyometra,
and cystiris; and those of cats, such as hemorrhagic pleuritis,
cystiris, chronic rhiniti, haemophylus infection, kitten diarrhea,
and mycoplasmal diseases.
The compound of the present invention can be formulated into
antimicrobial preparations in an appropriate dose form according to
administration route selected by the conventional preparation
methods. The dose form for oral administration includes tablets,
powders, granules, capsules, solutions, syrups, elixiers, and oily
or aqueous suspensions. Injections may contain, in addition to the
active ingredient, stabilizers, antiseptics, and solubilizing
agents. The solution which may contain such excipients is put in a
container and further, the solution may be subjected to
lyophilization or the like means to prepare solid preparations
which can be dissolved on use. The container may contain either a
single dose or several doses.
Dose forms for external administration include solutions,
suspensions, emulsions, ointments, gels, creams, lotions, and
sprays.
In the preparation of solid preparations, the active ingredient may
be mixed with appropriately selected pharmaceutically acceptable
excipients, such as fillers, extenders, binders, disintegrators,
dissolution accelerators, wetting agents, and lubricants.
Liquid preparations include solutions, suspensions, and emulsions.
They may contain excipients, such as suspension stabilizers and
emulsifiers.
The compound of the present invention can be administered to
animals orally either directly or as admixed to feedstuff, or its
solution may be given either directly or as admixed to water or
feedstuff. The compound may also be administered non-orally by, for
example, injection.
The compound of the invention can be formulated into preparations
for animals, such as powders, fine granules, solubilized powders,
syrups, solutions, and injections, by commonly employed preparation
methods.
As is the case with most inventions in the pharmaceutical arts,
there are certain preferred classes of compounds which fall within
formula (I). These are now discussed.
.[.An.]. .Iadd.In .Iaddend.formula (I) it is preferred that X.sup.2
is a fluorine atom or X.sup.1 is a fluorine atom and more preferred
that both X.sup.2 and X.sup.1 are fluorine atoms.
In formula (I), it is preferred that the
(1,2-cishalogenocyclopropyl) group at N.sub.1 be a substituent
which provides a stereoisomerically pure isomer (isomer embodiment)
and in the isomer embodiment it is preferred that the isomer be an
N.sub.1-[2-(S)-halogeno-1-(R)-cyclopropyl]substituted
pyridonecarboxyclic acid derivative ((S)/(R) acid embodiment), and
in this last case it is preferred that halo of halogeno is a
fluorine atom ((S)/(R) acid/fluorine embodiment).
Typical compounds in accordance with the present invention contain
three asymmetric carbon atoms and therefore have plural
stereoisomers. Among these stereoisomers, there are three kinds of
isomers, i.e., enantiomers, diastereomers and epimers. Accordingly,
the term "stereoisomerically" is meant to include all three kinds
of isomers.
In formula (I), in the isomer embodiment and in the (S)/(R) acid
embodiment, it is preferred that R.sup.2 is a cyclic amino group
which provides stereoisomerically pure enantiomer species
(enantiomer embodiment).
In formula (I) and in the isomer embodiment and in the (S)/(R) acid
embodiment, a, b, c, d, e, and f can have certain preferred values
or "Sets" as now defined for Sets 1 and 2 and are often used in
combination with certain preferred groups as are now discussed.
Set 1
1) a=b=O, c=d=1, e=f=O, 2) a=1, b=O, c=d=1, e=f=O, 3) a=b=O, c=d=1,
e=O, f=1, 4) a=1, b=O, c=d=1, e=O, f=1, 5) a=b=c=d=1, e=O, f=1, or
6) a=1, b=O, c=d=e=f=1. Set 2
Wherein Z represents >CHR.sup.11; a, c and d represents 1 and b,
.[.c.]. .Iadd.e .Iaddend.and f represent O.
When Set 2 is met for each of general formula (I), the isomer
embodiment and the (S)/(R) acid embodiment, it is preferred that:
(1) R.sup.3, R.sup.4, R.sup.7 and R.sup.8 represent hydrogen atoms
and R.sup.5 and R.sup.6 represent methyl groups; or (2) Z
represents >CHR.sup.11.Iadd.; .Iaddend.a, c and d represent 1
and b, .[.c.]. .Iadd.e .Iaddend.and f represent O.
When limit (2) for Set 2 above is met, it is then preferred that
limit (3) be met: (3) R.sup.3, R.sup.4, R.sup.7 and R.sup.8
represent hydrogen atoms and R.sup.5 and R.sup.6 form a methylene
chain of from 2 to 5 carbon atoms and in that case it is then most
preferred that R.sup.11 be an amino group.
In the above situation where R.sup.11 is an amino group, certain
even more preferred classes of compounds result when the following
limits (4) to (7) are met. (4) while R.sup.5 and R.sup.6 form a
methylene chain of 2 carbon atoms; or (5) where R.sup.5 and R.sup.6
form a methylene chain of 3 carbon atoms or (6) where X.sup.2 is a
fluorine atom and R.sup.1 is a hydrogen atom and A is C-X.sup.3
where X.sup.3 represents a hydrogen atom or a halogen atom or (7)
where R.sup.5 and R.sup.6 represent methyl groups.
When limit (6) is met, it is then preferred that R.sup.5 and
R.sup.6 form a methylene chain of 2 or 3 carbon atoms, more
preferred if such limits on R.sup.5 and R.sup.6 are met that
X.sup.1 be a fluorine atom and, if X.sup.1 is a fluorine atom, most
preferred that X.sup.3 be chlorine.
When limit (7) is met, i.e., R.sup.5 and R.sup.6 are both methyl
groups, then it is: preferred X.sup.2 be a fluorine atom, R.sup.1
be a hydrogen atom, A be C-X.sup.3 and X.sup.3 be a hydrogen atom
or halogen atom; then more preferred that X.sup.1 be a fluorine
atom; and then most preferred that X.sup.3 be a chlorine atom.
Certain preferences also exist for the case of the enantiomer
embodiment.
In that case, a preferred Set is Set 3.
Set 3
1) a=b=O, c=d=1, e=f=O, 2) a=1, b=O, c=d=1, e=f=O, 3) a=b=O, c=d=1,
e=O, f=1, 4) a=1, b=O, c=d=1, e=O, f=1, 5) a=b=c=d=1, e=O, f=1, or
6) a=1, b=O, c=d=e=f=1.
Another preferred Set for the enantiomer embodiment is Set 4.
Set 4
Wherein Z represents >CHR.sup.11; a, c and d represent 1 and b,
e and f represent O.
When Set 4 is met for the enantiomer embodiment, which is a
preferred embodiment of general formula (I) and the isomer
embodiment and the (S)/(R) acid embodiment, it is preferred that
(8) R.sup.3, R.sup.4, R.sup.7, R.sup.8 represent hydrogen atoms and
R.sup.5 and R.sup.6 form a methylene chain of from 2 to 5 carbon
atoms. (9) R.sup.3, R.sup.4, R.sup.7, and R.sup.8 represent
hydrogen atoms and R.sup.5 and R.sup.6 represent methyl groups.
When R.sup.3, R.sup.4, R.sup.7, R.sup.8, R.sup.5 and R.sup.6 meet
the above criteria of limit (8) for Set 4, then two preferred
classes of compounds begin: one where R.sup.11 is an amino group;
and one where R.sup.11 is an amino group plus the configuration at
the carbon atom to which R.sup.11 is attached is (S).
When R.sup.11 is an amino group and a spiro ring composed of a
methylene chain is present as a substituent, the configuration at
the amino group is not precisely known. However, when R.sup.11 is
an amino group and there is no spiro ring composed of a methylene
chain .[.and.]. .Iadd.or there .Iaddend.is a spiro ring composed of
a methylene chain having two carbon atoms, the preferred
configuration has been confirmed to be (S).
Namely, in the case of the compound having a cyclic amino group
having a spiro ring composed of a methylene chain having two carbon
atoms, it is also confirmed that the preferable configuration at
the carbon atom to which an amino group is attached is (S).
However, the preferable configuration is still unknown in the case
of a methylene chain having three carbon atoms.
With respect to the latter situation in the case of a compound
represented by the formula ##STR00009## it is preferable that the
configuration at the carbon atom to which the amino group is
attached is .[.(5).]. .Iadd.(S).Iaddend., but in the case of a
compound represented by the formula ##STR00010##
If either criterion on R.sup.11 is met, then more preferred classes
of compounds result when the following criteria are further
met.
In the above situation where R.sup.11 is an amino group, certain
even more preferred classes of compounds result when the following
limits (10) to (13) are met. (10) where R.sup.5 and R.sup.6 form a
methylene chain of 2 carbon atoms; (11) where R.sup.5 and R.sup.6
form a methylene chain of 3 carbon atoms or (12) where X.sup.2 is a
fluorine atom and R.sup.1 is a hydrogen atom and A is C--X.sup.3
where X.sup.3 represents a hydrogen atom or a halogen atom or (13)
wherein R.sup.5 and R.sup.6 represent methyl groups.
When limit (12) is met, it is then preferred that R.sup.5 and
R.sup.6 form a methylene chain of 2 or 3 carbon atoms, more
preferred if such limits on R.sup.5 and R.sup.6 are met that
X.sup.1 be a fluorine atom and, if X.sup.1 is a fluorine atom, most
preferred that X.sup.3 be chlorine.
When limit (13) is met, i.e., R.sup.5 and R.sup.6 are both methyl
groups, then it is: preferred X.sup.2 be a fluorine atom, R.sup.1
be a hydrogen atom, A be C--X.sup.3 and X.sup.3 be a hydrogen atom
or halogen atom; then more preferred that X.sup.1 be a fluorine
atom; and then most preferred that X.sup.3 be a chlorine atom.
A separate preferred Set 5 exists for formula (I) and the isomer
embodiment and the (S)/(R) acid embodiment.
Set 5
a=1, b=O, c=d=1, e=O, f=1; R.sup.3, R.sup.4, R.sup.7, R.sup.8,
R.sup.9 and R.sup.10 represent hydrogen atoms, R.sup.5 and R.sup.6
form a 2 carbon atom methylene chain; Z represents >NR.sup.12,
and R.sup.12 represents a hydrogen atom; X.sup.1 and X.sup.2
represent fluorine atoms; A represents C--X.sup.3, and X.sup.3
represents a hydrogen atom or a halogen atom.
Most highly preferred species within general formula (I), which are
also, of course, preferably also within the isomer embodiment or
the (S)/(R) acid embodiment are:
7-[7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-(1,2-cis-2-flu-
orocyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a
pharmaceutically acceptable salt thereof;
7-[8-amino-6-azaspiro[3.4]octan-6-yl]-8-chloro-6-fluoro-1-(1,2-cis-2-fluo-
rocyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a
pharmaceutically acceptable salt thereof; and
7-[4-amino-3,3-dimethyl-1-pyrrolidinyl]-8-chloro-6-fluoro-1-(1,2-cis-2-fl-
uorocyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a
pharmaceutically acceptable salt thereof.
The present invention is especially directed to an antibacterial
agent comprising a therapeutically effective amount of, as an
active ingredient, at least one
N.sub.1-(1,2-cis-2-halogenocyclopropyl)-substituted
pyridone-carboxylic acid derivative represented by formula (I) or a
pharmaceutically acceptable salt thereof in combination with a
pharmaceutically acceptable carrier, where the pharmaceutically
acceptable salt is most preferably the hydrochloride, sulfate,
phosphate, acetate, methanesulfonate, benzenesulfonate,
p-toluenesulfonate, citrate, maleate, fumerate or lactate, and to a
method for treating bacterial infections which comprises
administering a therapeutically effective amount of
N.sub.1-(1,2-cis-2-halogenocyclopropyl)-substituted
pyridonecarboxylic acid represented by the formula (I) or a
pharmaceutically acceptable salt thereof.
For treating bacterial infections by administering a
therapeutically effective amount thereof, or a therapeutically
effective amount of a pharmaceutically acceptable salt thereof, the
following are most highly preferred species as anti-bacterial
agents:
7-[7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[2-(S)-2-fluor-
o-1-(R)-cyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
7-[8-amino-6-azaspiro[3.4]octan-6-yl]-8-chloro-6-fluoro-1-[2-(S)-2-fluoro-
-1-(R)-cyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
and
7-[4-amino-3,3-dimethyl-1-pyrrolidinyl]-8-chloro-6-fluoro-1-[2-(S)-2-fluo-
ro-1-(R)-cyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid;
Formulation Examples are given below for illustrative purposes only
but not for limitation.
TABLE-US-00001 FORMULATION EXAMPLE 1 Capsule: Compound of Example 8
100.0 mg Corn starch 23.0 mg Calcium carboxymethyl cellulose 22.5
mg Hydroxypropylmethyl cellulose 3.0 mg Magnesium stearate 1.5 mg
total: 150.0 mg FORMULATION EXAMPLE 2 Solution: Compound of Example
7 1 to 10 g Acetic acid or sodium hydroxide 0.5 to 2 g Ethyl
p-hydroxybenzoate 0.1 g Purified water 88.9 to 98.4 g total: 100 g
FORMULATION EXAMPLE 3 Powder for Admixture with Feedstuff: Compound
of Example 6 1 to 10 g Corn starch 98.5 to 98.5 g Light anhydrous
silicic acid 0.5 g total: 100 g
The present invention is now illustrated in greater detail by way
of the following Examples and Reference Examples, but it should be
understood that the present invention is not deemed to be limited
thereto. Reference Examples describe the syntheses of optically
active skeletons from an optically active
cis-2-fluorocyclopropanecarboxylic acid.
Antimicrobial activity of the optically active compounds prepared
in Examples was evaluated in accordance with the standard method
specified by Nippon Kagakuryoho .[.gakkai.]. .Iadd.Gakkai.Iaddend.,
and results obtained are shown in Table 1 which precedes the claims
herein in terms of minimum inhibitory concentration (MIC:
.mu.g/m.sup.2).
Reference Example 1
N-[1-(R)-Phenylethyl]-1,2-cis-2-fluorocyclopropanecarboxamide (2a,
2b):
1.1. Carbonyldiimidazole Method:
One gram of cis-2-fluorocyclopropanecarboxylic acid was dissolved
in 30 ml of tetrahydrofuran (THF), and 1.78 g of
N,N'-carbonyldiimidazole was added thereto, and the mixture was
stirred at room temperature for 1 hour. To the solution was added
1.45 g of (R)-(+)-.alpha.-methylbenzylamine, and the stirring was
continued for 2 hours. The solvent was removed under reduced
pressure, and the residue was extracted with chloroform. The
extract was washed successively with a 10% citric acid aqueous
solution and water and dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure. From the residual
viscous oily substance, each stereoisomer was isolated by HPLC
under conditions shown below. Each isomer was recrystallized from
diisopropyl ether to yield the titled compound (2a) or (2b).
HPLC Conditions:
Column: Nucleosil 50-5 (20 mm ID.times.250 mm L) (senshu Pack SSC
Silica, 782-IN, produced by Senshu Kagaku)
Solvent: ethyl acetate-THF (9:1 by volume)
Flow Rate: 9.0 ml/min
Retention Time: 11 .[.mins,.]. .Iadd.mins. .Iaddend.for Compound
(2a).Iadd.; .Iaddend.13 mins. for Compound (2b)
Compound (2a):
Melting point: 108.degree. C.
Elementary Analysis for C.sub.12H.sub.14FNO: Calcd. (%): C 69.55; H
6.81; N 6.76 Found (%): C 69.31; H 7.01; N 6.65
[.alpha.].sub.D: +61.96.degree. (c=0.965, chloroform)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 0.92-1.34 (2H, m), 1.50 (3H,
d, J=7 Hz), 1.50-1.96 (1H, m), 4.68 (1H, dm, J=64 Hz), 5.14 (1H,
m), 7.40 (5H, s)
Physiochemical Properties of compound (2b):
Melting point: 102.degree. C.
Elementary Analysis for C.sub.12H.sub.14FNO: Calcd. (%): C 69.55; H
6.81; N 6.76 Found (%): C 69.45; H 6.87; N 6.70
[.alpha.].sub.D: +143.61.degree. (c=0.830, chloroform)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 0.98=1.34 (2H, m), 1.52 (3H,
d, J=7 Hz), 1.64-1.96 (1H, m), 4.58 (1H, dm, J=66 Hz), 5.24 (1H,
m), 7.40 (5H, m)
1-2. Mixed Anhydride Method:
In 50 ml of THF were dissolved 4.19 g of
2-fluorocyclopropanecarboxylic acid (cis-trans mixture) and 4.07 g
of triethylamine, and the solution was cooled to -10.degree. C. To
this was added a solution of 4.73 g of ethyl chloroformate in 20 ml
of THF and the mixture was stirred for 10 minutes. To the solution
was then added dropwise a solution of 4.88 g of
(R)-(+)-.alpha.-methylbenzylamine in 30 ml of THF at that
temperature, and the mixture was stirred at room temperature for 15
hours. The solvent was removed under reduced pressure, and the
residue was extracted with benzene. The extract was washed
successively with a 10% citric acid aqueous water and dried over
anhydrous sodium sulfate. The solvent was removed under reduced
pressure, and the resulting pale yellow oily substance was purified
by silica gel column chromatography using a mixed solvent of
benzene and ethyl acetate as an eluent to each of the titled
compounds (2a) and (2b).
Reference Example 2
.[.(+).]. .Iadd.(-).Iaddend.-cis-2-Fluorocyclopropanecarboxylic
acid (3a):
In 15 ml of concentrated hydrochloric acid was dissolved 530 mg of
the amide compound (2a) as prepared in Reference Example 1, and the
solution was heated at 100.degree. to 110.degree. C. for 5 hours
while stirring. To the reaction mixture was added 20 ml of water,
and the mixture was extracted with ethyl acetate. The extract was
then extracted with a sodium hydrogencarbonate aqueous solution and
this aqueous extract was washed with ethyl acetate. The aqueous
extract was adjusted to a pH of 5 with concentrated hydrochloric
acid and extracted with ethyl acetate. The extract was dried over
anhydrous sodium sulfate, and the solvent was removed under reduced
pressure to yield the titled compound (3a) as a pale yellow
oil.
[.alpha.].sub.D: -23.13.degree. (c=1.020, chloroform)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.0-1.42 (1H, m), 1.60-2.10
(2H, m), 4.82 (1H, dm, J=65 Hz), 12.0 (1H, s)
Reference Example 3
(+)-cis-2-Fluorocyclopropanecarboxylic acid (3b):
In 30 ml of concentrated hydrochloric acid was dissolved 1.65 g of
amide compound (2b) as prepared in Reference Example 1, and the
solution was heated at 100.degree. to 110.degree. C. for 5 hours
while stirring. The pH of the reaction mixture was adjusted between
8 and 9 with sodium hydrogencarbonate and then washed with
chloroform. The pH of aqueous layer was adjusted to 4 with
concentrated hydrochloric acid and extracted with ethyl acetate.
The extract was dried over anhydrous sodium sulfate, and the
solvent was removed under reduced pressure to give the titled
compound (3b) as a pale yellow oil.
[.alpha.].sub.D: +21.56.degree. (c=1.113, chloroform)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.0-1.42 (1H, m), 1.56-1.98
(2H, m), 4.76 (1H, dm, J=66 Hz), 11.32 (1H, s)
Reference Example 4
(+)-cis-1-(t-Butoxycarbonylamino)-2-fluorocyclopropane (4a):
In 5 ml of t-butanol were dissolved 200 mg of the carboxylic acid
(3a) as obtained in Reference Example 2, 603 mg of
diphenylphosphorylazide, and 203 mg of triethylamine, and the
solution was heated under reflux for 4.5 hours. After removing the
solvent under reduced pressure, the residue was extracted with
chloroform. The extract was washed successively with a 10% citric
acid aqueous solution, a 2% sodium hydroxide aqueous solution and
water, and dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure, and the residue was subjected to
silica gel column chromatography using chloroform as an eluent to
obtain the titled compound (4a) as a colorless crystal.
Melting Point: 73.degree. C.
[.alpha.].sub.D: +65.57.degree. (c=0.610, chloroform)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 0.6-1.3 (2H, m), 1.46 (9H,
s), 2.48-2.74 (1H, m), 4.62 (1H, dm, J=65 Hz), 4.6-5.1 (1H,
broad)
Reference Example 5
(-)-cis-1-(t-Butoxycarbonylamino)-2-fluorocyclopropane (4b):
In 6 ml of t-butanol were added 265 mg of the carboxylic acid (3b)
as obtained in Reference Example 3, 800 mg of
diphenylphosphorylazide, and 270 mg of triethylamine. The solution
was allowed to react and worked up in the same manner as in
Reference Example 4 to obtain the titled compound (4b).
Melting Point: 63.degree. C.
[.alpha.].sub.D: -60.27 (c=0.740, chloroform)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 0.66-1.3 (2H, m), 1.46 (9H,
s), 2.48-2.74 (1H, m), 4.58 (1H, dm, J=65 Hz), 4.6-5.1 (1H,
broad)
Reference Example 6
(-)-Ethyl-2-[(1,2-cis-2-fluorocyclopropan-1-yl)aminomethylene]-3-oxo-3-(2,-
4,5-trifluorophenyl)propionate (5a):
Ethyl 2,4,5-trifluorobenzoylacetate (234 mg), 2 ml of ethyl
orthoformate, and 4 ml of acetic anhydride were mixed and the
mixture was heated at 110.degree. to 120.degree. C. for 2 hours
while stirring. The solvent was removed under reduced pressure, and
the residue was dissolved in 10 ml of dichloromethane.
