U.S. patent application number 15/241150 was filed with the patent office on 2017-02-23 for novel annelated phenoxyacetamides.
The applicant listed for this patent is Boehringer Ingelheim International GmbH. Invention is credited to Dieter HAMPRECHT, Armin HECKEL, Joerg KLEY, Dieter WIEDENMAYER.
Application Number | 20170050992 15/241150 |
Document ID | / |
Family ID | 58157436 |
Filed Date | 2017-02-23 |
United States Patent
Application |
20170050992 |
Kind Code |
A1 |
HECKEL; Armin ; et
al. |
February 23, 2017 |
NOVEL ANNELATED PHENOXYACETAMIDES
Abstract
The present invention relates to compounds of formula (I)
##STR00001## wherein R.sup.1, R.sup.2, R.sup.3, and Z.sup.- have
one of the meanings as indicated in the specification or a
pharmaceutically acceptable salt thereof, to the use of compounds
of formula (I) as a medicament, to pharmaceutical compositions
comprising at least one compound of formula (I), as well as to
medicament combinations containing one or more compounds of formula
(I).
Inventors: |
HECKEL; Armin; (Biberach an
der Riss, DE) ; HAMPRECHT; Dieter; (Pozzolengo,
IT) ; KLEY; Joerg; (Mittelbiberach, DE) ;
WIEDENMAYER; Dieter; (Biberach an der Riss, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Boehringer Ingelheim International GmbH |
Ingelheim am Rhein |
|
DE |
|
|
Family ID: |
58157436 |
Appl. No.: |
15/241150 |
Filed: |
August 19, 2016 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
62207405 |
Aug 20, 2015 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 405/14 20130101;
C07C 53/18 20130101; A61K 31/541 20130101; C07C 53/06 20130101;
A61K 45/06 20130101; A61K 31/675 20130101; C07D 401/14 20130101;
C07D 403/12 20130101; A61K 31/497 20130101; C07F 9/65583
20130101 |
International
Class: |
C07F 9/6558 20060101
C07F009/6558; A61K 31/541 20060101 A61K031/541; A61K 45/06 20060101
A61K045/06; C07D 401/14 20060101 C07D401/14; A61K 31/675 20060101
A61K031/675; C07D 403/12 20060101 C07D403/12; A61K 31/497 20060101
A61K031/497; C07D 405/14 20060101 C07D405/14; C07C 53/18 20060101
C07C053/18 |
Claims
1. A compound of formula (I), ##STR00066## wherein R.sup.1 and
R.sup.2 are independently selected from ethyl, 2-hydroxyethyl,
2-tetrahydrofuranylmethyl and 4-tetrahydropyranylmethyl; R.sup.3 is
selected from a moiety NR.sup.aR.sup.b, wherein R.sup.a and R.sup.b
are independently selected from hydrogen, C.sub.1-C.sub.4-alkyl and
1-(2-ethoxyethyl)piperidin-4-yl, wherein C.sub.1-C.sub.4-alkyl may
carry 1 or 2 substituents selected from hydroxyl, amino,
C.sub.1-C.sub.4-alkylamino, di-C.sub.1-C.sub.4-alkylamino,
(dimethylphosphinoyl)methoxy, 4-(dimethylphosphinoyl)phenyl,
6-methyl-3-hydroxy-pyridin-2-yl and the oxyanion of
6-methyl-3-hydroxy-pyridin-2-yl, provided that at least one of
R.sup.a and R.sup.b is different from hydrogen, or wherein R.sup.a
and R.sup.b together with the nitrogen they are attached to form a
heterocyclic moiety selected from piperidine and
1-oxothiomorpholinyl, wherein the heterocyclic moiety may carry 1
or 2 substituents selected from NH.sub.2; and Z.sup.- is selected
from chloride, bromide, iodide, hydroxide, hydrogensulfate,
sulfate, nitrate, phosphate, formate, acetate, trifluoroacetate,
fumarate, citrate, tartrate, oxalate, succinate, mandelate,
methanesulfonate and p-toluenesulfonate, or Z.sup.- may be absent
if R.sup.a or R.sup.b is C1-C.sub.4-alkyl and carries the oxyanion
of 6-methyl-3-hydroxy-pyridin-2-yl; or a pharmaceutically
acceptable salt thereof.
2. The compound according to claim 1, wherein at least one of
R.sup.1 and R.sup.2 is ethyl; or a pharmaceutically acceptable salt
thereof.
3. The compound according to claim 2, wherein both of R.sup.1 and
R.sup.2 are ethyl; or a pharmaceutically acceptable salt
thereof.
4. The compound according to claim 1, wherein Z.sup.- is selected
from chloride, formate, and trifluoroacetate; or a pharmaceutically
acceptable salt thereof.
5. The compound according to claim 1, wherein R.sup.3 is selected
from ##STR00067## or a pharmaceutically acceptable salt
thereof.
6. The compound according to claim 1, selected from the group
consisting of ##STR00068## ##STR00069## ##STR00070## ##STR00071##
or a pharmaceutically acceptable salt thereof.
7. A method for the treatment of a disease selected from among
respiratory diseases or complaints and allergic diseases of the
airways, or dry eyes comprising administering a therapeutically
effective amount of a compound according to claim 1 to a patient in
need thereof.
8. The method according to claim 7, wherein the disease is selected
from among chronic bronchitis, acute bronchitis, bronchitis caused
by bacterial or viral infection or fungi or helminths, allergic
bronchitis, toxic bronchitis, chronic obstructive bronchitis
(COPD), asthma, paediatric asthma, bronchiectasis, allergic
alveolitis, allergic or non-allergic rhinitis, chronic sinusitis,
idiopathic pulmonary fibrosis, cystic fibrosis or mucoviscidosis,
alpha-1-antitrypsin deficiency, cough, pulmonary emphysema,
interstitial lung diseases, alveolitis, hyperreactive airways,
nasal polyps, pulmonary oedema, pneumonitis of different origins,
and dry eyes.
9. A pharmaceutical composition comprising at least one compound
according to claim 1 or a pharmaceutically acceptable salt thereof
and a pharmaceutically acceptable carrier.
10. The pharmaceutical composition according to claim 9, wherein
the composition further comprises as further active substances, one
or more compounds selected from among the categories of further
ENaC inhibitors, betamimetics, anticholinergics, corticosteroids,
PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine
agonists, H1-antihistamines, PAF-antagonists, MAP-kinase
inhibitors, MPR4-Inhibitors, iNOS-Inhibitors, SYK-Inhibitors,
correctors of the cystic fibrosis transmembrane regulator (CFTR)
and CFTR potentiators.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to compounds of formula
(I)
##STR00002##
wherein R.sup.1, R.sup.2, R.sup.3, and Z.sup.- have one of the
meanings as indicated in the specification or a pharmaceutically
acceptable salt thereof, to the use of compounds of formula (I) as
a medicament, to pharmaceutical compositions comprising at least
one compound of formula (I), as well as to medicament combinations
containing one or more compounds of formula (I).
