Note: Descriptions are shown in the official language in which they were submitted.
CA 02554527 2006-07-25
WO 2005/073231 PCT/EP2005/000373
Cycloalkyl substituted 7-amino-4-quinolone-3-carboxylic acid derivatives,
method for the
production thereof and their use as medicaments
The invention relates to cycloalkyl-substituted 7-amino-4-quinolone-3-
carboxylic acid
derivatives and to the physiologically tolerated salts and physiologically
functional derivatives
thereof.
Compounds of similar structure have already been described in the art (Link,
Helmut;
Bernauer, Karl; Englert Gerhard, Helvetica Chimica Acta 65(8), 1982, 2645-
2667).
The invention was based on the object of providing compounds which display a
therapeutically usable blood glucose-lowering effect.
The invention therefore relates to compounds of the formula I
R8 R6 O O
i
R7'N ~ R1
R5 X N R2
R3
in which the meanings are
Rl OH, O-(C1-C6)-alkyl, NHZ, NH-(C1-C6)-alkyl, N-((C~-C6)-alkyl)2 or
O-(C, -C6)-OCO-(C I -C6)-alkyl;
R2 H, (C1-C6)-alkyl or phenyl;
R3 H, (C~-C8)-alkyl, (C3-C7)-cycloalkyl, pyridyl or phenyl, where alkyl may be
substituted by R9 and where pyridyl or phenyl may be substituted by R10;
R9 NHz, NH-(C1-C6)-alkyl, N-((C~-C6)-alkyl)z, -(C3-C7)-cycloalkyl,
heteroalkyl,
heteroaryl, O-phenyl or phenyl, where phenyl and heteroaryl may be substituted
by Rl 1;
CA 02554527 2006-07-25
2
R10 F, Cl, Br, (C1-C6-alkyl), O-(C~-C6)-alkyl, COOH, COO-(C1-C6)-alkyl, N'H2,
NH-(Cl-C6)-alkyl or N-((C1-C6)-alkyl)2;
R11 F, Cl, (C1-C6-alkyl), O-(C1-C6)-alkyl, COON or COO-(C,-C4)-alkyl;
X N;
R5, R6, independently of one another, H, F, Cl, Br, OH, NOZ, CN, (C~-C6)-alkyl
or O-
(CI-C6)-alkyl, where alkyl may be substituted more than once by F, Cl or Br;
R7 H or (C1-C6)-alkyl;
R8 (C3-CIZ)-cycloalkyl, where cycloalkyl may be substituted by (C1-C4)-alkyl,
(C1-
Ca)-alkenyl, (C1-C4)-alkynyl, F, Cl, CN, CF3, COOH or COO-(C1-Ca)-alkyl;
and the physiologically tolerated salts thereof.
Preference is given to compounds of the formula I in which one or more
radicals have the
following meaning:
R1 OH, O-(C1-C6)-alkyl, NHZ, NH-(C~-C6)-alkyl, N-((C~-C6)-alkyl)Z or
O-(C1-C6)-OCO-(C~-C6)-alkyl;
R2 H;
R3 H, (C1-Cg)-alkyl, (C3-C~)-cycloalkyl, pyridyl or phenyl, where alkyl may be
substituted by R9 and where pyridyl or phenyl may be substituted by R10;
R9 NH2, NH-(C1-C6)-alkyl, N-((C1-C6)-alkyl)2, -(C3-C7)-cycloalkyl,
heteroalkyl,
heteroaryl, O-phenyl or phenyl, where phenyl and heteroaryl may be substituted
by Rl l;
R10 F, Cl, Br, (C1-C6-alkyl), O-(Cl-C6)-alkyl, COOH, COO-(C~-C6)-alkyl, NH2,
CA 02554527 2006-07-25
3
NH-(C1-C6)-alkyl or N-((C,-C6)-alkyl)2;
Rl 1 F, Cl, (C1-C6-alkyl), O-(C1-C6)-alkyl, COOH or COO-(C1-Ca)-alkyl;
X N;
RS H, F, Cl, Br, OH, N02, CN, (C1-C6)-alkyl or O-(C1-C6)-alkyl, where alkyl
may
be substituted more than once by F, Cl or Br;
R6 H;
R7 H;
R8 (C3-C~2)-cycloalkyl, where cycloalkyl may be substituted by (C~-C4)-alkyl,
(C1-
C4)-alkenyl, (C1-C4)-alkynyl, F, Cl, CN, CF3, COOH or COO-(C1-C4)-alkyl;
and the physiologically tolerated salts thereof.
