U.S. patent application number 11/880645 was filed with the patent office on 2008-05-08 for antibacterial optically pure benzoquinolizine carboxylic acids, processes, compositions and methods of treatment.
This patent application is currently assigned to WOCKHARDT LIMITED. Invention is credited to Shivkumar Agarwal, Nishith Chandra Chaturvedi, Noel John De Souza, Sreenivas Kandepu, Habil Fakhruddin Khorakiwala, Mahesh Vithalbhai Patel, Nitin Shetty, Abraham Thomas, Dilip Jatashankar Upadhyay.
Application Number | 20080108646 11/880645 |
Document ID | / |
Family ID | 26324122 |
Filed Date | 2008-05-08 |
United States Patent
Application |
20080108646 |
Kind Code |
A1 |
Patel; Mahesh Vithalbhai ;
et al. |
May 8, 2008 |
Antibacterial optically pure benzoquinolizine carboxylic acids,
processes, compositions and methods of treatment
Abstract
The present invention relates to optically pure
S-(-)-benzoquinolizine carboxylic acids, their derivatives, salts,
pseudopolymorphs, polymorphs and hydrates thereof, substantially
free of their R-(+)-isomers, to processes for preparation of the
optically pure S-(-)-benzoquinolizine carboxylic acids, their
derivatives, salts, pseudopolymorphs, polymorphs and hydrates
thereof substantially free of their R-(+)-isomers, and to
pharmaceutical compositions comprising the S(-)-benzoquinolizine
carboxylic acids, their derivatives, salts, pseudopolymorphs,
polymorphs and hydrates thereof.
Inventors: |
Patel; Mahesh Vithalbhai;
(Aurangabad, IN) ; Agarwal; Shivkumar;
(Aurangabad, IN) ; Kandepu; Sreenivas; (Guntur,
IN) ; Shetty; Nitin; (Kalyan, IN) ; Upadhyay;
Dilip Jatashankar; (Kalyan, IN) ; Chaturvedi; Nishith
Chandra; (Aurangabad, IN) ; Thomas; Abraham;
(Aurangabad, IN) ; De Souza; Noel John; (Mumbai,
IN) ; Khorakiwala; Habil Fakhruddin; (Mumbai,
IN) |
Correspondence
Address: |
Ladas & Parry
26 West 61st Street
New York
NY
10023
US
|
Assignee: |
WOCKHARDT LIMITED
|
Family ID: |
26324122 |
Appl. No.: |
11/880645 |
Filed: |
July 23, 2007 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
09566875 |
May 8, 2000 |
7247642 |
|
|
11880645 |
Jul 23, 2007 |
|
|
|
60170676 |
Dec 14, 1999 |
|
|
|
Current U.S.
Class: |
514/294 ;
546/94 |
Current CPC
Class: |
C07C 279/14 20130101;
A61P 31/06 20180101; A61P 31/04 20180101; A61K 31/4745 20130101;
C07B 2200/07 20130101; Y02A 50/473 20180101; C07D 455/04
20130101 |
Class at
Publication: |
514/294 ;
546/094 |
International
Class: |
A61K 31/473 20060101
A61K031/473; C07D 455/04 20060101 C07D455/04; A61P 31/04 20060101
A61P031/04 |
Foreign Application Data
Date |
Code |
Application Number |
May 7, 1999 |
IN |
PCT/IN99/00016 |
Claims
1. A S-(-)-optically pure benzoquinolizine carboxylic acid, its
derivatives, its pharmaceutically acceptable salts, derivatives,
pseudopolymorphs, polymorphs or hydrates thereof of formula I,
##STR6## wherein X is OR.sub.1, wherein R.sub.1 is hydrogen, a
pharmaceutically acceptable cation, aluminum, ammonium or
substituted ammonium salts, choline, an organic amine, a
heterocyclic amine or, a basic amino acid; or R.sub.1 is
C.sub.1-C.sub.6 alkyl; or R.sub.1 is
--(CH.sub.2)n-CHR.sub.4--OOCR.sub.5, wherein R.sub.4=H, or
CH.sub.3; n=0-3 and R.sub.5=C.sub.2H.sub.5, or C(CH.sub.3).sub.3;
or R.sub.1 is ##STR7## wherein A=CH or N, and when A=CH, Z=NH or
NCH.sub.3, and when A=N, Z=CH, O, N, S, or NCH.sub.3; p=0-2; and
q=0-2; X is NHR.sub.2, wherein R.sub.2 is hydrogen or NHR.sub.2 is
the residue of one of the 20 naturally occurring amino acids or the
optically active isomers thereof, or the racemic mixtures thereof;
y denotes an integer from 0 to 3 and any fractional numbers therein
depending on the moles of acid added to the basic molecule; z
denotes moles of water; HA represents an acid of an acid addition
salt; R.sub.3 is hydrogen, C.sub.1-C.sub.6 alkyl, glycosyl,
aralkyl, C.sub.1-C.sub.6 alkanoyl, or aminoalkanoyl or R.sub.3 is
an ester of gluconic acid, a phosphoric acid derivative, or a
sulphuric acid derivative; substantially free of their
R-(+)-isomers.
2. The compound of claim 1 wherein the pharmaceutically acceptable
cation is selected from lithium, sodium, potassium, magnesium or
calcium.
3. The compound of formula I as defined in claim 1 wherein the
basic amino acid is an optically pure or mixture of racemic isomers
of arginine, lysine, histidine or tryptophan.
4. The compound of formula I as defined in claim 1 wherein z is O,
0.2, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, or 3.
5. A compound of formula I as defined in claim 1 selected from
S-(-)-9-fluoro-6,7,-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H-
,5H-benzo[i,j]quinolizine-2-carboxylic acid;
S-(-)-9-fluoro-6,7,-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H-
,5H-benzo[i,j]quinolizine-2-carboxylic acid 0.2H.sub.2O;
S-(-)-9-fluoro-6,7,-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H-
,5H-benzo[i,j]quinolizine-2-carboxylic acid 0.5H.sub.2O;
S-(-)-9-fluoro-6,7,-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H-
,5H-benzo[i,j]quinolizine-2-carboxylic acid 0.75 H.sub.2O;
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid sodium salt;
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid, sodium salt
monohydrate;
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid, potassium salt
monohydrate;
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid, arginine salt;
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid, arginine salt
0.25H.sub.2O;
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid, arginine
salt.0.75H.sub.2O;
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid, lysine salt
monohydrate;
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid, histidine salt
0.2H.sub.2O;
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid, hydroxyethyl
pyrrolidine salt;
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H-
,5H-benzo[i,j]quinolizine-2-carboxylic acid, diethanolamine salt;
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid, choline salt and its
hydrates; Carboxymethyl
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylate sodium salt; Acetoxymethyl
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylate; Propionoxymethyl
S-(-)-9-fluoro-6,7-dihydro-8(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylate; Pivaloyloxymethyl
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylate; Pivaloyloxyethyl
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylate; N-methylpiperidin-4-yl
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxy
piperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate;
Pyrrolidin-2-yl-ethyl S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxy
piperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate;
Piperidin-2-yl-ethyl
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylate; Morpholin-2-yl-ethyl
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxy
piperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate;
9-fluoro-8(4-hydroxypiperidin-1-yl)-(5S)-methyl-6,7-dihydro-1-oxo-1H,5H--
benzo[i,j]quinolizine-2-[2(S)-amino-1,5-pentanedioic
acid]carboxamide, disodium salt;
9-fluoro-8-{4-hydroxypiperidin-1-yl}-5(S)-methyl-6,7dihydro-1-oxo-1H,5H-b-
enzo[i,j]quinolizine-2-[2(S)-amino-3-imidazolylpropionic
acid]carboxamide hydrochloride;
S-(-)-9-fluoro-6,7-dihydro-8-(4-methoxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid;
S-(-)-9-fluoro-6,7-dihydro-8-(4-[(.beta.-D-tetraacetylglucopyranosyl)oxy]-
-piperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic
acid;
S-(-)-9-fluoro-6,7-dihydro-8-(4-[(.beta.-D-glucopyranosyl)oxy]-pip-
eridin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic
acid;
S-(-)-9-fluoro-6,7-dihydro-8-(4-acetoxypiperidin-1-yl)-5-methyl-1-oxo-1H-
,5H-benzo[i,j]quinolizine-2-carboxylic acid;
S-(-)-9-fluoro-6,7-dihydro-8-(4-pivaloyloxypiperidin-1-yl)-5-methyl-1-oxo-
-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;
S-(-)-9-fluoro-8-[4-(phosphonoxy)-1-piperidin-1-yl)-5-methyl-1-oxo-1H,5H--
benzo[i,j]quinolizine-2-carboxylic acid;
8-{4-[2(S)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-di-
hydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;
8-{4-[2(S)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-di-
hydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid,
hydrochloride;
8-{4-[2(R)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-di-
hydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;
8-{4-[2(R)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-di-
hydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, acetate;
8-{4-[2(RS)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-d-
ihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;
8-{4-[(2S)-amino-propionyl-2S)-aminopropionyloxy]piperidin-1-yl}-9-fluoro-
-5(S)-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic
acid hydrochloride;
8-{4[(2R)-Amino-propionoyl-(2R)-aminopropionyloxy]piperidin-1-yl}-9-fluor-
o-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic
acid;
8-{4[(2R)-Amino-propionoyl-(2R)-aminopropionyloxy]piperidin-1-yl}--
9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carbox-
ylic acid hydrochloride;
8-{4[(2R)-Amino-propionoyl-(2R)-aminopropionyloxy]piperidin-1-yl}-9-fluor-
o-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic
acid acetate;
8-{4[(2S)-Methylamino-propionyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-6-
,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;
8-{4-[(2S)-Methylamino-propionyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl--
6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and
hydrochloride;
8-{4[2(S)-amino-3-carboxypropionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methy-
l-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid
hydrochloride;
8-{4[2(S)-amino-3-phenylpropionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-
-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid
hydrochloride;
8-{4[2(R)-amino-3-phenylpropionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-
-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid
hydrochloride;
8-{4[2(R)-amino-3-phenylpropionyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-
-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid
acetate;
8-{4[(2S)-Amino-3-methylbutanoyloxy]piperidin-1-yl}-9-fluoro-5S)-methyl-6-
,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;
8-{4[(2S)-Amino-3-methylbutanoyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl--
6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and
hydrochloride;
8-{4-[2(S)-Amino-4-methylpentanoyloxy]piperidin-1-yl}-9-fluoro-5(S)-methy-
l-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;
8-{4-[2(S)-Amino-4-methylpentanoyloxy]piperidin-1-yl}-9-fluoro-5(S)-methy-
l-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid,
hydrochloride;
8-{4[(2R)-Amino-4-methylpentanoyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-
-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid:
8-{4[(2R)-Amino-4-methylpentanoyloxy]piperidin-1-yl}-9-fluoro-5S)-methyl--
6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and
hydrochloride;
8-{4-[2(S),6-Diaminohexanoyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7d-
ihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;
8-{4-[2(S),6-Diaminohexanoyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7--
dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid,
dihydrochloride;
8-{4[(2S)-Amino-5-nitroguanidino-butanoyloxy]piperidin-1-yl}-9-fluoro-(5S-
)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic
acid;
8-{4[(2S)-Amino-5-nitroguanidino-butanoyloxy]piperidin-1-yl}-9-fluoro-(5S-
)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic
acid and hydrochloride;
8-{4[(2S)-Amino-5-guanidino-butanoyloxy]piperidin-1-yl}-9-fluoro-5S)-meth-
yl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;
8-{4[(2S)-Amino-5-guanidino-butanoyloxy]piperidin-1-yl}-9-fluoro-(5S)-met-
hyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid
and hydrochloride;
8-{4[(2S)-Amino-5-nitroguanidino-butanoyl(2S)-amino-5-nitroguanidino-buta-
noyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[-
i,j]quinolizine-2-carboxylic acid;
8-(4[(2S)-Amino-5-nitroguanidino-butanoyl-(2S)-amino-5-nitroguanidino-but-
anoyloxy]piperidin-1-yl)-9-fluoro-5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[-
i,j]quinolizine-2-carboxylic acid and hydrochloride;
8-{4[(2S)-Amino-5-guanidino-butanoyl-(2S)-amino-5-guanidino-butanoyloxy]p-
iperidin-1-yl}-9-fluoro-5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinol-
izine-2 carboxylic acid or
8-{4[(2S)-Amino-5-guanidino-butanoyl-(2S)-amino-5-guanidino-butanoyloxy]p-
iperidin-1-yl}-9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quino-
lizine-2-carboxylic acid and hydrochloride.
6. A compound of claim 5 selected from
S-(-)-9-fluoro-6,7-dihydro-8(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid 0.2 hydrate;
S-(-)-9-fluoro-6,7-dihydro-8(-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid sodium salt monohydrate;
8-{4-[2(R)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-di-
hydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, acetate;
8-{4-[2(S)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-di-
hydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid,
hydrochloride;
S-(-)-9-fluoro-6,7-dihydro-8-[4-(hydroxy)-1-piperidin-1-yl)-5-methyl-1-ox-
o-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt;
S-(-)-9-fluoro-6,7-dihydro-8-[4-(hydroxy)-1-piperidin-1-yl)-5-methyl-1-ox-
o-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt
0.25H.sub.20; or
S-(-)-9-fluoro-6,7-dihydro-8-[4-(hydroxy)-1-piperidin-1-yl)-5-methyl-1-ox-
o-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt
0.75H.sub.20.
7.
S-(-)-9-fluoro-6,7-dihydro-8(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dih-
ydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic
acid.0.2H.sub.2O, wherein the moisture content varies from 0.9% to
1.1%
8. A process for the preparation of
S(-)-9-Fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid.0.2H.sub.2O which
comprises dissolving
S(-)-9-Fluoro-8-(4-hydroxypiperidin-1-yl)-S-methyl-6,7-dihydro-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid in a minimum volume of
organic solvent, at an elevated temperature, adding an amount of
water sufficient to bring about crystallisation after cooling in
high yields, filtering and drying the separated crystals at
temperatures up to 40-50.degree. C. for 3-6 hours, in vacuo up to
50 mm of Hg to a constant weight.
9. A process for the preparation of
S(-)-9-fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid 0.5 hydrate which
comprises dissolving
S-(-)-9-fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid in an minimum volume of
organic solvent at reflux temperature, adding an amount of water at
ambient temperature, sufficient to bring about crystallisation
after cooling in high yields, filtering and drying the separated
crystals at temperatures up to <40.degree. C. for 3-6 hours.
10. A process for the preparation of
S(-)-9-fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid 0.75 hydrate which
comprises suspending
S-(-)-9-fluoro-8(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid in water, for formulating
into a slurry by stirring with an organic solvent, at 5.degree. C.
for 1-2 hours, filtering and drying the product at temperatures
<40.degree. C. for 3-6 hours.
11. A method for treating bacterial infections, mycobacterial
infections or nosocomial pathogen infections in humans and animals,
which comprises administering to a human or an animal in need of
such antiinfective therapy an amount of a compound of the formula I
as defined in claim 1, or a pharmaceutically acceptable salt,
derivative, hydrate, pseudopolymorph or polymorph thereof,
substantially free of its R-(+)-enantiomer said amount being
sufficient to eradicate said infections. ##STR8##
12. The method of claim 11 wherein, the compound of formula I, or a
pharmaceutically acceptable derivative, salt, pseudopolymorph,
polymorph or hydrate thereof is administered by intravenous
infusion, transdermal delivery, orally or topically.
13. The method of claim 11 wherein the amount administered is from
about 200 mg to about 1500 mg per day.
14. The method of claim 11 wherein the amount of the compound of
formula I, or a pharmaceutically acceptable derivative,
pseudopolymorph, polymorph, salt or hydrate thereof is greater than
approximately 90% by weight of the total weight of
S-(-)-isomer.
15. The method of claim 11 wherein the amount of the compound of
formula I or a pharmaceutically acceptable derivative, polymorph,
pseudopolymorph, salt or hydrate thereof, substantially free of its
R-(+)-enantiomer, is administered together with a pharmaceutically
acceptable carrier.
16. An anti-infective composition for the treatment of a human or
animal in need of therapy for a systemic or topical antibacterial
infection, specially against resistant Gram-positive organism
infections, Gram-negative organism infections, mycobacterial
infections or nosocomial pathogen infections, which comprises a
pharmaceutically acceptable carrier and a therapeutically effective
amount of a compound of formula I as defined in claim 1 or a
pharmaceutically acceptable derivative, salt, pseudopolymorph,
polymorph or hydrate thereof, substantially free of its
R-(+)-enantiomer.