BACKGROUND TO THE INVENTION
[0002] WO2011079087, WO2015007516, WO2015007519, and WO2015007517
disclose amides of 3,5-diamino-6-halo-pyrazine-2-carboxylic acid of
related structure showing ENaC (Epithelial Sodium Channel)
inhibitor activity.
[0003] Venanzi teaches that the amino group in position 5 of the
pyrazine moiety of amiloride and its analogs is essential for the
stability of the blocking complex with ENaC (Venanzi et al.,
Journal of Medicinal Chemistry, 1992, Vol. 35 (9), 1643-1649).
[0004] The problem of the present invention is to provide further
compounds for therapeutic use for the treatment of
pathophysiological processes treatable by the blockade of an
epithelial sodium channel, particularly for the treatment of the
lungs and airways.
[0005] Such compounds should be potent inhibitors of ENaC. Suitable
IC.sub.50 values determined in the Ussing Chamber assay are
typically below 30 nM.
[0006] Additionally, such compounds should exhibit a low
permeability which is beneficial for topical lung treatment.
Suitable permeability values determined in the CALU-3 cells assay
are typically below 6.times.10.sup.-7 cm/s.
[0007] Additionally, such compounds should have high solubility in
aqueous media which is beneficial for administration by inhalation
of an aqueous solution. Suitable solubility values in aqueous
buffer with a physiologically acceptable pH value are 2% or
higher.
[0008] Additionally, such compounds should have high hydrolytic
stability in aqueous media which is beneficial for administration
by inhalation of an aqueous solution.
[0009] Additionally, such compounds should inhibit in vivo water
resorption in the lung upon topical administration. Topical lung
administration of pharmacologically active doses of the compounds
of the present invention should not or only to a low extent
increase plasma aldosterone levels.
[0010] Surprisingly, it has been found that the claimed
3-amino-6-chloro-pyrazine-2-carboxylic acid derivatives which do
not possess an amino group in position 5 of the pyrazine moiety are
potent ENaC inhibitors and further possess the additional
characteristics outlined above.
DETAILED DESCRIPTION OF THE INVENTION
[0011] The present invention relates to compounds of formula
(I),
##STR00003## [0012] wherein [0013] R.sup.1 and R.sup.2 are
independently selected from ethyl, 2-hydroxyethyl,
2-tetrahydrofuranylmethyl and 4-tetrahydropyranylmethyl; [0014]
R.sup.3 is selected from a moiety NR.sup.aR.sup.b, wherein R.sup.a
and R.sup.b are independently selected from hydrogen,
C.sub.1-C.sub.4-alkyl and 1-(2-ethoxyethyl)piperidin-4-yl, wherein
said C.sub.1-C.sub.4-alkyl may carry 1 or 2 substituents selected
from hydroxyl, amino, C.sub.1-C.sub.4-alkylamino,
di-C.sub.1-C.sub.4-alkylamino, (dimethylphosphinoyl)methoxy,
4-(dimethylphosphinoyl)phenyl, 6-methyl-3-hydroxy-pyridin-2-yl and
the oxyanion of 6-methyl-3-hydroxy-pyridin-2-yl, provided that at
least one of R.sup.a and R.sup.b is different from hydrogen, [0015]
or wherein R.sup.a and R.sup.b together with the nitrogen they are
attached to form a heterocyclic moiety selected from piperidine and
1-oxothiomorpholinyl, wherein the heterocyclic moiety may carry 1
or 2 substituents selected from NH.sub.2; and [0016] Z.sup.- is
selected from chloride, bromide, iodide, hydroxide,
hydrogensulfate, sulfate, nitrate, phosphate, formate, acetate,
trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate,
mandelate, methanesulfonate and p-toluenesulfonate, [0017] or
Z.sup.- may be absent if R.sup.a or R.sup.b is
C.sub.1-C.sub.4-alkyl and carries the oxyanion of
6-methyl-3-hydroxy-pyridin-2-yl; [0018] or a pharmaceutically
acceptable salt thereof.
[0019] The compounds of formula (I) or the pharmaceutically
acceptable salts thereof as defined herein are particularly
suitable for the treatment of pathophysiological processes
treatable by the blockade of an epithelial sodium channel,
particularly for the treatment of the lungs and airways.
[0020] Accordingly the present invention further relates to
compounds of formula (I) as defined herein or pharmaceutically
acceptable salts thereof for use as a medicament.
[0021] The present invention further relates to compounds of
formula (I) as defined herein or pharmaceutically acceptable salts
thereof for use in the treatment of a disease selected from among
respiratory diseases or complaints and allergic diseases of the
airways.
[0022] The present invention further relates to compounds of
formula (I) as defined herein or pharmaceutically acceptable salts
thereof for use in the treatment of a disease selected from among
chronic bronchitis, acute bronchitis, bronchitis caused by
bacterial or viral infection or fungi or helminths, allergic
bronchitis, toxic bronchitis, chronic obstructive bronchitis
(COPD), asthma (intrinsic or allergic), pediatric asthma,
bronchiectasis, allergic alveolitis, allergic or non-allergic
rhinitis, chronic sinusitis, cystic fibrosis or mucoviscidosis,
alpha-1-antitrypsin deficiency, cough, pulmonary emphysema,
interstitial lung diseases, alveolitis, hyperreactive airways,
nasal polyps, pulmonary oedema, pneumonitis of different origins,
and dry eyes.
[0023] The present invention further relates to a pharmaceutical
composition comprising at least one compound of formula (I) as
defined herein or pharmaceutically acceptable salts thereof and a
pharmaceutically acceptable carrier.
[0024] The present invention further relates to medicament
combinations containing besides one or more compounds of formula
(I) as defined herein or pharmaceutically acceptable salts thereof,
as further active substance one or more compounds selected from
among the categories of further ENaC inhibitors, betamimetics,
anticholinergics, corticosteroids, PDE4-inhibitors,
LTD4-antagonists, EGFR-inhibitors, dopamine agonists, H1
antihistamines, PAF-antagonists, MAP-kinase inhibitors,
MPR4-Inhibitors, iNOS-Inhibitors, SYK-Inhibitors, corrections of
the cystic fibrosis transmembrane regulator (CFTR) and CFTR
potentiators or double or triple combinations thereof.
TERMS AND DEFINITIONS
[0025] Terms not specifically defined herein should be given the
meanings that would be given to them by one of skill in the art in
light of the disclosure and the context. As used in the
specification, however, unless specified to the contrary, the
following terms have the meaning indicated and the following
conventions are adhered to.
[0026] In the groups, radicals, or moieties defined below, the
number of carbon atoms is often specified preceding the group, for
example, C.sub.1-6-alkyl means an alkyl group or radical having 1
to 6 carbon atoms.