Particular preference is given to compounds of the formula I in which one or
more radicals
have the following meaning: -
R1 OH, O-(C,-C6)-alkyl;
R2 H;
R3 (C,-C8)-alkyl;
R9 NHZ, NH-(CI-C6)-alkyl, N-((C1-C6)-alkyl)2, -(C3-C7)-cycloalkyl,
heteroalkyl,
heteroaryl, O-phenyl or phenyl, where phenyl and heteroaryl may be substituted
by Rl l;
R10 F, Cl, Br, (C1-C6-alkyl), O-(Ci-C6)-alkyl, COOH, COO-(C~-C6)-alkyl, NH2,
NH-(Ci-C6)-alkyl or N-((C1-C6)-alkyl)Z;
CA 02554527 2006-07-25
4
R11 F, Cl, (C1-C6-alkyl), O-(C,-C6)-alkyl, COOH or COO-(Cl-C4)-alkyl;
X N;
RS H, F, Cl, Br, OH, N02, CN, (Ct-C6)-alkyl or O-(Cr-C6)-alkyl, where alkyl
may
be substituted more than once by F, Cl or Br;
R6 H;
R7 H;
R8 (C3-C,Z)-cycloalkyl, where cycloalkyl may be substituted by (Cr-C4)-alkyl,
(Cr-
C4)-alkenyl, (C~-C4)-alkynyl, F, Cl, CN, CF3, COOH or COO-(C~-Ca)-alkyl;
and the physiologically tolerated salts thereof.
The invention relates to compounds of the formula I in the form of their
racemates, racemic
mixtures and pure enantiomers and to their diastereomers and mixtures thereof.
The alkyl radicals in the substituents R1, R2, R3, RS, R6, R7, R8, R9, R10 and
R11 may be
both straight-chain and branched.
If radicals or substituents may occur more than once in the compounds of the
formula I, they
may all, independently of one another, have the stated meanings and be
identical or different.
Pharmaceutically acceptable salts are, because their solubility in water is
greater than that of
the initial or basic compounds, particularly suitable for medical
applications. These salts must
have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically
acceptable acid
addition salts of the compounds of the invention are salts of inorganic acids
such as
hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and
sulfuric acid, and of
organic acids such as, for example, acetic acid, benzenesulfonic, benzoic,
citric,
ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic,
malefic, malic,
methanesulfonic, succinic, p-toluenesulfonic and tartaric acid. Suitable
pharmaceutically
acceptable basic salts are ammonium salts, alkali metal salts (such as sodium
and potassium
CA 02554527 2006-07-25
salts), alkaline earth metal salts (such as magnesium and calcium salts),
trometamol (2-amino-
2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine, or ethylenediamine.
Salts with a pharmaceutically unacceptable anion such as, for example,
trifluoroacetate
likewise belong within the framework of the invention as useful intermediates
for the
preparation or purification of pharmaceutically acceptable salts and/or for
use in
nontherapeutic, for example in vitro, applications.
The term "physiologically functional derivative" used herein refers to any
physiologically
tolerated derivative of a compound of the formula I of the invention, for
example an ester,
which on administration to a mammal such as, for example, a human is able to
form (directly
or indirectly) a compound of the formula I or an active metabolite thereof.
Physiologically functional derivatives include prodrugs of the compounds of
the invention.
Such prodrugs can be metabolized in vivo to a compound of the invention. These
prodrugs
may themselves be active or not.
The compounds of the invention may also exist in various polymoiphous forms,
for example
as amorphous and crystalline polymorphous forms. All polymorphous forms of the
compounds of the invention belong within the framework of the invention and
are a further
aspect of the invention.
All references to "compound(s) of formula I" hereinafter refer to compounds)
of the
formula I as described above, and their salts, solvates and physiologically
functional
derivatives as described herein.
A heteroaryl radical means a pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl,
indolyl,
benzimidazolyl, thiophenyl or a furanyl radical.
The compounds) of the formula (I) can also be administered in combination with
further
active ingredient.