17. A composition according to claim 16 comprising: TABLE-US-00015
% w/v S-(-)-9-fluoro-8(4-hydroxypiperidin-1-yl)- Up to 10;
5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo [i,j]
quinolizine-2-carboxylic acid or an optically pure compound of the
invention of formula I. L-arginine 0.1-10; Sodium citrate 0-3.5;
Sodium hydroxide to adjust pH between 8.0-9.9 q.s; Disodium edetate
0-0.5; and Water for injection q.s. to 100.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to optically pure
S-(-)-benzoquinolizine carboxylic acids, their derivatives, salts,
pseudopolymorphs, polymorphs and hydrates thereof, substantially
free of their R-(+)-isomers, to processes for preparation of the
optically pure S-(-)-benzoquinolizine carboxylic acids, their
derivatives, salts, pseudopolymorphs, polymorphs and hydrates
thereof substantially free of their R-(+)-isomers, and to
pharmaceutical compositions comprising the S(-)-benzoquinolizine
carboxylic acids, their derivatives, salts, pseudopolymorphs,
polymorphs and hydrates thereof. These compounds and compositions
can be used to systemically and topically treat bacterial
Gram-positive, Gram-negative and anaerobic infections, specially
resistant Gram-positive organism infections, Gram-negative organism
infections, mycobacterial infections and emerging nosocomial
pathogen infections, while avoiding toxic effects associated with
the administration of the racemic mixture of
RS-(.+-.)-benzoquinolizine carboxylic acid. The compounds and
compositions of this invention can also be used to treat diseases
and disorders caused by Gram-positive, Gram-negative and anaerobic
bacteria, and diseases and disorders caused by resistant
Gram-positive organisms, Gram-negative organisms, mycobacteria and
nosocomial pathogens.
BACKGROUND OF THE INVENTION
[0002] Bacterial resistance to antibiotics is an increasingly
recurrent phenomenon. Of grave concern has been the development of
methicillin-resistant Staphylococcus aureus (MRSA) and
methicillin-resistant Streptococcus epidermidis (MRSE) strains,
which because of the phenomenon of cross-resistance, are now also
resistant to the larger class of .beta.-lactam antibiotics
including the cephalosporins and carbapenems. Of even graver
concern is the development of resistance in MRSA strains against
the class of antibacterial agents known as fluoroquinolones.
Several reports are known of MRSA strains displaying resistance to
fluoroquinolone agents such as ciprofloxacin, sparfloxacin and even
the more recently introduced trovafloxacin. In addition, for
trovafloxacin and for newer introductions like grepafloxacin,
moxifloxacin and gatifloxacin, a concern has been expressed about
their checkered safety records. The use of trovafloxacin has been
suspended or severely curtailed because of its association with
liver side effects. Grepafloxacin was withdrawn worldwide because
of severe cardiovascular side effects. The labelling on
gatifloxacin and moxifloxacin warns that they may prolong the QTc
interval on electrocardiograms in some patients.
[0003] The last line of defense against such
fluoroquinolone-resistant MRSA strains is the class of glycopeptide
antibiotics represented by vancomycin and teicoplanin. These
glycopeptide antibiotics are, however, laden with several
limitations. Vancomycin is encumbered with lack of oral
bioavailability, nephrotoxic potential, toxic effects such as
phlebitis and red-men syndrome. Moreover, the recent disturbing
wide spread emergence of Vancomycin resistant enterococci (VRE)
followed by the alarming reports of Vancomycin intermediate
resistance Staphylococcus aureus (VISA) strains from Japan and USA
have cast a shadow over the future of glycoside antibiotics in
clinical practice. In time, there is a relatively wide-spread
emergence of staphylococci, enterococci, pneumococci and
streptococci, which have become resistant to currently used first-
and second-line antibacterial agents such as penicillin, oxacillin,
vancomycin and erythromycin (SENTRY Programme: Antimicrobial Agents
& Chemotherapy 42 1762-1770, 1998).
[0004] Also, for primary skin infections such as impetigo and
folliculitis, and for secondary infections in humans such as
infected dermatitis, wounds and burns, as well as to eliminate
nasal carriage of MRSA in healthcare workers and patients, a
special antibiotic used topically is Mupirocin. Mupirocin has high
in vitro anti-staphylococcal and anti-streptococcal activity. There
has, however, been an increase of organisms, specially
staphylococci, developing resistance to Mupirocin. The emergence of
Mupirocin-resistant Methicillin-resistant Staphylococcus aureus
(MRSA) in infected patients in different countries like Canada,
Western Australia, UK, Spain and Switzerland is described in
different references in the medical and scientific literature viz.
J. Hosp. Infect. 39(1), 19-26 (1998); J. Hosp. Infect. 26(3),
157-165 (1994); Infect Control Hosp Epidemiol 17(2), 811-813
(1996); 38.sup.th Annual ICAAC Abstract C-75, 90 (1998); 38.sup.th
ICAAC Abstract 12-25, 507 (1998).
[0005] Furthermore, Gram-positive pathogens such as Staphylococci,
enterococci and Gram-negative pathogens E. coli, Klebsiella,
Proteus, Serratia, Citrobacter and Pseudomonas, frequently
encountered in urinary tract infections are susceptible to the
known fluoroquinolones, such as ciprofloxacin, levofloxacin,
ofloxacin and norfloxacin. The potency of these fluoroquinolones,
however, markedly deteriorates under the acidic conditions likely
to be encountered in urinary tract infections, rendering them
inadequate.
[0006] Furthermore, multidrug-resistant (MDR) mycobacterial strains
have emerged displaying resistance to first-line antimycobacterial
agents such as rifampicin, pyrazinamide and INH etc. thus severely
curtailing therapeutic options available for the management of
infections due to such strains. Usually, the antimycobacterial drug
regimen involves treatment spread over several months, and hence
the drug has to be tolerated well by the patients. Among the
fluoroquinolone antibiotics, sparfloxacin is reported to be highly
active against mycobacteria. It is not quite suitable, however, for
long-term therapy because of its potential to cause phototoxic side
effects in humans and laboratory animals such as mice and
guinea-pigs.
[0007] Furthermore, in the worldwide management of nosocomial
infections, besides the problematic strains of staphylococci and
enterococci, including MRSA, strains of Chryseobacteria have
recently emerged as new members of nosocomial pathogens causing
neonatal meningitis and pneumonia, as well as sepsis, in
immuno-compromised patients being treated in intensive care units.
Chryseobacteria are intrinsically resistant to .beta.-lactam
antibiotics including third-generation cephalosporins and
carbapenems. These factors reduce the treatment options available
to the clinicians.
[0008] The highly pressing need for other agents and methods of
treatment for infections arising from such emerging resistant
microorganisms, Gram-negative pathogens in acidic environments,
mycobacteria and nosocomial pathogens thus assumes great
significance.
[0009] Among other agents, one particular class of compounds the
benzoquinolizine carboxylic acids are of particular relevance.
Nadifloxacin is an example of a benzoquinolizine carboxylic acid.
Nadifloxacin is racemic
[(.+-.)-9-fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1-
H-5H-benzo[i,j]quinolizine-2-carboxylic acid and is disclosed in JP
Patent No. 58,90,511 and U.S. Pat. No. 4,399,134. Nadifloxacin has
an asymmetric carbon atom at the 5-position thereof.
RS-(.+-.)-Nadifloxacin comprises two optically active isomers. In
describing an optically active compound, the prefixes R and S or D
and L are used to denote the absolute configuration of the molecule
about its chiral centre(s). The prefixes (+) and (-) or d and l are
employed to designate the sign of rotation of plane-polarized light
by the compound, with (-) or l meaning that the compound is
levorotatory. A compound prefixed with (+) or d is dextrorotatory.
Compounds having a single chiral centre exist as a pair of
enantiomers, which are identical except that they are
non-superimposable mirror images of one another. A one-to-one
mixture of enantiomers is often referred to as a racemic mixture.
Racemic RS-(.+-.)-Nadifloxacin derives its biological activity
primarily from the S-(-)-enantiomer. The optically active
S-(-)-Nadifloxacin [.alpha.].sup.20.sub.D=-312.0 is obtained as
disclosed in Chem. Pharm. Bull 44 (1996), page nos. 642-5 and Jpn.
Kokai Tokyo Koho JP 63,192,753. The optically active
R-(+)-Nadifloxacin, [.alpha.].sup.20.sub.D=+312.0, is obtained as
disclosed in Jpn. Kokai Tokyo Koho JP 63,192,753. Pharmaceutical
compositions of RS-(.+-.)-Nadifloxacin are disclosed in U.S. Pat.
No. 4,399,134 and U.S. Pat. No. 4,552,879. Although these cited
patents disclose compositions of RS-(.+-.)-Nadifloxacin for oral,
parenteral and topical use, the only commercial product containing
RS-(.+-.)-Nadifloxacin as an active antibacterial compound is the
commercial product named Acuatim.RTM.. Acuatim.RTM. is available as
a cream and a lotion and incorporates racemic
RS-(.+-.)-Nadifloxacin as 1% of its composition for the topical
treatment of acne. Acuatim.RTM. has several drawbacks. It is
intended only for topical use and is registered only for the
treatment of acne caused by Propionibacterium species. One report
has appeared on the in-vitro activity of the fluoroquinolone,
Nadifloxacin, against methicillin resistant isolates of
Staphylococcus aureus from patients with skin infections (see
Nishijima et al., Drugs 49 (Suppl.) 230-232, 1995). There is no
report of RS-(.+-.)-Nadifloxacin being approved for systemic use
against any microbial infections, whether for sensitive or
resistant microbial strains.
[0010] S-(-)-Nadifloxacin is reported in Chem. Pharm, Bull 44
(1996) pages Nos. 421-423 to be approximately twice as active
in-vitro as racemic Nadifloxacin against Gram-positive and
Gram-negative bacteria. There is no previous report, however, of
the activity of S-(-)-Nadifloxacin in in-vivo systems against
Gram-positive bacteria, Gram-negative bacteria, anaerobes,
mycobacteria and emerging nosocomial pathogens.
[0011] RS-(.+-.)-Nadifloxacin is reported to exist in two
crystalline forms, one as an anhydrate and the other as a
hemihydrate (M. Kido and K. Hashimoto, Chem. Pharm. Bull, 42, 872
(1994)). There is no previous report, however, of any hydrate forms
of S-(-)-Nadifloxacin, although a non-hydrate form is reported (K.
Hashimioto et al., Chem. Pharm. Bull., 44, 642 (1996)).
[0012] There is no previous report of the utility of optically pure
benzoquinolizine carboxylic acids, their derivatives, salts,
pseudopolymorphs, polymorphs and hydrates thereof of the invention
in pharmaceutical compositions. There is also no previous report of
the systemic or topical use of optically pure benzoquinolizine
carboxylic acids, their derivatives, salts and hydrates thereof of
the invention, either alone or in compositions for treatment of
microbial infections diseases or disorders.
[0013] Our pending PCT patent application No. PCT/IN99/00016 filed
on May 7, 1999 describes optically pure and racemic
benzoquinolizine carboxylic acids, derivatives and salts thereof
for treatment of infections caused by Mupirocin-resistant bacterial
strains such as Mupirocin-resistant staphylococci,
Mupirocin-resistant streptococci and other Mupirocin-resistant
Gram-positive and Mupirocin-resistant Gram-negative bacteria, and
for treatment of dermal diseases such as impetigo, folliculitis,
infected dermatitis, wounds and burns. The subject matter of PCT
application PCT/IN99/00016 is incorporated herein by reference.
SUMMARY OF THE INVENTION
[0014] The present inventors obtained optically pure isomers of
Nadifloxacin and have conducted extensive studies to show that:
[0015] 1. S-(-)-Nadifloxacin is found to exist not only as an
anhydrate but also as three new different hydrates designated as
S-(-)-Nadifloxacin.nH.sub.2O, wherein n is equal to 0.2, 0.5 or
0.75. Among these forms of the anhydrate and the three hydrates,
S-Nadifloxacin.0.2H.sub.2O is now specifically found to be
preferred as a stable, non-hygroscopic crystalline modification
which is distinguished by an increased stability, neither losing
the water content therein nor absorbing moisture over a wide range
of ambient relative humidity conditions. In contrast, moisture
absorption by the anhydrate varies according to its method of
preparation and the relative humidity conditions to which it is
subjected. The other two hydrates, viz. the hemihydrate,
S-(-)-Nadifloxacin.0.5H.sub.2O and the hemisesquihydrate,
S-nadifloxacin.0.75H.sub.2O, both revert to
S-nadifloxacin.0.2H.sub.2O when dried in vacuo at ambient
temperature conditions. [0016] S-(-)-Nadifloxacin.0.2H.sub.2O has
considerable advantages over the anhydrate, the hemihydrate and the
hemisesquihydrate in storage and handling and in the preparation of
medicament forms. In particular, specially in tropical and
subtropical climates, where the ambient humidity is usually greater
than 70%, difficulty is encountered in the storage and handling of
the anhydrate. In the preparation of pharmaceutical preparations,
such as tablets, containing the anhydrate, the operations must be
carried out with attention to absorption or desorption of water of
crystallisation. More specifically, a room in which to handle the
anhydrate must be kept at low humidity and conversely, a room in
which to handle the hemihydrate and hemisesquihydrate must be kept
at low temperatures and high humidity. Unless these conditions are
provided, these compounds or preparations containing these
compounds would change in weight, and thus would not serve for
practical purposes and would lose their commercial value. By using
a stable non-hygroscopic, free-flowing active compound, as is
provided by S-(-)-Nadifloxacin 0.2H.sub.2O, a satisfactory dosing
consistency and accuracy is achieved during the preparation of
medicaments, which increases safety and therefore minimizes the
risk to the patient. [0017] 2. Crystalline salts of
S-(-)-Nadifloxacin, especially sodium, potassium, and arginine
salts, and hydrates thereof have been identified with increased
aqueous solubility over S-(-)-Nadifloxacin, and consequently with
superior properties for use in the preparation of parenteral
formulations, and with advantages of improved oral bioavailability
in solid oral dosage forms. [0018] 3. Derivatives of
S-(-)-Nadifloxacin are identified at the sites of the 2-COOH
function and the 4'-hydroxy moiety of the 9-4'-hydroxypiperidino)
group respectively, and salts and hydrates thereof. [0019] 4.
Processes are described to obtain the optically pure
benzoquinolizine carboxylic acids of the invention, the
derivatives, salts, pseudopolymorphs, polymorphs and hydrates
thereof mentioned under items 1-3 above and as described in detail
below. [0020] 5. RS-(.+-.)-Nadifloxacin, S-(-)-Nadifloxacin and
optically pure benzoquinolizine carboxylic acids, the derivatives,
salts, pseudopolymorphs, polymorphs and hydrates thereof have high
activity against Mupirocin-resistant microbial strains such as
Mupirocin-resistant staphylococci, Methicillin-resistant
staphylococcus aureus and Quinolone-resistant Staphylococcus
aureus, coagulase negative staphylococci, such as
Methicillin-resistant Staphylococcus epidermidis (MRSE),
enterococci, betahemolytic streptococci and viridans group of
streptococci. [0021] 6. RS-(.+-.)-Nadifloxacin, S-(-)-Nadifloxacin
and optically pure benzoquinolizine carboxylic acids, the
derivatives, salts, pseudopolymorphs, polymorphs and hydrates
thereof have activity against mycobacteria and newly emerging
nosocomial pathogens such as Chryseobacterium meningosepticum.
[0022] 7. S-(-)-Nadifloxacin and optically pure benzoquinolizine
carboxylic acids, the derivatives, salts, pseudopolymorphs,
polymorphs and hydrates thereof have 24 times higher antimicrobial
activity than racemic-Nadifloxacin against Mupirocin-resistant
staphylococci, Methicillin-resistant Staphylococcus aureus (MRSA),
Quinolone-resistant Staphylococcus aureus, coagulase negative
staphylococci, such as Methicillin-resistant Staphylococcus
epidermidis USE), enterococci, betahemolytic streptococci and
viridans group of streptococci, mycobacteria and newly emerging
nosocomial pathogens such as Chryseobacterium meningosepticum.
[0023] 8. S-(-)-Nadifloxacin and optically pure benzoquinolizine
carboxylic acids, the derivatives, salts, pseudopolymorphs,
polymorphs and hydrates thereof are not only bacteriostatic but
also bactericidal towards Mupirocin-resistant staphylococci,
Methicillin-resistant Staphylococcus aureus VERSA),
Quinolone-resistant Staphylococcus aureus, coagulase negative
staphylococci, such as Methicillin-resistant Staphylococcus
epidermidis (MRSE), enterococci at concentrations 24 times lower
than that of RS-(.+-.)-Nadifloxacin. [0024] 9. S-(-)-Nadifloxacin
and optically pure benzoquinolizine carboxylic acids, the
derivatives, salts, pseudopolymorphs, polymorphs and hydrates
thereof have 24 times higher antimicrobial activity against
Gram-positive pathogens such as staphylococci and enterococci and
Gram-negative pathogens such as E. coli, Klebsiella, Proteus,
Serratia and Citrobacter in the acidic environments encountered in
infection such as urinary tract infections. [0025] 10.