[0027] In general in single groups like HO, H.sub.2N, OS, O.sub.2S,
NC (cyano), HOOC, F.sub.3C or the like, the skilled artisan can see
the radical attachment point(s) to the molecule from the free
valences of the group itself. For combined groups comprising two or
more subgroups, the terminal term indicates the radical attachment
point, for example, the substituent "aryl-C.sub.1-3-alkyl" means an
aryl group which is bound to a C.sub.1-3-alkyl-group, the latter of
which is bound to the core or to the group to which the substituent
is attached.
[0028] If a compound of the present invention is depicted in form
of a chemical name and as a formula, in case of any discrepancy the
formula shall prevail.
[0029] Many of the following terms may be used repeatedly in the
definition of a formula or group and in each case have one of the
meanings given above, independently of one another.
[0030] Unless specifically indicated, according to the invention a
given chemical formula or name shall encompass tautomers and all
stereo, optical and geometrical isomers (e.g. enantiomers,
diastereomers, E/Z isomers etc.) and racemates thereof as well as
mixtures in different proportions of the separate enantiomers,
mixtures of diastereomers, or mixtures of any of the foregoing
forms where such isomers and enantiomers exist, as well as salts,
including pharmaceutically acceptable salts thereof and solvates
thereof such as for instance hydrates including solvates of the
free compounds or solvates of a salt of the compound.
[0031] The term "substituted" as used herein, means that any one or
more hydrogens on the designated atom is replaced with a selection
from the indicated group, provided that the designated atom's
normal valence is not exceeded, and that the substitution results
in a stable compound.
[0032] The expressions "prevention", "prophylaxis", "prophylactic
treatment" or "preventive treatment" used herein should be
understood synonymous and in the sense that the risk to develop a
condition mentioned hereinbefore is reduced, especially in a
patient having elevated risk for said conditions or a corresponding
anamnesis, e.g. elevated risk of developing metabolic disorder such
as diabetes or obesity or another disorder mentioned herein. Thus
the expression "prevention of a disease" as used herein means the
management and care of an individual at risk of developing the
disease prior to the clinical onset of the disease. The purpose of
prevention is to combat the development of the disease, condition
or disorder, and includes the administration of the active
compounds to prevent or delay the onset of the symptoms or
complications and to prevent or delay the development of related
diseases, conditions or disorders. Success of said preventive
treatment is reflected statistically by reduced incidence of said
condition within a patient population at risk for this condition in
comparison to an equivalent patient population without preventive
treatment.
[0033] The expression "treatment" or "therapy" means therapeutic
treatment of patients having already developed one or more of said
conditions in manifest, acute or chronic form, including
symptomatic treatment in order to relieve symptoms of the specific
indication or causal treatment in order to reverse or partially
reverse the condition or to delay the progression of the indication
as far as this may be possible, depending on the condition and the
severity thereof. Thus the expression "treatment of a disease" as
used herein means the management and care of a patient having
developed the disease, condition or disorder. The purpose of
treatment is to combat the disease, condition or disorder.
Treatment includes the administration of the active compounds to
eliminate or control the disease, condition or disorder as well as
to alleviate the symptoms or complications associated with the
disease, condition or disorder.
[0034] The term "pharmaceutically acceptable" is employed herein to
refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, and commensurate with a
reasonable benefit/risk ratio.
[0035] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound
is modified by making acid or base salts thereof. Examples of
pharmacologically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines;
alkali or organic salts of acidic residues such as carboxylic
acids; and the like. For example, such salts include salts from
ammonia, L-arginine, betaine, benethamine, benzathine, calcium
hydroxide, choline, deanol, diethanolamine
(2,2'-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol,
2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine,
1H-imidazole, lysine, magnesium hydroxide,
4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide,
1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine
(2,2',2''-nitrilotris(ethanol)), tromethamine, zinc hydroxide,
acetic acid, 2.2-dichloro-acetic acid, adipic acid, alginic acid,
ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid,
2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric
acid, (+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid,
citric acid, cyclamic acid, decanoic acid, dodecylsulfuric acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxy-ethanesulfonic acid, ethylenediaminetetraacetic acid,
formic acid, fumaric acid, galactaric acid, gentisic acid,
D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic
acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid,
glycine, glycolic acid, hexanoic acid, hippuric acid, hydrobromic
acid, hydrochloric acid, isobutyric acid, DL-lactic acid,
lactobionic acid, lauric acid, lysine, maleic acid, (-)-L-malic
acid, malonic acid, DL-mandelic acid, methanesulfonic acid,
galactaric acid, naphthalene-1,5-disulfonic acid,
naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic
acid, nitric acid, octanoic acid, oleic acid, orotic acid, oxalic
acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid,
propionic acid, (-)-L-pyroglutamic acid, salicylic acid,
4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid,
sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid,
p-toluenesulfonic acid and undecylenic acid. Further
pharmaceutically acceptable salts can be formed with cations from
metals like aluminium, calcium, lithium, magnesium, potassium,
sodium, zinc and the like. (also see Pharmaceutical salts, Berge,
S. M. et al., J. Pharm. Sci., (1977), 66, 1-19).
[0036] The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound which
contains a cationic group and optionally an additional basic or
acidic moiety by conventional chemical methods. Generally, such
salts can be prepared by reacting other salt forms of these
compounds with a sufficient amount of the appropriate base or acid
in water or in an organic diluent like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile, or a mixture thereof.
Moreover, counterions can generally be exchanged by ion exchange
chromatography.
[0037] Salts of other acids than those mentioned above which for
example are useful for purifying or isolating the compounds of the
present invention (e.g. trifluoro acetate salts) also comprise a
part of the invention.
[0038] The term "C.sub.1-n-alkyl", wherein n is an integer from 2
to n, either alone or in combination with another radical denotes
an acyclic, saturated, branched or linear hydrocarbon radical with
1 to n C atoms. For example the term C.sub.1-4-alkyl, as used
herein and in the terms C.sub.1-4-alkylamino and
di-C.sub.1-4-alkylamino, embraces the radicals H.sub.3C--,
H.sub.3C--CH.sub.2--, H.sub.3C--CH.sub.2--CH.sub.2--,
H.sub.3C--CH(CH.sub.3)--, H.sub.3C--CH.sub.2--CH.sub.2--CH.sub.2--,
H.sub.3C--CH.sub.2--CH(CH.sub.3)--,
H.sub.3C--CH(CH.sub.3)--CH.sub.2--, and
H.sub.3C--C(CH.sub.3).sub.2--.
[0039] In all cases of contradictions between structure and their
naming, structure shall prevail.
PREFERRED EMBODIMENTS
[0040] One particular embodiment of the present invention relates
to compounds of formula (I) or pharmaceutically acceptable salt
thereof, wherein at least one of R.sup.1 and R.sup.2 is ethyl.