The amount of a compound of formula I necessary to achieve the desired
biological effect
depends on a number of factors, for example the specific compound chosen, the
intended use,
CA 02554527 2006-07-25
6
the mode of administration and the clinical condition of the patient. The
daily dose is
generally in the range from 0.3 mg to 100 mg (typically from 3 mg and 50 mg)
per day and
per kilogram of bodyweight, for example 3-10 mg/kg/day. An intravenous dose
may be, for
example, in the range from 0.3 mg to 1.0 mg/kg, which can suitably be
administered as
infusion of 10 ng to 100 ng per kilogram and per minute. Suitable infusion
solutions for these
purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng
to 10 mg, per
milliliter. Single doses may contain, for example, from 1 mg to 10 g of the
active ingredient.
Thus, ampoules for injections may contain, for example, from 1 mg to 100 mg,
and single-
dose formulations which can be administered orally, such as, for example,
tablets or capsules,
may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg.
For the therapy
of the abovementioned conditions, the compounds of formula I may be used as
the compound
itself, but they are preferably in the form of a pharmaceutical composition
with an acceptable
carrier. The carnet must, of course, be acceptable in the sense that it is
compatible with the
other ingredients of the composition and is not harmful for the patient's
health. The carrier
may be a solid or a liquid or both and is preferably formulated with the
compound as a single
dose, for example as a tablet, which may contain from 0.05% to 95% by weight
of the active
ingredient. Other pharmaceutically active substances may likewise be present,
including other
compounds of formula I. The pharmaceutical compositions of the invention can
be produced
by one of the known pharmaceutical methods, which essentially consist of
mixing the
ingredients with pharmacologically acceptable carriers and/or excipients.
Pharmaceutical compositions of the invention are those suitable for oral,
rectal, topical,
peroral (for example sublingual) and parenteral (for example subcutaneous,
intramuscular,
intradermal or intravenous) administration, although the most suitable mode of
administration
depends in each individual case on the nature and severity of the condition to
be treated and
on the nature of the compound of formula I used in each case. Coated
formulations and coated
slow-release formulations also belong within the framework of the invention.
Preference is
given to acid- and gastric juice-resistant formulations. Suitable coatings
resistant to gastric
juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate,
hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic
acid and methyl
methacrylate.
Suitable pharmaceutical compounds for oral administration may be in the form
of separate
units such as, for example, capsules, cachets, suckable tablets or tablets,
each of which contain
CA 02554527 2006-07-25
7
a defined amount of the compound of formula I; as powders or granules; as
solution or
suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-
in-oil emulsion.
These compositions may, as already mentioned, be prepared by any suitable
pharmaceutical
method which includes a step in which the active ingredient and the carrier
(which may
consist of one or more additional ingredients) are brought into contact. The
compositions are
generally produced by uniform and homogeneous mixing of the active ingredient
with a liquid
and/or finely divided solid carrier, after which the product is shaped if
necessary. Thus, for
example, a tablet can be produced by compressing or molding a powder or
granules of the
compound, where appropriate with one or more additional ingredients.
Compressed tablets
can be produced by tableting the compound in free-flowing form such as, for
example, a
powder or granules, where appropriate mixed with a binder, glidant, inert
diluent and/or one
or more surface-active/dispersing agents) in a suitable machine. Molded
tablets can be
produced by molding the compound, which is in powder foml and is moistened
with an inert
liquid diluent, in a suitable machine.
Pharmaceutical compositions which are suitable for peroral (sublingual)
administration
comprise suckable tablets which contain a compound of formula I with a
flavoring, normally
sucrose and gum arabic or tragacanth, and pastilles which comprise the
compound in an inert
base such as gelatin and glycerol or sucrose and gum arabic.
Pharmaceutical compositions suitable for parenteral administration comprise
preferably sterile
aqueous preparations of a compound of formula I, which are preferably isotonic
with the
blood of the intended recipient. These preparations are preferably
administered intravenously,
although administration may also take place by subcutaneous, intramuscular or
intradermal
injection. These preparations can preferably be produced by mixing the
compound with water
and making the resulting solution sterile and isotonic with blood. Injectable
compositions of
the invention generally contain from 0.1 to S% by weight of the active
compound.