Compound (4a) as obtained in Reference Example 4 (167 mg) and 5 ml
of trifluoroacetic acid were mixed and the mixture was stirred at
room temperature for 20 minutes and concentrated to dryness under
reduced pressure (the resulting amine trifluoroacetate was used
without purification). The residue was dissolved in 10 ml of
dichloromethane and cooled to -10.degree. C. A solution of 230 mg
of triethylamine in 10 ml of dichloromethane was added dropwise
thereto. Thereafter, the above prepared dichloromethane solution
was added dropwise to the mixture, followed by stirring at room
temperature over-night. The solvent was evaporated to dryness under
reduced pressure, and the residue was subjected to silica gel
column chromatography using a mixed solvent of benzene and ethyl
acetate (2:1 by volume). A yellow oily substance was obtained from
the eluent after the .[.removed.]. .Iadd.removal .Iaddend.of the
solvent. The product was recrystallized from diisopropyl
ether-n-hexane to yield the titled compound (5a) as a colorless
crystals.
Melting Point: 69.degree.-70.degree. C.
[.alpha.].sub.D: .[.10.29.degree..]. .Iadd.-10.29.degree.
.Iaddend.(c=1.088, chloroform)
Reference Example 7
(+)-Ethyl-2-[(1,2-cis-2-fluorocyclopropan-1-yl)aminomethylene]-3-oxo-3-(2,-
4,5-trifluorophenyl)propionate (5b):
Ethyl 2,4,5-trifluorobenzoylacetate (337 mg), 2 ml of ethyl
orthoformate, and 4 ml of acetic anhydride were mixed, and the
mixture was heated at 110.degree. to 120.degree. C. for 2 hours
while stirring. The solvent was removed under reduced pressure, and
the residue was dissolved in 10 ml of dichloromethane.
Compound (4b) as obtained in reference Example 5 (240 mg) and 5 ml
of trifluoroacetic acid were mixed .[.an.]. .Iadd.and .Iaddend.the
mixture was stirred at room temperature for 1 hour followed by
concentration under reduced pressure (the amine trifluoroacetate
was used without purification).Iadd.. .Iaddend.The residue was
dissolved in 10 ml of dichloroethane, and the solution was cooled
to -10.degree. C. A solution of 230 mg of triethylamine in 10 ml of
dichloromethane was added thereto dropwise, and the above-prepared
dichloromethane solution was further added to the mixture, followed
by stirring at room temperature over-night. The solvent was removed
under reduced pressure, and the residue was subjected to silica gel
column chromatography using a mixed solvent of benzene and ethyl
acetate (2:1 by volume). A yellow oily substance was obtained from
the eluent after the removal of solvent. Recrystallization from
diisopropyl ether-n-hexane gave the titled compound (5b) as a
colorless crystal.
Melting Point: 69.degree.-70.degree. C.
[.alpha.].sub.D: +12.09 (c=0.645, chloroform)
Reference Example 8
(+)-6,7-Difluoro-1-(1,2-cis-2-fluorocyclopropyl)-4-oxo-1,4-dihydroquinolin-
e-3-carboxylate (6a):
In 15 ml of anhydrous dioxane was dissolved 180 mg of Compound (5a)
as obtained in Reference Example 6, and 200 mg of 60% sodium
hydride was added to the solution, followed by stirring at room
temperature for 2 days. The reaction mixture was added to a 10%
citric acid aqueous solution, followed by concentration under
reduced pressure. The residue was extracted with chloroform, and
the extract was dried over anhydrous sodium sulfate. The solvent
was removed under reduced pressure. The residue was purified by
silica gel preparative TLC using benzene-ethyl acetate (1:2 by
volume) as a developing solvent to yield the titled compound (6a)
as a colorless crystal.
Melting Point: 231.degree.-232.degree. C.
[.alpha.].sub.D: +27.20.degree. (c=0.610, chloroform)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.20 (3H, t, J=7 Hz), 1.6-1.9
(2H, m), 3.28-3.56 (1H, m), 4.42 (2H, q, J=7 Hz), 5.11 (1H, dm,
J=63 Hz), 7.60 (1H, dd, J=11 Hz & 7 Hz), 8.28 (1H, dd, J=10 Hz
& 11 Hz), 8.58 (1H, s)
Reference Example 9
(-)-Ethyl
6,7-difluoro-1-(1,2-cis-2-fluorocyclopropyl)-4-oxo-1,4-dihydroqu-
inoline-3-carboxylate (6b):
In 15 ml of anhydrous dioxane was dissolved 267 mg of Compound (5b)
as obtained in Reference Example 7, and 200 mg of 60% sodium
hydride was added thereto, and the mixture was stirred at room
temperature for 2 days. The reaction mixture was added to a 10%
citric acid aqueous solution, followed by concentration under
reduced pressure. The residue was extracted with chloroform and
dried over anhydrous sodium sulfate. The solvent was removed under
reduced pressure, and the residue was purified by silica gel
preparative TLC using benzene-ethyl acetate (1:2 by volume) as a
developing solvent to yield the titled compound (6b) as a colorless
crystal.
Melting Point: 226.degree.-227.degree. C.
[.alpha.].sub.D: -31.36.degree. (c=0.610, chloroform)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.22 (3H, t, J=7 Hz), 1.5-1.9
(2H, m), 3.26-3.52 (1H, m), 4.40 (2H, q, J=7 Hz), 5.10 (1H, dm,
J=63 Hz), 7.58 (1H, dd, J=11 Hz & 7 Hz), 8.26 (1H, dd, J=10 Hz
& 11 Hz), 8.55 (1H, s)
Reference Example 10
(+)-6,7-Difluoro-1-(1,2-cis-2-fluorocyclopropyl)-4-oxo-1,4-dihydroquinolin-
e-3-carboxylic acid (7a):
In 15 ml of concentrated hydrochloric acid was dissolved 106 mg of
the ester (6a) as obtained in Reference Example 8, and the solution
was heated at 100.degree. to 110.degree. C. for 2 hours while
stirring. To the reaction mixture was added 15 ml of water, and the
precipitate was collected by filtration to obtain the titled
compound (7a) as a colorless crystal.
Melting Point: 265.degree.-270.degree. C.
[.alpha.].sub.D: +3.66.degree. (c=0.383, acetic acid)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.75-1.95 (2H, m), 3.58 (1H,
m), 5.18 (1H, dm, J=64 Hz), 7.82 (1H, dd, J=12 Hz, & 7 Hz),
8.37 (1H, dd, J=18 Hz & 8 Hz), 8.94 (1H, s)
Reference Example 11
(-)-6,7-Difluoro-1-(1,2-cis-2-fluorocyclopropyl)-4-oxo-1,4-dihydroquinolin-
e-3-carboxylic acid (7b):
In 10 ml of concentrated hydrochloric acid was dissolved 150 mg of
the ester (6b) as obtained in Reference Example 9, and the solution
was heated at 110.degree. C. for 2 hours while stirring. To the
reaction mixture was added 20 ml of water, and the mixture was
extracted with chloroform. The extract was dried over anhydrous
sodium sulfate, and the solvent was removed under reduced pressure.
The residue was recrystallized from ethanol to yield the titled
compound (7b) as a colorless crystal.
Melting Point: 261.degree.-264.degree. C.
[.alpha.].sub.D: -4.08.degree. (c=0.343, acetic acid)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.75-1.95 (2H, m), 3.58 (1H,
m), 5.18 (1H, dm, J=64 Hz), 7.82 (1H, dd, J=12 Hz & 7 Hz), 8.37
(1H, dd, J=12 Hz & 8 Hz), 8.94 (1H s)
EXAMPLE 1
7-[3-(S)-t-Butoxycarbonylamino-1-pyrrolidinyl]-6-fluoro-1-(1,2-cis-2-fluor-
ocyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
(8a):
Seventy milligrams of the carboxylic acid (7a) as obtained in
Reference Example 10, 150 mg of
(S)-3-(t-butoxycarbonylamino)pyrrolidine, 200 mg of triethylamine,
and 20 ml of acetonitrile were mixed, and the mixture was heated
under reflux for 4 hours. The solvent was removed under reduced
pressure, and to the residue was added a 10% citric acid aqueous
solution, followed by extraction with chloroform. The extract was
dried over anhydrous sodium sulfate, and the solvent was removed
under reduced pressure. The residue was recrystallized from ethyl
acetate to obtain the titled compound (8a) as a yellow crystal.
Melting Point: 236.degree.-239.degree. C.
[.alpha.].sub.D: +1.0.degree. (c=0.200, chloroform)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.2-1.7 (2H, m), 1.46 (9H,
s), 1.7-1.9 (1H, m), 2.0-2.36 (1H, m), 3.3-4.0 (5H, m), 4.2-4.4
(1H, m), 5.06 (1H, dm, J=68 Hz), 6.68 (1H, d, J=7 Hz), 7.84 (1H, d,
J=14 Hz), 8.46 (1H, s)
EXAMPLE 2
7-[3-(S)-t-Butoxycarbonylamino-1-pyrrolidinyl]-6-fluoro-1-(1,2-cis-2-fluor-
ocyclopropyl)-4-oxo-1,4-dihydroquinolone-3-carboxylic acid
(8b):
The carboxylic acid as obtained in Reference Example 11 (7b) (112
mg), 200 mg of .[.(S)-3-(t-butoxycarboxylamino).].
.Iadd.(S)-3-(t-butoxycarbonylamino).Iaddend.pyrrolidine, 220 mg of
triethylamine, and 15 ml of acetonitrile were mixed, and the
mixture was heated under reflux for 4 hours. The solvent was
removed under reduced pressure, and to the residue was added a 10%
citric acid aqueous solution, followed by extraction with
chloroform. The extract was dried over anhydrous sodium sulfate,
and the solvent was removed under reduced pressure. The residue was
recrystallized from ethyl acetate to yield the titled compound (8b)
as a yellow crystal.
Melting Point: 242.degree.-243.degree. C.
[.alpha.].sub.D: -4.0.degree. (c=0.448, chloroform)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.0-1.7 (2H, m), 1.40 (9H,
s), 1.6-1.8 (1H, m), 1.9-2.1 (1H, m), 3.3-3.9 (5H, m), 4.2-4.5 (1H,
m), 5.00 (1H, dm, J=68 Hz), 6.58 (1H, d, J=7 Hz), 7.72 (1H, d, J=14
Hz), 8.32 (1H, s)
EXAMPLE 3
7-[3-(S)-Amino-1-pyrrolidinyl]-6-fluoro-1-(1,2-cis-2-fluorocyclopropyl)-4--
oxo-1,4-dihydroquinoline-3-carboxylic acid (9a):
In 10 ml of trifluoroacetic acid was dissolved 80 mg of the
carboxylic acid (8a) as obtained in Example 1. After stirring for
20 minutes, the reaction mixture was evaporated under reduced
pressure to dryness. To the residue was added 5 ml of water, and
was further added a 1N sodium hydroxide aqueous solution to
dissolve the residue. The pH of aqueous layer was adjusted to 7.5
with 1N hydrochloric acid, followed by extraction with chloroform.
The extract was dried over anhydrous sodium sulfate, and the
solvent was removed under reduced pressure. Recrystallization of
the residue from ethanol yielded the titled compound as a colorless
crystal.
Melting Point: 248.degree.-252.degree. C.
[.alpha.].sub.D: -31.35.degree. (c=0.370, 1N NaOH aqueous
solution)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.52-1.68 (2H, m), 1.68-1.80
(1H, m), 2.05-2.15 (1H, m), 3.13-3.22 (1H, m), 3.25-3.45 (2H, m),
3.45-3.65 (3H, m), 5.12 (1H, dm, J=65 Hz), 6.58 (1H, d, J=7 Hz),
7.58 (1H, d, J=14 Hz), 8.29 (1H, s)
EXAMPLE 4
7-[3-(S)-Amino-1-pyrrolidinyl]-6-fluoro-1-(1,2-cis-2-fluorocyclopropyl)-4--
oxo-1,4-dihydroquinoline-3-carboxylic acid .[.(9a.].
.Iadd.(9b).Iaddend.:
In 10 ml of trifluoroacetic acid was added 80 mg of the carboxylic
acid (8b) as obtained in Example 2. After stirring for 20 minutes,
the reaction mixture was evaporated to dryness under reduced
pressure. To the residue was added 5 ml of water, and was further
added a 1N sodium hydroxide aqueous solution to dissolve the
residue. The pH of aqueous layer was adjusted to 7.5 with 1N
hydrochloric acid and followed by extraction with chloroform. The
extract was dried over anhydrous sodium sulfate, and the solvent
was removed therefrom under reduced pressure. Recrystallization of
the residue from ethanol gave the titled compound (9b) as a
colorless crystal.
Melting Point: 236.degree.-240.degree. C.
[.alpha.].sub.D: +23.72 (c=0.413, 1N NaOH aqueous solution)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.55-1.69 (2H, m), 1.69-1.77
(1H, m), 2.07-2.15 (1H, m), 3.15-3.22 (1H, m), 3.37-3.47 (2H, m),
3.52-3.58 (2H, m), 3.58-3.66 (1H, m), 5.13 (1H, dm, J=65 Hz), 6.62
(1H, d, J=7 Hz), 7.61 (1H, d, J=14 Hz), 8.30 (1H, s)
Reference Example 12
.[.(-)-Ethyl
2-[[1,2-cis-2-fluoro-1-cyclopropyl)amino]-methylene]-3-oxo-3-(3-chloro-2,-
4,5-trifluorophenyl)propionate.]. .Iadd.(-)-Ethyl
2-[[(1,2-cis-2-fluoro-1-cyclopropyl)amino]-methylene]-3-oxo-3-(3-chloro-2-
,4,5-trifluorophenyl)propionate .Iaddend.(10a):
Ethyl 3-chloro-2,4,5-trifluorobenzoylacetate (1.5 g), 6 ml of ethyl
orthoformate, and 10 ml of acetic anhydride were mixed, and the
mixture was heated at 110.degree. to 120.degree. C. for 1.5 hours
while stirring. The reaction mixture was concentrated to dryness
under reduced pressure, and the residue was dissolved in 5 ml of
dichloromethane.
Seven milliliters of trifluoroacetic acid was cooled with ice, and
480 mg of (+)-cis-1-(t-butoxycarbonylamino)-2-fluorocyclopropane
(4a) was dissolved therein. The solution was stirred at room
temperature for 20 minutes, followed by evaporation under reduced
pressure to dryness. The residue was suspended in 10 ml of
dichloromethane, and 3 ml of triethylamine was added thereto under
ice-cooling. After stirring for 20 minutes, the above-prepared
dichloromethane solution was added thereto, and the mixture was
stirred for 1 hour. The reaction mixture was washed with water and
dried over anhydrous sodium sulfate. The solvent was removed under
reduced pressure. The residue was subjected to flash column
chromatography using a mixed solvent of benzene and ethyl acetate
(5:1 by volume) as an eluent. The solvent was removed under reduced
pressure, and the residue was washed with diisopropyl ether to
obtain 620 mg of the titled compound (10a).
Melting Point: 98.degree.-100.degree. C.
[.alpha.].sub.D: -6.66.degree. (c=0.998, chloroform)
Elementary Analysis for C.sub.15H.sub.12ClF.sub.4NO.sub.3: Calcd.
(%): C 49.26; H 3.31; N 3.83 Found (%): C 49.39; H 3.22; N 3.86
.sup.1-NMR (CDCl.sub.3) .delta. ppm: 0.95, 1.08 (3H, 1:2.5, each t,
J=7 HZ), 1.0-1.5 (2H, m) 2.8-3.15 (1H, m), 4.03, 4.07 (2H, 1:2.5,
each q, J=7 Hz), 4.78 (1H, dm, J=65 Hz), 7.13 (1H, ddd, J=5.9, 8.6,
& 9.5 Hz), 8.20, 8.25 (1H, 1:2.5, each d, J=14 HZ)
Reference Example 13
.[.(+)-2-[[1,2-cis-2-Fluoro-1-cyclopropyl)amino]methylene]-3-oxo-3-(3-chlo-
ro-2,4,5-trifluorophenyl)propionate.].
.Iadd.(+)-2-[[(1,2-cis-2-Fluoro-1-cyclopropyl)amino]methylene]-3-oxo-3-(3-
-chloro-2,4,5-trifluorophenyl)propionate .Iaddend.(10b):
Ethyl 3-chloro-2,4,5-trifluorobenzoylacetate (1.5 g), 6 ml of ethyl
orthoformate, and 10 ml of acetic anhydride were mixed, and the
mixture was heated at 110.degree. to 120.degree. C. for 1.5 hours
while stirring. The reaction mixture was concentrated to dryness
under reduced pressure, and the residue was dissolved in 10 ml of
dichloromethane.
Ten milliliters of trifluoroacetic acid were ice-cooled, and 1.12 g
of (-)-cis-1-(t-butoxycarbonylamino)-2-fluorocyclopropane (4b) was
dissolved therein. After stirring at room temperature for 20
minutes, the mixture was evaporated to dryness under reduced
pressure. The residue was suspended in 20 ml of dichloromethane,
and 2.0 g of triethylamine was added to the suspension under
ice-cooling. The above-prepared dichloromethane solution was then
added thereto, followed by stirring for 1 hour. The reaction
mixture was washed with water and dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure. The
residue was subjected to flash column chromatography which was
eluted with a mixed solvent of benzene and ethyl acetate (4:1 by
volume) The solvent of the eluent was removed under reduced
pressure. The residue was washed with diisopropyl ether-n-hexane to
obtain 1.74 g of crystals of the titled compound (10b).
Melting Point: 99.degree.-100.degree. C.
[.alpha.].sub.D: +6.70.degree. (c=0.895, chloroform)
Elementary Analysis for C.sub.15H.sub.12ClF.sub.4NO.sub.3: Calcd.
(%): C 49.26; H 3.31; N 3.83 Found (%): C 49.41; H 3.60; N 4.06
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 0.95, 1.08 (3H, 1:2.5, each
t, J=7 HZ), 1.0-1.5 (2H, m), 2.8-3.15 (1H, m), 4.03, 4.07 (2H,
1:2.5, each q, J=7 Hz), 4.78 (1H, dm, J=65 Hz), 7.13 (1H, ddd,
J=5.9, 8.6, & 9.5 Hz), 8.20, 8.25 (1H, 1:2.5, each d, J=14
HZ)
Reference Example 14
(+)-Ethyl
8-chloro-6,7-difluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-4-oxo-1-
,4-dihydroquinoline-3-carboxylate (11a):
In 7 ml of anhydrous dioxane was dissolved 620 mg of Compound (10a)
as prepared in Reference Example 12, and 80 mg of 60% sodium
hydride was added to the solution, followed by stirring at room
temperature for 1 hour. Ethyl acetate was added to the reaction
mixture, and the mixture was washed successively with a 10% citric
acid aqueous solution and water. The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed therefrom
under reduced pressure. The residue was washed with n-hexane to
obtain 551 mg of the titled compound (11a) as a colorless
crystal.
Melting Point: 181.degree.-184.degree. C.
[.alpha.].sub.D: +45.1.degree. (c=1.18, chloroform)
Elementary Analysis for .[.C.sub.15H.sub.12ClF.sub.4NO.sub.3.].
.Iadd.C.sub.15H.sub.11ClF.sub.3NO.sub.3.Iaddend.: Calcd. (%): C
52.12; H 3.21; N 4.05 Found (%): C 52.09; H 3.33; N 4.01
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.40 (3H, t, J=7 HZ), 1.4-1.9
(2H, m), 4.08 (1H, m), 4.39 (2H, q, J=7 HZ), 4.90 (1H, dm, J=65
Hz), 8.24 (1H, dd, J=10 & 11 Hz)
Reference Example 15
(-)-Ethyl
8-chloro-6,7-difluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-4-oxo-1-
,4-dihydroquinoline-3-carboxylate (11b):
In 10 ml of anhydrous dioxane was suspended 560 mg of 60% sodium
hydride having been washed twice with anhydrous n-hexane. The
suspension was added to a solution of 1.70 g of Compound (10b) in
20 ml of anhydrous dioxane, followed by stirring at room
temperature for 2 hours. The solvent was removed under reduced
pressure, and 0.1N hydrochloric acid was added to the residue. The
precipitated crystals were collected by filtration, washed
successively with water and diethyl ether, and dried under reduced
pressure to obtain 1.44 g of the entitled compound (11b) as a
colorless crystal.
X-ray analysis of the compound obtained in this Reference Example
established that the absolute configuration around the asymmetric
carbon of the N.sub.1-substituent of the compound obtained in this
Reference Example was 2-(S) and 1-(R). Thus, the titled compound is
correctly named (-)-ethyl
8-chloro-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-4-oxo--
1,4-dihydroquinoline-3-carboxylate.
Melting Point: 174.degree. C.
[.alpha.].sub.D: -45.3.degree. (c=1.05, chloroform)
Elemental Analysis for .[.C.sub.15H.sub.11ClF.sub.4NO.sub.3.].