Preferred are compounds of formula (I) or pharmaceutically
acceptable salt thereof, wherein both of R.sup.1 and R.sup.2 are
ethyl.
[0041] Another particular embodiment of the present invention
relates to compounds of formula (I) or pharmaceutically acceptable
salt thereof, wherein R.sup.1 or R.sup.2 is selected from
2-hydroxyethyl, (S)-2-tetrahydrofuranylmethyl, and
4-tetrahydropyranylmethyl.
[0042] Another particular embodiment of the present invention
relates to compounds of formula (I) or pharmaceutically acceptable
salts thereof, wherein Z is selected from chloride, formate, and
trifluoroacetate.
[0043] Another particular embodiment of the present invention
relates to compounds of formula (I) or pharmaceutically acceptable
salt thereof, wherein in R.sup.a or R.sup.b in the definition of
R.sup.3 is C.sub.1-C.sub.4-alkyl which carries 1 substituent
selected from dimethylphosphinoylmethoxy and
4-(dimethylphosphinoyl)phenyl.
[0044] Another particular embodiment of the present invention
relates to compounds of formula (I) or pharmaceutically acceptable
salt thereof, carrying at least one primary or secondary amino
group, i.e compounds of formula (I) or pharmaceutically acceptable
salt thereof, wherein at least one of R.sup.a or R.sup.b in the
definition of R.sup.3 is C.sub.1-C.sub.4-alkyl, wherein
C.sub.1-C.sub.4-alkyl carries at least one substituent selected
from amino and C.sub.1-C.sub.4-alkylamino, or compounds of formula
(I) or pharmaceutically acceptable salt thereof, wherein R.sup.a
and R.sup.b in the definition of R.sup.3 together with the nitrogen
they are attached to are piperidine carrying 1 or 2 substituents
selected from NH.sub.2.
[0045] Another particular embodiment of the present invention
relates to compounds of formula (I) or pharmaceutically acceptable
salt thereof, wherein R.sup.a or R.sup.b in the definition of
R.sup.3 is C.sub.1-C.sub.4-alkyl carrying
6-methyl-3-hydroxy-pyridin-2-yl or the oxyanion of
6-methyl-3-hydroxy-pyridin-2-yl.
[0046] Preferred are compounds of formula (I) or the
pharmaceutically acceptable salts thereof, wherein R.sup.3 is
selected from
##STR00004##
[0047] Another particular embodiment of the present invention
relates to compounds of formula (I) or pharmaceutically acceptable
salts thereof, selected from
##STR00005## ##STR00006## ##STR00007## ##STR00008##
[0048] Another particular embodiment of the present invention
relates to compounds of formula (I) characterized by a topological
polar surface area value (TPSA) of at least 150. The term
"topological polar surface area" as used herein refers to a value
calculated as disclosed for the fragment based PSA in Ertl P. et
al., J. Med. Chem, 43 (2000), 3714-3717. Such compounds of formula
(I) will usually have a TPSA value in the range of from 150 to 250.
Such compounds are in to particular compounds selected from
##STR00009## ##STR00010##
[0049] Any of the substituents defined above may be combined with
each other to form additional compounds not specifically
exemplified above. Particularly preferred are compounds of formula
(I) or the pharmaceutically acceptable salts thereof wherein at
least 2, 3, or 4 of the substituents defined herein have one of the
particular or preferred meanings as defined herein.
Preparation
[0050] The following methods are suitable for preparing compounds
of general formula (I).
[0051] The compounds according to the invention may be obtained
using methods of synthesis which are known to the one skilled in
the art and described in the literature of organic synthesis.
General methods for functional groups protection and deprotection
steps are described e.g. in: Greene, T. W. and Wuts, P. G. M.
(eds.): Protective Groups in Organic Synthesis, third edition 1999;
John Wiley and Sons, Inc. Preferably the compounds are obtained
analogously to the methods of preparation explained more fully
hereinafter, in particular as described in the experimental
section.
##STR00011##
[0052] Compounds of general formula (I) can be prepared by standard
amidation procedures from acids of general formula (IIa) and
primary or secondary amines of general formula R.sup.3H applying
e.g. the coupling reagent HATU. Obvious to the one skilled in the
art, the counterion Z.sup.- of a permanently charged product, e.g.
(I), may generally be different from the counterion Z of the
permanently charged starting material, e.g. (Ia), depending on the
conditions of synthesis and purification. Amines R.sup.3H can be
prepared using methods of synthesis which are known to one skilled
in the art and described in the literature of organic synthesis.
The scope of the substituents of amines R.sup.3H may exceed what is
claimed for compounds of general formula (I) hereinafter. The
substituents in compounds R.sup.3H may e.g. carry protecting groups
necessary or advantageous in the amidation step. R.sup.3 can be
modified in subsequent synthetic steps through e.g. deprotection
and/or amidation reactions.
[0053] Compounds of general formula (IIa) can be prepared by
standard ester cleavage procedures from esters of general formula
(II). The residue R in compounds of general formulas (II) through
(XI) may be selected from e.g. methyl, ethyl, or tert-butyl.
Furthermore, within the reaction sequence, the residue R may be
changed by applying e.g. ester cleavage followed by esterification
procedures.
[0054] Compounds of general formula (II) can be prepared by
standard amidation procedures from amines of general formula (III)
and 3-amino-6-chloro-pyrazine-2-carboxylic acid applying e.g. the
coupling reagent HATU.
[0055] Amines of general formula (III) can be prepared from
compounds of general formula (IV) by removing the phthalimide
protecting group applying standard deprotection procedures, e.g.
heating with hydrazine hydrate in ethanol.
[0056] Benzimidazolium compounds of general formula (IV) can be
prepared by alkylation of benzimidazoles of general formula (V) by
e.g. heating with an appropriate alkylating agent R.sup.1X or
R.sup.2X (e.g. an optionally substituted alkyl bromide) in a
suitable solvent like e.g. THF.
##STR00012##
[0057] Alternatively, compounds of general formula (I) can be
prepared by standard amidation procedures from
3-amino-6-chloro-pyrazine-2-carboxylic acid and primary amines of
general formula (VI) applying e.g. the coupling reagent HATU.
[0058] Amines of general formula (VI) can be prepared from
compounds of general formula (VII) by removing the phthalimide
protecting group applying standard deprotection procedures, e.g.
heating with hydrazine hydrate in ethanol.
[0059] Compounds of general formula (VII) can be prepared by
standard amidation procedures from acids of general formula (IVa)
and primary or secondary amines of general formula R.sup.3H
applying e.g. the coupling reagent HATU. Compounds of general
formula (IVa) can be prepared by standard ester cleavage procedures
from esters of general formula (IV). Alternatively, compounds of
general formula (VII) can be prepared by alkylation of
benzimidazoles of general formula (VIII) by e.g. heating with an
appropriate alkylating agent R.sup.1X or R.sup.2X (e.g. an
optionally substituted alkyl halide) in a suitable solvent like
e.g. THF.