S-(-)-Nadifloxacin, its derivatives, salts, pseudopolymorphs,
polymorphs and hydrates thereof have high potency against efflux
pump-bearing Staphylococcus strains and are thus of unique value in
treating infections caused by antibiotic-resistant microorganisms
for which the resistance mechanism is due to the presence of efflux
pumps. [0026] 11. S-(-)-Nadifloxacin, its derivatives, salts,
pseudopolymorphs, polymorphs and hydrates thereof have high
propensity to display resistance to resistance development, which
has been shown in studies involving sequential transfers/passages
of a S. aureus strain through respective drug containing media.
[0027] 12. The acute intravenous toxicity of S-(-)-Nadifloxacin and
its arginine salt is significantly lower than
RS-(.+-.)-Nadifloxacin (Biological Example 3). [0028] 13.
S-(-)-Nadifloxacin, its derivatives, salts and hydrates thereof
have a favourable toxicity profile in comparison with other
fluoroquinolone drugs in clinical use in respect of cytotoxic
effect on various cell lines (Biological Example 4), phototoxicity
(vide infra) and cardiotoxicity. [0029] 14. The oral
bioavailability of S-(-)-Nadifloxacin is 2-times higher than that
of RS-(.+-.)-Nadifloxacin (Biological Example 5).
[0030] Through their extensive studies, the present inventors have
shown for the first time a novel expanded set of clinically desired
antimicrobial attributes of efficacy and safety of
S-(-)-Nadifloxacin, which have been not reported in the literature
since the first disclosure of S-(-)-Nadifloxacin in JP 63, 192, 753
about twelve years ago and of RS-(.+-.)-Nadifloxacin in JP
58,90,511 about twenty years ago. New hydrates, salts, derivatives,
pseudopolymorphs, polymorphs and compositions of S-(-)-Nadifloxacin
have also been identified by the present inventors, which have in
addition to their biological properties mentioned above, newer
physico-chemical properties, thus permitting their utility in a
clinical and commercial exploitation in newer compositions for
newer diseases and newer methods of systemic and topical treatment
that were hitherto not possible.
[0031] It is, thus, an object of the present invention to provide
S-(-)-optically pure benzoquinolizine carboxylic acids, their
derivatives, salts, pseudopolymorphs, polymorphs and hydrates
thereof, of the formula I, substantially free of their
R-(+)-isomers. ##STR1##
[0032] It is another object of the present invention to provide a
process or processes for preparing the novel optically pure
S-(-)-optically pure benzoquinolizine carboxylic acids, their
derivatives, salts, pseudopolymorphs, polymorphs and hydrates
thereof, of the formula I.
[0033] A further object is to provide pharmaceutical compositions
comprising optically pure S-(-)-benzoquinolizine carboxylic acids,
the derivatives, pseudopolymorphs, hydrates and salts thereof as
potent antibacterial agents for treating systemic and topical
bacterial infections, especially infections caused by resistant
Gram-positive, sensitive and resistant Gram-negative organisms,
mycobacterial infections and nosocomial pathogen infections while
avoiding the toxic effects associated with the administration of
their R-(+)-isomers.
[0034] Another object of this inventions relates to a method of
treatment of infections caused by Mupirocin-resistant bacterial
strains such as Mupirocin-resistant staphylococci,
Mupirocin-resistant streptococci and other Mupirocin-resistant
Gram-positive and Mupirocin-resistant Gram-negative bacteria, and
of dermal diseases and disorders such as impetigo, folliculitis,
infected dermatitis, wounds and burns. Treatment comprises oral,
parenteral, administration and/or topical application of an
effective amount of a composition of S-(-)-Nadifloxacin or
optically pure benzoquinolizine carboxylic acids, their
derivatives, salts, pseudopolymorphs, polymorphs and hydrates
thereof of formula I, or of a composition of RS-(+)-Nadifloxacin
and pharmaceutically acceptable salts thereof.
[0035] A further object of the invention includes methods for
treating the infections in humans and animals caused by
Gram-positive, Gram-negative and anaerobic bacteria, resistant
Gram-positive organism such as Methicillin-resistant Staphylococcus
aureus (MRSA), Quinolone-resistant Staphylococcus aureus, coagulase
negative staphylococci, such as Methicillin-resistant
Staphylococcus epidermidis (MRSE), enterococci, betahemolytic
streptococci and viridans group of streptococci, mycobacteria and
newly emerging nosocomial pathogens such as Chryseobacterium
meningosepticum, and Gram-negative pathogens such as E. coli,
Klebsiella, Proteus, Serratia Citrobacter and Pseudomonas, while
avoiding the toxic effects that are associated with the racemic
mixture of Nadifloxacin by administering systemically or topically
S-(-)-Nadifloxacin or optically pure S-(-)-benzoquinolizine
carboxylic acids, their derivatives, salts, pseudopolymorphs,
polymorphs and hydrates thereof to the affected human or
animal.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] For a thorough understanding of the nature and objects of
the invention, reference should be made to the following detailed
description taken in connection with the accompanying drawings in
which
[0037] 1. FIG. 1 represents the moisture content of
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid anhydrate at a relative
humidity of 20% to 95%.
[0038] 2. FIG. 2 represents the equilibrium moisture content of
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.2 hydrate at a
relative humidity of 20% to 95%.
[0039] 3. FIG. 3 represents the X-ray diffraction pattern of
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid anhydrate.
[0040] 4. FIG. 4 represents the X-ray diffraction pattern of
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.2 hydrate.
[0041] 5. FIG. 5 represents the X-ray diffraction pattern of
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.5 hydrate.
[0042] 6. FIG. 6 represents the X-ray diffraction pattern of
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.75 hydrate.
[0043] 7. FIG. 7 represents the results of Differential Scanning
Calorimetry on
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid anhydrate
[0044] 8. FIG. 8 represents the results of Differential Scanning
Calorimetry on
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.2 hydrate.
[0045] 9. FIG. 9 represents the results of Differential Scanning
Calorimetry on
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.5 hydrate.
[0046] 10. FIG. 10 represents the results of Differential Scanning
Calorimetry on
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.75 hydrate.
DETAILED DESCRIPTION OF THE INVENTION
[0047] This invention relates to S-(-)-optically pure
benzoquinolizine carboxylic acids, of formula I, ##STR2## and their
pharmaceutically acceptable salts, derivatives, peudopolymorphs,
polmorphs and hydrates, substantially free of their
R-(.+-.)-isomers; wherein X is OR.sub.1, wherein R.sub.1 is
hydrogen, a pharmaceutically acceptable cation, such as those of
alkali metals such as lithium, sodium, potassium; alkaline earth
metals such as magnesium or calcium, aluminum, ammonium or
substituted ammonium salts; choline or organic amines such as
diethanolamine, guanidine or heterocyclic amines such as
piperidine, hydroxyethylpyrrolidine, hydroxyethylpiperidine,
morpholine, piperazine, N-methyl piperazine and the like or basic
amino acids such as optically pure and racemic isomers of arginine,
lysine, histidine, tryptophan and the like; or R.sub.1 is
C.sub.1-C.sub.6 alkyl, such as straight chain or branched chain
aliphatic residues such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, pentyl, hexyl and their branched chain isomers; or
R.sub.1 is --(CH.sub.2)n-CHR.sub.4--OOCR.sub.5, wherein R.sub.4=H,
or CH.sub.3; n=0-3 and R.sub.5=C.sub.2H.sub.5 or C(CH.sub.3).sub.3,
R.sub.1 is a group such as acetoxymethyl, pivaloyloxymethyl,
pivaloyloxyethyl group; or R.sub.1 is ##STR3## wherein A=CH or N,
and when A=CH, Z=NH or NCH.sub.3, and when A=N, Z=CH, O, N, S, or
NCH.sub.3; p=0-2; q=0-2, wherein R.sub.1 is a group such as
N-methylpiperidin-4-yl, pyrrolidin-2-yl-ethyl,
piperidin-2-yl-ethyl, or morpholin-2-yl-ethyl; or X is NHR.sub.2,
wherein R.sub.2 is hydrogen or NHR.sub.2 is the residue of one of
the 20 naturally occurring amino acids: alanine, arginine,
asparagine, aspartic acid, cysteine, glutamine, glutamic acid,
glycine, histidine, isoleucine, leucine, lysine, methionine,
phenylalanine, proline, serine, threonine, tryptophan, tyrosine or
valine or the optically active isomers thereof, or the racemic
mixtures thereof, R.sub.3 is hydrogen, C.sub.1-C.sub.6 alkyl
(C.sub.1-C.sub.6 alkyl is defined as above), glycosyl, aralkyl such
as benzyl, C.sub.1-C.sub.6 alkanoyl such as acetyl, propionyl,
pivaloyl; or aminoalkanoyl. The amino alkanoyl group may be an
amino acid residue derived from one of the 20 naturally occurring
amino acids or the optically active isomers thereof, or the racemic
mixtures thereof. The amino acid residue is derived from alanine,
arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic
acid, glycine, histidine, isoleucine, leucine, lysine, methionine,
phenylalanine, proline, serine, threonine, tryptophan, tyrosine or
valine. R.sub.3 may also be C.sub.6H.sub.11O.sub.6, PO.sub.3H.sub.2
or SO.sub.3H thus giving respectively, esters with gluconic acid,
phosphoric acid derivatives, or sulphuric acid derivatives of the
compounds. y denotes an integer from 0 to 3 and any fractional
numbers therein depending on the moles of acid added to the basic
molecule; z denotes moles of water, for example 0, 0.2, 0.25, 0.5,
0.75, 1, 1.25, 1.5, 2, 3, etc; and HA represents an acid as defined
below for acid addition salts.
[0048] Pharmaceutically acceptable salts are those salts already
included by definition of the symbol X in Formula I. In addition,
in view of the basic character of the compounds of Formula I and of
the basic amino acids used in the preparation of derivatives it is
possible to make acid addition salts. Also, because of the acidic
character introduced in the derivatives of Formula I, it is also
possible to make basic or alkali addition salts of the compounds of
Formula I. Preferred acid addition salts are those of
hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate and
salts of organic acids such as acetate, lactate, succinate,
oxalate, maleate, fumarate, malate, tartrate, citrate, ascorbate,
cinnamate, gluconate, benzoate, methane sulfonate and p-toluene
sulfonate. Preferred alkali addition salts are lithium, sodium, and
potassium salts, and alkaline earth salts are magnesium, and
calcium salts.
[0049] Specific compounds of the invention are: [0050] 1.
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid. [0051] 2.
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.2H.sub.2O. [0052] 3.
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.5H.sub.2O. [0053] 4.
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.75H.sub.2O. [0054] 5.
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid sodium salt. [0055] 6.
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid, sodium salt
monohydrate. [0056] 7.
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid, potassium salt
monohydrate. [0057] 8.
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid, arginine salt. [0058]
9.
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid, arginine salt
0.25H.sub.2O. [0059] 10.
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid, arginine
salt.0.75H.sub.2O. [0060] 11.
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid, lysine salt
monohydrate. [0061] 12.
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid, histidine salt
0.2H.sub.2O. [0062] 13.
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid, hydroxyethyl
pyrrolidine salt. [0063] 14.
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid, diethanolamine salt.
[0064] 15.
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-
-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, choline salt and
its hydrates. [0065] 16. Carboxymethyl
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylate sodium salt. [0066] 17.
Acetoxymethyl
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylate. [0067] 18. Propionoxymethyl
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylate. [0068] 19.
Pivaloyloxymethyl
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylate. [0069] 20. Pivaloyloxyethyl
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylate. [0070] 21.
N-methylpiperidin-4-yl S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxy
piperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate.
[0071] 22. Pyrrolidin-2-yl-ethyl
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxy
piperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate.
[0072] 23. Piperidin-2-yl-ethyl
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylate. [0073] 24.
Morpholin-2-yl-ethyl S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxy
piperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate.
[0074] 25.
9-fluoro-8(4-hydroxypiperidin-1-yl)-(5S)-methyl-6,7-dihydro-1-oxo-1H,5H-b-
enzo[i,j]quinolizine-2-[2(S)-amino-1,5-pentanedioic
acid]carboxamide, disodium salt. [0075] 26.
9-fluoro-8-{4-hydroxypiperidin-1-yl}-5(S)-methyl-6,7-dihydro-1-oxo-1H,5H--
benzo[i,j]quinolizine-2-[2(S)-amino-3-imidazolylpropionic
acid]carboxamide hydrochloride. [0076] 27.
S-(-)-9-fluoro-6,7-dihydro-8-(4-methoxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid. [0077] 28.
S-(-)-9-fluoro-6,7-dihydro-8-(4-[(.beta.-D-tetraacetylglucopyranosyl)oxy]-
-piperidin-1-yl)-5-methyl-1-oxo-1H,5,H-benzo[i,j]quinolizine-2-carboxylic
acid. [0078] 29.
S-(-)-9-fluoro-6,7-dihydro-8-(4-[(.beta.-D-glucopyranosyl)oxy]-piperidin--
1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid.
[0079] 30.
S-(-)-9-fluoro-6,7-dihydro-8-(4-acetoxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid. [0080] 31.
S-(-)-9-fluoro-6,7-dihydro-8-(4-pivaloyloxypiperidin-1-yl)-5-methyl-1-oxo-
-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid. [0081] 32.
S-(-)-9-fluoro-8-[4-(phosphonoxy)-1-piperidin-1-yl)-5-methyl-1-oxo-1H,5H--
benzo[i,j]quinolizine-2-carboxylic acid. [0082] 33.
8-{4-[2(S)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-di-
hydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid. [0083]
34.
8-{4-[2(S)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-di-
hydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid,
hydrochloride. [0084] 35.
8-{4-[2(R)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-di-
hydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid. [0085]
36.
8-{4-[2(R)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-di-
hydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, acetate.
[0086] 37.
8-{4-[2(RS)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-d-
ihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid. [0087]
38.
8-{4-[(2S)-amino-propionyl-(2S)-aminopropionyloxy]piperidin-1-yl}-9-fluor-
o-5(S)-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic
acid hydrochloride. [0088] 39.
8-{4[(2R)-Amino-propionoyl-(2R)-aminopropionyloxy]piperidin-1-yl}-9-fluor-
o-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic
acid. [0089] 40.
8-{4-[(2R)-Amino-propionoyl-(2R)-aminopropionyloxy]piperidin-1-yl}-9-fluo-
ro-(5S)-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic
acid hydrochloride. [0090] 41.
8-{4[(2R)-Amino-propionoyl-(2R)-aminopropionyloxy]piperidin-1-yl}-9-fluor-
o-(5S)-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic
acid acetate. [0091] 42.
8-{4-[(2S)-Methylamino-propionyloxy]piperidin-1-yl}-9-fluoro-5S)-methyl-6-
,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid.
[0092] 43.
8-{4-[(2S)-Methylamino-propionyloxy]piperidin-1-yl}-9-fluoro-5S)-meth-
yl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid
and hydrochloride. [0093] 44.
8-{4[2(S)-amino-3-carboxypropionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methy-
l-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid
hydrochloride. [0094] 45.
8-{4[2(S)-amino-3-phenylpropionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-
-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid
hydrochloride. [0095] 46.
8-{4[2(R)-amino-3-phenylpropionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-
-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid
hydrochloride. [0096] 47.
8-{4[2(R)-amino-3-phenylpropionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-
-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid
acetate. [0097] 48.
8-{4[(2S)-Amino-3-methylbutanoyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl--
6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid.
[0098] 49.
8-{4[(2S)-Amino-3-methylbutanoyloxy]piperidin-1-yl}-9-fluoro-(5S)-met-
hyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid
and hydrochloride. [0099] 50.
8-{4-[2(S)-Amino-4-methylpentanoyloxy]piperidin-1-yl}-9-fluoro-5(S)-methy-
l-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid.
[0100] 51.
8-{4-[2(S)-Amino-4-methylpentanoyloxy]piperidin-1-yl}-9-fluoro-5(S)--
methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic
acid, hydrochloride. [0101] 52.
8-{4[(2R)-Amino-4-methylpentanoyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-
-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid.
[0102] 53.
8-{4[(2R)-Amino-4-methylpentanoyloxy]piperidin-1-yl}-9-fluoro-(5S)-me-
thyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid
and hydrochloride. [0103] 54.
8-{4-[2(S),6-Diaminohexanoyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7--
dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid. [0104]
55.
8-{4-[2(S),6-Diaminohexanoyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7--
dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid,
dihydrochloride. [0105] 56.
8-{4[(2S)-Amino-5-nitroguanidino-butanoyloxy]piperidin-1-yl}-9-fluoro-(5S-
)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic
acid. [0106] 57.
8-{4[(2S)-Amino-5-nitroguanidino-butanoyloxy]piperidin-1-yl}-9-fluoro-(5S-
)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic
acid and, hydrochloride. [0107] 58.