.Iadd.C.sub.15H.sub.11ClF.sub.3NO.sub.3.Iaddend.: Calcd. (%): C
52.12; H 3.21; N 4.05 Found (%): C 51.80; H 3.45; N 4.15
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.40 (3H, t, J=7 HZ), 1.4-1.9
(2H, m), 4.08 (1H, m), 4.39 (2H, q, J=7 HZ), 4.90 (1H, dm, J=65
Hz), 8.24 (1H, dd, J=10 & 11 Hz)
IR(KRr); .nu..sub.max cm.sup.-1: 3100, 2998, 1731, 1638, 1614,
1470, 1317
Reference Example 16
(+)-8-chloro-6,7-difluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-4-oxo-1,4-dih-
ydorquinoline-3-carboxylic acid (12a):
The ester (11a) (540 mg), 5 ml of concentrated hydrochloric acid,
and 5 ml of acetic acid were mixed, and the mixture was heated at
120.degree.-130.degree. C. for 2 hours while stirring. To the
reaction mixture was added 50 ml of water, and the precipitated
crystals were collected by filtration, washed successively with
water and diethyl ether, and dried under reduced pressure to obtain
420 mg of the titled compound (12a) as a colorless crystal.
Melting Point: 170.degree.-171.degree. C.
[.alpha.].sub.D: +30.4.degree. (c=0.54, chloroform)
Elementary Analysis for C.sub.13H.sub.7ClF.sub.3NO.sub.3: Calcd.
(%): C 49.16; H 2.22; N 4.41 Found (%): C 49.21; H 2.49; N 4.27
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.3-2.0 (2H, m), 4.12-4.34
(1H, m), 4.95 (1H, dm, J=63 Hz), 8.27 (1H, dd, J=8 & 8 Hz),
8.87, 8.89 (1H, each s, split 1:1)
Reference Example 17
(-)-8-Chloro-6,7-difluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-4-oxo-1,4-dih-
ydroquinoline-3-carboxylic acid (12b)
The ester (11b) (1.40 g) and 10 ml of concentrated hydrochloric
acid were mixed and the mixture was heated at 110.degree. C. for
2.5 hours under stirring. To the reaction mixture was added 50 ml
of water, and the precipitated crystals were collected by
filtration, washed with water and diethyl ether, and dried under
reduced pressure to obtain 1.16 g of the titled compound (12b) as a
colorless crystal.
Melting Point: 177.degree.-182.degree. C.
[.alpha.].sub.D: -26.8.degree. (c=0.90, chloroform)
Elementary Analysis for C.sub.13H.sub.7ClF.sub.3NO.sub.3: Calcd.
(%): C 49.16; H 2.22; N 4.41 Found (%): C 49.28; H 2.40; N 4.66
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.3-2.0 (2H, m), 4.12-4.34
(1H, m), 4.95 (1H, dm, J=63 Hz), 8.27 (1H, dd, J=8 & 8 Hz),
8.87, 8.89 (1H, each s, split 1:1)
EXAMPLE 5
(+)-7-[3-(S)-Amino-1-pyrrolidinyl]-8-chloro-6-fluoro-1-(1,2-cis-2-fluoro-1-
-cyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
(13a):
Five milliliters of trifluoroacetic acid was cooled with ice, and
230 mg of
3-(S)-1-t-(butoxycarbonyl-3-(t-butoxycarbonylamino)pyrrolidine was
dissolved therein, followed by stirring at room temperature for 20
minutes. The reaction mixture was evaporated to dryness under
reduced pressure, and the residue was dissolved in 15 ml of
acetonitrile. To the solution were added 170 mg of the carboxylic
acid (12a) and 400 mg of triethylamine, followed by refluxing for
6.5 hours. The reaction mixture was evaporated to dryness under
reduced pressure, and to the residue was added 1N hydrochloric
acid. The mixture was washed with chloroform. The pH of the aqueous
layer was adjusted to 12 with a 1N sodium hydroxide aqueous
solution and washed with chloroform. The pH of the aqueous layer
was readjusted to 7.6 with hydrochloric acid and extracted with
chloroform. The extract was dried over anhydrous sodium sulfate,
and the solvent was evaporated. The residue was recrystallized from
aqueous ammonia-ethanol to obtain 138 mg of the titled compound
(13a) as a colorless crystal.
Melting Point: 214.degree.-217.degree. C. (with decomposition)
[.alpha.].sub.D: +120.8.degree. (c=0.475, 0.1N NaOH aqueous
solution)
Elementary Analysis for
C.sub.17H.sub.16ClF.sub.2N.sub.3O.sub.3.1/2H.sub.2O: Calcd. (%): C
51.98; H 4.36; N 10.70 Found (%): C 52.07; H 4.71; N 10.72
.sup.1H-NMR (NaOD) .delta. ppm: 1.28 (1H, dm, J=27 Hz), 1.69-1.78
(2H, m), 3.39-3.42 (1H, m), 3.51-3.61 (3H, m), 3.69-3.72 (1H, m),
4.13-4.17 (1H, m), 4.99 (1H, dm, J=70 Hz), 7.72 (1H, d, J=14 Hz),
8.44, 8.45 (1H, each s, split, 1:1)
EXAMPLE 6
(-)-7-[3-(S)-Amino-1-pyrrolidinyl]-8-chloro-6-fluoro-1-(1,2-cis-2-fluoro-1-
-cyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
.[.(13a).]. .Iadd.(13b).Iaddend.:
Five milliliters of trifluoroacetic acid was cooled with ice, and
230 mg of
3-(S)-t-butoxycarbonyl-3-(t-butoxycarbonylamino)pyrrolidine was
dissolved therein, followed by stirring at room temperature for 20
minutes. The reaction mixture was evaporated to dryness under
reduced pressure, and the residue was dissolved in 15 ml of
acetonitrile. To the solution were added 170 mg of the carboxylic
acid (12b) .[.add.]. .Iadd.and .Iaddend.400 mg of triethylamine,
and the mixture was heated under reflux for 6.5 hours. The reaction
mixture was evaporated to dryness under reduced pressure. A 1N
hydrochloric acid was added to the residue, and the mixture was
washed with chloroform. The aqueous layer was adjusted to a pH of
12 with a 1N sodium hydroxide aqueous solution, and the aqueous
layer was adjusted to a pH of 7.6 with hydrochloric acid and
extracted with chloroform. The extract was dried over anhydrous
sodium sulfate, and the solvent was evaporated. The residue was
recrystallized from aqueous ammonia-ethanol to give 158 mg of the
titled compound (13b) as a colorless crystal.
Melting Point: 247.degree.-252.degree. C. (with decomposition)
[.alpha.].sub.D: -94.7.degree. (c=0.378, 0.1N HaOH aqueous
solution)
Elementary Analysis for
C.sub.17H.sub.16ClF.sub.2N.sub.3O.sub.3.H.sub.2O: Calcd. (%): C
50.82; H 4.52; N 10.46 Found (%): C 50.97; H 5.14; N 10.42
.sup.1H-NMR (NaOD) .delta. ppm: 1.32 (1H, dm, J=27 Hz), 1.73-1.80
(2H, m), 2.15-2.19 (1H, m), 3.19-3.22 (1H, m), 3.45-3.50 (1H, m),
3.58-3.62 (1H, m), 3.85-3.88 (2H, m), 4.16-4.20 (1H, m), 4.99 (1H,
dm, J=63 Hz), 7.76 (1H, d, J=14 Hz), 8.54, 8.44 (1H, each s, split,
1:1)
Reference Example 18
(-)-Ethyl
2-[[(1,2-cis-2-fluoro-1-cyclopropyl)amino]methylene]-3-oxo-3-(2,-
3,4,5-tetrafluoro-6-nitrophenyl)-propionate (14a):
Ethyl 2,3,4,5-tetrafluoro-6-nitrobenzoylacetate (1.5 g), 6 ml of
ethyl orthoformate, and 10 ml of acetic anhydride were mixed, and
the mixture was heated at 120.degree. C. for 2 hours. The reaction
mixture was concentrated to dryness, and the residue was dissolved
in 10 ml of dichloromethane.
Ten milliliters of trifluoroacetic acid was cooled with ice, and
1.1 g of (+)-cis-1-(t-butoxycarbonylamino)-2-fluorocyclopropane
(4a) was dissolved therein. The solution was stirred at room
temperature for 20 minutes, followed by evaporating to dryness
under reduced pressure. The residue was suspended in 20 ml of
dichloromethane, and 2.0 g of triethylamine was added thereto under
ice-cooling, followed by stirring for 20 minutes. The
above-prepared dichloromethane solution was then added thereto,
followed by stirring for 30 minutes. The reaction mixture was
washed with water and dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure. The residue was
subjected to flash column chromatography using benzene as an
eluent. The fractions of the compound (14a) were combined, and the
solvent was removed under reduced pressure. The residue was washed
with n-hexane to yield 1.57 g of crystals of the titled compound
(14a).
Melting Point: 99.degree.-100.degree. C.
[.alpha.].sub.D: .[.10.3.degree..]. .Iadd.-10.3.degree.
.Iaddend.(c=1.25, chloroform)
Elementary Analysis for C.sub.15H.sub.11F.sub.5N.sub.2O.sub.5
Calcd. (%): C 45.70; H 2.81; N 7.10 Found (%): C 45.60; H 3.01; N
7.03
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.10 (3H, t, J=7 Hz),
1.2-1.55 (2H, m), 2.88-3.16 (1H, m), 4.09 (2H, q, J=7 Hz), 4.45
(1H, dm, J=63 Hz), 8.29 (1H, d, J=14 Hz)
IR(KBr): .nu..sub.max cm.sup.-1: 3454 1734, 1626, 1566, 1521,
1482
Reference Example 19
(+)-Ethyl
2-[[(1,2-cis-2-fluoro-1-cyclopropyl)amino]-methylene]-3-oxo-3-(2-
,3,4,5-tetrafluoro-6-nitrophenyl)-propionate (14b):
Ethyl 2,3,4,5-tetrafluoro-6-nitrobenzoylacetate (1.5 g), 6 ml of
ethyl orthoformate and 10 ml of acetic anhydride were mixed, and
the mixture was heated at 110.degree. to 120.degree. C. for 1 hour
while stirring. The reaction mixture was concentrated to dryness,
and the residue was dissolved in 10 ml of dichloromethane.
Ten milliliters of trifluoroacetic acid was ice-cooled, and 1.10 g
of (-)-cis-1-(t-butoxycarbonylamino)-2-fluorocyclopropane (4b) was
dissolved therein, followed by stirring at room temperature for 20
minutes. The reaction mixture was evaporated to dryness under
reduced pressure, and the residue was suspended in 20 ml of
dichloromethane. To the suspension was added 1.8 g of triethylamine
under ice-cooling, followed by stirring for 20 minutes. To the
mixture was added the above-prepared dichloromethane solution,
followed by stirring for 2 hours. The reaction mixture was washed
with water and dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure, and the residue was subjected to
flash column chromatography using benzene as an eluent. The
fractions of the product (14b) were combined, and the solvent was
removed under reduced pressure. The residue was washed with
n-hexane to yield 1.50 g of crystals of the titled compound
(14b).
Melting Point: 98.degree.-100.degree. C.
[.alpha.].sub.D: -10.1.degree. (c=2.09, chloroform)
Elementary Analysis for C.sub.15H.sub.11F.sub.5N.sub.2O.sub.5
Calcd. (%): C 45.70; H 2.81; N 7.10 Found (%): C 45.77; H 3.38; N
7.18
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.10 (3H, t, J=7 Hz), 1.2-1.5
(2H, m), 2.88-3.12 (1H, m), 4.09 (2H, q, J=7 Hz), 4.45 (1H, dm,
J=63 Hz), 8.30 (1H, d, J=14 Hz)
IR(KBr): .nu..sub.max cm.sup.-1: 3454 1695, 1638, 1554, 1515
Reference Example 20
(+)-Ethyl
6,7,8-trifluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-5-nitro-4-oxo-
-1,4-dihydroquinoline-3-carboxylate (15a):
In 20 ml of anhydrous dioxane was suspended 580 mg of 60% sodium
hydride having been washed twice with n-hexane. The suspension was
added to a solution of 1.90 g of Compound (14a) in 20 ml of
anhydrous dioxane. The mixture was stirred at room temperature for
1 hour, and the solvent was removed from the reaction mixture under
reduced pressure. To the residue was added 0.1N hydrochloric acid.
The crystals thus formed were collected by filtration, washed
successively with water and diethyl ether, and dried under reduced
pressure to obtain 1.65 g of the titled compound (15a) as a
colorless crystal.
Melting Point: 172.degree.-176.degree. C.
[.alpha.].sub.D: +10.7.degree. (c=1.12, chloroform)
Elementary Analysis for C.sub.15H.sub.10F.sub.4N.sub.2O.sub.5
Calcd. (%): C 48.14; H 2.69; N 7.49 Found (%): C 48.29; H 2.78; N
7.20
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.36 (3H, t, J=7 Hz),
1.4-1.92 (2H, m), 3.80-4.08 (1H, m), 4.34 (2H, q, J=7 Hz), 4.99
(1H, dm, J=63 Hz), 8.55 (1H, s)
IR(KBr): .nu..sub.max cm.sup.-1: 3454 1734, 1626, 1566, 1521
1482
Reference Example 21
(-)-Ethyl
6,7,8-trifluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-5-nitro-4-oxo-
-1,4-dihydroquinoline-3-carboxylate (15b):
In 10 ml of anhydrous dioxane was suspended 440 mg of 60% sodium
hydride having been washed twice with n-hexane. The suspension was
added to a solution of 1.45 g of Compound (14b) in 20 ml of
anhydrous dioxane, followed by stirring at room temperature for 30
minutes. The solvent was removed from the reaction mixture under
reduced pressure. To the residue was added 0.1N hydrochloric acid,
and the formed crystals were collected by filtration, washed
successively with water and diethyl ether, and dried under reduced
pressure to obtain 1.18 g of the titled compound (15b) as a
colorless crystal.
Melting Point: 171.degree.-175.degree. C.
[.alpha.].sub.D: .[.11.1.degree..]. .Iadd.-11.1.degree.
.Iaddend.(c=0.27, chloroform)
Elementary Analysis for C.sub.15H.sub.10F.sub.4N.sub.2O.sub.5
Calcd. (%): C 48.14; H 2.69; N 7.49 Found (%): C 48.44; H 3.17; N
7.48
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.36 (3H, t, J=7 Hz),
1.4-1.92 (2H, m), 3.74-4.02 (1H, m), 4.36 (2H, q, J=7 Hz), 4.94
(1H, dm, J=62 Hz), 8.54 (1H, s)
IR(KBr): .nu..sub.max cm.sup.-1: 1731, 1626, 1566, 1485, 1323,
1275
Reference Example 22
(+)-Ethyl
5-amino-6,7,8-trifluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-4-oxo-
-1,4-dihydroquinoline-3-carboxylic acid (16a):
The nitro compound (15a) (1.60 g), 6 ml of Raney nickel, and 200 ml
of ethanol were mixed, and the mixture was shaken for 2.5 hours in
a hydrogen atmosphere. The catalyst was removed by filtration
through Celite, and the filtrate was concentrated under reduced
pressure. The residue was subjected to silica gel column
chromatography using chloroform as an eluent. The fractions of
product (16a) were combined, and the solvent was removed therefrom
under reduced pressure. The residue was recrystallized from ethanol
to obtain 770 mg of the title compound (16a) as a pale yellow
crystal.
Melting Point: 190.degree.-191.degree. C.
[.alpha.].sub.D: +26.0.degree. (c=0.76, chloroform)
Elementary Analysis for C.sub.15H.sub.12F.sub.4N.sub.2O.sub.3
Calcd. (%): C 52.33; H 3.51; N 8.14 Found (%): C 52.13; H 3.95; N
8.13
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.39 (3H, t, J=7 Hz), 1.4-1.8
(2H, m), 3.60-3.88 (1H, m), 4.38 (2H, q, J=7 Hz), 4.87 (1H, dm,
J=63 Hz), 6.8-7.1 (2H, m), 8.37 (1H, s)
IR(KBr): .nu..sub.max cm.sup.-1: 3436, 1683, 1653, 1557, 1461,
1284
Reference Example 23
(-)-Ethyl
5-amino-6,7,8-trifluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-4-oxo-
-1,4-dihydroquinoline-3-carboxylate (16b):
The nitro compound (15b) (1.60 g), 3 ml of Raney nickel, and 120 ml
of ethanol were mixed, and the mixture was shaken for 4.5 hours in
a hydrogen atmosphere. The catalyst was removed by filtration
through Celite, and the filtrate was concentrated under reduced
pressure. The residue was subjected to silica gel column
chromatography using chloroform as an eluent. The fractions of
product (16b) were combined, and the solvent was removed under
reduced pressure. The residue was recrystallized from ethanol to
obtain 620 mg of the titled compound (16b) as a pale yellow
crystal.
Melting Point: 191.degree.-193.degree. C.
[.alpha.].sub.D: -25.9.degree. (c=0.65, chloroform)
Elementary analysis for C.sub.15H.sub.12F.sub.4N.sub.2O.sub.3
Calcd. (%): C 52.33; H 3.51; N 8.14 Found (%): C 52.16; H 3.54; N
8.08
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.39 (3H, t, J=7 Hz), 1.4-1.8
(2H, m), 3.60-3.88 (1H, m), 4.38 (2H, q, J=7 Hz), 4.87 (1H, dm,
J=63 Hz), 6.8-7.1 (2H, m), 8.38 (1H, s)
IR(KBr): .nu..sub.max cm.sup.-1: 3436, 1683, 1653, 1593, 1464,
1284
Reference Example 24
5-Amino-6,7,8-trifluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-4-oxo-1,4-dihyd-
roquinoline-3-carboxylic acid (17a):
The ester (16a) (750 mg) and 10 ml of concentrated hydrochloric
acid were mixed and the mixture was heated at 100.degree. C. for 2
hours while stirring. To the reaction mixture was added 20 ml of
water, and the precipitated crystals were collected by filtration
to obtain 610 mg of the titled compound (17a) as a colorless
crystal.
Melting Point: 297.degree.-300.degree. C.
Elementary Analysis for C.sub.13H.sub.8F.sub.4N.sub.2O.sub.3 Calcd.
(%): C 49.38; H 2.55; N 8.86 Found (%): C 49.43; H 2.91; N 8.84
.sup.1H-NMR (DMSO-d.sub.6) .delta. ppm: 1.4-2.1 (2H, m), 3.9-4.2
(1H, m), 5.08 (1H, dm, J=65 Hz), 7.72 (1H, s), 8.62 (1H, s)
IR(KBr): .nu..sub.max cm.sup.-1: 3448, 3334, 1725, 1656, 1596,
1566, 1518
Reference Example 25
5-Amino-6,7,8-trifluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-4-oxo-1,4-dihyd-
roquinoline-3-carboxylic acid (17b):
The ester (16b) (588 mg) and 10 ml of concentrated hydrochloric
acid were mixed and the mixture was heated at 100.degree. to
110.degree. C. for 2 hours while stirring. To the reaction mixture
was added 20 ml of water, and the precipitated crystals were
collected by filtration to obtain 514 mg of the titled compound
(17b) as a colorless crystal.
Melting Point: 295.degree.-300.degree. C.
Elementary Analysis for C.sub.13H.sub.8F.sub.4N.sub.2O.sub.3 Calcd.
(%): C 49.38; H 2.55; N 8.86 Found (%): C 49.41; H 2.81; N 8.88
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.4-2.1 (2H, m), 3.9-4.2 (1H,
m), 5.08 (1H, dm, J=65 Hz), 7.72 (1H, s), 8.62 (1H, s)
IR: .nu..sub.max cm.sup.-1: 3448, 3334, 1725, 1656, 1596, 1566,
1518
EXAMPLE 7
(-)-5-Amino-7-[3-(S)-amino-1-pyrrolidinyl]-6,8-difluoro-1-(1,2-cis-2-fluor-
o-1-cyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
(18a):
Five milliliters of trifluoroacetic acid was cooled with ice, and
230 mg of
3-(S)-1-t-butoxycarbonyl-3-(t-butoxycarbonylamino)pyrrolidine was
dissolved therein, followed by stirring at room temperature for 30
minutes. The reaction mixture was evaporated to dryness under
reduced pressure, and the residue was dissolved in 25 ml of
acetonitrile. To the solution were added 160 mg of the carboxylic
acid (17a) and 400 mg of triethylamine, and the mixture was heated
under reflux for 12 hours. The reaction mixture was evaporated to
dryness under reduced pressure, and 1N hydrochloric acid was added
to the residue. After washing the mixture with chloroform, the
aqueous layer was adjusted to a pH of 12 with a 1N sodium hydroxide
aqueous solution, followed by washing with chloroform. The aqueous
layer was then adjusted to a pH of 7.6 with hydrochloric acid,
followed by extraction with chloroform. The extract was dried over
anhydrous sodium sulfate, and the solvent was removed under reduced
pressure. The residue was recrystallized from aqueous
ammonia-ethanol to obtain 128 mg of the titled compound (18a) as a
colorless crystal.