[0060] Compounds of general formula (VIII) can be prepared by
standard amidation procedures from acids of general formula (Va)
and primary or secondary amines of general formula R.sup.3H
applying e.g. the coupling reagent HATU. Compounds of general
formula (Va) can be prepared by standard ester cleavage procedures
from esters of general formula (V).
##STR00013##
[0061] Benzimidazoles of general formula (V) can be prepared from
phenylenediamines (IX) in a two step prodecure comprising (i)
amidation with N-phthaloylglycine using e.g. the coupling reagent
TBTU and (ii) ring closure under acid catalysis, e.g. in glacial
acetic acid at elevated temperature. Phenylenediamines of general
formula (IX) can be prepared from the respective nitroanilines (X)
by standard nitro reduction conditions (e.g. catalytic
hydrogenation using raney-nickel as a catalyst).
[0062] Nitroaninlines of general formula (X) can be prepared from
aryl halides of general formula (XI) by nucleophilic substitution
with a primary amine H.sub.2N--R.sup.1 or H.sub.2N--R.sup.2. The
leaving group X in compounds (XI) may be F or Cl. The substituents
R.sup.1 or R.sup.2 present in the amine applied may exceed the
claims for R.sup.1 and R.sup.2 in compounds of general formula (I).
R.sup.1 and R.sup.2 may e.g. contain protective groups that can be
removed at later stages by standard deprotection procedures.
[0063] Aryl halides of general formula (XI) can be prepared by
alkylation of appropriate nitro-halo-phenols (XII) with bromo- or
chloroacetic acid esters at elevated temperature in the presence of
a base like e.g. potassium carbonate in a solvent like e.g.
ACN.
[0064] Compounds of formula (I), as defined hereinbefore, are salts
containing an anion Z.sup.-. These anions Z.sup.- may be derived
from synthesis or purification or changed from one anionic species
to another suitable anionic species by methods known to those
skilled in the art. Examples of such methods are ion exchange using
for example ion exchange resins or displacement of an acid
counterion from its salt using another, usually stronger, acid. For
example, treatment of a compound of formula (I), as defined
hereinbefore, where Z.sup.- is CF.sub.3COO.sup.-, with HCl in a
suitable solvent, such as water, methanol or diethyl ether, may
produce a compound of formula 1, as defined hereinbefore, where
Z.sup.- is Cl.sup.-.
[0065] Certain compounds of formula (I), as defined hereinbefore,
may contain groups that may be further converted into the salts
thereof, for pharmaceutical use particularly into pharmaceutically
acceptable salts with inorganic or organic acids and bases. Acids
which may be used for this purpose include for example hydrochloric
acid, hydrobromic acid, sulphuric acid, methanesulphonic acid,
phosphoric acid, fumaric acid, succinic acid, lactic acid, citric
acid, tartaric acid or maleic acid. Corresponding processes are
known to the skilled person.
[0066] Moreover, where one or more stereoisomers may exist, the
compounds of general formula (I) or intermediates in the synthesis
of compounds of general formula (I) may be obtained as mixtures and
then resolved into their stereoisomers, e.g. enantiomers and/or
diastereomers. Thus, for example, cis/trans mixtures may be
resolved into their cis and trans isomers, and racemic compounds
may be separated into their enantiomers.
[0067] Thus, for example, the cis/trans mixtures may be resolved by
chromatography into the cis and trans isomers thereof. The
compounds of general formula (I) or intermediates in the synthesis
of compounds of general formula (I), which occur as racemates may
be separated by methods known per se (cf. Allinger N. L. and Eliel
E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience,
1971) into their optical antipodes and compounds of general formula
(I) or intermediates in the synthesis of compounds of general
formula (I) with at least 2 asymmetric carbon atoms may be resolved
into their diastereomers on the basis of their physical-chemical
differences using methods known per se, e.g. by chromatography
and/or fractional crystallization, and, if these compounds are
obtained in racemic form, they may subsequently be resolved into
the enantiomers as mentioned above.
[0068] The racemates are preferably resolved by column
chromatography on chiral phases or by crystallization from an
optically active solvent or by reacting with an optically active
substance which forms salts or derivatives such as esters or amides
with the racemic compound. Salts may be formed with
enantiomerically pure acids for basic compounds and with
enantiomerically pure bases for acidic compounds. Diastereomeric
derivatives are formed with enantiomerically pure auxiliary
compounds, e.g. acids, their activated derivatives, or alcohols.
Separation of the diastereomeric mixture of salts or derivatives
thus obtained may be achieved by taking advantage of their
different physico-chemical properties, e.g. differences in
solubility; the free antipodes may be released from the pure
diastereomeric salts or derivatives by the action of suitable
agents. Optically active acids in common use for such a purpose are
e.g. the D- and L-forms of tartaric acid, dibenzoyltartaric acid,
ditoluoyltartaric acid, malic acid, mandelic acid, camphorsulfonic
acid, glutamic acid, aspartic acid, or quinic acid. Optically
active alcohols applicable as auxiliary residues may be, for
example, (+) or (-)-menthol and optically active acyl groups in
amides may be, for example, (+)- or (-)-menthyloxycarbonyl.
[0069] The substances according to the invention are isolated and
purified in a manner known per se, for example by distilling off
the solvent under reduced pressure and recrystallizing the residue
obtained from a suitable solvent or subjecting it to one of the
customary purification methods, such as, for example, column
chromatography on a suitable support material.
[0070] The compounds according to the invention are advantageously
obtainable using the methods described in the examples that follow,
which may also be combined for this purpose with methods known to
the skilled person from his/her expert knowledge. Likewise, further
compounds according to this invention, whose preparation are not
explicitly described in the following examples, can be prepared
analogously or similarly to the examples.
EXAMPLES
[0071] Other features and advantages of the present invention will
become apparent from the following more detailed examples which
illustrate, by way of example, the principles of the invention.
[0072] Where no salt forms of compounds are specified, the compound
may exist as a free base or a salt or a zwitterion, depending on
the chemical structure, the synthesis conditions and the processes
of workup and purification applied. The skilled person will
appreciate that the compound is not limited to a certain salt form.
Where salt forms of compounds are specified, the stoichiometry of
the counterion is usually omitted. In case of multiply charged
counterions the skilled person will appreciate that the resulting
salt form is uncharged, leading to the corresponding stoichiometry.
The skilled person will appreciate that the compound is not limited
to the mono salt form and that it may exist as a disalt, trisalt or
other compound: counterion stoichiometries. Furthermore, the
skilled person will appreciate that such compound may unexpectedly
exist as a salt with a different counterion, depending on the
synthesis conditions and the processes of workup and purification
applied. Solely for the purpose of yield determination, an estimate
of the nature of the counterion and of compound: counterion
stoichiometry is made (as indicated by the formula given).