Pharmaceutical compositions suitable for rectal administration are preferably
in the form of
single-dose suppositories. These can be produced by mixing a compound of the
formula I
with one or more conventional solid carriers, for example cocoa butter, and
shaping the
resulting mixture.
Pharmaceutical compositions suitable for topical use on the skin are
preferably in the form of
CA 02554527 2006-07-25
8
ointment, cream, lotion, paste, spray, aerosol or oil. Carriers which can be
used are
petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or
more of these
substances. The active ingredient is generally present in a concentration of
from 0.1 to 15% by
weight of the composition, for example from 0.5 to 2%.
Transdermal administration is also possible. Pharmaceutical compositions
suitable for
transdermal uses can be in the form of single plasters which are suitable for
long-term close
contact with the patient's epidermis. Such plasters suitably contain the
active ingredient in an
aqueous solution which is buffered where appropriate, dissolved and/or
dispersed in an
adhesive or dispersed in a polymer. A suitable active ingredient concentration
is about 1 % to
35%, preferably about 3% to 15%. A particular possibility is for the active
ingredient to be
released by electrotransport or iontophoresis as described, for example, in
Pharmaceutical
Research, 2(6): 318 (1986).
Further active ingredients suitable for combination products are:
all antidiabetics mentioned in the Rote Liste 2001, chapter 12. They may be
combined with
the compounds of the formula I of the invention in particular for a
synergistic improvement of
the effect. Administration of the active ingredient combination may take place
either by
separate administration of the active ingredients to the patient or in the
form of combination
products in which a plurality of active ingredients are present in one
pharmaceutical
preparation. Most of the active ingredients listed below are disclosed in the
USP Dictionary of
USAN and International Drug Names, US Pharmacopeia, Rockville 2001.
Antidiabetics include insulin and insulin derivatives such as, for example,
Lantus~ (see
www.lantus.com) or HIVIR 1964, fast-acting insulins (see US 6,221,633), GLP-1
derivatives
such as, for example, those disclosed in WO 98/08871 of Novo Nordisk A/S, and
orally
effective hypoglycemic active ingredients.
The orally effective hypoglycemic active ingredients include, preferably,
sulfonylureas,
biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones,
glucosidase inhibitors,
glucagon antagonists, GLP-1 agonists, potassium channel openers such as, for
example, those
disclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin
sensitizers,
inhibitors of liver enzymes involved in the stimulation of gluconeogenesis
and/or
glycogenolysis, modulators of glucose uptake, compounds which alter lipid
metabolism, such
as antihyperlipidemic active ingredients and antilipidemic active ingredients,
compounds
CA 02554527 2006-07-25
9
which reduce food intake, PPAR and PXR agonists and active ingredients which
act on the
ATP-dependent potassium channel of the beta cells.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with an HMGCoA reductase inhibitor such as simvastatin,
fluvastatin,
pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a cholesterol absorption inhibitor such as, for example,
ezetimibe, tiqueside,
pamaqueside.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a PPAR gamma agonist, such as, for example, rosiglitazone,
pioglitazone,
JTT-501, Gl 262570.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with PPAR alpha agonist, such as, for example, GW 9578, GW 7647.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a mixed PPAR alpha/gamma agonist, such as, for example, GW
1536,
AVE 8042, AVE 8134, AVE 0847, or as described in PCT/US 11833, PCT/US 11490,
DE10142734.4.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a fibrate such as, for example, fenofibrate, clofibrate,
bezafibrate.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with an MTP inhibitor such as, for example, implitapide, BMS-
201038,
R-103757.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with bile acid absorption inhibitor (see, for example, US
6,245,744 or
US 6,221,897), such as, for example, HMR 1741.
CA 02554527 2006-07-25
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a CETP inhibitor, such as, for example, JTT-705.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a polymeric bile acid adsorbent such as, for example,
cholestyramine,
colesevelam.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with an LDL receptor inducer (see US 6,342,512), such as, for
example,
10 HMR1171, HMR1586.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with an ACAT inhibitor, such as, for example, avasimibe.
1 S In one embodiment of the invention, the compounds of the formula I are
administered in
combination with an antioxidant, such as, for example, OPC-14117.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a lipoprotein lipase inhibitor, such as, for example, NO-
1886.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with an ATP-citrate lyase inhibitor, such as, for example, SB-
204990.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a squalene synthetase inhibitor, such as, for example, BMS-
188494.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a lipoprotein(a) antagonist, such as, for example, CI-1027 or
nicotinic acid.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a lipase inhibitor, such as, for example, orlistat.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with insulin.