Melting Point: 224.degree.-230.degree. C.
[.alpha.].sub.D: -4.72.degree. (c=0.888, 0.1N NaOH aqueous
solution)
Elementary Analysis for C.sub.17H.sub.17F.sub.3N.sub.4O.sub.3
Calcd. (%): C 53.40; H 4.48; N 14.65 Found (%): C 53.28; H 4.08; N
14.54
.sup.1H-NMR (NaOD)) .delta. ppm: 1.47-1.58 (1H, m), 1.67-1.78 (2H,
m), 2.07-2.11 (1H, m), 3.28-3.44 (1H, m), 3.48-3.52(1H, m),
3.60-3.66 (1H, m), 3.71-3.78 (2H, m), 4.92 (1H, dm, J=72 Hz), 8.18
(1H, s)
IR: .nu..sub.max cm.sup.-1: 3400, 1728, 1635, 1605, 1518, 1433,
1350, 1308
EXAMPLE 8
(+)-5-Amino-7-[3-(S)-amino-1-pyrrolidinyl]-6,8-difluoro-1-(1,2-cis-2-fluor-
o-1-cyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
(18b):
Five milliliters of trifluoroacetic acid was cooled with ice, and
230 mg of
3-(S)-1-t-butoxycarbonyl-3-(t-butoxycarbonylamino)pyrrolidine was
dissolved therein, followed by stirring at room temperature for 30
minutes. The reaction mixture was evaporated to dryness under
reduced pressure, and the residue was dissolved in 25 ml of
acetonitrile. To the solution were added 160 mg of the carboxylic
acid (17b) and 400 mg of triethylamine, and the mixture was heated
under reflux for 12 hours. The reaction mixture was evaporated to
dryness under reduced pressure, and 1N hydrochloric acid was added
to the residue. After washing the mixture with chloroform, the
aqueous layer was adjusted to a pH of 12 with a 1N sodium hydroxide
aqueous solution, followed by washing with chloroform. The aqueous
layer was then adjusted to a pH of 7.6 with hydrochloric acid,
followed by extraction with chloroform. The extract was dried over
anhydrous sodium sulfate, and the solvent was removed under reduced
pressure. The residue was recrystallized from aqueous
ammonia-ethanol to obtain 68 mg of the titled compound (18b) as a
colorless crystal.
Melting Point: 214.degree.-217.degree. C.
[.alpha.].sub.D: +31.3.degree. (c=0.268, 0.1N NaOH aqueous
solution)
Elementary Analysis for
C.sub.17H.sub.17F.sub.3N.sub.4O.sub.3.1/2H.sub.2O: Calcd. (%): C
52.18; H 4.64; N 14.32 Found (%): C 52.22; H 4.93; N 14.23
.sup.1H-NMR (NaOD) .delta. ppm: 1.48-1.58 (1H, m),, 1.66-1.79 (2H,
m), 2.06-2.12 (1H, m), 3.29-3.32 (1H, m), 3.48-3.52 (1H, m),
3.60-3.64 (1H, m), 3.70-3.78 (2H, m), 4.92 (1H, dm, J=72 Hz), 8.19
(1H, s)
1H: .nu. max cm-.sup.1; 3490, 1716, 1635, 1521, 1437, 1356,
1305
REFERENCE EXAMPLE 26
.[.Synthesis of Optically Active 7-Amino-5-azaspiro[2.4]-heptane.].
.Iadd.Synthesis of Optically Active
7-Amino-5-azaspiro[2.4]heptane.Iaddend.:
.[.5-[(1R)-Phenylethyl]-4.7-dioxo-5-azaspiro[2.4]-heptane.].
.Iadd.5-[(1R)-Phenylethyl]-4,7-dioxo-5-azaspiro[2.4]heptane
.Iaddend.(19):
To 10.4 g of ethyl acetoacetate were added 15 g of
1,2-dibromoethane, 23 g of potassium carbonate, and 150 ml of
N,N-dimethylformamide (DMF), and the mixture was stirred at room
temperature for 2 days. Any insoluble matter was removed by
filtration, and the filtrate was evaporated to dryness under
reduced pressure. To the residue was added water, and the mixture
was extracted with chloroform. The chloroform extract was dried
over anhydrous sodium sulfate, and the solvent was removed under
reduced pressure. The resulting pale yellow oily substance was
subjected to distillation under reduced pressure to obtain 7.5 g of
ethyl 1-acetyl-1-cyclopropanecarboxylate having a boiling point of
70.degree. to 71.degree. C./2 to 3 mmHg.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.30 (3H, t, J=7 Hz), 1.48
(4H, s), 2.49 (3H, s), 4.24 (2H, q, J=7 Hz)
In 200 ml of ethanol was dissolved 35.7 g of the above obtained
compound, and 40 g of bromide was added dropwise to the solution at
room temperature while stirring. After the stirring was continued
at room temperature for 2 hours, the excess bromine and the solvent
were removed under reduced pressure to obtain ethyl
1-bromoacetyl-1-cyclopropanecarboxylate, which was then, without
further purification, dissolved in 200 ml of ethanol. To the
solution were simultaneously added dropwise 33 g of
R-(+)-1-phenylethylamine and 27 g of triethylamine over a period of
1 hour while stirring under ice-cooling. After the addition, the
reaction temperature was raised to room temperature, and the
stirring was continued at room temperature for 2 days. Any
insoluble matter was removed by filtration, and ethanol was removed
from the filtrate under reduced pressure. The residue was dissolved
in 300 ml of ethyl acetate, and the solution was washed
successively with 1N hydrochloric acid, a saturated sodium
hydrogen-carbonate aqueous solution, and a saturated sodium
chloride aqueous solution in this order. The organic layer was
dried over anhydrous sodium sulfate, and the solvent was removed
under reduced pressure. The residue was subjected to 200 g of
silica gel column which was eluted with 0 to 2% methanolic
chloroform to obtain the titled compound (19) as a colorless
crystal.
Melting Point: 98.degree.-103.degree. C.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.62 (3H, d, J=7.2 Hz), 3.5
(1H, d, J=18 Hz), 3.9 (1H, d, J=18 Hz), 5.82 (1H, q, J=7.2 Hz),
7.36 (5H, s)
2) 5-[(1R)-Phenylethyl]-7-hydroxyimino-4-oxo-5-azaspiro[2.4]heptane
(20):
To 3.35 g of Compound (19) were added 1.6 g of hydroxylamine
hydrochloride, 2.3 g of triethylamine, and 80 ml of ethanol, and
the mixture was stirred at room temperature for 2 hours. The
solvent was removed under reduced pressure, and chloroform was
added to the residue. The mixture was washed successively with a
10% citric acid aqueous solution and a saturated sodium chloride
aqueous solution. The organic layer was dried over anhydrous sodium
sulfide. The solvent was removed under reduced pressure to obtain
3.5 g of the titled compound (20) as a colorless crystal.
Melting Point: 188.degree.-194.degree. C.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.2-1.4 (2H, m), 1.53 (3H, d,
J=7.2 Hz & 2H, m), 3.8 (1H, d, J=18 Hz), 4.16 (1H, d, J=18 Hz),
5.63 (1H, q, J=7.2 Hz), 7.32 (5H, s)
3) 7-Amino-4-oxo-5-[(1R)-Phenylethyl]-5-azaspiro[2.4]-heptane (21a,
21b):
To 150 ml of methanol were added 3.5 g of Compound (20) and 7.5 ml
of Raney nickel, and catalytic reduction was carried out at room
temperature for 12 hours. After the catalyst was removed by
filtration, the solvent was removed from the filtrate under reduced
pressure. The residue was subjected to a 100 g of silica gel column
eluted with a mixed solvent of 5% methanol/chloroform which was to
yield 1.0 g of the entitled compound (21b) from the earlier
fraction and 0.8 g of the titled compound (21a) from the later
fraction each as a colorless oily substance.
Compound (21b):
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 0.8-1.4 (4H, m), 1.52 (3H, d,
J=7 Hz), 2.87 (1H, dd, J=10, & 3 Hz), 3.3-3.9 (2H, m), 4.27
(2H, br. s), 5.42 (1H, q, J=7 Hz), 7.29 (5H, s)
Compound (21a):
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 0.6-1.3 (4H, m), 1.40 (2H,
s), 1.53 (3H, d, J=7.2 Hz), 2.99 (1H, dd, J=12.8, & 7.2 Hz),
3.15-3.45 (2H, m), 5.52 (1H, q, J=7.2 Hz), 7.30 (5H, s)
4) 7-Amino-5-[(1R)-Phenylethyl]-5-azaspiro[2.4]heptane (22a,
22b):
To 50 ml of anhydrous tetrahydrofuran were added 1.0 g of Compound
(21b) and 500 mg of lithium aluminum hydride, and the mixture was
refluxed for 17 hours. After cooling, 0.5 ml of water, 0.5 ml of a
15% sodium hydroxide aqueous solution, and 1.5 ml of water were
successively added to the reaction mixture in this order, followed
by stirring well at room temperature for 30 minutes. Any insoluble
matter was removed by filtration and thoroughly washed with
tetrahydrofuran. The filtrate and the washing were combined and
dried. The solvent was removed under reduced pressure to obtain 940
mg of the titled compound (22b) as a pale yellow oily substance. In
the same manner, 755 mg of the titled compound (22a) was obtained
from 800 mg of Compound (21a).
.[.Compound (21b).]. .Iadd.Compound (22b).Iaddend.:
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 0.2-0.8 (4H, m), 1.35(3H, d,
J=6.6 Hz), 1.6-2.0 (2H, br, m), 2.2-3.1 (4H, m), 3.24 (1H, q, J=6.6
Hz), 3.5-3.9 (1H, m), 7.28 (5H, br. s)
Compound (22a):
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 0.3-0.9 (4H, m), 1.36 (3H, d,
J=6.7 Hz), 1.8-2.2 (2H, m), 2.2-3.2 (4H, m), 3.24 (1H, q, J=6.7
Hz), 3.6-3.9 (1H, m), 7.28 (5H, br, s)
5)
7-(t-Butoxycarbonylamino)-5-[(1R)-phenylethyl]-5-azaspiro[2.4]heptane
(23a, 23b):
To 20 ml of anhydrous tetrahydrofuran were added 764 mg of Compound
(22b) and 1.3 g of Boc-ON [Boc-ON;
.[.2-(t-Butoxycarbonyloxyimino]-2-phenylacetonitrile.].
.Iadd.2-(t-Butoxycarbonyloxyimino)-2 phenylacetonitrile .Iaddend.
##STR00011## and the mixture was stirred at room temperature for 4
hours. Ethyl acetate was added to the reaction mixture, and the
mixture was washed twice with a 1N sodium hydroxide aqueous
solution and then once with water, followed by extraction with a
10% citric acid aqueous solution. The aqueous extract was washed
once with ethyl acetate, and a 15% sodium hydroxide aqueous
solution was added to the aqueous layer under cooling to make it
alkaline. The mixture was extracted three times with chloroform,
and the organic layer was washed with a saturated sodium chloride
aqueous solution and then dried. The solvent was removed under
reduced pressure, and the residue was subjected to silica gel
column chromatography (silica gel: 20 g; eluent:
chloroform:methanol=20:1, 10:1) to obtain 690 mg of the titled
compound (23b). This compound was allowed to stand to crystallize,
followed by washing with n-hexane. The titled compound (23a) was
obtained in the same manner. Compound (23b) (colorless
crystal):
Melting Point: 103.degree.-105.degree. C.
[.alpha.].sub.D: .[.15.2.degree..]. .Iadd.-15.2.degree.
.Iaddend.(c=1.475, chloroform)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 0.4-0.9 (4H, m), 1.36 (3H, d,
J=7.2 Hz), 1.44 (9H, s), 2.42 (2H, AB q, J=10.2 Hz), 2.79 (2H, d,
J=5.6 Hz), 3.24 (1H, q, J=7.2 Hz), 3.6-4.0 (1H, m), 4.6-5.1 (1H,
br, d), 7.28 (5H, s)
Elementary .[.qAnalysis.]. .Iadd.Analysis .Iaddend.for
C.sub.19H.sub.28N.sub.2O.sub.2: Calcd. (%): C 72.12; H 8.92; N 8.85
Found (%): C 71.63; H 9.07; N 8.64
Compound (23a) (colorless crystal):
Melting Point: 94.degree.-97.degree. C.
[.alpha.].sub.D: +47.6.degree. (c=0.89, chloroform)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 0.4-0.9 (4H, m), 1.33 (3H, d,
J=6.6 Hz), 1.40 (9H, s), 2.29 (1H, d, J=9 Hz), 2.44 (1H, dd, J=10.8
& 3.6 Hz), 2.77 (1H, d, J=9 Hz), 2.88 (1H, dd, J=10.8 & 5.3
Hz), 3.22 (1H, q, J=6.6 Hz), 3.6-3.9 (1H, m), 4.7-5.2 (1H, br, d),
7.27 (5H, s)
Elementary .[.a.]. Analysis for C.sub.19H.sub.28N.sub.2O.sub.2:
Calcd. (%): C 72.12; H 8.92; N 8.85 Found (%): C 71.86; H 9.36; N
8.68
6) 7-t-Butoxycarbonylamino-5-azaspiro[2.4]heptane (24a, 24b)
To 30 ml of ethanol were added 650 mg of Compound (23b) and 500 mg
of 50% hydrated palladium-on-carbon, and catalytic reduction was
effected under heating at a pressure of 4.2 .[.atoms.].
.Iadd.atms.Iaddend.. After 6 hours, the catalyst was removed by
filtration, and the solvent was removed under reduced pressure. To
the oily residue was added ethyl acetate, followed by extracting
twice with a 10% citric acid aqueous solution. The aqueous extract
was made alkaline with a 15% sodium hydroxide aqueous solution and
then extracted three times with chloroform. The chloroform layer
was washed with water and dried. The solvent was removed under
reduced pressure to yield 440 mg of the titled compound (24b) as a
crude product. The titled compound (24a) was obtained in the same
manner as above. The .Iadd..sup.1H-.Iaddend.NMR spectra of
Compounds .[.24b).]. .Iadd.(24b) .Iaddend.and (24a) were in
complete agreement with each other.
Compound (24)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 0.4-1.0 (4H, m), 1,42 (9H,
s), 2.71 (1H, d, J=10.2 Hz), 2.92 (1H, dd, J=10.8 & 3.6 Hz),
3.01 (1H, d, J=10.2 Hz), 3.33 (1H, dd, J=10.8 & 5.4 Hz),
3.5-3.9 (1H, m), 5.0-5.4 (1H, br, d)
EXAMPLE 9
7-(7-t-Butoxycarbonylamino-5-azaspiro[2.4]heptan-5-yl)-8-chloro-6-fluoro-1-
-(1,2-cis-2-fluoro-1-cyclopropyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic
acid (25bb):
In 0.6 ml of acetonitrile were dissolved 160 mg of
8-chloro-6,7-difluoro-1-(1,2-cis-2-fluoro-1-cylopropyl)-1,4-dihydro-4-oxo-
quinoline-3-carboxylic acid (12b), 150 mg of the amine compound
(24b), and 0.5 ml of triethylamine, and the solution was heated
under reflux for 5 hours. After cooling, the precipitated colorless
crystals were collected by filtration. The solvent of the mother
liquor was removed under reduced pressure, and the residue was
purified by silica gel preparative TLC using a developing solvent
of chloroform-methanol (5:1 by volume). The purified product and
the above-obtained crystals were combined to give 255 mg of the
titled compound (25bb).
Melting Point: 213.degree.-218.degree. C.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 0.6-1.0 (6H, m), 1,45 (9H,
s), 7.99 (1H, d, J=13.1 Hz), 8.74, 8.78 (each 0.5H, s)
EXAMPLE 10
(-)-7-(7-Amino-5-azaspiro[2.4]heptan-5-yl)-8-chloro-6-fluoro-1-(1,2-cis-2--
fluoro-1-cylcopropyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid
(16bb):
To 255 mg of the Boc-compound (25bb) as obtained in Example 9 were
added 0.5 ml of anisole and 10 ml of trifluoroacetic acid under
ice-cooling. After warming to room temperature, the mixture was
stirred for 30 minutes. The solvent was removed under reduced
pressure, a 1N sodium hydroxide aqueous solution was added to the
residue adjusting a pH .[.of.]. .Iadd.to .Iaddend.11 to 12. The
alkaline aqueous solution was washed twice with chloroform. The
aqueous layer was adjusted to a pH of about 7 with concentrated
hydrochloric acid and a 10% citric acid aqueous solution and
extracted three times with chloroform. The extract was washed with
water and dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure, and the resulting solid was
recrystallized from ethanol-concentrated aqueous ammonia to obtain
142 mg of the titled compound (26bb) as a colorless crystal.
Melting Point: 127.degree.-140.degree. C. (with decomposition)
[.alpha.].sub.D: .[.199.2.degree..]. .Iadd.-199.2.degree.
.Iaddend.(c=0.24, 1N NaOH)
Elementary Analysis for
.[.C.sub.19H.sub.18N3O.sub.3F.sub.2Cl.1/4H.sub.2O.].
.Iadd.C.sub.19H.sub.18N.sub.3O.sub.3F.sub.2Cl 1/4H.sub.2O
.Iaddend.Calcd. (%): C 55.08; H 4.50; N 10.14 Found (%): C 54.86; H
4.80; N 10.03
As the compound obtained in this experiment was obtained by a
convention of compound 11b, so the titled compound is correctly
named
.[.(-)-7-17-amino-3-azaspiro[2.4]heptan-5-yl)-8-chloro-6-fluoro-1-[2-(S)--
2-fluoro-1-(R)-cyclopropyl]-4-oxo-1,4-dihydroquinoline-7-carboxylic
acid.].
.Iadd.(-)-7-(7-amino-3-azaspiro[2.4]heptan-5-yl)-8-chloro-6-fluor-
o-1-[2-(S)-2-fluoro-1-(R)-cyclopropyl]-4-oxo-1,4-dihydroquinoline-7-carbox-
ylic acid.Iaddend..
Recrystallization of the compound obtained in this Example from an
aqueous ethanol gave another crystal showing the following physical
data.
Melting Point: 127.3.degree.-135.5.degree. C.
[.alpha.].sub.D: .[.179.degree..]. .Iadd.-179.degree.
.Iaddend.(c=1.12, 1N NaOH)
Elementary Analysis for
C.sub.19H.sub.18N.sub.3O.sub.3F.sub.2Cl.3/2H.sub.2O: Calcd. (%): C
52.23; H 4.85; N 9.61 Found (%): C 52.16; H 4.70; N 9.53
And it was further confirmed that the configuration around the
carbon atom at 7-position in the 7-amino-5-azaspiro[2.4]heptan-5-yl
group was (S).
EXAMPLE 11
Synthesis of Compound (26ab)
Compound (26ab) was obtained from Compound (12a) and Compound (24b)
in the same manner as described in Examples 9 an 10.
Melting Point: 123.degree.-128.degree. C. (with decomposition)
[.alpha.].sub.D: +21.5.degree. (c=0.195, 1N NaOH)
Elementary Analysis for
.[.C.sub.19H.sub.18N3O.sub.3F.sub.2Cl.1/2H.sub.2O.].
.Iadd.C.sub.19H.sub.18N.sub.3O.sub.3F.sub.2. 1/2H.sub.2O
.Iaddend.Calcd. (%): C 54.49; H 4.57; N 10.03 Found (%): C 54.33; H
4.73; N 9.81
EXAMPLE 12
Synthesis of Compound (26ba)
Compound (26ba) was synthesized from Compound (12b) and Compound
(24a) in the same manner as described in Examples 9 and 10.
Melting Point: 121.degree.-127.degree. C. (with decomposition)
[.alpha.].sub.D: .[.21.1.degree..]. .Iadd.-21.1.degree.
.Iaddend.(c=0.275, 1N NaOH)
Elementary Analysis for
C.sub.19H.sub.18N.sub.3O.sub.3F.sub.2Cl.1/2H.sub.1O Calcd. (%): C
54.49; H 4.57; N 10.03 Found (%): C 54.77; H 4.43; N 9.86
EXAMPLE 13
Synthesis of Compound (26aa)
Compound (26aa) was synthesized from Compound (12a) and Compound
(24a) in the same manner as in Examples 9 and 10.
Melting Point: 126.degree.-145.degree. C. (with decomposition)
[.alpha.].sub.D: +186.6.degree. (c=0.228, 1N NaOH)
Elementary Analysis for
C.sub.19H.sub.18N.sub.3O.sub.3F.sub.2Cl.3/4H.sub.2O: Calcd. (%): C
53.91; H 4.64; N 9.93 Found (%): C 53.80; H 4.47; N 9.82
Reference Example 27
(-)-Ethyl
7-chloro-6-fluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-4-oxo-1,4-d-
ihydro-1,8-naphthyridine-3-carboxylate (29a)
A mixture of 1 g of ethyl 2,6-dichloro-5-fluoronicotinoylacetate
(27), 3 ml of ethyl orthoformate, and 6 ml of acetic anhydride was
heated at 120.degree. C. for 1 hour while stirring. The reaction
mixture was evaporated to dryness under reduced pressure, and the
residue was dissolved in 10 ml of dichloromethane.