Synthesis of Intermediates
[0073] The following intermediates can be prepared as described in
the literature given in the table:
TABLE-US-00001 Intermediate No. Structure Literature and comments
I.1 ##STR00014## US2015/18315 ("compound VII.2") I.2 ##STR00015##
US2009/163552 I.3 ##STR00016## Intermediate I.3 can be prepared
starting from 4- fluoro-3-nitrophenol analogously to the procedure
described for the synthesis of intermediate I.2 (US2009/163552).
I.4 ##STR00017## Zeitschrift fuer Naturforschung, B: Chemical
Sciences 50,7 (1995) 1086-90 I.5 ##STR00018## Intermediate I.5 can
be prepared analogously to the procedure described for the
synthesis of 6-Methyl- 2-(methylaminomethyl)-pyridin-3-ol in J. Am.
Chem. Soc. 71 (1949) 2968-71.
Intermediate II.1
##STR00019##
[0075] A mixture of the aryl halide intermediate 1.3 (17.2 g; 63.6
mmol), (tetrahydropyran-4-yl)methylamine (11.5 g; 99.6 mmol) and
potassium carbonate (13.2 g; 95.3 mmol) in ACN (100 ml) is stirred
at 60.degree. C. for 2 h. The mixture is evaporated and the residue
is taken up in EE and washed with brine. The organic layer is
separated, dried (MgSO.sub.4) and evaporated.
[0076] C.sub.18H.sub.26N.sub.2O.sub.6 ESI Mass spectrum: m/z=367
[M+H]+
[0077] The following intermediates are prepared accordingly from
the respective aryl halide and the respective amine as indicated.
Depending on conditions applied, the syntheses may yield a free
base, a TFA salt or other salt forms which can be applied equally
to the syntheses of example compounds described below.
TABLE-US-00002 Intermediate Aryl halide amine No. Structure applied
applied Synthesis comment II.2 ##STR00020## I.1 ##STR00021## 2 eq.
amine; no additional base; solvent: methyl-THF II.3 ##STR00022##
I.2 ##STR00023## 2 eq. amine; no additional base; solvent: THF;
reaction at r.t. II.4 ##STR00024## I.1 ##STR00025## 2 eq. amine; no
additional base; solvent: THF; reaction at r.t.
##STR00026##
[0078] Intermediate II.1 (23.1 g; 63.1 mmol) in THF (200 ml) is
hydrogenated in a Parr apparatus (50.degree. C.; 3 bar hydrogen;
catalyst: 2.00 g Raney-Nickel. The catalyst is filtered off and the
solvent is evaporated.
[0079] C.sub.18H.sub.28N.sub.2O.sub.4
[0080] HPLC analytics: RT=0.45 min (HPLC method A)
[0081] The following intermediates are prepared accordingly from
the respective starting material as indicated. Depending on
conditions applied, the syntheses may yield a free base, a TFA salt
or other salt forms which can be applied equally to the syntheses
of example compounds described below.
TABLE-US-00003 Starting Intermediate material No. Structure applied
Synthesis comment III.2 ##STR00027## II.2 III.3 ##STR00028## II.3
Reaction at r.t.; catalyst: Pd/C 5% III.4 ##STR00029## VII.1
Reaction in methanolic ammonia at r.t. III.5 ##STR00030## II.4
catalyst: Pd/C 5%
Intermediate IV. 1
##STR00031##
[0082] Step 1:
[0083] A mixture of the diamino intermediate III.1 (21.2 g; 63.1
mmol), THF (250 ml), N-phthaloyl glycine (13.0 g; 63.1 mmol), TBTU
(20.3 g; 63.14 mmol) and triethylamine (9.63 ml; 69.4 mmol) is
stirred at RT for 4 h. The mixture is poured on ice-water (800 ml)
and stirred until the ice is melted. The precipitate is filtered
off with suction, washed with water and dried at 65.degree. C.
Step 2:
[0084] The so formed intermediate is taken up in acetic acid (30
ml) and dioxane (120 ml) and stirred at 95.degree. C. overnight.
The mixture is evaporated, taken up in EE and extracted
successively with Na.sub.2CO.sub.3 solution and water. The organic
layer is separated and evaporated. The residue is triturated with
TBDME, filtered off with suction and dried at 50.degree. C.
[0085] C.sub.28H.sub.31N.sub.3O.sub.6 ESI Mass spectrum: m/z=506
[M+H]+
[0086] The following intermediates are prepared accordingly from
the respective diamino compound as indicated. In cases where
precipitation does not occur, the intermediates are extracted.
Depending on conditions applied, the syntheses may yield a free
base, a TFA salt or other salt forms which can be applied equally
to the syntheses of example compounds described below.
TABLE-US-00004 diamino Intermediate compound No. Structure applied
Synthesis comment IV.2 ##STR00032## III.2 Crystallization from EE
IV.3 ##STR00033## III.3 Step 2: reaction in AcOH at 100.degree. C.;
crude product stirred in HCl (4M in dioxane) at 100.degree. C. for
4 h, evaporated, triturated with diethyl ether IV.4 ##STR00034##
III.5 Crystallized from ACN
Intermediate V.1
##STR00035##
[0088] A mixture of the acid intermediate IV.3 (2.00 g; 4.24 mmol),
the amine thiomorpholine-1-oxide (505 mg; 4.24 mmol), TBTU (1.36 g;
4.24 mmol), triethylamine (1.19 ml; 8.48 mmol) and DMF (20 ml) is
stirred at r.t. for 2 h. The mixture is poured on ice-water, then
extracted with EE. The organic layer is separated, dried
(MgSO.sub.4), filtered and evaporated. The residue is purified by
silica gel chromatography (DCM/MeOH 0->10%).
[0089] C.sub.27H.sub.28N.sub.4O.sub.6S ESI Mass spectrum: m/z=537
[M+H]+
[0090] The following compounds are prepared accordingly applying
the respective acid and amine as indicated. Depending on conditions
applied, the procedures may yield a chloride salt, a TFA salt or
bis-TFA salt, a zwitterion or other salt forms.
TABLE-US-00005 Intermediate Acid Amine Synthesis No. Structure
applied applied comment V.2 ##STR00036## ##STR00037## XI.1
Purification by RP-HPLC (C18; water- ACN--TFA)
Intermediate VI.1
##STR00038##
[0092] Step 1: A mixture of the benzimidazole intermediate IV.2
(5.00 g; 11.8 mmol), iodoethane (4.77 ml; 59.0 mmol) and ACN 50 ml)
is heated to 120.degree. C. (microwave irradiation; closed vessel)
for 2 h.
[0093] Step 2: The mixture is evaporated and the residue is stirred
at 65.degree. C. for 1 h in aq. HCl (4 mol/l; 50 ml; 200 mmol). The
mixture is freeze-dried.