CA 02554527 2006-07-25
11
In one embodiment, the compounds of the formula I are administered in
combination with a
sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or
glimepiride.
In one embodiment, the compounds of the formula I are administered in
combination with a
biguanide, such as, for example, metformin.
In one further embodiment, the compounds of the formula I are administered in
combination
with a meglitinide, such as, for example, repaglinide.
In one embodiment, the compounds of the formula I are administered in
combination with a
thiazolidinedione, such as, for example, troglitazone, ciglitazone,
pioglitazone, rosiglitazone
or the compounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation,
in
particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-
quinazolinylmethoxy]phenyl]methyl]-
2,4-thiazolidinedione.
1n one embodiment, the compounds of the formula I are administered in
combination with an
a-glucosidase inhibitor, such as, for example, miglitol or acarbose.
1 S In one embodiment, the compounds of the formula I are administered in
combination with an
active ingredient which acts on the ATP-dependent potassium channel of the
beta cells, such
as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or
repaglinide.
In one embodiment, the compounds of the formula I are administered in
combination with
more than one of the aforementioned compounds, e.g. in combination with a
sulfonylurea and
metformin, with a sulfonylurea and acarbose, repaglinide and metformin,
insulin and a
sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and
lovastatin, etc.
In a further embodiment, the compounds of the formula I are administered in
combination
with CART modulators (see "Cocaine-amphetamine-regulated transcript influences
energy
metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M.:
Hormone and
Metabolic Research (2001), 33(9), 554-558), NPY antagonists, e.g. naphthalene-
1-sulfonic
acid {4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexylmethyl}amide;
hydrochloride
(CGP 71683A)), MC4 agonists (e.g. 1-amino-1,2,3,4-tetrahydronaphthalene-2-
carboxylic acid
[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-
yl)-
1-(4-chlorophenyl)-2-oxoethyl]-amide; (WO 01/91752)), orexin antagonists (e.g.
CA 02554527 2006-07-25
12
1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea; hydrochloride (SB-
334867-A)),
H3 agonists (3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-
c]pyridin-
5-yl)propan-1-one oxalic acid salt (WO 00/63208)); TNF agonists, CRF
antagonists (e.g.
[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine
(WO
00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists, [i3
agonists (e.g.
1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1 H-indol-6-
yloxy)-
ethylamino]-ethanol hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating
hormone)
agonists, CCK-A agonists (e.g. {2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-
cyclohexyl-
ethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}acetic acid
trifluoroacetic acid salt
(WO 99/15525)), serotonin reuptake inhibitors (e.g. dexfenfluramine), mixed
sertoninergic
and noradrenergic compounds (e.g. WO 00/71549), SHT agonists e.g. 1-(3-
ethylbenzofuran-
7-yl)piperazine oxalic acid salt (WO 01/09111), bombesin agonists, galanin
antagonists,
growth hormone (e.g. human growth hormone), growth hormone-releasing compounds
(6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1 H-isoquinoline-
2-carboxylic acid tent-butyl ester (WO 01/85695)), TRH agonists (see, for
example,
EP 0 462 884), uncoupling protein 2 or 3 modulators, leptin agonists (see, for
example, Lee,
Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia.
Leptin
agonists as a potential approach to the treatment of obesity. Drugs of the
Future (2001), 26(9),
873-881), DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors
(e.g.
WO 00/40569), PPAR modulators (e.g. WO 00/78312), RXR modulators or TR-[3
agonists.
In one embodiment of the invention, the other active ingredient is leptin;
see, for example,
"Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-
Ambrosi, Javier;
Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-1622.
In one embodiment, the other active ingredient is dexamphatamine or
amphetamine.
In one embodiment, the other active ingredient is fenfluramine or
dexfenfluramine.
In another embodiment, the other active ingredient is sibutramine.
In one embodiment, the other active ingredient is orlistat.
In one embodiment, the other active ingredient is mazindol or phentermine.