8-{4[(2S)-Amino-5-guanidino-butanoyloxy]piperidin-1-yl}-9-fluoro-(5S)-met-
hyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid.
[0108] 59.
8-{4[(2S)-Amino-5-guanidino-butanoyloxy]piperidin-1-yl}-9-fluoro-(5S)-met-
hyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid
and hydrochloride. [0109] 60.
8-{4[(2S)-Amino-5-nitroguanidino-butanoyl-(2S)-amino-5-nitroguanidino-but-
anoyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo-
[i,j]quinolizine-2-carboxylic acid. [0110] 61.
8-{4[(2S)-Amino-5-nitroguanidino-butanoyl-(2S)-amino-5-nitroguanidino-but-
anoyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo-
[i,j]quinolizine-2-carboxylic acid and hydrochloride. [0111] 62.
8-{4[(2S)-Amino-5-guanidino-butanoyl-(2S)-amino-5-guanidino-butanoyloxy]p-
iperidin-1-yl}-9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quino-
lizine-2-carboxylic acid. [0112] 63.
8-{4[(2S)-Amino-5-guanidino-butanoyl-(2S)-amino-5-guanidino-butanoyloxy]p-
iperidin-1-yl}-9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quino-
lizine-2-carboxylic acid and hydrochloride.
[0113] The hydrates of all the above compounds are also compounds
of the invention. Hydrate may be represented by the term hydrate or
H.sub.2O.
[0114] One embodiment of the invention are the salts and hydrates
of S-(-)-Nadifloxacin. Another embodiment of the invention are the
derivatives and salts of the S-(-)-benzoquinolizine carboxylic
acids of the invention which are essentially prodrugs of compounds
of the formula I having free carboxylic acid groups or hydroxy
groups. Prodrugs are understood to be esters of the free carboxylic
acid group, or amides of the free carboxylic acid group with
ammonia, organic amines or the amino group of an amino acid
residue, or a polypeptide chain of two or more, such as up to four,
amino acids residues which are covalently joined through peptide
bonds. Prodrugs are also understood to be ethers of the free 4-OH
group of the piperidinyl moiety or esters of the free 4-OH-group of
the piperidinyl moiety with a carboxylic acid residue as defined
for formula I above or with the carboxylic acid group of an organic
acid, organic dibasic acid or an amino acid residue, or a
polypeptide chain of two or more, such as up to four, amino acid
residues which are covalently joined through peptide bonds. The
amino acid residues of use include the 20 naturally occurring amino
acids alanine, arginine, asparagine, aspartic acid, cysteine,
glutamine, glutamic acid, glycine, histidine, isoleucine, leucine,
lysine, methionine, phenylalanine, proline, serine, threonine,
tryptophan, tyrosine or valine. Preferred amino acid residues are
those with a basic-polar group such as Nitro-Arg, Arg, Lys, His,
and those with a polar group such as Ala, Val, Nval, Leu, Met, Gly,
Pro, Phe. Prodrugs at the free 4-OH group may also be phosphoric
acid esters and sulfonic acid esters.
[0115] Particularly, the preferred compounds of the present
invention are: [0116]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid [0117]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.2 hydrate [0118]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid sodium salt [0119]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid sodium salt monohydrate
[0120]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H-
,5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt
0.25H.sub.2O [0121]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-
-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid arginine
salt.0.75H.sub.2O [0122]
8-{4-[2(S)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-di-
hydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid [0123]
8-{4-[2(S)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-di-
hydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid,
hydrochloride [0124]
8-{4-[2(R)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methy-
l-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid
acetate [0125]
8-{4[(2S)-Methylamino-propionyloxy]piperidin-1-yl}-9-fluoro-(5S)--
methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic
acid [0126]
8-{4[(2S)-Methylamino-propionyloxy]piperidin-1-yl}-9-fluoro-(5S)--
methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic
acid, hydrochloride
[0127] Even more preferred compounds of the invention are: [0128]
S-(-)-9-fluoro-6,7-dihydro-8(-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.2 hydrate. [0129]
S-(-)-9-fluoro-6,7-dihydro-8(-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid sodium salt monohydrate.
[0130]
8-{4-[2(R)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methy-
l-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid,
acetate. [0131]
8-{4-[2(S)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-di-
hydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid,
hydrochloride. [0132]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-
-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt
0.25H.sub.20. [0133]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt
0.75H.sub.20.
[0134] Even more preferred compounds of the invention are
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt 0.25
H.sub.2O and
S-(-)-9-fluoro-6,7-dihydro-(8-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid arginine
salt.0.75H.sub.2O.
[0135] In addition to their favourable aqueous solubility, the
respective arginine salts on repeated i.v. administration in rats
did not cause phlebitis at doses double those of the corresponding
sodium salt. This feature would make
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt 0.25
H.sub.20 and
S-(-)-9-fluoro-6,7-dihydro-8-[4-(hydroxy)-1-piperidin-1-yl)-5-methyl-1-ox-
o-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt
0.75H.sub.20 suitable for long term i.v. administration which is
commonly undertaken for critically ill patients or patients in
intensive care unit.
[0136] The compounds, derivatives, salts, pseudopolymorphs,
polymorphs and hydrates of the invention as defined above exhibit
the same potent antibacterial activity as S-(-)-Nadifloxacin and
also have one or more desirable physico-chemical properties such as
constant moisture content, excellent solubility etc. regardless of
the ambient relative humidity, and also have desirable
bioavailability and safety profiles.
[0137] Generally, conversion of a pharmacologically active compound
into a salt or hydrate form induces a change in the compound's
physicochemical properties such as solubility, absorption velocity,
etc. Therefore, study about an effective salt or hydrate form for
developing a successful new medicine has been conventionally made.
Pharmaceutically more desirable crystal form may be selected by
studying whether or not any polymorphs or pseudopolymorph can be
produced and its physicochemical properties (see, Remington's
Pharmaceutics, Chapter 75 Preformulation; Byrn, S. R. Solid
Chemistry of Drugs, Academic Press, New York, 1982). The hydrate,
one such polymorph or pseudopolymorph, has water molecules inside
the crystal, and thus has a crystalline structure different from
that of the anhydrate, as can be verified from their respective
X-ray diffraction patterns. A polymorph or pseudopolymorph differs
from the original compound not in its chemical properties, such as
pharmacological activity, but in its physical properties, such as
crystallinity, hygroscopicity, melting point, solubility,
solubilizing velocity, etc. So, the polymorph or pseudopolymorph
has been recognised as pharmaceutically important (see, Morris, K.
P. et. al. Int. J. Pharm., 108, 15-206 (1994)). In the process of
identifying the physico-chemical properties of S-(-)-Nadifloxacin,
the compound has been found to exist as a stable hydrate wherein
the proportion of water molecules contained in one molecule varies
within a specific range. Here, stability does not mean chemical
stability but the difficulty of removing water molecules. That is,
a stable hydrate neither loses the water molecule contained
therein, nor absorbs moisture over a wide range of ambient relative
humidity. In contrast, moisture absorption by the anhydrate can
vary greatly with the ambient relative humidity. As a result of
experiments carried out by the present inventors,
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid has been shown to exist
as a stable hydrate for values of the hydration number z equal to
0.2, 0.5 or 0.75. In addition to the anhydrate S-(-)-Nadifloxacin,
the inventors have now found that
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid may exist as a 0.2
hydrate, 0.5 hydrate and 0.75 hydrate crystal forms. Among these,
0.2 is preferred since the change in moisture content is the lowest
at the hydration number. Although stable hemihydrate and the
hemisesquihydrate forms can be prepared, they alter also to the 0.2
hydrate on vacuum drying at room temperature.
[0138] The moisture content of the hydrate varies with the
hydration number (z) of the hydrated molecule. The actual moisture
content may however, differ from the calculated moisture content
depending on differences in recrystallization conditions, drying
conditions, etc. The range of the actual moisture content for the
0.2 hydrate is from 0.9% to 1.1%, even though the calculated
moisture content is 0.99%.
[0139] It has also been found that the relative humidity range at
which the moisture content of the anhydrate and the 0.2 hydrate can
be maintained constant differ from each other. That is, although
the anhydrate has a constant moisture content at a relative
humidity of 20% to 75%, the 0.2 hydrate is constant at a relative
humidity of 20% to 95% (see FIGS. 1 and 2).
[0140] The hydrates of formula I may be prepared by means of
conventional methods well known in the art to which the present
invention pertains. Particularly, the different hydrates may be
prepared merely by changing recrystallization conditions, and the
temperature/vacuum conditions under which the crystals are dried.
The 0.2 hydrate is prepared by dissolving
S-(-)-9-fluoro-8(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-j-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid in a minimum volume of
organic solvent, preferably acetonitrile or ethanol at an elevated
temperature, preferably at the reflux temperature of the solvent
and adding an amount of water sufficient to bring about
crystallisation after cooling in high yields, filtering and drying
the separated crystals at temperatures up to 40-50.degree. C. for
3-6 hours, preferably 5 hours, in vacuo up to 50 mm of Hg to a
constant weight. The 0.2 hydrate can also be prepared by dissolving
S-(-)-9-fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid in alkali, preferably 1
molar aqueous sodium hydroxide, heating to 55-60.degree. C.,
acidifying, preferably with concentrated hydrochloric acid, at
55-60.degree. C., maintaining the suspension at 50-70.degree. C.,
preferably at 60.degree. C. for at least 30 minutes, cooling,
filtering, washing with water and drying the separated crystals at
temperatures up to 40-50.degree. C. for 3-6 hours, preferably 5
hours, in vacuo up to 50 mm of Hg to a constant weight.
[0141] The 0.5 hydrate can be prepared by dissolving
S-(-)-9-fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid in an minimum volume of
organic solvent such as acetone at reflux temperature adding an
appropriate amount of water at ambient temperature, sufficient to
bring about crystallisation after cooling in high yields, filtering
and drying the separated crystals at temperatures up to
<40.degree. C. for 3-6 hours, preferably 5 hours to a constant
weight.
[0142] The 0.75 hydrate can be prepared by suspending
S-(-)-9-fluoro-8(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid in water, preferably at
10% (weight by volume) suspension, formulating into a slurry by
vigorous stirring continuing stirring at 5.degree. C. for 1-2
hours, adding acetone ca. 5% (weight by volume) with continuation
of stirring at 5.degree. C. for 4-5 hours, filtering and drying the
product at temperatures <40.degree. C. for 3-6 hours, preferably
5 hours, to a constant weight.
[0143] The methods as stated above will be more specifically
explained in the examples described in appropriate later section of
this text.
[0144] The novel compounds of the Formula I with pharmaceutically
acceptable cations are prepared by reacting an appropriate
benzoquinolizine carboxylic acid, for example, S-(-)-nadifloxacin
with a base capable of releasing the cation X, wherein X is as
defined in OR.sub.1 above to give the desired salt of Formula I.
Examples of bases capable of releasing the cation X and examples of
reaction conditions are given below. [0145] a) Salts of the formula
I, wherein the cation R.sub.1 is lithium, sodium or potassium are
prepared by treating a compound of the formula I wherein X=OH with
LiOH, NaOH, NaHCO.sub.3, Na.sub.2CO.sub.3, KOH, KHCO.sub.3 or
K.sub.2CO.sub.3 in an aqueous or non-aqueous medium. [0146] b)
Salts of the formula I, wherein the cation R.sub.1 is magnesium, or
calcium, are prepared by treating a compound of the formula I
wherein X=OH with Mg(OH).sub.2, or Ca(OH).sub.2, in an aqueous or
non-aqueous medium. [0147] c) Salts of the formula I, wherein the
cation R.sub.1 is a basic compound like a basic amino acid or an
organic basic amine are prepared by treating a compound of the
formula I, wherein X=OH with an aqueous or alcoholic solution of
the appropriate basic amino acid or organic basic amine. [0148] d)
The compound I of the invention which are esters at the carboxylic
acid group may be prepared by treating the free acid compound I in
solution in an appropriate solvent, preferably N,N-dimethyl
formamide, with the corresponding halo compound, preferably chloro
or bromo-compound, in the presence of a base, preferably anhydrous
potassium carbonate, at an elevated temperature, preferably
50.degree. C. for an extended period of time, preferably 6 hours.
[0149] e) The compounds I of the invention which are amides at the
carboxylic acid groups may be prepared by coupling the free acid
compound I with ammonia or an appropriate amine or an amino acid
appropriately protected at the acid functionality of the amino
acids with a protecting group. The --COOH protecting groups for
amino acids are known in the art. Examples of suitable --COOH
protecting groups for amino acids are methyl, ethyl, t-butyl and
benzyl groups. The --COOH protecting group is removed by hydrolysis
or by hydrogenation. The coupling of the --COOH group of compound I
with the amino group of the amino acid is also known in the art.
The reaction may be conducted with or without a solvent at a range
of temperatures in the presence of a coupling agent. [0150] f) The
compounds I of the invention which are ethers at the 4-OH group may
be conveniently prepared by condensing the previously prepared
4-alkoxypiperidine with
S-(-)-diacetoxy-(8,9-difluoro-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizi-
ne-2-carboxyl) borane. The reaction may be conducted with or
without a solvent at a range of temperatures in the presence of a
condensing agent. [0151] g) The compounds of the invention which
are esters at the 4-OH group may be prepared by treating the free
4-OH compound I with an organic acid, an organic dibasic acid or
appropriate N-protected amino acid or polypeptide as defined above.
Nitrogen protecting groups are known in the art. Examples of
suitable nitrogen protecting groups are C.sub.1-C.sub.6 acyl,
C.sub.2-C.sub.6 alkoxycarbonyl optionally substituted
benzyloxycarbonyl, aryloxycarbonyl, silyl, trityl,
tetrahydropyranyl, vinyloxycarbonyl, O-nitrophenylsulfonyl,
diphenylphosphinyl, p-toluenesulfonyl, and benzyl. The nitrogen
protecting group is removed by methods known in the art such as
hydrogenation or hydrolysis. The ester forming reaction may be
conducted with or without a solvent at a range of temperatures in
the presence of a suitable condensing agent, known to those skilled
in the art. [0152] h) The pharmaceutically acceptable acid addition
salts of compounds I are prepared in a conventional manner by
treating a solution or suspension of the free base I with about one
chemical equivalent of a pharmaceutically acceptable acid.
Conventional concentration and recrystallisation techniques are
employed in isolating the salts. Illustrative of suitable acids are
acetic, lactic, oxalic, succinic, maleic, tartaric, citric,
gluconic, ascorbic, benzoic, methanesulfonic, p-toluenesulfonic,
cinnamic, fumaric, phosphoric, hydrochloric, hydrobromic,
hydroiodic, sulfamic, and sulfonic acid. [0153] i) The
pharmaceutically acceptable cationic salts of compounds I may be
prepared by conventional methods from the corresponding acids e.g.
by reaction with about one equimolar amount of a base. Examples of
suitable cationic salts are those of alkali metals such as sodium
or potassium, alkaline earth metals such as magnesium or calcium
and ammonium or organic amines such as diethanolamine or
N-methylglucamine.
[0154] The present invention encompasses a method of treating
bacterial infections, especially resistant Gram-positive organism
infections, Gram-negative organism infections, mycobacterial
infections and nosocomial pathogen infections in humans and
animals, which comprises administering systemically or topically to
a human or animal in need of such antiinfective therapy an amount
of S-(-)-Nadifloxacin or an optically pure benzoquinolizine
carboxylic acid, their derivatives, salts, pseudopolymorphs,
polymorphs and hydrates thereof, of the formula I as defined above,
substantially free of its R-(+)-enantiomer, said amount being
sufficient to eradicate such infections. The method avoids the
concomitant liability of toxic effects associated with the
administration of RS-(.+-.)-isomers by providing an amount of
S-(-)-Nadifloxacin or an optically pure benzoquinolizine carboxylic
acid, their derivatives, salts, pseudopolymorphs, polymorphs and
hydrates thereof, of the invention, which is insufficient to cause
the toxic effects associated with the racemic mixture of the
isomers.
[0155] The present invention also encompasses an antiinfective
composition for the treatment of humans and animals in need of
therapy for systemic or topical infections especially resistant
Gram-positive organism infections, Gram-negative organism
infections, mycobacterial infections and nosocomial pathogen
infections, which comprises an amount of S-(-)-Nadifloxacin and
optically pure benzoquinolizine carboxylic acids, the derivatives,
salts, pseudopolymorphs, polymorphs and hydrates thereof, of
Formula I as defined above, substantially free of their
R-(+)-enantiomers, said amount being sufficient to eradicate said
infection. The composition should provide a therapeutic dose, which
is insufficient to cause the toxic effects associated with the
comparable compositions comprised of racemic RS-(.+-.)-isomeric
mixture.