[0094] Workup: The residue is purified by RP-HPLC (C18;
water/ACN/TFA).
[0095] C.sub.22H.sub.22N.sub.3O.sub.6 ESI Mass spectrum: m/z=424
[M+H]+
[0096] HPLC analytics: RT=0.37 min (HPLC method A)
[0097] The following intermediates are prepared accordingly from
the respective benzimidazole as indicated. Depending on conditions
applied, the syntheses may yield a free base, a TFA salt or other
salt forms which can be applied equally to the syntheses of example
compounds described below.
TABLE-US-00006 Intermediate Benzimidazole No. Structure applied
Synthesis comment VI.2 ##STR00039## IV.1 Step 2: reaction at
80.degree. C.; product filtered off upon cooling to r.t.; no
freeze-drying nor chromatography VI.3 ##STR00040## V.1 Step 2
omitted VI.4 ##STR00041## IV.4 Step 2 omitted
Intermediate VII.1
##STR00042##
[0099] A mixture of 4-iodobenzonitrile (2.29 g; 10.0 mmol),
dimethylphosphinoxide (800 mg; 10.3 mmol), triethylamine (6.97 ml;
50 mmol) and ACN (50 ml) is degassed and kept under Argon
atmosphere. Xantphos (400 mg; 0.691 mmol),
tris(dibenzylideneacetone)dipalladium (300 mg; 0.328 mmol) and
cesium carbonate (4.0 g; 12.3 mmol) are added and the mixture is
stirred under Argon at 80.degree. C. for 2 h. Water is added and
the mixture is extracted with EE. The organic layer is separated,
dried (MgSO.sub.4) and evaporated. The residue is purified by
silica gel chromatpgraphy (DCM/MeOH 0->15%).
[0100] C.sub.9H.sub.10NOP
[0101] HPLC analytics: RT=0.59 min (HPLC method B)
Intermediate VIII. 1
##STR00043##
[0103] Step 1: The acid intermediate VI.1 (1.06 g; 1.97 mmol) is
taken up in THF (10 ml).
[0104] Step 2: TBDMS chloride (594 mg; 3.94 mmol) and imidazole
(268 mg; 3.94 mmol) are added and the mixture is stirred at r.t.
for 3 days. Step 3: CDI (479 mg; 2.96 mmol) is added, and after 30
min stirring, the amine intermediate II1.4 (360 mg; 1.97 mmol) is
added and the mixture is further stirred overnight.
[0105] Step 4: TFA (3 ml) is added and the mixture is stirred at
r.t for 1 h.
[0106] Workup: The mixture is evaporated and the residue is
purified by RP-HPLC (C18; water/ACN/TFA).
[0107] C.sub.31H.sub.34N.sub.4O.sub.6P ESI Mass spectrum: m/z=589
[M+H]+
[0108] HPLC analytics: RT=0.39 min (HPLC method A)
[0109] The following compounds are prepared accordingly applying
the respective acid and amine as indicated. Depending on conditions
applied, the procedures may yield a chloride salt, a TFA salt or
bis-TFA salt, a zwitterion or other salt forms.
TABLE-US-00007 Intermediate Acid Amine No. Structure applied
applied Synthesis comment VIII.2 ##STR00044## VI.2 I.5 Steps 2 and
4 omitted
Intermediate IX.1
##STR00045##
[0111] A mixture of intermediate VIII.1 (210 mg; 0.254 mmol),
hydrazine hydrate (57.8 .mu.l; 0.762 mmol) and ethanol (5 ml) is
stirred at 70.degree. C. (bath temperature) for 2 h. Insolubles are
filtered off by suction, the filtrate is evaporated and purified by
RP-HPLC (C18, water/ACN/TFA).
[0112]
C.sub.23H.sub.32N.sub.4O.sub.4P.times.C.sub.2O.sub.2F.sub.3.times.C-
.sub.2HO.sub.2F.sub.3 ESI Mass spectrum: m/z=459 [M+H]+
[0113] HPLC analytics: RT=0.26 min (HPLC method A)
[0114] The following intermediates are prepared accordingly from
the respective protected amines as indicated. Depending on
conditions applied, the syntheses may yield a TFA salt or other
salt forms which can be applied equally to further synthesis
steps.
TABLE-US-00008 Protected amine Intermediate Structure applied
Synthesis comment IX.2 ##STR00046## VIII.2 IX.3 ##STR00047## VI.3
IX.4 ##STR00048## VI.4 Reaction in ACN/EtOH 1:1; 5 eq. hydrazine
hydrate
Intermediate X.1
##STR00049##
[0116] A mixture of intermediate IX.4 (13.5 g; 32.2 mmol) and aq.
HCl (4 mol/l; 100 ml; 400 mmol) is stirred at 80.degree. C. for 2
h, then cooled to r.t. Insolubles are filtered off and discarded.
The filtrate is freeze-dried after addition of ACN.
[0117] C.sub.14H.sub.20N.sub.3O.sub.3.times.HCl.times.Cl ESI Mass
spectrum: m/z=278 [M]+
Intermediate XI.1
##STR00050##
[0119] A mixture of intermediate X.1 (14.3 g; 40.8 mmol) and
methanolic HCl (50 ml) is refluxed for 30 min, then filtered hot
and evaporated to dryness.
[0120] C.sub.15H.sub.22N.sub.3O.sub.3.times.HCl.times.Cl ESI Mass
spectrum: m/z=292 [M]+
Intermediate XII.1
##STR00051##
[0122] A mixture of intermediate V.2 (2.00 g; 3.57 mmol) and aq.
HCl (1 mol/l; 7.13 ml; 7.13 mmol) is stirred at 50.degree. C.
overnight. The mixture is cooled to 1.degree. C., the precipitate
formed is filtered off with suction and dried at 50.degree. C.
[0123] C.sub.19H.sub.22ClN.sub.6O.sub.4.times.Cl ESI Mass spectrum:
m/z=433 [M]+
Intermediate XIII.1
##STR00052##
[0125] Step 1: To a mixture of 4-(BOC-amino)-piperidine (1.00 g;
4.99 mmol), DIPEA (1.72 ml; 9.99 mmol) and DMF (3.0 ml) is added
dropwise at r.t. 2-bromoethyl-ethylether (840 mg; 5.49 mmol). The
mixture is stirred for further 2 h, then water is added and the
mixture is extracted with diethyl ether. The organic layer is
separated, dried and evaporated to dryness.
[0126] Step 2: The BOC-protected intermediate obtained from step 1
is suspended in aq. HCl (6.10 ml; 24.4 mmol). The mixture is
stirred at r.t. for 1 h, then evaporated to dryness.