CA 02554527 2006-07-25
13
In one embodiment, the compounds of the formula I are administered in
combination with
bulking agents, preferably insoluble bulking agents (see, for example,
carob/Caromax~ (Zunft
H J; et al., Carob pulp preparation for treatment of hypercholesterolemia,
ADVANCES IN
THERAPY (2001 Sep-Oct), 18(5), 230-6.) Caromax is a carob-containing product
from
Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark
Hochst, 65926
Frankfurt/Main)). Combination with Caromax~ is possible in one preparation or
by separate
administration of compounds of the formula I and Caromax~. Caromax~ can in
this
connection also be administered in the form of food products such as, for
example, in bakery
products or muesli bars.
It will be appreciated that every suitable combination of the compounds of the
invention with
one or more of the aforementioned compounds and optionally one or more further
pharmacologically active substances will be regarded as falling within the
protection
conferred via the present invention.
CA 02554527 2006-07-25
14
CHa
~N / OiCHa
CHa ~ J
N
O~NH CHa HaC CHa
S
\ CHa %Ha OPC-14117
/ O
Ci \
/ ,,, O 00
Ci ''~ 'OH
\ O SB-204990 HO
N ~- O O~CHa
N , \\ i
P
/ w0~\CHa
N
NO-1886 O OH
OH O CHa
H3C
HaC O CHa
O CI-1027
HO.~, // CH
\ / S~ H3C a
O
/ O \ ~ P/OV0 CHa
O ~ ~ H3C O CHa
O'~/O CHa
BMS-188494
O
CHa
O
r N O
O
CHa
O \
/ o
N O p H
G I 262
CA 02554527 2006-07-25
Preparation of the compounds of the formula I is described in the following
schemes:
Compounds of the formula II can be reacted under Buchwald conditions with
amines of the
formula III to give compounds of the formula IV in which R1' has the meaning
of an ester. In
this case, Y is Br, I or tr~iflate. With these Buchwald conditions it is
possible to employ
5 catalyst systems with Pd(OAc)Z or Pd2(dba)3 as palladium sources, BINAP,
xanthphos and
DPPF as ligands and Cs2C03, K3P04 or NaOtBu as bases. Solvents which can be
used are, for
example, toluene, DME, dioxane, THF or DMF. The reaction conditions may be
chosen from
conventional heating or heating and reaction in a microwave. (Literature:
Buchwald, Acc.
Chem. Res. 1998, 31, 805)
10 Optional subsequent hydrolysis of the compounds of the formula IV and
optional conversion
to different amides or esters lead to compounds of the formula I.
Scheme l:
Rs
Rs ~ R'~N~H Rs Rs ~ Rs Rs
i
Y ~ Rr 111 ~~Id ~ r Rr~N I ~ I 2Rv
R 'R
~ ~ ~~ i
R5 ' X- 'NI _RZ R5 I XI 'N_ 'RZ R X N, R
Rs Ra R
N
The examples listed below serve to illustrate the invention but without
restricting it.
CA 02554527 2006-07-25
16
Table 1:
R8
I
R7'N ~
R5
ExampleR1 R2 R3 X RS R6 R7 R8
1 OEt H Et N Me H H
2 OEt H Et N Me H H
1
~x
3 OH H Et N Me H H
X
4 OH H Et N Me H H
The activity of the compounds was assayed as follows:
Glyco~pho~hor~rlase a activity assay
The effect of compounds on the activity of the active form of glycogen
phosphorylase (GPa)
was measured in the reverse direction by following the synthesis of glycogen
from glucose
1-phosphate by determining the liberation of inorganic phosphate. All the
reactions were
carried out as duplicate determinations in microtiter plates with 96 wells
(Half Area Plates,
Costar No 3696), measuring the change in absorption owing to the formation of
the reaction
product at the wavelength specified hereinafter in a Multiskan Ascent Elisa
Reader (Lab
Systems, Finland).
CA 02554527 2006-07-25
17
In order to measure the GPa enzymic activity in the reverse direction, the
general method of
Engers et al. (Engers HD, Shechosky S, Madsen NB, Can J Biochem 1970
Ju1;48(7):746-754)
was used to measure the conversion of glucose 1-phosphate into glycogen and
inorganic
phosphate, with the following modifications: human glycogen phosphorylase a
(for example
with 0.76 mg of protein/ml (Aventis Pharma Deutschland GmbH), dissolved in
buffer solution
E (25 mM (3-glycerophosphate, pH 7.0, 1 mM EDTA and 1 mM dithiothreitol) was
diluted
with buffer T (50 mM Hepes, pH 7.0, 100 mM KCI, 2.5 mM EDTA, 2.5 mM MgCl2-
6HZ0)
and addition of 5 mg/ml glycogen to a concentration of 10 ~g of protein/ml.