[0156] S-(-)-Nadifloxacin and the compounds of the invention have
2-4 times higher antimicrobial activity than RS-(.+-.)-Nadifloxacin
against Mupirocin-resistant staphylococci, Methicillin-resistant
Staphylococcus aureus (MRSA), Quinolone-resistant Staphylococcus
aureus, coagulase negative staphylococci, such as
Methicillin-resistant Staphylococcus epidermidis (MRSE),
enterococci, betahemolytic streptococci and viridans group of
streptococci. The antimicrobial profile of S-(-)-Nadifloxacin and
the compounds of the invention have, thus, a potential to address
several unmet antibacterial treatment needs ascribed to the most
frequently encountered Gram-positive bacterial pathogens in
clinical settings. S-(-)-Nadifloxacin and the compounds of the
invention possesses superior antibacterial activity against such
Gram-positive pathogens which have now become refractory to older
first- and second-line antibacterials mentioned above (cf.
Biological Example 1). Infections such as impetigo, pneumonia,
bronchitis, pharyngitis, endocarditis, urinary tract infections and
bacteremias caused by Staphylococcus aureus, coagulase negative
staphylococci, enterococci, beta haemolytic streptococci and
viridans group of streptococci are potentially amenable to
successful treatment with S-(-)-Nadifloxacin and the compounds of
the invention. Intrinsically high potency of S-(-)-Nadifloxacin and
the compounds of the invention coupled with their powerful
bactericidal action against organisms such as S. aureus, Coagulase
negative staphylococci and enterococci renders S-(-)-Nadifloxacin
and the compounds of the invention eminently suitable for the
treatment of infections caused by multi-drug resistant strains
belonging to this group.
[0157] There is a surge of mycobacterial infections due to the
spread of AIDS such as in several countries of Europe, USA and
Asia. AIDS and other immunocompromised patients frequently contract
mycobacterial infections due to multi-drug resistant M.
tuberculosis and other atypical mycobacteria such as M.
intracellulare and M. avium. An embodiment of this invention is
that the antimycobacterial profile of S-(-)-Nadifloxacin and the
compounds of the invention have been found to display significant
activity against such organisms and provide a valuable option for
the treatment of such problematic diseases. In addition,
S-(-)-Nadifloxacin and the compounds of the invention have been
shown by the present inventors to display negligible phototoxicity
potential than the comparator fluoroquinolone drug sparfloxacin. In
studies conducted by the present inventors Sparfloxacin was found
to be phototoxic at dosages 25 times lower than S-(-)-Nadifloxacin
and the compounds of the invention.
[0158] S-(-)-Nadifloxacin and the compounds of the invention also
possesses high level of activity against newly emerging
Gram-negative pathogens such as Chryseobacterium meningosepticum
and Chryseobacterium indologense. These organisms frequently infect
immunocompromised adults as well as premature neonats. These
organisms are nosocomial pathogens against which most of the
currently available antibacterial agents possess either poor or
only borderline activity. The present investigations have shown
that S-(-)-Nadifloxacin and the compounds of the invention in
possessing superior activity against chryseobacteria and other
nosocomial pathogens such as MRSA, enterococci and methicillin
susceptible strains of staphylococci have a potential to become
excellent drugs for the treatment of hospital acquired infections
(cf. Biological Example 1).
[0159] Against bacterial organisms which proliferate in acidic
environment such as the urinary tract, S-(-)-Nadifloxacin and the
compounds of the invention behave in a characteristically different
pattern than do the known fluoroquinolones, such as Ciprofloxcin,
Levofloxacin, Ofloxacin and Norfloxacin. In studies carried out by
the present inventors the antibacterial potency, that is MIC value,
as well as bactericidal action of S-(-)-Nadifloxacin against
Gram-positive pathogens such as staphylococci and enterococci, and
Gram-negative pathogens such as E. coli, Klebsiella, Proteus,
Serratia, Citrobacter, and Pseudomonas, unlike that of
Ciprofloxacin and Levofloxacin, is not affected at all by the
acidic pH of 5.5. On the contrary, for some organisms the MIC of
S-(-)-Nadifloxacin improves by 100% while that for Ciprofloxacin
and Levofloxacin deteriorates in the range of from 50% to 99%
(Biological Example 2). Further confirmation of these results were
obtained by comparatively evaluating the antibacterial activity of
S-(-)-Nadifloxacin, Ciprofloxacin and Levofloxacin in normal human
urine against a range of organisms frequently encountered in
urinary tract infections. For Ciprofloxacin and Levofloxacin the
loss in antibacterial activity coupled with the abolition of
bactericidal action occurring at acidic pH would lead to recurrent
episodes of urinary tract infections in patients receiving such
fluoroquinolone antibacterial drugs, whereas treatment with
S-(-)-Nadifloxacin and the compounds of the invention, would lead
to successful and consistent cure, irrespective of the pH or the
nature of the environment in which bacterial pathogens are
proliferating. This unpredictable finding with S-(-)-Nadifloxacin
is of great clinical relevance and would provide a unique advantage
to patients on a regimen of the compounds of the invention for
urinary tract infections.
[0160] In gram-positive bacteria, especially Staphylococcus
strains, resistance to most of the fluoroquinolones in clinical use
is mediated by the presence of efflux pumps, in particular Nor A
efflux pumps, which affects the accumulation of the antibiotics
within the cell by enhancing efflux, thus preventing the antibiotic
action. Current estimates of prevalence of Nor A bearing strains
among ciprofloxacin resistant staphylococci is about 30-80%.
[0161] The present inventors have surprisingly and unexpectedly
found that in studies with fluoroquinolone-resistant Staphylococcus
strains with efflux pumps, while most of the fluoroquinolones in
current clinical use have shown significantly reduced potency
against the efflux-pump bearing Staphylococcus strains,
S-(-)-Nadifloxacin, its hydrates, salts, pseudopolymorphs,
polymorphs and derivatives thereof, have shown no loss in potency
of activity in both in-vitro and in-vivo conditions (Biological
Examples 6 & 7). These results support the reduced
effectiveness of the current fluoroquinolones in clinical use in
treating infections caused by such efflux-pump-bearing
staphylococcal strains. These results, thus, create a novel
opportunity for clinical use of the compounds of the invention in
treating infections caused by efflux-pump bearing strains, in
particular efflux-pump bearing Staphylococcal strains.
[0162] The finding of this property of the compounds of the
invention is not suggested by the prior art. In thus behaving
differently from the general class of fluoroquinolones,
S-(-)-Nadifloxacin and the compounds of the invention display a
property hitherto not yet shown. It has arisen because of the
in-depth studies undertaken by the inventors of the compounds of
the invention, without any reasonable expectation of the kind of
result that has been obtained.
[0163] The high propensity of S-(-)-Nadifloxacin to display
resistance to resistance development in comparison to current
fluoroquinolone drugs in clinical use has also now been shown for
the first time by the inventors. In studies, which mimic the
clinical scenario, S-(-)-Nadifloxacin was evaluated in comparison
with trovafloxacin and gatifloxacin by sequential transfer/passages
through respective drug containing media. Although initially all
the three drugs had comparable activity against S. aureus strain
042, after six passages in drug containing media, whilst
S-(-)-Nadifloxacin showed a marginal rise of 4% in MIC value,
trovafloxacin and gatifloxacin showed approximately 300% and 700%
rise respectively in MIC values. This property of
S-(-)-Nadifloxacin to display resistance to resistance development
has considerable value clinically. In clinical settings, the
ability of pathogenic bacteria to select a drug resistant
variant/subclone while the patient is on antibacterial drug therapy
often determines the outcome of the therapy. A drug to which such
resistant variant comes up readily, often witnesses failure of
therapy, or a need to increase the dosage significantly, thereby
dramatically increasing the chances of exposing patients to adverse
side effects also.
[0164] These combined features of S-(-)-Nadifloxacin and optically
pure benzoquinolizine carboxylic acids, the derivatives, salts,
pseudopolymorphs, polymorphs and hydrates thereof of activity
against bacterial organisms which proliferate in acidic
environment, of an ability to resist the action of efflux pump
present in drug resistant microbial strains and of a propensity to
display resistance to resistance development, endows the compounds
of the invention with a unique clinical potential yet not realised
in other fluoroquinolone antibacterials in current medical use.
[0165] The above list of pathogens is merely by way of example and
is in no way to be interpreted as limiting. Examples which may be
mentioned of diseases, which can be prevented, alleviated and/or
cured by the formulations according to the invention are otitis
externa, otitis media; pharyngitis; pneumonia; peritonitis;
pyelonephritis; cystitis; endocarditis; systemic infections;
bronchitis; arthritis; local infections; and septic diseases.
[0166] These findings have an important implication from the point
of view of the systemic use of S-(-)-Nadifloxacin and the compounds
of the invention, which in view of their superior potency, superior
bactericidal activity, expanded biospectrum, better bioavailability
and improved tolerability are now enabled to be administered
systemically in doses that are insufficient to cause the toxic
effects associated with the administration of racemic
RS-(.+-.)-Nadifloxacin and corresponding racemic mixtures of
compounds of the invention.
[0167] Utilising the substantially optically pure or optically pure
isomer of Nadifloxacin or optically pure benzoquinolizine
carboxylic acids, the derivatives, salts, hydrates,
pseudopolymorphs, or polymorphs thereof, whether in systemic or
topical dosage form, results in clearer dose-related definitions of
efficacy, diminished toxic effects and accordingly an improved
therapeutic index. It is, therefore, more desirable to administer
the S-(-)-isomer of Nadifloxacin and S-(-)-optically pure
benzoquinolizine carboxylic acid, their derivatives, salts,
pseudopolymorphs, polymorphs and hydrates thereof, than
RS-(.+-.)-Nadifloxacin and racemic mixtures of compounds of the
invention.
[0168] The term "substantially free of its R-(+)-enantiomer" as
used herein means that the compositions contain a greater
proportion of the S-isomer of Nadifloxacin or an optically pure
benzoquinolizine carboxylic acid, their derivatives, salts,
pseudopolymorphs, polymorphs and hydrates thereof, in relation to
the R-isomer. In a preferred embodiment, the term "substantially
free of its R-isomer" as used herein means that the composition is
at least 90% by weight of S-(-)-Nadifloxacin or an optically pure
benzoquinolizine carboxylic acid, their derivatives, salts,
pseudopolymorphs, polymorphs and hydrates thereof, and 10% by
weight or less of the corresponding R-(+)-isomer. In a more
preferred embodiment the term "substantially free of the
R-enantiomer" means that the composition is at least 99% by weight
of S-(-)-Nadifloxacin or an optically pure benzoquinolizine
carboxylic acid, their derivatives, salts, pseudopolymorphs,
polymorphs and hydrates thereof, and 1% by weight or less of the
corresponding R-(+)-isomer. In the most preferred embodiment the
term "substantially free of the R-enantiomer" means that the
composition contains greater than 99% by weight of
S-(-)-Nadifloxacin or an optically pure benzoquinolizine carboxylic
acid, their derivatives, salts, pseudopolymorphs, polymorphs and
hydrates thereof. These percentages are based on the total amount
of Nadifloxacin in the composition. The terms "substantially
optically pure S-isomer of Nadifloxacin or an optically pure
benzoquinolizine carboxylic acid, their derivatives, salts,
pseudopolymorphs, polymorphs and hydrates thereof" or
"substantially optically pure S-Nadifloxacin or an optically pure
benzoquinolizine carboxylic acid, their derivatives, salts,
pseudopolymorphs, polymorphs and hydrates thereof" and "optically
pure S-enantiomer of Nadifloxacin or an optically pure
benzoquinolizine carboxylic acid, their derivatives, salts,
pseudopolymorphs, polymorphs and hydrates thereof" or "optically
pure S-Nadifloxacin or an optically pure benzoquinolizine
carboxylic acid, their derivatives, salts, pseudopolymorphs,
polymorphs and hydrates thereof" are also encompassed by the above
described amounts.
[0169] The pharmaceutical compositions are prepared according to
conventional procedures used by persons skilled in the art to make
stable and effective compositions. In the solid, liquid, parenteral
and topical dosage forms, an effective amount of the active
compound or the active ingredient is any amount, which produces the
desired results.
[0170] For the purpose of this invention the pharmaceutical
compositions may contain the active compounds, S-(-)-Nadifloxacin
or an optically pure benzoquinolizine carboxylic acid, their
derivatives, salts, pseudopolymorphs, polymorphs and hydrates
thereof, in a form to be administered alone, but generally in a
form to be administered in admixture with a pharmaceutical carrier
selected with regard to the intended route of administration and
standard pharmaceutical practice. Suitable carriers which can be
used are, for example, diluents or excipients such as fillers,
extenders, binders, emollients, wetting agents, disintegrants,
surface active agents, humectants, antioxidants, sequestering
agents and lubricants which are usually employed to prepare such
drugs depending on the type of dosage form.
[0171] Any suitable route of administration may be employed for
providing the patient with an effective dosage of
S-(-)-Nadifloxacin or an optically pure benzoquinolizine carboxylic
acid, their derivatives, salts, pseudopolymorphs, polymorphs and
hydrates thereof. For example, oral, rectal, parenteral
(subcutaneous, intramuscular, intravenous), transdermal, topical
and like forms of administration may be employed. Dosage forms
include (solutions, suspensions, etc) tablets; pills, powders,
troches, dispersions, suspensions, emulsions, solutions, capsules,
injectable preparations, patches, ointments, creams, lotions, gels,
sprays, shampoos and the like.
[0172] Pharmaceutical compositions of the present invention
suitable for oral administration may be presented as discrete units
such as capsules, cachets, or tablets, or aerosol sprays, each
containing a predetermined amount of the active ingredient, as a
powder or granules, or as a solution or a suspension in an aqueous
liquid, a non-aqueous liquid, an oil-in-water emulsion, or a
water-in-oil liquid emulsion. Such compositions may be prepared by
any of the methods of pharmacy, but all methods include the step of
bringing into association the active ingredient with the carrier
which constitutes one or more necessary ingredients. In general,
the compositions are prepared by uniformly and intimately admixing
the active ingredient with liquid carriers or finely divided solid
carriers or both, and then, if necessary, shaping the product into
the desired presentation.
[0173] The compositions of the present invention include
compositions such as suspensions, solutions, elixirs, aerosols, and
solid dosage forms. Carriers as described in general above are
commonly used in the case of oral solid preparations (such as
powders, capsules and tablets), with the oral solid preparations
being preferred over the oral liquid preparations. The most
preferred oral solid preparation is tablets.
[0174] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit form, in
which case solid pharmaceutical carriers are employed. Examples of
suitable carriers include excipients such as lactose, white sugar,
sodium chloride, glucose solution, urea, starch, calcium carbonate,
kaolin, crystalline cellulose and silicic acid, binders such as
water, ethanol, prepanol, simple syrup, glucose, starch solution,
gelatin solution, carboxymethyl cellulose, shellac, methyl
cellulose, potassium phosphate and polyvinyl pyrrolidone,
disintegrants such as dried starch, sodium alginate, agar powder,
laminaria powder, sodium hydrogen carbonate, calcium carbonate,
Tween (fatty acid ester of polyoxyethylenesorbitan), sodium lauryl
sulfate, stearic acid monoglyceride, starch, and lactose,
disintegration inhibitors such as white sugar, stearic acid
glyceryl ester, cacao butter and hydrogenated oils, absorption
promoters such as quaternary ammonium bases and sodium lauryl
sulfate, humectants such as glycerol and starch, absorbents such as
starch, lactose, kaolin, bentonite and colloidal silicic acid, and
lubricants such as purified talc, stearic acid salts, boric acid
powder, polyethylene glycol and solid polyethylene glycol.
[0175] The tablet, if desired, can be coated, and made into
sugar-coated tablets, gelatin-coated tablets, enteric-coated
tablets, film-coated tablets, or tablets comprising two or more
layers.
[0176] If desired, tablets may be coated by standard aqueous or
nonaqueous techniques.
[0177] Desirably, each tablet, cachet, capsule contains from about
200 mg to about 1500 mg of the active ingredient. Most preferably,
the tablet, cachet or capsule contains either one of three dosages,
about 200 mg, about 400 mg, or about 600 mg of the active
ingredient.
[0178] In molding the pharmaceutical composition into pills, a wide
variety of conventional carriers known in the art can be used.
Examples of suitable carriers are excipients such as glucose,
lactose, starch, cacao butter, hardened vegetable oils, kaolin and
talc, binders such as gum arabic powder, tragacanth powder,
gelatin, and ethanol, and disintegrants such as laminaria and
agar.
[0179] In molding the pharmaceutical composition into a suppository
form, a wide variety of carriers known in the art can be used.
Examples of suitable carriers include polyethylene glycol, cacao
butter, higher alcohols, gelatin, and semi-synthetic
glycerides.
[0180] A second preferred method is parenterally for intramuscular,
intravenous or subcutaneous administration.