Ten milliliters of trifluoroacetic acid was cooled with ice, and
750 mg of (+)-cis-1-(t-butoxycarbonylamino)-2-fluorocyclopropane
(4a) was dissolved therein. The solution was stirred at room
temperature for 20 minutes, followed by evaporation to dryness
under reduced pressure. The residue was suspended in 20 ml of
dichloromethane, and 2.0 g of triethylamine was added thereto under
ice-cooling. To the suspension was further added the above-prepared
dichloromethane solution, followed by stirring at room temperature
for 30 minutes.
The reaction mixture was washed with water and dried over anhydrous
sodium sulfate. The solvent was removed under reduced pressure. The
residue was subjected to column chromatography using 50 g of silica
gel using chloroform as an eluent to yield 1.29 g of ethyl
2-(2,6-dichloro-5-fluoronicotinoyl)-3-(1,2-cis-2-fluoro-1-cyclopropyl)acr-
ylate (28a) as a colorless oil.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.06 (3H, t, J=7 Hz), 1.1-1.6
(2H, m), 2.86-3.18 (1H, m), 4.05 (2H, q, J=7 Hz), 4,78 (1H, dm,
J=63 Hz), 7.36 (1H, d, J=7 Hz), 8.31 (1H, d, J=14 Hz)
In 25 ml of anhydrous dioxane was dissolved 1.29 g of Compound
(28a), and 300 mg of 60% sodium hydride was added to the solution,
followed by stirring for 1 hour. The reaction mixture was
concentrated under reduced pressure, and to the residue was added
0.1N hydrochloric acid. The precipitated crystals were collected by
filtration and washed successively with water and diethyl ether to
obtain 860 mg of the titled compound (29a) as a colorless
crystal.
Melting Point: 184.degree.-185.degree. C.
[.alpha.].sub.D: -1.26.degree. (c=0.793, chloroform)
Elementary Analysis for .[.C.sub.14H.sub.11F.sub.2N.sub.2O.sub.3.].
.Iadd.C.sub.14H.sub.11F.sub.2N.sub.2O.sub.3Cl .Iaddend.Calcd. (%):
C 51.16; H 3.37; N 8.52 Found (%): C 51.12; H 3.26; N 8.52
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.41 (3H, t, J=7 Hz),
1.4-1.84 (2H, m), 3.50 (1H, m), 4.40 (2H, q, J=7 Hz), 5.02 (1H, dm,
J=65 Hz), 8.43 (1H, d, J=7 Hz), 8.66 (1H, s)
Reference Example 28
(+)-Ethyl
7-chloro-6-fluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-4-oxo-1,4-d-
ihydro-1,8-naphthyridine-3-carboxylate (29b):
A mixture of 1.0 g of ethyl 2,6-dichloro-5-fluoronicotinoylacetate
(27), 3 ml of ethyl orthoformate, and 6 ml of acetic anhydride was
heated at 120.degree. C. for 1.5 hours while stirring. The reaction
mixture was evaporated to dryness under reduced pressure, and the
residue was dissolved in 10 ml of dichloromethane.
The milliliters of trifluoroacetic acid was cooled with ice, and
750 mg of (-)-cis-1-(t-butoxycarbonylamino)-2-fluorocyclopropane
(4b) was dissolved therein. The solution was stirred at room
temperature for 20 minutes, followed by evaporation to dryness
under reduced pressure. The residue was suspended in 30 ml of
dichloromethane, and 2.0 g of triethylamine was added thereto under
ice-cooling. To the suspension was further added the above-prepared
dichloromethane solution, and the mixture was stirred at room
temperature for 30 minutes.
The reaction mixture was washed with water and dried over anhydrous
sodium sulfate. The solvent was evaporated, and the residue was
purified by column chromatography using 50 g of silica gel and
chloroform as an eluent to obtain 1.29 g of ethyl
2-(2,6-dichloro-5-fluoronicotinoyl)-3-(1,2-cis-2-fluoro-1-cyclopropyl)acr-
ylate (28b) as a colorless oil.
Compound (28b) (1.29 g) was reacted in the same manner as for
Compound (28a) to obtain 936 mg of the titled compound (29b) as a
colorless crystal.
Melting Point: 183.degree.-185.degree. C.
[.alpha.].sub.D: +1.12.degree. (c=1.07, chloroform)
Elementary Analysis for .[.C.sub.14H.sub.11F.sub.2N.sub.2O.sub.3.].
.Iadd.C.sub.14H.sub.11F.sub.2N.sub.2O.sub.3Cl .Iaddend.Calcd. (%):
C 51.16; H 3.37; N 8.52 Found (%): C 51.39; H 3.24; N 8.49
Reference Example 29
(-)-7-chloro-6-fluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-4-oxo-1,4-dihydro-
-1,8-naphthyridine-3-carboxylic acid (30a):
A mixture of 800 mg of Compound (29a) and 15 ml of concentrated
hydrochloric acid was heated at 100.degree. C. for 1.5 hours while
stirring. Water was added to the reaction mixture, and the
precipitated crystals were collected by filtration to yield 610 mg
of the titled compound (30a) as a colorless crystal.
Melting Point: 215.degree.-219.degree. C.
[.alpha.].sub.D: -20.65.degree. (c=0.910, chloroform)
Reference Example 30
(+)-7-chloro-6-fluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-4-oxo-1,4-dihydro-
-1,8-naphthyridine-3-carboxylic acid (30b):
A mixture of 870 mg of Compound (29b) and 20 ml of concentrated
hydrochloric acid was heated at 100.degree. C. for 2 hours while
stirring. Water was added to the reaction mixture, and the
precipitated crystals were collected by filtration to yield 715 mg
of the titled compound (30b) as a colorless crystal.
Melting Point: 218.degree.-220.degree. C.
[.alpha.].sub.D: +22.34.degree. (c=0.555, chloroform)
EXAMPLE 14
7-[4-(S)-Amino-2-(S)-methyl-1-pyrrolidinyl]-6-fluoro-1-(1,2-cis-2-fluoro-1-
-cyclopropyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(31a):
In 15 ml of trifluoroacetic acid was dissolved 300 mg of
4-(S)-amino-1-t-butoxycarbonyl-2-(S)-methylpyrrolidine .[.(32).].
(cf. Terry Ronson, et al., J. Med. Chem., Vol. 31, p.1598 (1988)),
and the solution was stirred at room temperature for 20 minutes,
followed by evaporation to dryness under reduced pressure. The
residue was dissolved in 20 ml of acetonitrile, and 150 mg of
Compound (30a) and 2 ml of triethylamine were added to the
solution, followed by refluxing for 30 minutes. The reaction
mixture was evaporated to dryness under reduced pressure, and
hydrochloric acid was added to the residue. The mixture was washed
with chloroform. The aqueous layer was adjusted to a pH of 13 with
sodium hydroxide and washed with chloroform. The aqueous layer was
adjusted to a pH of 7.5 and extracted with chloroform. The organic
layer was dried over anhydrous sodium sulfate, and the solvent was
removed under reduced pressure. Recrystallization of the residue
from aqueous ammonia-ethanol yielded 150 mg of the titled compound
(31a) as a colorless crystal.
Melting Point: 255.degree.-258.degree. C.
[.alpha.].sub.D: -14.52.degree. (c=0.413, 0.1N NaOH)
Elementary Analysis for
C.sub.17H.sub.18F.sub.2N.sub.4O.sub.3.1/4H.sub.2O: Calcd. (%): C
55.36; H 5.06; N 15.19 Found (%): C 55.09; H 5.40; N 15.04
EXAMPLE 15
(-)-7-[3-(R)-[1-(S)-Aminoethyl]-1-pyrrolidinyl]-8-chloro-6-fluoro-1-(1,2-c-
is-2-fluorocyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid (34b):
A mixture of 159 mg of
(-)-8-chloro-6,7-difluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-4-oxo-1,4-di-
hydroquinoline-3-carboxylic acid (12b), 160 mg of
3-(R)-[1-(S)-t-butoxycarbonylaminoethyl]pyrrolidine .Iadd.(32)
.Iaddend.(cf. JP-A-61-311992), 400 mg of triethylamine, and 20 ml
of acetonitrile was heated under reflux for 12 hours. The reaction
mixture was concentrated under reduced pressure, and the residue
was dissolved in chloroform. The organic solution was washed
successively with a 10% citric acid aqueous solution and water, and
dried over anhydrous sodium sulfate. The solvent was evaporated,
and the residue was recrystallized from ethyl acetate-isopropyl
ether to yield 220 mg of
(-)-7-[3-(R)-[1-(S)-t-butoxycarbonylaminoethyl]-1-pyrrolidinyl]-8-chloro--
6-fluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-4-oxo-1,4-dihydroquinoline-3-c-
arboxylic acid (33b).
Melting Point: 189.degree.-193.degree. C.
[.alpha.].sub.D: .[.205.degree..]. .Iadd.-205.degree.
.Iaddend.(c=0.985, chloroform)
Elementary Analysis for C.sub.24H.sub.28ClF.sub.2N.sub.3O.sub.5
Calcd. (%): C 56.31; H 5.51; N 8.21 Found (%): C 56.16; H 5.48; N
8.21
In 10 ml of trifluoroacetic acid was dissolved 200 mg of Compound
(33b), and the solution was stirred for 30 minutes. The reaction
mixture was evaporated to dryness under reduced pressure, and the
residue was dissolved in a 1N sodium hydroxide aqueous solution and
washed with chloroform. The aqueous layer was adjusted to a pH of
7.4 with hydrochloric acid and extracted with chloroform. The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was evaporated. The residue was recrystallized from aqueous
ammonia-ethanol to obtain 140 mg of the titled compound (34b) as a
colorless crystal.
Melting Point: 204.degree.-207.degree. C.
[.alpha.].sub.D: .[.160.0.degree..]. .Iadd.-160.0.degree.
.Iaddend.(c=0.605, 0.1N NaOH)
Elementary Analysis for
C.sub.19H.sub.20ClF.sub.2N.sub.3O.sub.3.H.sub.2O: Calcd. (%): C
53.09; H 5.38; N 9.77 Found (%): C 53.20; H 5.17; N 9.66
Reference Example 31
Ethyl
2-(3-acetoxy-2,4,5-trifluorobenzoyl)-3-(1,2-cis-2-fluoro-1-cycloprop-
yl)acrylate (36b):
A mixture of 1.0 g of ethyl 3-acetoxy-2,4,5-trifluorobenzoylacetate
(35) (cf. JP-A-87-175485), 6 ml of ethyl orthoformate, and 6 ml of
acetic anhydride was heated at 120.degree. C. for 3 hours under
stirring. The reaction mixture was evaporated to dryness under
reduced pressure, and the residue was dissolved in 10 ml of
dichloromethane.
In 5 ml of trifluoroacetic acid was dissolved 467 mg of
(-)-cis-1-t-butoxycarbonylamino-2-fluorocyclopropane (4b), and the
solution was stirred for 20 minutes, followed by evaporation to
dryness under reduced pressure. The residue was suspended in 20 ml
of dichloromethane, and 5 ml of a dichloromethane solution
containing 500 mg of triethylamine was added dropwise thereto under
ice-cooling, followed by stirring for 10 minutes. To the solution
was added the above-prepared dichloromethane solution, and the
mixture was stirred at room temperature for 16 hours. The reaction
mixture was washed successively with a 10% citric acid aqueous
solution and water. The organic layer was dried over anhydrous
sodium sulfate, followed by evaporation under reduced pressure to
obtain 1.25 g of the titled compound (36b).
Reference Example 32
(-)-Ethyl
6,7-difluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-8-methoxy-4-oxo--
1,4-dihydroquinoline-3-carboxylate (37b):
In 40 ml of dioxane was dissolved 1.25 g of Compound (36b), and 440
mg of potassium carbonate and 10 ml of water were added thereto,
followed by stirring at room temperature for 19 hours. The reaction
mixture was neutralized with hydrochloric acid, concentrated under
reduced pressure, and extracted with chloroform. The extract was
dried over anhydrous sodium sulfate, and the solvent was removed
under reduced pressure. The residue was dissolved in 40 ml of
anhydrous dioxane, and 300 mg of 60% sodium hydride and 1 ml of
.[.ethyl.]. .Iadd.methyl .Iaddend.iodide were added thereto,
followed by stirring at room temperature for 24 hours. The reaction
mixture was concentrated under reduced pressure, and the residue
was extracted with chloroform, washed with water, and dried over
anhydrous sodium sulfate. The solvent was evaporated. The residue
was recrystallized from isopropyl ether to obtain 235 mg of the
titled compound (37b) as a colorless crystal.
Melting Point: 163.degree.-64.degree. C.
[.alpha.].sub.D: .[.22.9.degree..]. .Iadd.-22.9.degree.
.Iaddend.(c=0.490, chloroform)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.40 (3H, t, J=7 Hz), 1.3-1.8
(2H, m), 3.7-4.0 (1H, m), 4.10 (3H, d, J=2 Hz), 4.38 (2H, q, J=7
Hz), 4.85 (1H, dm, J=63 Hz), 8.02 (1H, dd, J=9 Hz, & 8.5 Hz),
8.55 (1H, s)
Elementary Analysis for C.sub.16H.sub.14F.sub.3NO.sub.4 Calcd. (%):
C 56.31; H 4.13; N 4.10 Found (%): C 56.62; H 4.18; N 4.11
Reference Example 33-1
(.+-.)-cis-4-Amino-1-benzyl-3-methyl-2-oxypyrrolidine (45):
A mixture of 5.13 g of ethyl
1-benzyl-4-methyl-5-oxo-3-pyrrolidinecarboxylate (42, cf.
JP-A-62-4284), 40 ml of 50% ethanol, and 2 g of sodium hydroxide
was stirred at room temperature for 42 hours. To the reaction
mixture was added 100 ml of water, and the mixture was washed with
chloroform. The aqueous layer was neutralized with hydrochloric
acid and extracted with ethyl acetate. The extract was dried over
anhydrous sodium sulfate. The solvent was evaporated to obtain 3.40
g of (.+-.)-1-benzyl-4-methyl-5-oxo-3-pyrrolidinecarboxylic acid
(43) as a colorless crystal.
Compound (43) (3.40 g), 4.45 g of diphenylphosphorylazide, 1.9 of
triethylamine, and 50 ml of t-butyl alcohol were mixed and the
mixture was heated under reflux for 12 hours. The reaction mixture
was concentrated under reduced pressure, and the residue was
dissolved in chloroform. The solution was washed successively with
a 10% citric acid aqueous solution, a 2% sodium hydroxide aqueous
solution, and water and dried over anhydrous sodium sulfate. The
solvent was evaporated, and the residue was purified by silica gel
column chromatography using chloroform-methanol (97.5:2.5 by
volume) as an eluent to obtain 1.76 g of
(.+-.)-cis-1-benzyl-4-t-butoxycarbonylamino-3-methyl-2-oxopyrrolidine
(44) as a colorless oil.
In 15 ml of trifluoroacetic acid was dissolved 1.76 g of Compound
(44). After 1 hour, the solution was concentrated under reduced
pressure. To the residue was added 100 ml of water, and the mixture
was washed with benzene. The aqueous layer was adjusted to a pH of
12 with sodium hydroxide and extracted with chloroform. The organic
layer was dried over anhydrous sodium sulfate, and the solvent was
evaporated to obtain the titled compound (45) as a colorless
oil.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.25 (3H, d, J=7 Hz), 1.44
(2H, s), 2.16 (1H, dt, J=7 Hz), 2.83 (1H, dd, J=6.7 Hz & 8 Hz),
3.14 (1H, m), 3.38 (1H, dd, J=6.7 Hz & 8 Hz), 4.48 (2H, s),
7.28 (5H, s)
Reference Example 33-2
Optical Resolution of
cis-4-Amino-1-benzyl-3-methyl-2-oxopyrrolidine (45):
In 40 ml of dichloromethane were dissolved 4.17 g of Compound (45)
and 3.3 ml of pyridine, and a solution of 7.7 g of
(S)-N-p-toluenesulfonylpyrolyl chloride in 50 ml of dichloromethane
was added thereto dropwise, followed by stirring for 4 hours.
The reaction mixture was washed successively with 1N hydrochloric
acid, a saturated sodium hydrogen-carbonate aqueous solution, and
water, and dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure, and the residue was subjected to
silica gel column chromatography using ethyl acetate as an eluent
to isolate the isomers. Each of the isomers was recrystallized from
ethyl acetate to obtain 3.3 g and 3.6 g of
cis-1-benzyl-3-methyl-4-[(S)-N-p-toluenesulfonylprolylamino]-2-oxopyrroli-
dine (46a) and (46b), respectively.
Compound (46a):
Rf (silica gel TLC; ethyl acetate): 0.69
Melting Point: 162.degree. C.
[.alpha.].sub.D: 87.3.degree. (c=0.735, chloroform)
Compound (46b):
Rf (silica gel TLC; ethyl acetate): 0.61
Melting Point: 175.degree.-177.degree. C.
[.alpha.].sub.D: -148.6.degree. (c=0.665, chloroform)
Reference Example 33-3
(+)-cis-1-Benzyl-3-t-butoxycarbonylamino-4-methylpyrrolidine
(47a):
A mixture of 3.23 g of Compound (46a) and 50 ml of concentrated
hydrochloric acid .[.as.]. .Iadd.was .Iaddend.heated under reflux
for 5 hours, followed by concentration under reduced pressure. To
the residue was added a 1N sodium hydroxide aqueous solution, and
the solution was extracted with chloroform. The organic layer was
dried over anhydrous sodium sulfate, and the solvent was evaporated
to obtain 1.48 g of Compound (45a) as a colorless oil.
The product was dissolved in 10 ml of tetrahydrofuran, and the
solution was added dropwise to a suspension of 2.0 g of lithium
aluminum hydride in 50 ml of tetrahydrofuran. The mixture was
heated under reflux for 24 hours. To the reaction mixture was added
dropwise 10 ml of water under ice-cooling, and, after stirring for
30 minutes, any insoluble matter was removed by filtration. To the
filtrate was added 1.92 g of Boc-ON, followed by stirring for 24
hours. The reaction mixture was concentrated under reduced
pressure, and the residue was extracted with chloroform. The
extract was washed successively with a 5% sodium hydroxide aqueous
solution and water, and dried over anhydrous sodium sulfate. The
solvent was then evaporated.
The residue was purified by silica gel column chromatography using
chloroform-methanol (1:0 to 9:1 by volume) as an eluent to obtain
1.76 g of a crystal. To the product was added n-hexane, and the
mixture was stirred thereby precipitating a dl compound. The
crystals were collected by filtration, and the filtrate was
concentrated. This procedure was repeated twice. One hundred
milligrams of the dl compound was obtained from the filter cake and
1.61 g of the titled optically active compound (47a) from the
mother liquor.
Melting Point: 48.degree.-52.degree. C.
[.alpha.].sub.D: +27.2.degree. (c=2.33, chloroform)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.07 (3H, d, J=7 Hz), 1.43
(9H, s), 1.78-2.02 (2H, m), 2.62 (2H, d, J=5 Hz), 2.84-3.10 (1H,
m), 3.55 (2H, s), 3.5-3.8 (1H, m), 4.8-5.2 (1H, broad), 7.23 (5H,
s)
Reference Example 33-4
(-)-cis-1-Benzyl-3-t-butoxycarbonylamino-4-methylpyrrolidine
(47b):
In the same manner as for the synthesis of Compound (47a) but
starting with 3.52 g of Compound (46b), 1.72 g of the titled
compound (47b) was obtained.
Melting Point: 57.degree.-61.degree. C.
[.alpha.].sub.D: .[.31.21.degree..].
.Iadd.-31.21.degree..Iaddend.
Reference Example 33-5
cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (39a), (39b):
Compound (47a) (1.61 g), 1.5 g of 5% palladium-on-carbon, and 80 ml
of ethanol were mixed, and catalytic reduction was carried out for
5 hours while irradiating the mixture with an infrared lamp in a
hydrogen atmosphere at a pressure of 4 .[.atoms.].
.Iadd.atms.Iaddend.. After the reaction, the catalyst was removed
by filtration, and the filtrate was concentrated to obtain 1.09 g
of a crude product as a colorless oil. The product solidified as a
carbonate on standing, which was used without purification.
In the same manner as for the synthesis of Compound (39a), 1.1 g of
Compound (39b) was obtained as a colorless oil from 1.70 g of
Compound (47b).
Reference Example 34
Ethyl
2-(2,4,5-trifluoro-3-methylbenzoyl)-3-(1,2-cis-2-fluoro-1-cyclopropy-
l)acrylate (50b):
A mixture of 710 mg of ethyl
2,4,5-trifluoro-3-methyl-benzoylacetate (prepared from
2,4,5-trifluoro-3-.[.methylbenzxoic.]. .Iadd.methylbenzoic
.Iaddend.acid (48), cf. JP-A-62-215572), 6 ml of ethyl
orthoformate, and 6 ml of acetic anhydride was heated at
120.degree. C. for 2 hours while stirring. The reaction mixture was
evaporated to dryness under reduced pressure, and the residue was
dissolved in 10 ml of dichloromethane.