Test substances
were prepared as 10 mM solution in DMSO and diluted to SO uM with buffer
solution T. To
10 ~1 of this solution were added 10 ~l of 37.5 mM glucose, dissolved in
buffer solution T,
and 5 mg/mL glycogen, plus 10 ~1 of a solution of human glycogen phosphorylase
a (10 ~g of
protein/ml) and 20 ul of glucose 1-phosphate, 2,5 mM. The baseline glycogen
phosphorylase
a activity in the absence of test substance was determined by adding 10 ~1 of
buffer solution T
(0.1 % DMSO). The mixture was incubated at room temperature for 40 minutes,
and the
1 S liberated inorganic phosphate was measured by the general method of
Drueckes et al.
(Drueckes P, Schinzel R, Palm D, Anal Biochem 1995 Sep 1;230(1):173-177) with
the
following modifications: 50 ~1 of a stop solution of 7.3 mM ammonium
molybdate, 10.9 mM
zinc acetate, 3.6% ascorbic acid, 0.9% SDS are added to 50 ~l of the enzyme
mixture. After
incubation at 45°C for 60 minutes, the absorption at 820 nm was
measured. To determine the
background absorption, in a separate mixture the stop solution was added
immediately after
addition of the glucose 1-phosphate solution.
This test was earned out with a concentration of 10 ~M of the test substance
in order to
determine the particular inhibition of glycogen phosphorylase a in vitro by
the test substance.
Table 2: Biological activity
Ex. % inhibition
at 10 M
1 24
2 42
3 35
4 16
It is evident from the table that the compounds of the formula I inhibit the
activity of glycogen
phosphorylase a and are thus very suitable for lowering the blood glucose
level.
CA 02554527 2006-07-25
18
The preparation of some examples is described in detail below, and the other
compounds of
the formula I were obtained analogously:
Experimental part:
Example 2
Ethyl 1-ethyl-6-( 1-ethynylcyclohexylamino)-7-methyl-4-oxo-1,4-dihydro-[
1,8]naphthyridine-
3-carboxylate
\\ H O O
N I ., i o--~.
N~NI
100 mg of ethyl 6-bromo-1-ethyl-8-methyl-4-oxo-1,4-dihydroquinolone-3-
carboxylate were
transferred together with 36 mg of 1-ethynylcyclohexylamine, 6.6 mg of
Pd(OAc)Z, 36 mg of
XANTPHOS and 200 mg of cesium carbonate into a suitable reaction vessel, a
protective gas
atmosphere was generated with argon, and 10 ml of dioxane were added. The
mixture was
then heated at 80°C for 8 hours. The pure product was isolated from the
reaction solution by
chromatography on an HPLC system. This entailed use of a Merck Purospher- RP
18 column
and an acetonitrile:water mixture as eluent; the initial acetonitrile content
was 15% and rose to
95% over the course of 20 minutes.
Yield: 4%
CA 02554527 2006-07-25
19
Example 3
1-Ethyl-6-( 1-ethynylcyclohexylamino)-7-methyl-4-oxo-1,4-dihydro[
1,8]naphthyridine-
3-carboxylic acid
o 0
OH
N
Ethyl 1-ethyl-6-( 1-ethynylcyclohexylamino)-7-methyl-4-oxo-1,4-dihydro [ 1, 8]
naphthyridine-
3-carboxylate (10 mg) was dissolved in 5 ml of dioxane, 2.5 equivalents of a 1
N NaOH
solution were added, and the mixture was heated at 60°C for 4 h.
Removal of the solvent in
vacuo was followed by chromatography on an HPLC system to purify the product.
The pure
product was isolated from the reaction solution by chromatography on an HPLC
system. This
entailed use of a Merck Purospher-RP 18 column and an acetonitrile:water
mixture as eluent;
the initial acetonitrile content was 15% and rose to 95% over the course of 20
minutes.
Yield: 85