[0181] A third preferred route of administration is topically, for
which creams, ointments, sprays, shampoos, lotions, gels, dusting
powders and the like are well suited. Generally, an effective
amount of the compound according to this invention in a topical
form is 0.1% to about 10% by weight of the total composition.
Preferably, the effective amount is 1% by weight of the total
composition.
[0182] For topical application, there are employed as non-sprayable
forms, viscous to semi-solid or solid forms comprising a carrier
compatible with topical application and having a dynamic viscosity
preferably greater than water. Suitable formulations include but
are not limited to solutions, suspensions, emulsions, creams,
ointments, powders, liniments, salves, aerosols, etc., which are,
if desired, sterilized or mixed with auxiliary agents, e.g.
preservatives, antioxidants, stabilizers, wetting agents, buffers
or salts for influencing osmotic pressure, etc. For topical
application, also suitable are sprayable aerosol preparations
wherein the active ingredient preferably in combination with a
solid or liquid inert carrier material.
[0183] In addition to the common dosage forms set out above, the
compounds of the present invention may also be administered by
controlled release means and/or delivery devices such as those
described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;
3,598,123 and 4,008,719; the disclosures of which are hereby
incorporated by reference.
[0184] When the pharmaceutical composition is formulated into an
injectable preparation, in formulating the pharmaceutical
composition into the form of a solution or suspension, all diluents
customarily used in the art can be used. Examples of suitable
diluents are water, ethyl alcohol, polypropylene glycol,
ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and
sorbitan esters. Sodium chloride, glucose or glycerol may be
incorporated into a therapeutic agent.
[0185] The antimicrobial pharmaceutical composition may further
contain ordinary dissolving aids, buffers, pain-alleviating agents,
and preservatives, and optionally coloring agents, perfumes,
flavors, sweeteners, and other drugs.
[0186] A specific embodiment of the invention is the preparation of
storage stable compositions of the compounds of the invention of
formula I. Such stable compositions can be advantageously made
through the use of selective stabilizers. Different stabilizers are
known to those skilled in the art of making pharmaceutical
compositions. Of special utility for making storage stable
compositions of the compound of the invention of formula I,
stabilizers such as disodium EDTA, tromethamine, cyclodextrins such
as gamma-cyclodextrin, beta-cyclodextrin,
hydroxy-propyl-gamma-cyclodextrin have been found to be useful.
[0187] A specific embodiment of the invention utilises arginine as
an excipient in compositions to facilitate the aqueous solubility
of the compounds of the invention which comprises utilising an
appropriate molar amount of arginine with a specific compound of
the invention. For example, a 0.7 molar amount of arginine added to
a molar amount of
S-(-)-9-fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,-
5Hbenzo[i,j]quinolizine-2-carboxylic acid arginine salt
0.75H.sub.2O, raises the aqueous solubility of the salt from 94
mg/ml to a value >200 mg/ml.
[0188] In a specific embodiment of the invention, the
pharmaceutical compositions contain an effective amount of the
active compounds of
S-(-)-9-fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,-
5H benzo[i,j]quinolizine-2-carboxylic acid (also called
S-(-)-Nadifloxacin) or one of the specific optically pure
derivatives, salts, pseudopolymorphs, polymorphs or hydrates
thereof described in this specification in admixture with a
pharmaceutically acceptable carrier, diluent or excipients, and
optionally other therapeutic ingredients.
[0189] The prophylactic or therapeutic dose of S-(-)-Nadifloxacin
and optically pure benzoquinolizine carboxylic acids, the
derivatives, salts, pseudopolymorphs, polymorphs or hydrates
thereof, in the acute or chronic management of disease will be
calculated based on the prophylactic or therapeutic dose of
S-(-)-9-fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-6,7dihydro-1-oxo-1H,5-
H benzo[i,j]quinolizin-2-carboxylic acid and will vary with the
severity of condition to be treated, and the route of
administration. In addition, the dose, and perhaps the dose
frequency, will also vary according to the age, body weight and
response of the individual patient. In general, the total daily
dose range, for S-(-)-Nadifloxacin or an optically pure
benzoquinolizine carboxylic acids, the derivatives, salts,
pseudopolymorphs, polymorphs or hydrates thereof, for the
conditions described herein, is from about 200 mg to about 1500 mg,
in single or divided doses. Preferably, a daily dose range should
be between about 400 mg to 1200 mg, in single or divided dosage,
while most preferably a daily dose range should be between about
500 mg to about 1000 mg in divided dosage. While intramuscular
administration may be a single dose or up to 3 divided doses,
intravenous administration can include a continuous drip. It may be
necessary to use dosages outside these ranges in some cases as will
be apparent to those skilled in the art. Further, it is noted that
the clinician or treating physician will know how and when to
interrupt, adjust, or terminate therapy in conjunction with
individual patient's response. The term "an amount sufficient to
eradicate such infections but insufficient to cause said toxic
effect" is encompassed by the above-described dosage amount and
dose frequency schedule.
[0190] The invention is further defined by reference to the
following examples describing in detail the preparation of the
composition of the present invention as well as their utility. It
will be apparent to those skilled in the art that many
modifications, both to materials and methods may be practiced
without departing from the purpose and scope of this invention.
[0191] The following examples illustrate the methods of preparation
of the compounds of the invention and are provided only as
examples, but not to limit the scope of the compounds of the
invention.
EXAMPLE 1
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid anhydrate
Method A
[0192]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1--
oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (3.0 g) obtained
according to the process described in literature [K. Hashimoto et.
al., Chem. Pharm. Bull. 44, 642-5 (1996)] was dissolved in
acetonitrile (250 ml) at 85.degree. C. The resulting clear solution
was filtered (to remove if any fibrous material is in suspension).
The filtrate was concentrated to 125 ml and left at room
temperature for crystallization. The crystals thus separated were
filtered and dried in a drying cabinet at 40.degree. C. for 2 hr in
vacuum at 50 mm of Hg to obtain constant weight. Yield 2.6 g
(86%).
Method B:
[0193]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1--
oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (2.0 g) obtained
according to the process described in literature [K. Hashimoto et.
al., Chem. Pharm. Bull. 44, 642-5 (1996)] was dissolved in ethyl
alcohol (95%; 200 ml) at 80.degree. C. The obtained clear solution
was filtered (to remove if any fibrous material is in suspension),
concentrated to 100 ml and left for crystallization. The separated
solid was filtered and dried in a drying cabinet at 40.degree. C.
for 3 hr in vacuum at 50 mm of Hg to obtain constant weight. Yield
1.7 g (85%).
[0194] M.p. 258-62.degree. C., moisture content 0% (by Karl Fisher
method) [.alpha.].sub.D.sup.26 -299.degree., HPLC purity 99.8%
[0195] The X-ray diffraction pattern and the DSC analysis of the
sample were identical to that of the anhydrate shown in FIG. 3 and
FIG. 7 respectively.
EXAMPLE 2
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid 0.2 hydrate
Method A:
[0196]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1--
oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (5.0 g) was
dissolved in acetonitrile (500 ml) at 100.degree. C. and filtered
to remove suspended fibrous impurities. Distilled water (1500 ml)
was added. On standing overnight at 5.degree. C., the solid
separated was filtered and dried at <50.degree. C. for 5 hrs in
vacuum at 50 mm of Hg to obtain constant weight. Yield 3.5 g
(70%).
Method B:
[0197]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1--
oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (4.0 g) was
dissolved in ethyl alcohol (200 ml) at 85.degree. C. to obtain
clear solution and distilled water (700 ml) was added. On standing
overnight at 5.degree. C., the solid thus separated was filtered
and dried at <50.degree. C. for 5 hrs in vacuum at 50 mm of Hg
to obtain constant weight. Yield 3.1 g (77%).
Method C:
[0198]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1--
oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (1.0 g) was
dissolved in aqueous NaOH (1M, 10 ml) with stirring at room
temperature, and filtered to remove suspended fibrous impurities.
The obtained clear solution was heated at 55-60.degree. C. with
stirring for 15 min and acidified with 35% HCl (1.5 ml) in hot. The
suspension was stirred at 50-70.degree. C. preferably at 60.degree.
C. for at least 30 min, cooled at room temperature, filtered and
washed with water (10 ml) to furnish the hydrate. The obtained
hydrate was dried at <50.degree. C. for 3 hrs in vacuum at 50 mm
of Hg to obtain constant weight. Yield 0.7 g (70%).
[0199] M.p. 248-52.degree. C., moisture content 0.9-1.04% (by Karl
Fisher method), [.alpha.].sub.D.sup.26 -259.75.degree. and HPLC
99.74%.
[0200] The X-ray diffraction pattern and the DSC analysis of the
sample were identical to that of the 0.2 hydrate shown in FIG. 4
and FIG. 8 respectively.
EXAMPLE 3
[0201]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1--
oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid 0.5 hydrate
(hemihydrate)
[0202]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1--
oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (8.0 g) was
suspended in acetone (400 ml) and refluxed to obtain a clear
solution. Heating was stopped and water (1500 ml) was added. The
obtained mixture was kept over night at 5.degree. C. The solid thus
separated was filtered, washed with chilled acetone (5 ml) and
dried at room temperature for 48 hr to obtain constant weight.
Yield 6.2 g (77.5%).
[0203] M.p. 256-58.degree. C., moisture content 2.42% (by Karl
Fisher method), HPLC purity 99.34% and [.alpha.].sub.D.sup.26
-260.degree..
[0204] The X-ray diffraction pattern and the DSC analysis of the
sample were identical to that of the hemihydrate shown in FIG. 5
and FIG. 9 respectively.
EXAMPLE 4
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid 0.75 hydrate
(hemisesquihydrate)
[0205]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1--
oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (10.0 g) was
suspended in water (100 ml) and formulated into a slurry over a
period of at least 1 hr with vigorous stirring. The obtained slurry
was stirred at 5.degree. C. for 1 hr, acetone (200 ml) was added
and stirring continued at 5.degree. C. for at least 4 hr. The solid
thus separated was filtered, washed with chilled acetone (5 ml) and
dried at room temperature for 24 hr to obtain constant weight.
Yield 2.95 g (30%).
[0206] M.p. 256-58.degree. C., moisture content 3.294% (by Karl
Fisher method) HPLC purity 99.44% and [.alpha.].sub.D.sup.26
-253.degree..
[0207] The X-ray diffraction pattern and the DSC analysis of the
sample were identical to that of the hemisesquihydrate shown in
FIG. 6 and FIG. 10 respectively.
EXAMPLE 5
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid, sodium salt
monohydrate
Method A:
[0208]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1--
oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (1.0-g, 2.777
mmole) was dissolved in acetonitrile (100 ml) at 90.degree. C. to
obtain clear solution, aqueous NaOH (2.67 ml, 1.04 mole) was added
dropwise, the mixture was refluxed for 30 min and allowed to cool
at room temperature for crystallization. The crystals thus
separated were filtered and dried at 50.degree. C. for 3 hr in
vacuum at 50 mm of Hg to obtain constant weight. Yield 0.86 g
(81%).
Method B:
[0209] The experiment was repeated using acetone in place of
acetonitrile to give the same product.
Method C:
[0210] Aqueous sodium hydroxide solution (1N, 1.39 ml, 1.39 mmol)
was added to the stirred powder of
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid (0.5 g, 1.39 mmol) and
diluted with water (10 ml). The resulting solution was stirred for
30 min., passed through micro filter and freeze dried to furnish
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1,5-
H-benzo[i,j]quinolizine-2-carboxylic acid sodium salt monohydrate.
Yield 0.54 g (98%).
[0211] M.p. 285.degree. C. (dec), m/z 383 (M+H),
[.alpha.].sub.D.sup.21 -261.degree. (1% water solution), solubility
>1000 mg/ml in water, PMR (D.sub.2O) .delta.ppm: 1.29 (3H, d,
j=7.0 Hz, CH.sub.3), 1.43-1.65 (2H, m, H.sub.6), 1.65-2.1 (4H, m,
H.sub.3' and H.sub.5'), 2.6-3.2 (6H, m, H.sub.2', H.sub.6' and
H.sub.7), 3.71 (1H, m, H.sub.4'), 4.47 (1H, m, H.sub.5), 7.63 (1H,
d, J=16.5 Hz, H.sub.10), 8.32 (1H, S, H.sub.3), moisture content
5.06% (by Karl Fisher method) and HPLC purity 98.7%.
EXAMPLE 6
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid potassium salt
monohydrate
[0212] Aqueous potassium hydroxide solution (0.5%, 15.6 ml, 1.39
mmol) was added to the stirred powder of
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid (0.5 g, 1.39 mmol). The
resulting solution was stirred for 30 min., passed through micro
filter and freeze dried to provide
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid potassium salt. Yield
0.568 g (99%), m.p. >300.degree. C., m/z 399 (M+H),
[.alpha.].sub.D.sup.25 -255.degree. (1% water solution), solubility
>1000 mg/ml in water, PMR (DMSO-d.sub.6) .delta.ppm: 1.3 (3H, d,
j=6.8 Hz, CH.sub.3), 1.4-1.7 (2H, m, H.sub.6), 1.7-1.95 (2H, m,
H.sub.3' and H.sub.5'), 1.95-2.2 (2H, m, H.sub.3' and H.sub.5'),
2.75-2.98 (2H, m, H.sub.2' and H.sub.7), 2.98-3.3 (4H, m, H.sub.2',
H.sub.6' and H.sub.7), 4.1 (1H, m, H.sub.4'), 4.5 (1H, m, H.sub.5),
7.84 (1H, d, J=12.6 Hz, H.sub.10), 8.3 (1H, S, H.sub.3).
EXAMPLE 7
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid, L-arginine salt 0.25
hydrate
[0213] Aqueous L-arginine solution (1%, 24.2 ml, 1.39 mmol) was
added to the stirred solution of
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid (0.5 g, 1.39 mmol) in
methanol (20 ml). The resulting solution was stirred for 30 min.,
passed through a micro filter and concentrated to dryness to
furnish
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid, L-arginine salt. Yield
0.7 g (93.4%), m.p. 255-60.degree. C., m/z 535 (M+H),
[.alpha.].sub.D.sup.25 -193.30 (1% methanol solution) solubility
>75 mg/ml in water, PMR (D.sub.2O) .delta.ppm: 1.32 (3H, d,
j=6.8 Hz, CH.sub.3), 1.5-1.7 (2H, m, H.sub.6), 1.7-2.2 (8H, m,
H.sub.3' H.sub.5' and 2.times.CH.sub.2), 2.7-3.3 (8H, m, H.sub.2',
H.sub.6', H.sub.7 and NCH.sub.2), 3.5 (1H, m, CH), 3.75 (1H, m,
H.sub.4'), 4.5 (1H, m, H.sub.5), 7.85 (1H, d, J=12.6 Hz, H.sub.10)
8.5 (1H, S, H.sub.3).
EXAMPLE 8
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid, L-arginine salt 0.75
hydrate
[0214] L-(+)-Arginine (0.958 g., 5.5 mmoles) was added in portions
to a suspension solution of
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.2 hydrate (2.0 g., 5.5
mmole) in methanol (400 ml). The obtained solution was concentrated
in vacuum to give the desired product as a yellow solid, which was
dried at 50.degree. C. at 50 mm/Hg for 5 hours. Yield 3.0 g.
(100%), m.p. 220-223.degree. C. (dec), m/z 535 (M+H), moisture
content 2.3% (by Karl Fisher, required 2.46%),
[.alpha.].sub.D.sup.25 -144.degree. (1% methanol c=1), solubility
93 mg/ml.
EXAMPLES 9 & 10
[0215] Similarly prepared were
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid L-lysine salt
monohydrate, and
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid L-histidine salt 0.2
hydrate.
[0216]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1--
oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-lysine salt
monohydrate
[0217] Yield 0.7 g (99%), m.p. 235-40.degree. C., m/z 506 (M+H),
[.alpha.].sub.D.sup.25 -177.degree. (1% methanol solution)
solubility 75 mg/ml in water. PMR (DMSO-d.sub.6) .delta.ppm: 1.38
(3H, d, j=6.8 Hz, CH.sub.3), 1.48-2.25 (10H, m, H.sub.3' H.sub.5',
H.sub.6 and 2.times.CH.sub.2), 2.5-2.83 (4H, m, 2.times.CH.sub.2),
2.85-3.4 (6H, m, H.sub.2', H.sub.6', and H.sub.7), 3.72-3.88 (2H,
m, H.sub.4' and CH), 4.75 (1H, m, H.sub.5), 7.78 (1H, d, J=12.6 Hz,
H.sub.10), 8.8 (1H, S, H.sub.3).