In 5 ml of trifluoroacetic acid was dissolved 580 mg of
(-)-cis-1-t-butoxycarbonylamino-2-fluorocyclopropane (4b), and the
solution was stirred for 30 minutes, followed by evaporation to
dryness under reduced pressure. The residue was suspended in 20 ml
of dichloromethane, and 700 mg of triethylamine was added thereto
under ice-cooling. After stirring for 10 minutes, the
above-prepared dichloromethane solution was added thereto, followed
by allowing to stand overnight. The reaction mixture was washed
with water and dried over anhydrous sodium sulfate. The solvent was
evaporated and the residue was crystallized from n-hexane to obtain
787 mg of the titled compound (50b) as a pale yellow crystal.
Reference Example 35
.[.(-)-Ethyl
6.7-difluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-8-methyl-4-oxo-1,4-dihydr-
oquinoline-3-carboxylate.]. .Iadd.(-)-Ethyl
6,7-difluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-8-methyl-4-oxo-1,4-dihydr-
oquinoline-3-carboxylate .Iaddend.(51b):
In 20 ml of anhydrous dioxane was dissolved 600 mg of Compound
(50b), and a suspension of 100 mg of 60% sodium hydride having been
washed with n-hexane in a small amount of anhydrous dioxane was
added to the solution. The mixture was stirred at room temperature
for 1 hour, and 10 ml of a 10% citric acid aqueous solution was
added thereto, followed by concentration under reduced pressure.
The precipitated crystals were collected by filtration, washed
successively with water, a small amount of ethanol, and diethyl
ether to obtain 480 mg of the titled compound (51b) as a colorless
crystal.
Melting Point: 230.degree.-231.degree. C.
[.alpha.].sub.D: -80.0.degree. (c=0.350, chloroform)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.40 (3H, t, J=7 Hz), 1.1-1.7
(2H, m), 2.71 (3H, d, J=3.3 Hz), 3.77-3.98 (1H, m), 4.38 (2H, q,
J=7 Hz), 4.85 (2H, dm, J=64 Hz), 8.12 (1H, dd, J=10 Hz), 8.54 (1H,
d, J=3 Hz)
Reference Example 36
(-)-6,7-Difluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-8-methyl-4-oxo-1,4-dih-
ydroquinoline-3-carboxylic acid (52b):
A mixture of 480 mg of the ester compound (51b) and 10 ml of
concentrated hydrochloric acid was heated at 120.degree. C. for 75
minutes while stirring. After cooling, the precipitated crystals
were collected by filtration and washed with water and ethanol to
obtain 380 mg of the titled compound (52b) as a colorless
crystal.
Melting Point: 204.degree. C.
[.alpha.].sub.D: -60.0.degree. (c=0.100, chloroform)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.3-1.9 (2H, m), 2.80 (3H, d,
J=5.8 Hz), 4.1-4.4 (1H, m), 4.15 (1H, dm, J=64 Hz), 8.17 (1H, dd,
J=16 Hz), 8.82 (1H, d, J=4 Hz), 14.2 (1H, s)
EXAMPLE 16
(-)-7-[3-(R)-(1-(S)-Aminoethyl)-1-pyrrolidinyl]-6-fluoro-1-(1,2-cis-2-fluo-
ro-1-cyclopropyl)-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid hydrochloride (54b):
A mixture of 198 mg of Compound (52b), 350 mg of
3-(R)-[1-(S)-t-butoxycarbonylaminoethyl]pyrrolidine, 5 ml of
dimethyl sulfoxide, and 1.5 g of triethylamine was heated at
110.degree. to 120.degree. C. for 5 hours while stirring. The
reaction mixture was evaporated to dryness under reduced pressure.
The residue was dissolved in chloroform and the solution was washed
with a 10% citric acid aqueous solution and then with water, and
dried over anhydrous sodium sulfate. The solvent was
evaporated.
The residue was subjected to preparative TLC which was developed
with a mixed solvent to chloroform-methanol (95:5 by volume) to
obtain 110 mg of
.[.7-[3-(R)-[1-(S)-t-butoxycarbonylaminoethyl]pyrrolidinyl]6-fluoro-8-met-
hyl-4-dihydroquinoline-3-carboxylic acid.].
.Iadd.7-[3-(R)-[1-(S)-t-butoxycarbonylaminoethyl]pyrrolidinyl-6-fluoro-8--
methyl-1,4-dihydroquinoline-3-carboxylic acid] .Iaddend.(53b) as a
pale yellow powder.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.24 (3H, d, J=7 Hz), 1.45
(9H, s), 1.2-1.9 (2H, m), 2.52 (3H, s), 1.9-2.7 (3H, m), 3.2-4.2
(6H, m), 4.73 (1H, d, J=8 Hz), 4.98 (1H, dm, J=65 Hz), 7.77 (1H, d,
J=13 Hz), 8.70 (1H, d, J=3.5 Hz)
To 110 mg of Compound (53b) was added 5 ml of concentrated
hydrochloric acid, and the mixture was stirred at room temperature
for 10 minutes, followed by evaporation to dryness under reduced
pressure. The residue was recrystallized from ethanol-diethyl ether
to obtain 62 mg of the titled compound (54b) as a yellow
crystal.
Melting Point: 149.degree.-153.degree. C.
[.alpha.].sub.D: .[.34.4.degree..]. .Iadd.-34.4.degree.
.Iaddend.(c=0.168, 1N HCl)
EXAMPLE 17
5-Amino-7-(7-amino-5-azaspiro[2,4]heptan-5-yl)-6,8-difluoro-1-(1,2-cis-2-f-
luoro-1-cyclopropyl) 4-oxo-1,4-dihydroquinoline-3-carboxylic acid
.[.(56b).]. .Iadd.(56bb).Iaddend.:
A mixture of 100 mg of
(-)-5-amino-6,7,8-trifluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-4-oxo-1,4--
dihydroquinoline-3-carboxylic acid (17b), 100 mg of
7-t-butoxycarbonylamino-5-azaspiro[2.4]heptane (24b), 300 mg of
triethylamine, and 20 ml of acetonitrile was heated under reflux
for 23 hours.
The reaction mixture was evaporated to dryness under reduced
pressure, and the residue was dissolved in 100 ml of chloroform.
The solution was washed successively with a 10% citric acid aqueous
solution and water. The organic layer was dried over anhydrous
sodium sulfate, and the solvent was evaporated. The residue was
recrystallized from acetonitrile to obtain 120 mg of
.[.5-amino-7-[7-t-butoxycarbonylamino-5-azaspiro[2.4]-heptan-5-yl]-6,8-di-
fluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-4-oxo-1,4-dihydroquinoline-3-car-
boxylic acid.].
.Iadd.5-amino-7-[7-t-butoxycarbonylamino-5-azaspiro[2.4]heptan-5-yl]-6,8--
difluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-4-oxo-1,4-dihydroquinoline-3-c-
arboxylic acid .Iaddend.(55bb) as a yellow needle-like crystal.
Melting Point: 250.degree.-253.degree. C.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 0.6-0.8 (2H, m), 0.8-1.0 (2H,
m), 1.45 (9H, s), 1.3-1.8 (2H, m), 3.2-3.4 (1H, m), 3.6-3.9 (3H,
m), 3.9-4.3 (2H, m), 4.85 (1H, dm, J=63 Hz), 4.7-5.0 (1H, broad),
8.51 (1H, s)
In 5 ml of trifluoroacetic acid was dissolved 120 mg of Compound
(55bb), and the solution was stirred for 30 minutes, followed by
evaporation to dryness under reduced pressure. The residue was
dissolved in hydrochloric acid and the solution was washed with
chloroform. The aqueous layer was adjusted to a pH of 7.4 and
extracted with chloroform. The extract was dried over anhydrous
sodium sulfate, and the solvent was evaporated under reduced
pressure. The residue was recrystallized from aqueous
ammonia-ethanol to obtain 65 mg of the titled compound (56bb) as a
yellow crystal.
Melting Point: 213.degree.-217.degree. C.
[.alpha.].sub.D: -96.7.degree. (c=0.120, DMF)
EXAMPLE 18
7-[4-(S)-Amino-2-(S)-methyl-1-pyrrolidinyl]-6-fluoro-1-(1,2-cis-2-fluoro-1-
-cyclopropyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(31b):
In 15 ml of trifluoroacetic-acid was dissolved 300 mg of
4-(S)-amino-1-t-butoxycarbonyl-2-(S)-methylpyrrolidine (32), and
the solution was stirred at room temperature for 20 minutes,
followed by evaporation to dryness under reduced pressure. The
residue was dissolved in 20 ml of anhydrous acetonitrile, and 150
mg of Compound (30b) and 2 ml of triethylamine were added to the
solution, followed by refluxing for 15 minutes. The reaction
mixture was evaporated to dryness under reduced pressure, and 1N
hydrochloric acid was added to the residue. The mixture was washed
with chloroform. The aqueous layer was made alkaline with 1N sodium
hydroxide aqueous solution and washed with chloroform. The aqueous
layer was adjusted to a pH of 7 and extracted with chloroform. The
organic layer was dried and the solvent was evaporated. The residue
was recrystallized from aqueous ammonia-ethanol to yield 130 mg of
the titled compound (31b).
Melting Point: 274.degree.-255.degree. C. (with decomposition)
[.alpha.].sub.D: +120.degree. (c=0.950, 1N NaOH)
Elementary Analysis for
C.sub.17H.sub.18F.sub.2N.sub.4O.sub.3.1/4H.sub.2O Calcd. (%): C
55.36; H 5.06; N 15.19 Found (%): C 55.50; H 5.25; N 14.97
EXAMPLE 19
.[.5-Amino-6,8-difluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-7-piperzinyl-4--
oxo-quinoline-3-carboxylic acid.].
.Iadd.5-Amino-6,8-difluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-7-piperazin-
yl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid .Iaddend.(57b)
A mixture of 75 mg of Compound (17b), 45 mg of anhydrous piperazine
in 5 ml of acetonitrile was heated under reflux for 2 hours. The
reaction mixture was evaporated under reduced pressure and the
residue was recrystallized from ethanol to yield 72 mg of the
titled compound (57b) as a yellow crystal.
Melting Point: 230.degree.-239.degree. C.
[.alpha.].sub.D: +8.00.degree. (c=0.225, 1N NaOH)
Reference Example 37
.[.8,7-Difluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-8-methoxy-4-oxo-1,4-dih-
ydroquinoline-3-carboxylic acid BF.sub.2-chelate.].
.Iadd.6,7-Difluoro-1-(1,2-cis-2-fluoro-1-cyclopropyl)-8-methoxy-4-oxo-1,4-
-dihydro quinoline-3-carboxylic acid BF.sub.2-chelate
.Iaddend.(38b):
A mixture of 230 mg of the ester compound (37b) and 5 ml of 42%
borofluoric acid was heated at 110.degree. C. with stirring for 2
hours. After cooling, precipitated crystal was collected by
filtration and washed with water to yield 210 mg of colorless
crystal of the titled compound.
Melting Point: 281.degree.-271.degree. C.
By the reaction of cis-3-t-butoxycarbonylamino-4-methylpyrrolidine
.[.(38a).]. .Iadd.(39a) .Iaddend.and the chelate compound (38b),
.[.7-(cis-3-amino-4-methylpyrrolidinyl)-8-fluoro-8-methoxy-4-oxo-1,4-dihy-
droquinoline-3-carboxylic acid.].
.Iadd.7-(cis-3-amino-4-methylpyrrolidinyl)-6-fluoro-1-(1,2-cis-2-fluoro-1-
-cyclopropyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid .Iaddend.(40ba) is obtained. And further, by the reaction of
the amine compound (24b) and the chelate compound (38b),
.[.7-(7-amino-5-azaspiro
[2.4]heptan-5-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxy-
lic acid.].
.Iadd.7-(7-amino-5-azaspiro[2.4]heptan-5-yl)-6-fluoro-1-(1,2-cis-2-fluoro-
-1-cycloproyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid .Iaddend.(41bb) is obtained. .Iadd.Compound (41bb) is more
precisely named as
7-[(7S)-7-amino-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)--
2-fluoro-1-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid..Iaddend.
One synthesis route for an optically active
8-amino-6-azaspiro[3.4]octane derivative as a homologue of compound
26bb C.sub.7-substituent is given below. ##STR00012##
##STR00013##
Reference Example 38-1
Ethyl hydrogen cyclobutane-1,1-dicarboxylate:
To an ice-cooled solution of 100 ml of diethyl
cyclobutane-1,1-dicarboxylate in 110 ml of methanol was added 290
ml of a 10% (w/w) sodium hydroxide aqueous solution over a period
of 60 minutes while stirring. The solution was then stirred at room
temperature for 18 hrs. The organic solvent methanol was then
removed under reduced pressure. The aqueous layer was washed with
chloroform and the aqueous layer was then acidified with conc.
hydrochloric acid to a pH of 2.5. The aqueous layer was extracted
with ethyl acetate, and the extract was washed with a sat. sodium
chloride aqueous solution. The extract was dried and the solvent
ethyl acetate was removed under reduced pressure. The residue was
purified by vacuum distillation to yield 85 g of the titled
compound as a colorless oil.
.sup.1H-NMR(CDCl.sub.3) .delta. ppm: 1.30 (3H, t, J=7.2 Hz),
1.9-2.2 (2H, m), 2.5-2.8 (4H, m), 4.25 (2H, q, J=7.2 Hz)
Reference Example 38-2
.[.Ethyl 1-[N-[1-(R)-phenylethyl]amido]-cyclobutane
1-carboxylate.]. .Iadd.Ethyl
1-[N-[1-(R)-phenylethyl]amido]-cyclobutane-1-carboxylate.Iaddend.:
To an ice-cooled solution of 55.5 g of ethyl hydrogen
cyclobutane-1,1-dicarboxylate and 40.2 g of triethylamine in 300 ml
of chloroform was added a solution of 38.6 g of ethyl chloroformate
in 100 ml of chloroform with stirring, and the mixture was then
stirred at room temperature for 20 min. The mixture was cooled on
an ice bath and there was then added thereto a solution of 40.2 g
of (R)-D-(+)-phenylethylamine in 100 ml of chloroform while
stirring, and the mixture was then stirred at room temperature for
30 min. The mixture was then washed with 10% (w/w) aqueous citric
acid and then washed with a sat. sodium chloride aqueous solution
and dried. The solvent was removed under reduced pressure to yield
88 g of the titled compound as a colorless oil.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm; 1.24 (3H, t, J=7.2 Hz), 1.48
(3H, d, J=7.2 Hz), 1.7-2.2 (2H, m), 2.3-2.8 (4H, m), 4.22 (2H, q,
J=7.2 Hz), 5.15 (1H, quint., J=7.2 Hz), 6.4-6.7 (1H, m), 7.36 (5H,
s)
Reference Example 38-3
1-[N-[1-(R)-phenylethyl]amido]-cyclobutane-1-carboxylic acid:
A mixture of 88 g of .[.ethyl
1-[N-{1-(R)-phenylethyl]amido]-cyclobutane-1-carboxylate.].
.Iadd.ethyl
1-[N-[1-(R)-phenylethyl]amido]-cyclobutane-1-carboxylate.Iaddend.,
90 ml of a 20% (w/w) sodium hydroxide aqueous solution and 200 ml
of ethanol was stirred at room temperature for 1 hr. Water was
added to the mixture water and the mixture was washed with
chloroform. The aqueous layer which was present was cooled on an
ice bath and was acidified with conc. hydrochloric acid. The
mixture was extracted with ethyl acetate and the extract was washed
with water and dried. The solvent was removed under reduced
pressure and the residual crystals were washed with n-hexane to
yield 73 g of the title compound.
mp: 103.degree.-106.degree. C.
[.alpha.].sub.D +55.5.degree. (c=0.804, CHCl.sub.3)
.sup.1H-NMR(CDCl.sub.3) .delta. ppm;1.50 (3H, d, J=7.2 Hz), 1.7-2.2
(2H, m), 2.4-2.8 (4H, m), 5.18 (1H, quint. J=7.2 Hz), 6.90 (1H,
br.d, J=7.2 Hz), 7.36 (5H, s), 9.80 (1H, br.s)
Anal. Calcd. for C.sub.14H.sub.17NO.sub.3: C, 68.00; H, 6.93; N,
5.66 Found: C, 67.94; H, 6.86; N, 5.52
Reference Example 38-4
N-[1-(R)-Phenylethyl]-1-acetyl-1-cyclobutane-carboxamide:
A mixture of 20 g of
1-[N-[1-(R)-phenylethyl]amido]cyclobutane-1-carboxylic acid, 100 ml
of thionyl chloride and 200 ml of anhydrous benzene was heated
under reflux for 3 hrs. The solvent was removed under reduced
pressure to yield the acid chloride as colorless crystals. To 600
ml of anhydrous tetrahydrofuran there was added 33.5 g of cuprous
iodide, and the mixture was cooled so that the temperature of the
reaction mixture in the reactor was -20.degree. C. under a nitrogen
atmosphere. To the cold mixture was added 100 ml of an ethereal
solution of methyl lithium (1.6M ethereal solution, commercially
available) over a period of 30 mins. The mixture was stirred at
-20.degree. C. for 20 mins. To the stirred mixture there was
dropwise added a solution of the acid chloride obtained above in
100 ml of anhydrous tetrahydrofuran keeping the temperature of the
system in the reactor at -20.degree. C., and the mixture was
stirred at -20.degree. C. for 2 hrs., whereafter the temperature of
the reaction system was raised to room temperature. The mixture was
then stirred at room temperature for 2 hrs. To the mixture was
added 30 ml of 1N hydrochloric acid and the solvent was removed
under reduced pressure. To the resulting residue, ethyl acetate was
added and insoluble material was removed by filtration. The
resulting organic layer was washed with a 5% (w/w) sodium
thiosulfate aqueous solution and then with water and dried. The
solvent was removed under reduced pressure and the resulting
crystalline residue was washed with isopropyl ether to yield 9.7 g
of the titled compound. The solvent of the filtrate was removed
under reduced pressure and the resulting residue was purified by
flash column chromatography using 100 g of silica gel eluted by a
mixture of n-hexane and ethyl acetate (2:1, v/v). As a result of
this purification, 2.8 g of the titled compound was obtained.
mp; 57.degree.-60.degree. C.
.sup.1H-NMR(CDCl.sub.3) .delta. ppm; 1.45 (3H, d, J=7.2 Hz),
1.7-2.2 (2H, m), 2.10 (3H, s), 2.3-2.7 (4H, m), 5.10 (1H, quint.,
J=7.2 Hz), 5.8-6.0 (1H, m), 7.30 (5H, s)
Anal. Calcd. for C.sub.15H.sub.19NO.sub.2: C, 73.44, H, 7.81; N,
5.71 Found: C, 73.12; H, 7.71; N, 5.66
Reference Example 38-5
N-[1-(R)-phenylethyl]-1-(1,1-ethylenedioxyethyl)-1-cyclobutanecarboxamide-
:
A mixture, of 13.9 g of
N-[1-(R)-phenylethyl]-1-acetyl-1-cyclobutanecarboxamide, 15 ml of
ethylene glycol, a catalytic amount of p-toluenesulfonic acid and
100 ml of benzene was heated under reflux for 3 hrs. The water
formed in the reaction was removed using a Dean-Stark apparatus.
After cooling, the mixture was washed with a saturated sodium
bicarbonate aqueous solution, then washed with water and then
dried. The solvent was removed under reduced pressure to yield 16.5
g of the titled compound as a colorless oil.
.sup.1H-NMR(CDCl.sub.3) .delta. ppm; 1.14 (3H, s), 1.48 (3H, d,
J=7.2 Hz), 1.7-2.1 (2H, m), 2.1-2.7 (4H, m), 4.10 (4H, s), 5.16
(1H, quint, J=7.2 Hz), 6.9-7.1 (1H, m), 7.40 (5H, s)
Reference Example 38-6
N-[1-(R)-phenylethyl]-1-(2-bromo-1,1-ethylenedioxoethyl)-1-cyclobutanecarb-
oxamide:
To 40 ml of anhydrous dioxane .[.that.]. was dropwise added 13 g of
bromine and the mixture was then stirred at room temperature for 20
min. To the solution was added a solution of 18.3 g of
N-[1-(R)-phenylethyl]-1-(1,1-ethylenedioxyethyl)-1-cyclobutanecarboxamide
in 50 ml of anhydrous dioxane and the mixture was stirred at room
temperature for 20 hr. Ethyl acetate was added to the mixture and
the mixture was washed with a 5% (w/w) sodium thiosulfate aqueous
solution and then with water and then dried. The solvent was
removed under reduced pressure to yield 23 g of the titled compound
as a yellow oil. This product was used in the following reaction
(Ref. Ex. 38-7) without further purification.
.sup.1H-NMR(CDCl.sub.3) .delta. ppm; 1.48 (3H, d, J=7.2 Hz),
1.6-2.1 (2H, m), 2.1-2.7 (4H, m), 3.34 (2H, AB-q, J=11 Hz), 4.0-4.6
(4H, m), 5.10 (1H, quint, J=7.2 Hz), 6.70 (1H, br.d, J=7.2 Hz),
7.36 (5H, s)
Reference Example 38-7
5,8-Dioxo-6-[1-(R)-phenylethyl]-6-azaspiro [3,4]octane-8-ethylene
acetal:
A solution of 32.4 g of the
.[.N-[1-(R)-phenylethyl]-1-(2-bromo-1,ethylenedioxyethyl)-1-cyclobutaneca-
rboxamide.].