[0218]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1--
oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-histidine salt
0.2 hydrate
[0219] Yield 0.67 g (94%), m.p. 270-80.degree. C., m/z 515 (M+H),
[.alpha.].sub.D.sup.25 -25-216.degree. (1% methanol solution)
solubility 75 mg/ml in water, PMR (DMSO-d.sub.6) .delta.ppm: 1.42
(3H, d, j=6.8 Hz, CH.sub.3), 1.48-1.70 (2H, m, H.sub.6), 1.75-2.23
(4H, m, H.sub.3' and H.sub.5'), 2.78-3.31 (6H, m, H.sub.2',
H.sub.6', and H.sub.7), 3.5 (1H, m, CH), 3.71 (2H, m, CH), 4.15
(1H, m, H.sub.4'), 4.78 (1H, m, H.sub.5), 6.9 (1H, s, imidazole H),
7.62 (1H, s, imidazole H), 7.83 (1H, d, J=12.5 Hz, H.sub.10), 8.86
(1H, S, H3).
EXAMPLE 11
Pivaloyloxymethyl
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylate
[0220]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1--
oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (1.0 g, 2.77
mmol) was dissolved in N,N-dimethyl formamide (25 ml) and solution
was stirred at 50.degree. C. Powdered anhydrous potassium carbonate
(0.385 g, 2.77 mmol) was added to stirred solution and stirring was
continued for 6 hr at 50.degree. C. Chloro methyl pivalate (2.0 g,
13.88 mmol) was added to the resulting mixture and stirred for 40 h
at 50.degree. C. The reaction mixture was concentrated, triturated
with water, extracted with chloroform to give crude product, which
was purified by chromatography. Yield 0.9 g (71%), m.p
198-200.degree. C., m/z 475(M+H).
EXAMPLE 12
[0221] Similarly prepared to the product of Example 11 were
Acetoxymethyl
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylate. Chloromethyl acetate was
used in place of chloromethyl pivalate. Yield 0.35 g (56%), m.p.
180.degree. C., m/z 433(M+1), [.alpha.].sub.D.sup.22.5 -251.degree.
(1% CHCl.sub.3 solution).
EXAMPLE 13
[0222] Similarly prepared to the product of Example 11 was
Pivaloyloxyethyl
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylate. Chloroethyl pivalate was
used in place of chloromethyl pivalate. Yield 0.08 g (59%), m.p.
92-95.degree. C., m/z 489(M+1), [.alpha.].sub.D.sup.22.5
-174.5.degree. (0.4% methanol solution).
EXAMPLE 14
[0223] Similarly prepared to the product of Example 11 was
Propionoxymethyl
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylate. Bromoethyl acetate was used
in place of chloromethyl pivalate. Yield 0.4 g (67%), m.p.
185-187.degree. C., m/z 447 (M+1), [.alpha.].sub.D.sup.22.5
-186.degree. (1% chloroform solution).
EXAMPLE 15
Carboxymethyl
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylate (sodium salt)
[0224]
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1--
oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (0.72 g, 2 mmol)
was dissolved in N,N-dimethyl formamide (25 ml) and solution was
stirred at 50.degree. C. Powdered anhydrous potassium carbonate
(0.385 g, 2.77 mmol) was added to stirred solution and stirring was
continued for 6 hr at 50.degree. C. Bromo acetic acid t-Butyl ester
(1.9 g, 10 mmol) was added to the resulting mixture and stirred for
40 h at 50.degree. C. The reaction mixture was concentrated,
triturated with water, extracted with chloroform to give crude
product, which was purified by chromatography. Yield 0.76 g
(80%).
[0225] The t-Butyl group was removed by treatment with
trifluoroacetic acid to get the desired product.
EXAMPLE 16
S-(-)-9-fluoro-6,7-dihydro-8-(4-methoxypiperidin-1-yl)-5-methyl-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid
[0226] A mixture of
S-(-)-diacetoxy-(8,9-difluoro-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizi-
ne-2-carboxyl)borane (0.2 g, 0.49 mmol) and 4-methoxypiperidine
(0.226 g, 1.9 mmol) in acetonitrile (8 ml) was stirred at
100.degree. C. for 24 h. The reaction mixture was concentrated,
triturated with water and filtered. The obtained solid was
dissolved in acetonitrile (8 ml), treated with 1N aqueous NaOH
solution (10 ml) and stirred to obtain a clear solution. The
resulting solution was acidified with conc. HCl, the separated
precipitate was filtered, washed with water and dried. The obtained
crude product was purified by chromatography. Yield 0.07 g (38%),
m.p 194.degree. C., m/z 375(M+H), [.alpha.].sub.D.sup.26
-209.75.degree. (0.5% methanol solution), PMR(CDCl.sub.3) 5 ppm:
1.55 (3H, d, j=6.8 Hz, CH.sub.3), 1.8-1.9 (2H, m, H.sub.6), 1.9-2.3
(4H, m, H.sub.3' and H.sub.5'), 2.8-3.2 (6H, m, H.sub.2', H.sub.6'
and H.sub.7), 3.25 (1H, m, H.sub.4'), 3.45 (3H, s, CH.sub.3), 4.55
(1H, m, H.sub.5), 8.2 (1H, d, J=16.5 Hz, H.sub.10), 8.7 (1H, S,
H.sub.3), 15.1 (1H, bs, COOH, D.sub.2O exchangeable).
EXAMPLE 17
S-(-)-9-fluoro-6,7-dihydro-8-(4-acetoxypiperidin-1-yl)-5-methyl-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid
[0227] Acetic anhydride (0.312 g, 3.6 mmol) was added to a stirred
mixture of
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-1-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid (0.65 g, 1.8 mmol) and
N,N-4-dimethylaminopyridine (0.01 g) in pyridine (10 ml), stirring
was continued for 3 h at ambient temperature. The reaction mixture
was concentrated, triturated with water, filtered, washed with
water and dried. The obtained crude product was purified by
chromatography. Yield 0.69 g (95%), m.p 230-35.degree. C., m/z
403(M+H), [.alpha.].sub.D.sup.25 -239.degree. (1% methanol
solution), PMR(CDCl.sub.3) .delta.ppm: 1.51 (3H, d, j=6.8 Hz,
CH.sub.3), 1.85-1.9 (2H, m, H.sub.6), 2.1 (3H, s, COCH.sub.3),
1.9-2.3 (4H, m, H.sub.3' and H.sub.5'), 2.9-3.4 (6H, m, H.sub.2',
H.sub.6' and H.sub.7), 4.5 (1H, m, H.sub.5), 5.0 (1H, m, H.sub.4'),
8.2 (1H, d, J=16.5 Hz, H.sub.10), 8.7 (1H, S, H.sub.3) 15.1 (1H,
bs, COOH, D.sub.2O exchangeable).
EXAMPLE 18
S-(-)-9-fluoro-6,7-dihydro-8-(4-pivaloyloxypiperidin-1-yl)-5-methyl-1-oxo--
1H,5H-benzo[i,j]quinolizine-2-carboxylic acid
[0228] Pivaloyl chloride (0.08 g, 0.66 mmol) was added to a stirred
mixture of
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid (0.08 g, 0.22 mmol) and
N,N-4-dimethylaminopyridine (0.005 g) in pyridine (5 ml), stirring
was continued for 3 h at ambient temperature. The reaction mixture
was concentrated, triturated with water, filtered, washed with
water and dried. The obtained crude product was purified by
chromatography. Yield 0.05 g (50%), m.p 200-05.degree. C., m/z
445(1+H), [.alpha.].sub.D.sup.26 -199.5.degree. (0.5% methanol
solution), PMR (CDCl.sub.3) .delta.ppm: 1.26 (9H, S,
3.times.CH.sub.3), 1.57 (3H, d, j=6.8 Hz, CH.sub.3), 1.8-1.95 (2H,
m, H.sub.6), 1.95-2.36 (4H, m, H.sub.3' and H.sub.5'), 2.9-3.5 (6H,
m, H.sub.2', H.sub.6' and H.sub.7), 4.58 (1H, m, H.sub.5), 5.05
(1H, m, H.sub.4'), 8.22 (1H, d, J=16.5 Hz, H.sub.10), 8.74 (1H, S,
H3).
EXAMPLE 19
S-(-)-9-fluoro-6,7-dihydro-8-(4-[(.beta.-D-tetraacetylglucopyranosyl)oxy]--
piperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic
acid
[0229] A solution of acetobromoglucose (1.71 g., 4.16 mmol) in
dichloroethane (20 ml.) was added to
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid (1.0 g, 2.77 mmol),
4.degree. A molecular sieves (.about.100 g) and silver carbonate
(3.066 g., 11.11 mmol). The reaction mixture was heated at
60-70.degree. C. under argon atmosphere for 20 hrs. in the dark.
The solids were filtered off and the filtrate was concentrated in
vacuum to give the product. Column chromatography of the crude
product gave the tetraacetate. Yield 1.75 g. m.p 157-158.degree.
C., m/z 691(M+H), [.alpha.].sub.D.sup.26 -199.5.degree. (0.5%
methanol solution), PMR (CDCl.sub.3) .delta.ppm: 1.42 (3H, d, j=6.8
Hz, CH.sub.3), 1.73-1.98 (2H, m, H.sub.6), 2.01 (3H, s, COCH3) 2.20
(9H, s, 3.times.COCH3), 2.60-3.40 (8H, m), 3.80-4.52 (7H, m),
5.46-5.42 (4H, m) 5.98 (1H, d, J=10.1 Hz), 7.91 (1H, d, J=12.5 Hz),
8.77 (1H, s).
EXAMPLE 20
S-(-)-9-fluoro-6,7-dihydro-8-(4-[(.beta.-D-glucopyranosyl)oxy]-piperidin-1-
-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic
acid
[0230]
S-(-)-9-fluoro-6,7-dihydro-8-(4-[(.beta.-D-tetraacetylglucopyranos-
yl)oxy]-piperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carbo-
xylic acid (0.144 g., 0.20 mmol) was dissolved in a 3:1 mixture of
methanol and water. Lithium hydroxide (87 mg., 2.00 mmol) was added
to the solution and the mixture was stirred at room temperature for
0.5 hr. The mixture was evaporated to dryness and the residue was
dissolved in small amount of methanol, filtered and the filtrate
was evaporated to give the product.
EXAMPLES 21 TO 23
[0231] General method for making amides of
S-(-)-9-fluoro-8(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid with an amino acid e.g.
glutamic acid.
[0232]
9-fluoro-8(4-hydroxypiperidin-1-yl)-5(S)-methyl-6,7-dihydro-1-oxo--
1H,5H-benzo[i,j]quinolizine-2-[2(S)-amino-1,5-pentanedioic
acid]carboxamide, disodium salt: ##STR4##
[0233]
S-(-)-9-Fluoro-8(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-o-
xo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (360 mg, 1.0 mmol)
and triethylamine (0.145 ml, 1.0 mmol) were dissolved in
dimethylacetamide (15 ml). Isobutylchloroformate (0.13 ml, 1.0
mmol) was added under ice cooling and stirred for 5 min. A solution
of S-glutamic acid dimethyl ester hydrochloride (422 mg, 2.0 mmol)
and triethylamine (2 mmol, 0.28 ml) in dimethylacetamide (10 ml)
was added, followed by addition of 4-(dimethylamino) pyridine (125
mg, 1.0 mmol) and the mixture was stirred at RT overnight. The
reaction mixture was diluted with ethyl acetate (50 ml), washed
with 0.5 N HCl, saturated NaHCO.sub.3 solution, brine, dried
(Na.sub.2SO.sub.4) and evaporated under vacuum. The residue was
dissolved in methanol (10 ml), added 1N NaOH (1.1 ml) and stirred
for 2-3 h at RT. The reaction mixture was concentrated, acidified
with 1N HCl and dissolved in ethyl acetate (50 ml). The organic
layer was washed with brine, dried (Na.sub.2SO.sub.4), solvent was
evaporated, residue purified by column chromatography and freeze
dried to give the free acid. Yield (150 mg, 30%). Dissolved the
free acid (150 mg, 0.3 mmol) and NaHCO.sub.3 (50 mg, 0.6 mmol) in
water and freeze dried to give the product.
[0234] Similarly made were amides using the amino acids such as
alanine and histidine.
EXAMPLES 24-37
[0235] General method for making the amino acid esters of the 4'
hydroxy of piperidinyl moiety of
S-(-)-9-Fluoro-8(4-hydroxypiperidin-1-yl)-(5S)-methyl-6,7-dihydro-1-oxo-1-
H,5H-benzo[i,j]quinolizine-2 carboxylic acid, e.g. the lysine
ester.
[0236]
8-{4-2(S),6-Diaminohexanoyloxy]piperidin-1-yl}-9-fluoro-5(S)methyl-
-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid,
dihydrochloride: ##STR5##
[0237]
S(-)-9-Fluoro-8(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-ox-
o-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (360 mg, 1.0 mmol)
and triethylamine (0.14 ml, 1.0 mmol) were dissolved in
dimethylacetamide (15 ml). Bis-t-butyloxycarbonyl-5-lysine (415 mg,
1.2 mmol) and 4-(dimethylamino)pyridine (150 mg, 1.2 mmol) were
added, followed by the addition 1,3-dicyclohexylcarbodiimide (206
mg, 1.0 mmol) under ice cooling. The reaction mixture was stirred
for 30 minutes at 0.degree. C. followed by overnight stirring at
RT. The reaction mixture was filtered, diluted with ethyl acetate,
washed with 0.5 N HCl, saturated NaHCO.sub.3 solution, brine, dried
(Na.sub.2SO.sub.4) and evaporated to give residue. The residue was
treated with trifluoroacetic acid (10 ml), stirred the mixture at
RT for 30 min. and evaporated under reduced pressure. The residue
was triturated with ether to give the precipitated. The
precipitates were further purified by column chromatography,
dissolved in 0.1 N HCl and freeze dried to give the product. Yield
(374 mg, 69%)
[0238] Similarly esters were made with the following amino acids:
S-Ala, S-Ala-S-Ala, R-Ala, R-Ala-R-Ala, N-Methyl S-Ala, S-Leu,
R-Leu, S-Phe, S-Pro, S-Asp, Nitro-S-Arg, S-Arg,
Nitro-S-Arg-Nitro-S-Arg, S-Arg-S-Arg, The data corresponding to the
respective compounds made are provided in the following table:
TABLE-US-00001 Amino acid linked Melting HPLC at 4-OH group of
Point MASS Purity Moisture Example 1 compound Salt Yield % .degree.
C. (M + H) (%) Content 25. S-Ala HCl, H.sub.2O 95 160-5(d) 432 99.0
3.4 26. R-Ala HCl, H.sub.2O 92 225 432 99.0 4.7 27. R-Ala-S-Ala
HCl, 0.5H.sub.2O 90 190-93 503 97.0 1.1 28. R-Leu HCl, H.sub.2O 94
220-33 474 99.0 3.4 29. N-Me-S-Ala HCl, 0.5H.sub.2O 91 140-50 446
97.5 1.9 30. R-Ala AcOH 98 125-27 432 99.7 -- 31. S-Val HCl,
0.75H.sub.2O 93 160-61 460 96.2 2.7 32. S-Ala-S-Ala HCl 60 175-80
503 97.8 -- 33. R-Ala-R-Ala HCl 75 95-100 503 98.0 -- 34. S-Arg
(Nitro) HCl 70 113-16 588 93.0 -- 35. S-Arg HCl 70 178-82 603 94.0
-- 36. [S-Arg(Nitro)].sub.2 HCl 37. S-Arg-S-Arg 3HCl
BIOLOGICAL EXAMPLES
[0239] Microbiological and pharmacological studies can be used to
determine the relative potency, and the profile of specificity of
the optically pure enantiomers, and the racemic mixture of
Nadifloxacin as antibacterial agent with a spectrum of activity as
described in the specification above.
Biological Example 1
In-Vitro Antimicrobial Activity Test
[0240] The activity of the compounds of the invention in vitro can
be illustrated as follows:
[0241] The comparative antimicrobial activity of
S-(-)-Nadifloxacin, RS-(.+-.)-Nadifloxacin, Mupirocin and
Levofloxacin against various microorganisms is given in Table 1.
The test method was in accordance with the standard NCCLS protocol.
TABLE-US-00002 TABLE 1 Comparative MICs (.mu.g/ml) of
S-(-)-Nadifloxacin, RS-(.+-.)-Nadifloxacin, Mupirocin and
Levofloxacin S-(-)- RS-(.+-.)- ORGANISMS NADIFLOXACIN NADIFLOXACIN
MUPIROCIN LEVOFLOXACIN Staphylococcus aureus ATCC 25923 0.025 0.05
0.4 0.2 MRSA STA-4 0.4 0.8 0.4 >12.5 MRSE STE-22 0.4 1.56 0.2
>12.5 Mupirocin-resistant Staph STA-34 0.4 1.56 >400 12.5
Propioni bacterium acnes 0.1 0.2 >1000 1.0 Streptococcus
pneumoniae ATCC 6303 0.2 0.4 0.2 0.8 Streptococcus pyogenes 0.2 0.4
0.025 0.4 Viridans group Streptococci 0.2 0.4 0.2 1.56 Enterococcus
faecalis ATCC 29212 0.2 0.4 >12.5 0.8 Enterococcus faecium 0.4
0.8 >0.8 1.56 Corynebacterium jeikeium 0.05 0.2 >12.5 0.4
Haemophilus influenzae 0.025 0.05 N.A. 0.03 Escherichia coli ATCC
25922 0.2 0.8 N.A. 0.05 Serratia marcescens 0.4 1.56 N.A. 0.1
Pseudomonas aeruginosa 1.56 3.12 N.A. 3.12 Bacteroides fragilis 0.8
3.12 N.A. 6.25 Mycobacterium tuberculosis ATCC 0.8 1.56 -- 0.4
27294 Mycobacterium intracellulare 1.56 3.12 -- 0.8 Mycobacterium
avium 3.12 6.25 -- 12.5 Chryseobacterium meningosepticum 0.8 1.56
-- 6.25
[0242] 1. Mupirocin resistant MRSA strains with very high MICs of
>400 .mu.g/ml can effectively be inhibited by S-(-)-Nadifloxacin
or racemic Nadifloxacin at much lower MICs of 0.4-1.56 .mu.g/ml.
For such strains, levofloxacin is 30 times less active than
S-(-)-Nadifloxacin and 8 times less active than RS(O)Nadifloxacin.
[0243] 2. S-(-)-Nadifloxacin has 2-4 times higher activity than
racemic-Nadifloxacin. [0244] 3. S-(-)-Nadifloxacin has 48 times
higher activity than levofloxacin against nosocomial pathogens like
enterococci and chryseobacterium meningosepticum.
Biological Example 2
Effect of pH on Potency of Fluoroquinolones
[0245] The test method was in accordance with the standard NCCLS
protocol employing test media adjusted at pH 5.5 and 7.0.
TABLE-US-00003 TABLE 2 Effect of pH at 5.5 on % loss (-)/gain (+)
in potency of Fluoroquinolones against Urinary Tract Pathogens %
CHANGE IN POTENCY AT pH 5.5* ORGANISM S-(-)-Nadi Cipro Levo S.
aureus 25923 +100 -75 -75 S. aureus 1199-B +100 -75 -75 E. faecalis
+100 -87.5 -75 E. coli 2015 +100 -94 -87.5 E. coli 25922 +100 -97.5
-96 P. mirabilis 37 +100 -96 -94 P. rettgeri N 1764 0.00 -94 -94 P.
vulgaris 66 +100 -96 -94 Klebsiella 24037 +100 -97 -94 Serratia
marcescens 2702 0.00 -99 -98 Acinetobacter 3109 +100 -97 -94 Ps.
Aeruginosa +100 -87 -50 *% Change in Potency at pH 5.5 = 100 (-MIC
pH 7/MIC pH 5.5 .times. 100)
Biological Example 3
Acute Toxicity
[0246] The acute intravenous toxicity of RS-(.+-.)- and S-(-)-
forms of Nadifloxacin in mice is shown in Table 3 below:
TABLE-US-00004 TABLE 3 COMPOUND LD.sub.50 (mg/kg)
RS-(.+-.)-Nadifloxacin 311 S-(-)-Nadifloxacin >400* *LD.sub.50
400 mg/kg i.e. no mortality observed at a dose of 400 mg/kg.
Biological Example 4
Hepatotoxicity Differential Between S-(-)-Nadifloxacin and
Trovafloxacin
Human Liver Cell Line Cytotoxicity Assay
[0247] The procedure involved cultivation of cells of human liver
cell-line Hep-G2 in DMEM medium containing 5% foetal bovine and
exposure to various concentrations of trovafloxacin and
S-(-)-Nadifloxacin for 3 hours. The drug containing medium was then
replaced with a fresh medium and cells were incubated in 5% CO2
atmosphere at 37.degree. C. for 4 days. Almar blue dye which is an
indicative of active respiration was then added to individual
sample to access the toxicity of the drugs. The hepatotoxic
potential of a drug is expressed in terms of Minimum Toxic Dose
(MTD) which is defined as minimum concentration of a drug which
brings about inhibition of colour change from blue to pink.
[0248] Using above test method, S-(-)-Nadifloxacin was found to be
tolerated well by Hep-G-2 Cells at dosages 4 times higher than
trovafloxacin.
Biological Example 5
Bioavailability
[0249] The blood levels of RS-(.+-.)-Nadifloxacin and
S-(-)-Nadifloxacin administered orally to Swiss mice at a dose of
30 mg/kg are shown in Table 3 with respect to the AUC (.mu.g/mlhr),
monitored from 15 minutes to 4 hours. TABLE-US-00005 TABLE 4
COMPOUNDS AUC ((.mu.g/ml hr) RS-(.+-.)-Nadifloxacin 16.9
S-(-)-Nadifloxacin 33.58 S-(-)-Nadifloxacin has increased oral
bioavailability compared to racemic Nadifloxacin.
Biological Example 6
Effect of NorA Efflux Pump on Fluoroquinolone Potency
[0250] According to NCCLS protocols, comparative MICs were
determined for S. aureus strain bearing Nor A efflux pump and a
corresponding patent strain devoid of efflux pump. Using this set
of MIC values, % loss in potency due to efflux was calculated for
each of the fluoroquinolone in Table 5 TABLE-US-00006 TABLE 5 %
loss in potency for S. aureus bearing Fluoroquinolone Efflux pump
S-(-)-Nadifloxacin 0 Norfloxacin 97 Ciprofloxacin 94 Levofloxacin
75 Gemifloxacin 75 Clinafloxacin 87.5 Gatifloxacin 75
Biological Example 7
Fold Elevation in ED.sub.50 Dose of Fluoroquinolones
For S. aureus with Nor A Efflux Pump
[0251] In mouse model of infection caused by S. aureus with and
without efflux pump, 50% protective dosages were determined for
Ciprofloxacin, Ofloxacin, Levofloxacin and S-(-)-Nadifloxacin. From
these experimentally determined values, fold increase in 50%
protective dose was calculated and is shown in Table 6
TABLE-US-00007 TABLE 6 Fluoroquinolone Fold Increase Ciprofloxacin
>10 Ofloxacin 10 Levofloxacin 8-10 S-(-)-Nadifloxacin 0
Test Example 1
[0252] Equilibrium Moisture Content Determination of
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid anhydrate and
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.2 hydrate.
[0253] Silica (anhydrous) and three saturated solutions of
electrolytes prepared by dissolving the respective salts in water
were each introduced into different desiccators to control the
inner relative humidity to a specific value as represented in the
following Table 7. Then, the equilibrium moisture contents of
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid anhydrate and
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.2 hydrate prepared in
Examples 1 and 2 respectively were determined at several relative
humidities. TABLE-US-00008 TABLE 7 Powder/Saturated salt solutions
inside the dessicator. Powder/Salt Solution Relative humidity (%)
at 27.degree. C. Silica 20% Ammonium Nitrate 58% Sodium Chloride
75% Potassium Nitrate 95%
[0254] Specifically, 1 g of the sample was spread on a pre-weighed
petridish and the total weight was accurately measured, then both
the samples were placed in each desiccator of Table 8 The
dessicators were allowed to stand at normal temperature for at
least 3 days and the weight was measured agingly over this period.
The weight changes were tabulated. At the end of 3 days all samples
were taken to be weighed. The moisture content of each sample was
determined by Karl Fischer analysis. Equilibrium moisture content
at each relative humidity is represented in FIG. 1 (anhydrate) and
FIG. 2 (0.2 hydrate). FIG. 2 shows that the moisture content of the
0.2 hydrate is maintained around 1% for the whole humidity range
tested (20% to 95%). FIG. 1 shows that the moisture content of the
anhydrate is maintained around 0.1% at the relative humidity 20% to
58%. At humidities of about 75% the anhydrate shows weight change
and reaches a new equilibrium which is maintained around 1% for the
relative humidity range 75% to 95% and corresponds to the 0.2
hydrate (by Karl Fisher measurements and X-ray diffraction
analysis). The 0.2 hydrate displays superior stability since it
keeps a constant equilibrium moisture content regardless of
relative humidity change.
Test Example 2
X-Ray Diffraction Analysis
[0255] After 300 mg each of
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid anhydrate (prepared as
in Example 1) and
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1,5-
H-benzo[i,j]quinolizine-2-carboxylic acid 0.2 hydrate (prepared as
in Example 2) were thinly spread on the sample holder X-ray
diffraction analyses (40 kv.times.40 mA Rigaku D/max 2200) were
performed under the conditions listed below:
scan speed (2.theta.) 5.degree./min
sampling time 7 min
scan mode: continuos
2.theta./.theta. reflection
Cu target (No filter)
[0256] Results of the X-ray diffraction analysis on anhydrate and
0.2 hydrate were as depicted in FIGS. 3 and 4 respectively. From
these spectra it can be verified that their crystal forms differ
from each other.
Test Example 3
[0257] Thermal Analysis of the
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid anhydrate (prepared as
in Example 1) and
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.2 hydrate anhydride
(prepared as in Example 2).
[0258] For the Differential Scanning Calorimetry, PERKIN ELMER DSC
7 system was used. 3 mg of the sample was weighed into the
aluminium pan, which was then press sealed with an aluminium lid.
After three tiny needle holes were made on the lid the sample was
tested by heating from (15.degree. C.) to (300.degree. C.) at a
rate of 20.degree. C./min. As can be seen from the FIG. 8 there is
an endothermic peak which begins at around 150.degree. C., and an
exothermic peak due to thermal decomposition at around 240.degree.
C. to 264.degree. C. In contrast the anhydrate shows only an
exothermic peak at around 245.degree. C. to 268.degree. C. without
any endothermic peak.
Test Example 4
Chemical Stability Under Heating
[0259] The chemical stability of
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid anhydrate (prepared as
in Example 1) and
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.2 hydrate (prepared as
in Example 2),
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.5 hydrate (prepared as
in Example 3) and
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.75 hydrate (prepared
as in Example 4) were compared in order to determine the effect on
chemical stability of the extent of hydration.
[0260] The anhydride and hydrates were each introduced into a glass
vial and maintained at 70.degree. C. Thus the thermal decomposition
with elapsed time was analysed by HPLC and the results thus
obtained are described in Table 8 TABLE-US-00009 TABLE 8 Thermal
stability with elapsed time at 70.degree. C. (Unit %) Time (week)
Sample Initial 1 2 Anhydrate 98.9 98.7 98.6 0.2 hydrate 98.7 98.0
98.1 0.5 hydrate 98.1 97.0 96.1 0.75 hydrate 98.3 97.1 97.2
[0261] As can be seen the 0.2 hydrates shows the same degree of
chemical stability as the anhydrate, whilst the 0.5 hydrate and
0.75 hydrate decompose with time.
Test Example 5
[0262] Water Solubility of
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid anhydrate (prepared as
in Example 1),
S-(-)-9-Fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid 0.2 hydrate (prepared as
in Example 2),
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid sodium salt monohydrate
(prepared as in Example 5),
S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-
5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt 0.75
hydrate (prepared as in Example 8),
8-{4[2(R)-amino-3-phenylpropionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-
-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid
acetate (prepared as in Example 30).
[0263] Water solubilities of the compounds listed above were
measured. The measurement results are listed in Table 9
TABLE-US-00010 TABLE 9 Water Solubility at 27.degree. C. Distilled
Water Sample (pH 6.8) Anhydrate 0.19 mg/ml 0.2 hydrate 0.24 mg/ml
Na Salt.cndot.H.sub.2O >1000 mg/ml Arginine Salt.cndot.0.25
H.sub.2O 75 mg/ml Arginine Salt.cndot.0.75 H.sub.2O 94 mg/ml
D-Ala-S-(Nadifloxacin).cndot.AcOH >250 mg/ml
[0264] As can be seen from the above results, the salt shows
superior water solubility.
[0265] The following examples relate to
S-(-)-9-fluoro-8(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid, its salts, prodrugs,
derivatives and hydrates thereof of the Formula I, wherein the
percentages indicated in the examples for the salts, prodrugs,
derivatives and hydrate of the compounds of the invention are
calculated on the basis of
S-(-)-9-fluoro-8(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid.
Composition Example 1
[0266] TABLE-US-00011 Tablet composition Ingredient % w/w 1.
S-(-)-9-fluoro-8(4-hydroxypiperidin-1-yl)- 10-90
5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]
quinolizine-2-carboxylic acid or an optically pure compound of the
invention of formula I. 2. Cyclodextrin & derivatives 5-40 3.
Sodium citrate 0.1-5 4. Microcrystalline cellulose 1-50 5.
Polyvinyl pyrrolidone 0.1-9 6. Cross carmellose sodium 0.1-5 7.
Starch 2-30 8. Lactose 2-40 9. Magnesium stearate 0.1-5 10. Talc
purified 0.1-5 11. Hydroxypropyl methyl cellulose 0.1-6 12.
Polyethylene glycol 400 0.1-2 13. Titanium Dioxide 0.1-2
[0267] The active ingredient
S-(-)-9-fluoro-8(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid or an optically pure
compound of the invention of formula I is mixed with cyclodextrin
and its derivatives, sodium citrate, microcrystalline cellulose,
corn starch and lactose. Wet granulate with polyvinyl pyrrolidone.
Dry the granulate. Mix with cross carmellose sodium, magnesium
stearate and talc purified. Compress the tablets. Film coat the
tablets using mixture of hydroxypropylmethyl cellulose,
polyethylene glycol 400 and titanium dioxide in appropriate
solvent.
Composition Example 2
[0268] TABLE-US-00012 Injection Composition Ingredient % w/v 1.
S-(-)-9-fluoro-8(4-hydroxypiperidin-1-yl)- Up to 10
5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]
quinolizine-2-carboxylic acid or an optically pure compound of the
invention of formula I. 2. Sodium citrate 0-3 3. Sodium hydroxide
q.s. and trometamol q.s. to q.s. adjust pH between 8.0-9.9 4.
Disodium edetate 0-0.5 5. Water for injection q.s. to 100
[0269] The active ingredient
S-(-)-9-fluoro-8(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid or an optically pure
compound of the invention of formula I and sodium citrate is
dissolved in water for injection. Disodium edetate is added and
dissolved. pH is adjusted with 1% sodium hydroxide solution and
trometamol. Volume to be made. Filter through 0.2 micron membrane
filter. Fill in vials and autoclave at 121.degree. C. for 15
minutes.
Composition Example 3
[0270] TABLE-US-00013 Injection Formulation Ingredient % w/v 1.
S-(-)-9-fluoro-8(4-hydroxypiperidin-1-yl)- Up to 10
5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo [i,j]
quinolizine-2-carboxylic acid or an optically pure compound of the
invention of fomula I. 2. L-arginine 0.1-10 3. Sodium citrate 0-3.5
4. Sodium hydroxide to adjust pH between 8.0-9.9 q.s. 5. Disodium
edetate 0-0.5 6. Water for injection q.s. to 100
[0271] Dissolve L-arginine in water for injection. Add and dissolve
S-(-)-9-fluoro-8(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid or an optically pure
compound of the invention of formula I by stirring in above
solution. Add sodium citrate and dissolve. Add disodium edetate and
dissolve by stirring. Check pH and adjust if necessary with 1%
sodium hydroxide solution. Make up volume with water for injection.
Sterilise by filtration through 0.2.mu. membranes. Fill in to
containers aseptically and seal.
Composition Example 4
Topical Composition
[0272] A typical pharmaceutical cream containing 1%
S-(-)-9-fluoro-8(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid or an optically pure
compound of the invention of formula I was prepared using the
following composition: TABLE-US-00014 Ingredient % w/v
S-(-)-9-fluoro-8(4-hydroxypiperidin-1-yl)-5-methyl- 0.1-10
6,7-dihydro-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid or
an optically pure compound of the invention of formula I
Diethanolamine 0.1-2 Trometamol 0-0.5 Sodium hydroxide q.s. to
adjust pH between 8.0-9.9 q.s. Liquid paraffin 0-20
Microcrystalline wax 0-10 Cetomacrogol 1000 0.1-5 Propylene glycol
0-20 Disodium EDTA 0-0.5 Sodium disulphite 0-0.5 Cetostearyl
alcohol 0.1-15 Purified water q.s. to 100
[0273] The active ingredient is
S-(-)-9-fluoro-8(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid or an optically pure
compound of the invention of formula I. The remaining components
are inert or auxiliary. The composition of liquid paraffin,
microcrystalline wax and cetomacrogol 1000 is prepared and added to
the solution of
S-(-)-9-fluoro-8(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5-
H-benzo[i,j]quinolizine-2-carboxylic acid or an optically pure
compound of the invention of formula I in a mixture of
diethanolamine/trometamol. The mixture is homogenised and to the
resultant cream is added propylene glycol, sodium bisulphite and
disodium EDTA. The composition is made up to 100% with purified
water to give the final composition. The cream is stable when
stored at a temperature not exceeding 35.degree. C. The pH of
stability is between 8.0 to 9.5.
* * * * *