.Iadd.N-[1-(R)-phenylethyl]-1-(2-bromo-1,1-ethylenedioxyethyl)-1-cyclobut-
anecarboxamide .Iaddend.reaction production obtained in Ref. Ex.
38-6 in 150 ml of anhydrous N,N-dimethylformamide was cooled on an
ice bath, and a suspension of 4.2 g of 60% sodium hydride (oil
dispersion, the oil was removed by washing with n-hexane prior to
use) in a small amount of anhydrous N,N-dimethylformamide was added
to the solution. The mixture was stirred for 1 hr. The reaction
mixture was diluted with ethyl acetate and the mixture was washed
with a 10% (w/w) citric acid aqueous solution and then with water
and then dried. The solvent was removed under reduced pressure and
the residue was purified through flask column chromatography using
500 g of silica gel eluted by a mixture of n-hexane and ethyl
acetate (2:1, v/v) to yield 23 g of the titled compound as a
yellowish oil.
.sup.1H-NMR(CDCl.sub.3) .delta. ppm; 1.48 (3H, d, J=7.2 Hz),
1.6-2.6 (6H, m), 2.80 (1H, d, J=10.5 Hz), 3.08 (1H, d, J=10.5 Hz),
3.96 (4H, m), 5.52 (1H, q, J=7.2 Hz), 7.30 (5H, s),
Reference Example 38-8
5,8-dioxo-5-[1-(R)-phenylethyl]-6-azaspiro [3.4]octane:
A mixture of 23 g of
5,8-dioxo-6-[1-(R)-phenylethyl]-6-azaspiro[3,4]octane-8-ethyleneacetal,
2 g of p-toluene-sulfonic acid, 200 ml of acetic acid and 100 ml of
water was heated under reflux for 7 hrs. The solvent was then
removed under reduced pressure. Ethyl acetate was added to the
residue and the mixture was washed with a 1N sodium hydroxide
aqueous solution and then with water and then dried. The solvent
was removed under reduced pressure and the resulting residual
crystal were washed with isopropyl ether to yield 15 g of the
titled compound. The titled compound also was obtained from the
filtrate.
mp; 68.degree.-69.degree. C.
[.alpha.].sub.D +171.2.degree. (c=0.819, CHCl.sub.3)
.sup.1H-NMR(CDCl.sub.3) .delta. ppm; 1.56 (3H, d, J=7.2 Hz),
1.8-2.8 (6H, m), 3.32 (1H, d, J=17.5 Hz), 3.68 (1H, d, J=17.5 Hz),
5.78 (1H, J=7.2 Hz), 7.32 (5H, s)
Anal. Calcd. for .[.C.sub.15H.sub.17NO2.].
.Iadd.C.sub.15H.sub.17NO.sub.2.Iaddend.: C, 74.05; H, 7.04; N, 5.76
Found: C, 74.21; H, 7.05; N, 5.62
Reference Example 38-9
6-[1-(R)-phenylethyl]-8-hydroxyimino-5-oxo-6-azaspiro
[3.4]octane
To a solution of 15 g of
5,8-dioxo-5-[1-(R)-phenylethyl]-6-azaspiro[3.4]octane, 12 g of
hydroxylamine hydrochloride in 100 ml of ethanol was added along
with 18 g of triethylamine. The mixture was stirred at room
temperature for 30 min. and then at 70.degree. C. for 1 hr. The
solvent was removed under reduced pressure and chloroform was added
to the residue. The resulting chloroform layer was washed with
water, a 10% (w/w) aqueous citric acid solution and with a
saturated sodium chloride aqueous solution. The solvent was removed
under reduced pressure and the resulting residual solid was washed
with isopropyl ether to yield 12 g of the titled compound as
colorless crystals.
mp; 203.degree.-208.degree. C.
.sup.1H-NMR(CDCl.sub.3) .delta. ppm; 1.56 (3H, d, J=7.2 Hz),
1.9-2.8 (6H, m), 3.68 (1H, d, J=17 Hz), 4.08 (1H, d, J=17 Hz), 5.64
(1H, q, J=7.2 Hz), 7.32 (5H, s),
Reference Example 38-10
8-amino-5-oxo-6-[1-(R)-phenylethyl]-6-azaspiro[3.4]octane:
To a solution of 8.75 g of
6-[1-(R)-phenylethyl]-8-hydroxyimino-5-oxo-6-azaspiro[3.4]octane in
300 ml of methanol there was added 26 ml of Raney nickel, and
reduction was carried out under a hydrogen atmosphere at room
temperature for 14.5 hr. The catalyst was removed by filtration and
the solvent was removed under reduced pressure. By the same
procedure, 1.65 g of
.[.6-[1-(R)-phenylethyl]-8-hydroxyimino-5-oxo-6-azaspiro-[3.4]octane.].
.Iadd.6-[1-(R)-phenylethyl]-8-hydroxyimino-5-oxo-6-azaspiro [3.4]
octane .Iaddend.was reduced using 5 ml of Raney nickel. The crude
products were combined and purified by column chromatography using
a column containing 380 g of silica gel. From a fraction of an
eluant of 1% (v/v) methanolic chloroform, 3.2 g of the less polar
isomer of the titled compound was obtained and 1.8 g of the more
polar isomer thereof along with 4.4 g of a mixture of the two
isomers.
.sup.1H-NMR(CDCl.sub.3) .delta. ppm; 1.48 (3H, d, J=7.2 Hz),
1.70-2.40 (6H, m), 2.50 (1H, dd, J=7.2, 12.6 Hz), 3.20-3.52 (2H,
m), 5.50 (1H, q, J=7.2 Hz), 7.32 (5H, s)
The .[.RF.]. .Iadd.Rf-.Iaddend.value of the less polar isomer is
larger than that of the more polar isomer (silica gel TLC plate;
developing solvent, methanol: chloroform=1:20 (v/v))
Reference Example 38-11
8-amino-6-[1-(R)-phenylethyl]-6-azaspiro [3.4]octane (from the less
polar amino compound.Iadd.).Iaddend.:
To an ice-cooled solution of 3.2 g of
8-amino-5-oxo-6-[1-(R)-phenylethyl]-6-azaspiro[3.4]octane (the less
polar compound obtained in Ref. Ex. 38-10) in 130 ml of anhydrous
tetrahydrofuran there was gradually added 1 g of lithium aluminum
hydride and then the mixture was heated under reflux for 2.5 hr.
After cooling, 1 ml of water, 1 ml of a 15% (w/w) aqueous sodium
hydroxide solution and 3 ml of water were added, in that order, to
the ice-cooled reaction mixture. A resulting insoluble material was
removed by filtration, and the solvent was removed under reduced
pressure to yield 2.9 g of the titled compound.
.sup.1H-NMR(CDCl.sub.3) .delta. ppm; 1.22-1.50 (1H, m) 1.35 (3H, d,
J=7.2 Hz), 1.50-2.00 (6H, m), 2.60-3.50 (3H, m), 2.67 (2H, br.s),
7.32 (5H, s)
Reference Example 38-12
8-tert-butoxycarbonyl-6-[1-(R)-phenylethyl]-6-azaspiro[3.4]octane:
To an ice-cooled solution of 2.9 g of
8-amino-6-[1-(R)-phenylethyl]-6-azaspiro[3.4]octane in 30 ml of
tetrahydrofuran there was added 3.3 g of
2-(tertbutoxycarbonylamino)-2-phenylacetonitrile and the resulting
mixture was stirred at room temperature for 30 min. The solvent was
removed under reduced pressure, and ethyl acetate was added to the
resulting residue. The mixture was washed with a 1N sodium
hydroxide aqueous solution three times and then dried. The solvent
was removed under reduced pressure and the resulting residue was
purified by column chromatography using 50 g of silica gel. The
column was eluted with chloroform, chloroform containing methanol
and 4.1 g of the titled compound was obtained from a eluate when
the eluant was chloroform containing 1% (v/v) of methanol.
.sup.1H-NMR(CDCl.sub.3) .delta. ppm; 1.32 (3H, d, J=7.2 Hz), 1.47
(9H, s), 1.60-2.20 (6H, m), 2.30-2.90 (4H, m), 3.60 (1H., q, J=7.2
Hz), 3.80-4.15 (1H, m), 4.90 (1H, bs), 7.28 (5H, s)
Reference Example 38-13
8-tert-butoxycarbonylamino-6-azaspiro[3.4]octane:
To a solution of 4.1 g of
8-tert-butoxycarbonylamino-6-[1-(R)-phenylethyl]-6-azaspiro[3.4]octane
in 60 ml of ethanol there was added 4.5 g of 5% palladium on
charcoal (50% wet) and reduction was carried out under a hydrogen
atmosphere (H.sub.2 pressure: 4 atm.) for 5 hrs. During the
reduction, the reaction vessel was warmed by irradiation with a
tungsten lamp. At 1 hr. from the beginning of the reduction, 2 g of
the same catalyst was further added and the reduction continued for
an additional 4 hours at the same condition to total 5 hours. The
catalyst was removed by filtration and the solvent was removed
under reduced pressure to yield 2.88 g of the titled compound.
.sup.1H-NMR(CDCl.sub.3) .delta. ppm; 1.47 (9H, s), 1.70-2.40 (6H,
m), 2.90-3.60 (4H, m), 4.20 (1H, br.s)
"Palladium on charcoal (50% wet) is a commercially available
catalyst containing water in an amount of 50 wt % based on the
total weight of the catalyst.
Reference Example 38-14
.[.8-tert-butoxycarbonylamino-6-azaspiro[3.4]-octane.].
.Iadd.8-tert-butoxycarbonylamino-6-azaspiro[3.4]octane
.Iaddend.(from the more polar amino compound):
To a mixture of 1.8 g of the more polar amine compound having a
lower Rf-value obtained in Ref. Ex. 38-10 in 80 ml of anhydrous
terahydrofuran there was added 1 g of lithium aluminum hydride. The
mixture was then heated under reflux for 13 hrs. After cooling on
ice there was added thereto 1 ml of water 0.1 ml of a 15% (w/w)
sodium hydroxide aqueous solution, 3 ml of water and the mixture
was stirred for 30 min. A resulting insoluble material was removed
by filtration. The filtrate was dried over anhydrous sodium sulfate
and the solvent was removed under reduced pressure to yield 1.6 g
of .[.8-amino-6-[1-(R)-phenylethyl]-6-azaspiro[3.4]-octane.].
.Iadd.8-amino-6-[1-(R)-phenylethyl]-6-azaspiro[3.4]octane
.Iaddend.as a colorless oil. A mixture of 1.6 g of the product thus
obtained, 20 ml of anhydrous tetrahydrofuran and 2 g of
2-(tert-butoxycarbonylamino)-2-phenylacetronitrile was stirred at
room temperature for 2 hrs. To the mixture there was added ethyl
acetate and the mixture was washed with a 1N sodium hydroxide
aqueous solution and then with water and then dried. The solvent
was removed under reduced pressure. The residue was purified by
flash column chromatography using 50 g of silica gel. From a
fraction eluted with chloroform and methanol (99:(v/v)) 1.9 g of
.[.8-tertbutoxycarbonylamino).]. .Iadd.8-(tertbutoxycarbonylamino)
.Iaddend.derivative was obtained. A mixture of 1.75 g of the
8-(tert-butoxycarbonylamino) derivative thus obtained and 2.5 g of
5% Pd/C (50% wet) in 40 ml of ethanol was shaken under a hydrogen
atmosphere (H.sub.2 pressure: 3 atm.) for 6 hrs. During the
reaction, the reaction vessel was warmed by irradiation with a
tungsten lamp. The catalyst was removed by filtration and then the
solvent was removed under reduced pressure from the filtrate to
yield 1.24 g of the
8-tert-butoxycarbonylamino-6-azaspiro[3.4]octane of higher
polarity.
EXAMPLE 20
(-)-7-(8-amino-6-azaspiro[3.4]octane-6-yl)-8-chloro-6-fluoro-1-(1,2-cis-2--
fluoro-1-cyclopropyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid
(58b):
To a solution of 412 mg of the carboxylic acid (12b) found in Ref.
Ex. 17 in 10 ml of anhydrous acetonitrile there were then added 409
mg of the 8-tertbutoxycarbonylamino-6-azaspiro[3.4]octane obtained
in Ref. Ex. 38-12 and 2 ml of triethylamine, and the mixture was
heated under reflux for 20 hr. The solvent was removed under
reduced pressure. To the residue was added 3 ml of conc.
hydrochloric acid and the mixture was stirred at room temperature
for 1 hr. The mixture was then washed with chloroform and the
resulting aqueous layer was made alkaline to pH 10 by adding
thereto a sodium hydroxide aqueous solution. The mixture was washed
with chloroform and the aqueous layer was adjusted to a pH of 7 by
adding conc. hydrochloric acid then dilute hydrochloric acid. The
aqueous laser was extracted with chloroform and the extract was
dried. The solvent was removed under reduced pressure. The residue
was purified by recrystallization from a mixture of aqueous ammonia
and ethanol to yield about 300 mg of the crude titled product.
About 200 mg of the crude product was purified by preparative TLC
using a developing solvent of a mixture of CHCl.sub.3:MeOH:H.sub.2
O=7:3:1 (v/v) and 130 mg of the titled compound was obtained after
recrystallization of the material obtained by preparative TLC
purification from a mixture of aqueous ammonia and ethanol.
mp; 135.degree.-141.degree. C.
[.alpha.].sub.D -152.43.degree. (c=0.925, 1N NaOH)
Reference Example 39-1
N-[1-(R)-Phenylethyl]-3-oxobutanamide
To a solution of 31 g of (R)-D-(+)-phenylethylamine in 84 ml of dry
dichloromethane was added dropwise a solution of 21 g of diketene
in 15 ml of dry dichloromethane on an ice bath. During the
addition, the highest temperature of the reaction mixture was
15.degree. C. The reaction mixture was stirred at room temperature
for 15 hr. The mixture was washed with a 10% (w/v) citric acid
aqueous solution and then with a saturated sodium bicarbonate
aqueous solution and then dried. Solvent was removed under reduced
pressure to yield 53.7 g of the titled compound.
.sup.1H-NMR(CDCl.sub.3) .delta. ppm; 1.48 (3H, d, J=5.4 Hz), 2.24
(3H, s), 3.40 (2H, s), 5.14 (1H, q, J=5.4 Hz), 7.35 (5H, s)
Reference Example 39-2
2,2-Dimethyl-N-[1-(R)-phenylethyl]-3-oxo-butanamide
To a solution of 48.5 g of N-[1-(R)-Phenylethyl]-3-oxobutanamide in
250 ml of dry N,N-dimethylformamide was added 84 g of methyl
iodide. To the resulting mixture was added 65.3 g of potassium
carbonate under ice cooling, and then the mixture was stirred at
room temperature for one week. Insoluble material was removed by
filtration and the filtrate was concentrated to dryness. Water was
added to the residue and the resulting mixture was extracted with
ethyl acetate. The extract was washed with water and dried. Solvent
was removed under reduced pressure to yield 50 g of crude
crystalline titled product. The crude product was washed with
isopropyl ether to yield 33 g of the titled product.
.sup.1H NMR(CDCl.sub.3) .delta. ppm; 1.40 (3H, s), 1.42 (3H, s),
1.50 (3H, d), 2.17 (3H, s), 5.08 (1H, q, J=5.4 Hz), 7.32 (5H,
s)
Reference Example 39-3
2-Methyl-2-[1-methyl-1-[N-(R)-1-phenylethyl]carbmoyl]ethyl]-1,3-dixolane
To a solution of 11.65 g of
2,2-Dimethyl-N-[1-(R)-phenylethyl]-3-oxo-butanamide in 220 ml of
benzene were added 18 g of ethylene glycol and 1 g of
p-toluenesulfonic acid. The mixture was heated under reflux for 3
days. During the reaction, water formed was removed using
Dean-Stark apparatus. After cooling, the reaction mixture was
poured into a saturated sodium bicarbonate aqueous solution and the
organic layer which resulted was separated. This organic layer was
dried, and solvent was removed under reduced pressure to yield 15.2
g of the titled compound.
.sup.1H-NMR(CDCl.sub.3) .delta. ppm; 1.20 (3H, s), 1.22 (3H, s),
1.23 (3H, s), 1.50 (3H, d, j=5.4 Hz), 3.95 (4H, s), 5.12 (1H, q,
J=5.4 Hz), 7.12 (1H, brs), 7.32 (5H, s)
Reference Example 39-4
2-Bromomethyl-2-[1-methyl-1-[N-(R)-phenylethyl]carbamoyl]ethyl-1,3-dixolan-
e
To a solution of 37.68 g of
.[.2-methyl-2-[1-methyl-1[N-(R)-phenylethyl]carbamoyl]ethyl]-1,3-dixolane-
.].
.Iadd.2-methyl-2-[1-methyl-1-[N-(R)-phenylethyl]carbamoyl]ethyl]-1,3-d-
ixolane .Iaddend.in 400 ml of 1,4-dixoane there was dropwise added
22 g of bromine and the mixture was then stirred at room
temperature for about 4 hrs. Solvent was removed under reduced
pressure, and chloroform was added to the residue. The resulting
mixture was washed with a saturated sodium bicarbonate aqueous
solution, then with a 5% (w/w) sodium thiosulfate aqueous solution
and finally with water and then dried. Solvent was removed under
reduced pressure to yield 45.25 g of the titled compound.
.sup.1H-NMR(CDCl.sub.3) .delta. ppm; 1.24 (3H, d, J=3.6 Hz), 1.42
(3H, s), 1.54 (3H, s), 3.58 (2H, ABq, J=10.8 Hz), 3.90-4.50 (4H,
m), 5.05 (1H, q, J=3.6 Hz), 7.00 (1H, br.s), 7.30 (5H, s)
Reference Example 39-5
9,9-Dimethyl-8-oxo-7-[1-(R)-phenylethyl]-7-aza-1,4-diazaspiro[4.4]nonane
To a solution of 45.25 g of
2-bromomethyl-2-[1-methyl-1-[N-(R)-phenylethyl]carbamoyl]ethyl-1,3-dixola-
ne in 150 ml of dry N N-dimethylformamide there was added 6.5 g of
60% sodium hydride and the mixture was stirred at room temperature
for 18 hrs. The reaction mixture was then poured into ice water and
the mixture was extracted with benzene. The extract was washed with
water and then dried. Solvent was removed under reduce pressure.
The residue was purified by chromatography through 250 g of silica
gel in a column while eluting with a mixture of n-hexane and ethyl
acetate (3:1, v/v) to yield 18.23 g of the titled compound.
.sup.1H-NMR(CDCl.sub.3) .delta. ppm; 1.18 (3H, d, J=4.0 Hz), 1.50,
1.58 (each 3H, s), 3.04 (2H, ABq, J=10 Hz), 3.75-4.10 (4H, m), 5.60
(1H, q, J=4 Hz), 7.32 (5H, s)
Reference Example 39-6
3,3-Dimethyl-1-[1-(R)-phenylethyl]-pyrrolidin-2,4-dione
A mixture of 18.23 g of
9,9-dimethyl-8-oxo-7-[1-(R)-phenylethyl]-7-aza-1,4-dioxaspiro[4.4]nonane,
70 ml of 1N hydrochloric acid and 20 g of p-toluenesulfonic acid in
250 ml of acetone was heated under reflux for 20 hrs. During the
reaction, 20 g of p-toluenesulfonic acid was further added. Solvent
was removed under reduced pressure and the residue was extracted
with chloroform. The extract was washed with a saturated sodium
bicarbonate aqueous solution and dried. Solvent was removed under
reduced pressure, and the residue was purified by silica gel
chromatography (300 g of silica gel in a column) while eluting with
a mixture of n-hexane and ethyl acetate (4:1, v/v) to yield 11.85 g
of the titled compound.
.sup.1H-NM(CDCl.sub.3) .delta. ppm; 1.20, 1.26 (each 3H, s), 1.60
(2H, ABq, J=16 Hz), 5.80 (1H, q, J=7.2 Hz), 7.32 (5H, s)
Reference Example 39-7
.[.3-3-Dimethyl-4-hydroxyimino-1-[1-(R)-phenylethly]pyrrolidin-2-one.].
.Iadd.3,3-Dimethyl-4-hydroxyimino-1-[1-(R)-phenylethyl]pyrrolidin-2-one.I-
addend.
To a solution of 11.85 g of
3,3-dimethyl-1-[1-(R)-phenyethyl]-pyrrolidin-2,4-dione in 100 ml of
ethanol there were added 8 g of hydroxylamine hydrochloride and 45
ml of triethylamine. The mixture was heated under reflux with
stirring for 1 hr. Solvent was removed under reduced pressure, and
the residue was extracted with chloroform. The extract was washed
with a 10% (w/v) citric acid aqueous solution and then with water
and then dried. Solvent was removed under reduced pressure to give
11.5 g of the titled compound.
.sup.1H-NMR(CDCl.sub.3) .delta. ppm; 1.30, 1.34 (each 3H, s), 1.58
(3H, d, J=7.2 Hz), 3.90 (2H, Abq, J=16.2 Hz), 5.65 (1H, q, J=7.2
Hz), 7.36 (5H, s)
Reference Example 39-8
4-Amino-3,3-dimethyl-1-[1-phenylethyl]-pyrrolidin-2-one
To a solution of 8.75 g of
3,3-dimethyl-4-hydroxyimino-1-[1-(R)-phenylethyl]-pyrrolidin-2-one
in 300 ml of methanol there was added 20 ml of Raney-nickel, and
reduction was carried out under a hydrogen atmosphere at room
temperature for 16 hr (H.sub.2 pressure: 1 atm). The catalyst was
removed by filtration and the solvent of the filtrate was removed
under reduced pressure. The residue was purified through column
chromatography using a column filled with 300 g of silica gel. From
a fraction eluted with a mixture of methanol and chloroform (1:30,
v/v), 3.75 g of the less polar isomer of the titled compound was
obtained along with 10.2 g of a mixture of the less polar and more
polar titled compound.
.sup.1H-NMR(CDCl.sub.3) (of less polar isomer) .delta. ppm; 0.95,
1.18 (each 3H, s), 1.52 (3H, d, J=7.2 Hz), 2.40-2.55 (1H, m),
3.00-3.50 (2H, m), 5.52 (1H, q, J=7.2 Hz), 7.30 (5H, s)
Reference Example 39-9
4-Amino-3,3-dimethyl-1-[1-(R)-phenylethyl]-pyrrolidine (from the
less polar amino compound):
To an ice cooled solution of 3.7 g of
4-amino-3,3-dimethyl-1-[1-(R)-phenylethyl]-pyrrolidin-2-one in 150
ml of anhydrous tetrahydrofuran there was gradually added 2 g of
lithium aluminum hydride and then the mixture was heated under
reflux for 2.5 hr. After cooling on ice, 2 ml of water, 2 ml of a
15% (w/w) aqueous sodium hydroxide solution and 6 ml of water were
added to the ice cooled reaction mixture (in that order). Insoluble
material was removed by filtration, and the solvent of the filtrate
was removed under reduced pressure to yield 3.69 g of the titled
compound. This product was used in the following reaction without
further purification.
Reference Example 39-10
4-tert-Butoxycarbonylamino-3,3-dimethyl-1-[1-(R)-phenylethyl]-pyrrolidine
To an ice cooled solution of 3.69 g of
4-amino-3,3-dimethyl-1-[1-(R)-phenylethyl]-pyrrolidine in 40 ml of
anhydrous tetrahydrofuran there was added 4.92 g of
2-(tert-butoxycarbonylamino)-2-phenylacetonitrile and the mixture
was stirred at room temperature for 1 hr. Solvent was removed under
reduced pressure, and to the residue there was added ethyl acetate.
The mixture was washed with a 1N sodium hydroxide aqueous solution
three times and then dried. Solvent was then removed under reduced
pressure. The residue was purified through column chromatography
using 200 g of silica gel in a column with chloroform as the eluant
containing from 1% to 5% methanol to yield 4.32 g of the titled
compound.
.sup.1H-NMR(CDCl.sub.3) .delta. ppm; 1.00, 1.16 (each 3H, s), 1.40
(3H, d, J=7.2 Hz), 1.52 (9H, s), 2.00-3.62 (5H, m), 3.85-4.10 (1H,
m), 4.90 (1H, bs), 7.38 (5H, s)
Reference Example 39-11
tert-Butoxycarbonylamino-3,3-dimethyl-pyrrolidine
To a solution of 4.32 g of
.[.4-tert-butoxycarbonylamino-3,3-dimethyl-1-[1-(R)-phenylethyl]-pyrrolid-
ine.].
.Iadd.4-tert-butoxycarbonylamino-3,3-dimethyl-1-[1-(R)-phenylethyl]-
-pyrrolidine .Iaddend.in 90 ml of ethanol .[.thee.]. .Iadd.there
.Iaddend.was added 4 g of 10% palladium on charcoal and reduction
was carried out under a hydrogen atmosphere (H.sub.2 pressure: 4
atm) for 7 hrs. During the reduction, the reaction vessel was
warmed by irradiation with a tungsten lamp. The catalyst was
removed by filtration and the solvent of the filtrate was removed
under reduced pressure. To the resulting residue there was added
ethyl acetate and the mixture was washed with a 10% (w/v) citric
acid aqueous solution twice. The citric acid layer which resulted
was rendered alkaline by adding a sodium hydroxide aqueous
solution. The resulting mixture was then extracted with chloroform.
The resulting extract was dried and the solvent was removed under
reduced pressure to yield 2.5 g of the titled compound.
.sup.1H-NMR(CDCl.sub.3) .delta. ppm; 0.98, 1.08 (each 3H, s), 1.48
(9H, s), 2.30-4.00 (6H, m), 4.50 (1H, br.s)
EXAMPLE 21
(-)-7-(4-Amino-3,3-dimethyl-1-pyrrolidinyl)-8-chloro-6-fluoro-1-[2-(S)-flu-
oro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid
(59b):
To a solution of 476 mg of carboxylic acid (12b) in 15 ml of
anhydrous acetonitrile there were added 800 mg of the less polar
isomer of 4-tert-butoxycarbonylamino-3,3-dimethyl-pyrrolidine
obtained in REFERENCE EXAMPLE 39-11 and 2 ml of triethylamine, and
the mixture was heated under reflux for 6.5 hrs. Solvent was then
removed under reduced pressure. The residue was purified through
column chromatography using 150 g of silica gel using as eluents
chloroform containing 3,5 and 10% (v/v) of methanol and with
CHCl.sub.3:MeOH:H.sub.2O=7:3:1 (v/v) to yield
7-(4-tertbutoxycarbonylamino-3,3-dimethyl-1-pyrrolidinyl)-8-chloro-6-fluo-
ro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxy-
lic acid. This material was recrystallized from a mixture of
n-hexane and ethyl acetate to yield 550 mg of the crystalline
product. To this crystalline product there was added concentrated
hydrochloric acid and the mixture was stirred at room temperature
for 1 hr. The mixture was washed with chloroform and to the aqueous
layer which resulted was added a sodium hydroxide aqueous solution
until the pH became 7. The mixture was then extracted with
chloroform and the extract was dried. Solvent was then removed
under reduced pressure and the product in the residue was purified
by preparative TLC using a mixture of
CHCl.sub.3:MeOH:H.sub.2O=7:3:1 (v/v) as a developing solvent. As a
result, 170 mg of the titled compound was obtained after
recrystallization of the material obtained by preparative TLC
purification from a mixture of aqueous ammonia and ethanol.
mp; 118.degree.-121.degree. C.
[.alpha.].sub.D 13.08. (c=0.764, 1N NaOH)
Anal. Calcd. for C.sub.19H.sub.20N.sub.3O.sub.3F.sub.2Cl: c, 55.41;
H, 4.89; N, 10.20 Found: C, 55.22; H, 4.93; N, 9.69
Reference Example 40
1) Diethyl cyclobutylidenemalonate (compound 60)
A solution of 15.68 ml of titanium tetrachloride in 35.7 ml of
carbon tetrachloride was rapidly dropwise added to 285 ml of
tetrahydrofuran which was cooled to -30.degree. C. while stirring
the system. 5 g of cyclobutanone and 10.83 g of diethyl malonate
were then added to the mixture. A solution of 23.1 ml of pyridine
in 50 ml of tetrahydrofuran was then dropwise added thereto over 1
hour while the temperature of the reaction mixture was maintained
below -10.degree. C. The mixture was stirred for 18 hours keeping
the temperature of the mixture at about 0.degree. C. Water was
added to the mixture and the mixture was then extracted with
diethyl ether. The resulting ether layer was separated and the
remaining aqueous layer was extracted with diethyl ether. The
combined organic layers were washed with a saturated sodium
chloride aqueous solution, a saturated sodium bicarbonate aqueous
solution and a saturated sodium chloride aqueous solution in that
sequence. The resulting organic layer was dried over anhydrous
sodium sulfate. Solvent was then removed under reduced pressure to
yield 17.265 g of the titled compound 60 as a colorless oil.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.29 (6H, 6, J=7.3 Hz),
1.7-2.4 (2H, m), 3.15 (4H, t, J=7.7 Hz), 4.22 (4H, q, J=7.3 Hz)
By a similar procedure, diethyl cyclopentylidenemalonate (compound
61) (.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.29 (6H, t, J=7 Hz),
1.6-2.0 (4H, m), 2.6-2.8 (4H, m), 4.24 (4H, q, J=7 Hz)) and diethyl
cyclohexylidenemalonate (compound 62) (.sup.1H-NMR (CDCl.sub.3)
.delta. ppm: 1.28 (6H, t, J=7.2 Hz), 1.4-1.85 (6H, br), 2.3-2.6
(4H, br), 4.22 (4H, q, J=7.2 Hz)) were obtained.
2) Diethyl (1-nitromethyl-1-cyclobutyl) malonate (compound 63)
A mixture of 15.32 g of compound 60, 59 ml of nitromethane and 4.5
ml of tetramethylguanidine was stirred at room temperature for 16
hours. To the mixture was added a 10% citric acid aqueous solution
and the mixture was shaken. The organic layer was separated and
washed with a saturated sodium chloride aqueous solution and then
dried over anhydrous sodium sulfate. Solvent was removed under
reduced pressure to yield 19.03 g of titled compound 63 as a yellow
oil.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.29 (6H, t, J=7.1 Hz),
1.8-2.4 (6H, m), 3.80 (1H, s), 4.20 (4H, q, J=7.1 Hz), 4.82 (2H,
s)
Using a similar procedure, diethyl
(1-nitro-methyl-1-cyclopentyl)malonate (compound 64) (.sup.1H-NMR
(CDCl.sub.3) .delta. ppm: 1.27 (6H, t, J=7 Hz), 1.6-2.0 (8H, m),
3.79 (1H, s), 4.20 (4H, q, J=7 Hz), 4.71 (2H, s)) and diethyl
(1-nitromethyl-1-cyclohexyl)malonate (compound 65) (.sup.1H-NMR
(CDCl.sub.3) .delta. ppm: 1.27 (6H, t, J=7 Hz), 1.4-1.8 (10H, m),
3.88 (1H, s), 4.20 (4H, q, J=7 Hz), 4.96 (2H, s) were obtained.
Ethyl 7-oxo-6-azaspiro[3.4]octane-8-carboxylate (compound 66)
30 ml of Raney nickel which had been washed with water and ethanol
was added to a solution of 19.03 g of compound 63 in 400 ml of
ethanol. Catalytic reduction was then conducted for 2 days at room
temperature (H.sub.2 pressure: 1 atm). The catalyst was removed by
filtration and solvent was removed under reduced pressure. To the
residue were added ethyl acetate and 1N hydrochloric acid and the
mixture was shaken. The organic layer was dried over anhydrous
sodium sulfate and solvent was removed under reduced pressure. The
residue was purified by silica gel column chromatography (100 g of
silica gel) while eluting with chloroform containing 0-3% methanol
to yield 2.97 g of titled compound 66. The hydrochloric acid layer
which resulted was neutralized with sodium bicarbonate and the
mixture was extracted with ethyl acetate. The organic layer which
resulted was dried over anhydrous sodium sulfate and solvent was
removed under reduced pressure to yield 1.58 g of titled compound
66. Finally, 4.56 g total of titled compound 66 was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.28 (3H, t, J=7.1 Hz),
1.8-2.2 (6H, m), 3.21 (1H, s), 3.41 (1H, dd, J=9.7 & 1.4 Hz),
3.60 (1H, d, J=9.7 Hz), 4.20 (2H, q, J=7.1 Hz), 7.21 (1H, br)
By a similar procedure, ethyl
3-oxo-2-azaspiro[4.4]nonane-4-carboxylate (compound 67)
(.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.28 (3H, t, J=7.3 Hz),
2.6-2.8 (8H, br), 3.07 (1H, s), 3.01 (1H, dd, J=9.3 & 1.3 Hz),
3.45 (1H, d, J=9.3 Hz), 4.20 (2H, q, J=7.3 Hz), 7.30 (1H, br)) and
ethyl 3-oxo-2-azaspiro [4.5]decane-4-carboxylate (compound 68)
(.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.29 (3H, t, J=7.3 Hz),
1.3-1.7 (10H, br), 3.05 (1H, s), 3.17 (1H, dd, J=9.9 & 1.4 Hz),
4.20 (2H, q, J=7.3 Hz), 7.30 (1H, br)) were obtained.
4) .[.7-Oxo-6-azaspiro3.4octane-8-carboxylic acid.].
.Iadd.7-Oxo-6-azaspiro[3.4]octane-8-carboxylic acid
.Iaddend.(compound 69)
20 ml of water and 0.8 g of sodium hydroxide were added to a
solution of 1.97 g of compound 66 in 20 ml of ethanol. The
resulting was refluxed for 2 hours. Ethanol was removed under
reduced pressure and the aqueous layer which resulted was washed
with chloroform. The aqueous layer was neutralized with 1N
hydrochloric acid while ice cooling. The aqueous layer was then
extracted with 2-butanone, and the extract was dried over anhydrous
magnesium sulfate. Solvent was removed to yield 1.57 g of titled
compound 69 as colorless crystals.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.6-2.7 (6H, m), 3.15 (1H, s)
3.40 (1H, d, J=9.2 Hz), 3.60 (1H, d, J=9.2 Hz), 6.2 (1H, br)
By a similar procedure,
.[.3-oxo-2-azaspiro-[4.4]nonane-4-carboxylic acid.].
.Iadd.3-oxo-2-azaspiro[4.4]nonane-4-carboxylic acid
.Iaddend.(compound 70) (.sup.1H-NMR (CDCl.sub.3) .delta. ppm:
1.5-2.3 (8H, m), 3.15 (1H, d, J=9.5 Hz), 3.28 (1H, s), 3.33 (1H, d,
J=9.5 Hz), 6.45 (1H, br)) and
3-oxo-2-azaspiro[4.5]decane-4-carboxylic acid (compound 71)
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.2-2.0 (10H, m), 3.06 (1H,
s), 3.11 (1H, d, J=9.8 Hz), 3.48 (1H, d, J=9.8 Hz), 6.47 (1H, br))
were obtained.
5) 8-tert-Butoxycarbonylamino-7-oxo-6-azaspiro[3.4]octane (compound
72)
2.2 ml of diphenyl phosphorylazide and 1.55 ml of triethylamine
were added to a suspension of 1.57 g of compound 69 in 20 ml of
benzene with stirring. The resulting mixture was refluxed for 1.5
hours. Then, 4.4 ml of tert-butanol was added to the mixture and
the mixture was refluxed for 16 hours. The solvent was removed
under reduced pressure. The residue was extracted with ethyl
acetate and the extract was washed with a saturated sodium
bicarbonate aqueous solution, a saturated sodium chloride aqueous
.[.solution.]. .Iadd.solution, .Iaddend.a 10% (v/w) citric acid
aqueous solution and a saturated sodium chloride aqueous solution
in that order. The washings were extracted with ethyl acetate and
the combined extracts were dried over anhydrous sodium sulfate.
Solvent was then removed under reduced pressure. The residue was
purified by silica gel column chromatography (50 g of silica gel)
while eluting with chloroform containing 0-3% methanol to yield
0.56 g of titled compound 72.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.48 (9H, s), 1.5-2.5 (6H, m)
3.27 (1H, d, J=9.9 Hz), 3.44 (1H, d, J=9.9 Hz), 4.18 (1H, d, J=7.7
Hz), 5.20 (1H, d, J=7.7 Hz), 7.13 (1H, br s)
By a similar procedure,
4-tert-butoxy-carbonylamino-3-oxo-2-azaspiro[4.4]nonane (compound
73) (.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.45 (9H, s), 1.2-1.8
(8H, m), 3.13 (2H, s), 4.35 (1H, d, J=7.9 Hz), 5.15 (1H, d, J=7.9
Hz), 7.21 (1H, br s)) and
4-tert-butoxycarbonyl-amino-3-oxo-2-azaspiro[4.5]decane (compound
74) (.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.46 (9H, s), 1.0-1.8
(10H, m), 2.9-3.4 (2H, m), 4.15 (1H, d, J=8.6 Hz), 4.89 (1H, d,
J=8.6 Hz), 6.71 (1H, br s)) were obtained.
6)
6-tert-Butoxycarbonyl-8-tert-butoxycarbonylamino-6-azaspiro[3.4]octane
(compound 77)
15 ml of trifluoroacetic acid was added to 560 mg of ice cooled
compound 72 while stirring. The mixture was then stirred at room
temperature for 1.5 hours. The trifluoroacetic acid was then
removed under reduced pressure and the residue was dissolved in 30
ml of anhydrous tetrahydrofuran. The solution was cooled over ice
and 884 mg of lithium aluminum hydride was added to the mixture.
The mixture was then refluxed for 16 hours. The mixture was cooled
with ice and then water was added with stirring. Insoluble material
was removed by filtration and the collected material was washed
with tetrahydrofuran. The filtrate and washings of the collected
material were combined and there was added thereto 1.02 g of
di-tertbutyl dicarbonate. The resulting mixture was stirred at room
temperature for 16 hours. Solvent was then removed under reduced
pressure. The residue was purified by silica gel column
chromatography (50 g of silica gel) while eluting with a mixture of
ethyl acetate and n-hexans (1:10 v/v) to yield 273 mg of titled
compound 77.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.45 (18H, s), 1.7-2.1 (6H,
m). 3.0-3.6 (4H, m), 3.8-4.2 (1H, m), 5.1 (1H, br d)
By a similar procedure,
.[.2-tert-butoxy-carbonyl-4-tert-butoxycarbonylamino-2-azaspiro[4,4]-nona-
ne.].
.Iadd.2-tert-butoxycarbonyl-4-tert-butoxycarbonylamino-2-azaspiro[4.-
4]nonane .Iaddend.(compound 80) (3.27 (1H, d, J=9.9 Hz), 3.44 (1H,
d, J=9.9 Hz), (.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.45 (18H, s),
1.3-1.8 (8H, m), 3.0-3.3 (3H, m), 3.4-3.7 (1H, m), 3.7-4.1 (1H, m),
4.55 (1H, br d)) and
.[.2-tert-butoxy-carbonyl-4-tert-butoxycarbonylamino-2-azaspiro[4-
,5]-decane.].
.Iadd.2-tert-butoxycarbonyl-tert-butoxycarbonylamino-2-azaspiro[4.5]decan-
e .Iaddend.(compound 83) (.sup.1H-NMR (CDCl.sub.3) .delta. ppm:
1.0-1.9 (28H, m), 2.9-4.1 (5H, m), 4.51 (1H, br d)) were obtained.
##STR00014## ##STR00015## ##STR00016## ##STR00017## ##STR00018##
##STR00019## ##STR00020## ##STR00021## ##STR00022##
Another synthesis route of amino substituted azabicyclalkane.
##STR00023## ##STR00024##
TABLE-US-00002 TABLE 1 Antimicrobial activity (MIC, .mu.g/ml)
bacteria\ Compound 9a 9b 13a 13b 18a 18b 26bb 26aa E. coli., NIHJ
0.10 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.- 1 Pr.
vulgaris, <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1
<- 0.1 08601 Ser. 0.20 0.10 <0.1 <0.1 <0.1 <0.1
<0.1 0.10 marcescens, 10100 Ps. aeruginosa, 0.39 0.10 <0.1
<0.1 <0.1 <0.1 <0.1 0.39 32104 Ps. aeruginosa, 0.10
<0.1 <0.1 <0.1 <0.1 <0.1 <0.1 0.10 32121 S.
aureus, 0.10 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1
<0.1 209 P S. epidermidis, 0.39 0.39 <0.1 <0.1 <0.1
<0.1 <0.1 0.20 56500 Str. faecalis, 1.57 0.79 0.20 0.20 0.20
0.10 0.20 0.39 ATCC 19433 bacteria\ Compound 26ba 26ab 31b 34b 54b
56b 58b 59b E. coli., NIHJ <0.1 <0.1 <0.1 <0.1 <0.1
<0.1 <0.1 <- ;0.1 Pr. vulgaris, <0.1 <0.1 <0.1
<0.1 <0.1 <0.1 <0.1 <- 0.1 08601 Ser. <0.1
<0.1 0.10 <0.1 0.10 <0.1 <0.1 <0.1 marcescens, 10100
Ps. aeruginosa, 0.20 0.20 0.20 0.10 0.20 <0.1 0.10 0.20 32104
Ps. aeruginosa, 0.10 <0.1 0.10 <0.1 0.10 <0.1 <0.1
<0.1 32121 S. aureus, <0.1 <0.1 <0.1 <0.1 <0.1
<0.1 <0.1 <0.1- 209 P S. epidermidis, 0.20 0.10 0.20
<0.1 <0.1 <0.1 <0.1 <0.1 56500 Str. faecalis, 0.39
0.20 0.39 <0.1 0.10 0.10 <0.1 0.10 ATCC 19433
While the invention has been described in detail and with reference
to specific embodiments thereof, it will be apparent to one skilled
in the art that various changes and modifications can be made
therein without departing from the spirit and scope thereof.
* * * * *