[0127] C.sub.9H.sub.20N.sub.2O.times.HCl
SYNTHESIS OF EXAMPLES
Example 1.01
##STR00053##
[0129] A mixture of 3-amino-6-chloro-pyrazine-2-carboxylic acid
(26.0 mg; 0.150 mmol), the amine intermediate IX.3 (100 mg; 0.151
mmol), TBTU (53.0 mg; 0.165 mmol), triethylamine (63.2 .mu.l; 0.450
mmol) and DMF (5.0 ml) is stirred at r.t. overnight. Volatiles are
evaporated and the residue is purified by RP-HPLC (C18;
water-ACN-TFA).
[0130]
C.sub.26H.sub.33ClN.sub.7O.sub.5S.times.C.sub.2O.sub.2F.sub.3 ESI
Mass spectrum: m/z=590 [M+H]+
[0131] HPLC analytics: RT=0.42 min (HPLC method D)
[0132] The following example compounds are prepared accordingly
from the respective amine as indicated. Depending on conditions
applied, the syntheses may unexpectedly yield other counterion
stoichiometries or other salt forms.
TABLE-US-00009 Ex- ample Amine RT HPLC No. Structure applied M+
(min) method 1.02 ##STR00054## IX.1 614 0.39 A 1.03 ##STR00055##
IX.2 681 (M + H)+ 0.38 A
Example 2.01
##STR00056##
[0134] Step 1: To a mixture of intermediate XII.1 (120 mg; 0.243
mmol), TBTU (156 mg; 0.486 mmol), triethylamine (101 .mu.l; 0.729
mmol) and DMF (3.0 ml) is added the amine tert-butyl
N-(3-aminopropyl)carbamate (42.3 mg; 0.243 mmol). The mixture is
stirred at r.t. for 3 h, then evaporated.
[0135] Step 2: The BOC-protected intermediate is purified by
RP-HPLC (C18; water-ACN-TFA), taken up in aq. HCl (37%; 1.0 ml) and
evaporated to dryness.
[0136] Step 3: The crude product is purified by RP-HPLC (C18;
water-ACN-TFA).
[0137]
C.sub.22H.sub.30ClN.sub.8O.sub.3.times.C.sub.2O.sub.2F.sub.3.times.-
C.sub.2HO.sub.2F.sub.3 ESI Mass spectrum: m/z=489 [M+H]+
[0138] HPLC analytics: RT=3.02 min (HPLC method C)
[0139] The following example compounds are prepared accordingly
from the respective amine as indicated. Depending on conditions
applied, the syntheses may unexpectedly yield other counterion
stoichiometries or other salt forms.
TABLE-US-00010 Example Amine Synthesis RT HPLC No. Structure
applied comment M+ (min) method 2.02 ##STR00057## ##STR00058## 489
2.97 C 2.03 ##STR00059## ##STR00060## Step 3 omitted 515 3.05 C
2.04 ##STR00061## I.4 Step 2 omitted 566 0.38 A 2.05 ##STR00062##
I.5 Step 2 omitted 611 0.37 A 2.06 ##STR00063## ##STR00064##
Footnote (a) 503 3.03 C 2.07 ##STR00065## XIII.1 Footnote (a) 587
3.28 C (a) Step 2 omitted; purification by RP-HPLC (C18;
water-ACN-formic acid)
Analytical Methods and Preparative Chromatography
[0140] As a rule, 1H-NMR and mass spectra have been obtained for
the compounds prepared. Mass peaks given (e.g. (M)+, (M+H)+,
(M+HCOO)--) refer to monoisotopic molecular weight.
Preparative HPLC:
[0141] Stationary phase (unless stated otherwise): XBridge C18; 10
.mu.m or SunFire C18; 10 .mu.m (both from waters,
www.waters.com)
Analytical HPLC/MS Methods
[0142] The HPLC retention times given are measured under the
following parameters.
HPLC Method A
TABLE-US-00011 [0143] Column: SunFire C18, 2.1 .times. 30 mm, 2.5
.mu.m (Waters) Gradient time % Sol % Sol Flow Temp [min] [H2O, 0.1%
TFA] [ACN] [ml/min] [.degree. C.] 0.00 99 1 1.5 60 0.02 99 1 1.5 60
1.00 0 100 1.5 60 1.10 0 100 1.5 60
HPLC Method B
TABLE-US-00012 [0144] Column: SunFire, 3 .times. 30 mm, 2.5 .mu.m
(Waters) Gradient time % Sol % Sol Flow Temp [min] [H2O, 0.1% TFA]
[ACN] [ml/min] [.degree. C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20
0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60
HPLC Method C
TABLE-US-00013 [0145] Column: Atlantis dC18 5 .mu.m 4.6 .times. 50
mm, Temp 35.degree. C. Mobile phase: A = H2O 90% + 10% CH3CN +
CF3COOH 0.05% B = CH3CN 90% + 10% H2O Time in min % A % B flow rate
in ml/min 0.00 100 0 1.3 0.70 100 0 1.3 4.5 0 100 1.3 5.80 0 100
1.3 6.00 100 0 1.3
HPLC Method D
TABLE-US-00014 [0146] Column: XBridge BEH C18, 2.1 .times. 30 mm,
1.7 .mu.m (Waters) Gradient time % Sol % Sol Flow Temp [min]
[H.sub.2O, 0.1% TFA] [ACN] [ml/min] [.degree. C.] 0.00 99 1 1.6 60
0.02 99 1 1.6 60 1.00 0 100 1.6 60 1.10 0 100 1.6 60
[0147] The following abbreviations are used above and hereinafter:
[0148] ACN Acetonitrile [0149] Aq. Aqueous [0150] BOC
tert-Butoxycarbonyl [0151] Cbz Carbobenzyloxy [0152] CH Cyclohexane
[0153] DCM Dichloromethane [0154] DIPEA Diisopropyl-ethylamine
[0155] DMAP 4-Dimethylaminopyridine [0156] DMF
N,N-Dimethylformamide [0157] DPPF
1,1'-Bis(diphenylphosphino)ferrocene [0158] EDC
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride [0159]
EE Ethyl acetate [0160] Eq. Molar equivalent [0161] ESI
Electrospray ionization [0162] h Hour [0163] HATU
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0164] HCl Hydrochloric acid [0165] KOH
Potassium hydroxide [0166] l Litre [0167] LiHMDS Lithium
bis(trimethylsilyl)amide [0168] M mol/l [0169] Min Minutes [0170]
Mp melting point [0171] NaOH Sodium hydroxide [0172] n.d. not
determined [0173] NMP N-Methylpyrrolidone [0174] Pd/C palladium on
charcoal [0175] r.t. ambient temperature (about 20.degree. C.)
[0176] RT retention time [0177] TBME Methyl tert-butyl ether [0178]
TBDMS Tert-butyl-dimethylsilyl- [0179] TBTU
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborat-
e [0180] TEA Triethylamine [0181] TFA Trifluoroacetic acid [0182]
THF Tetrahydrofurane [0183] TLC Thin Layer Chromatography [0184]
TMS Trimethylsilyl [0185] Xantphos
4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
Pharmacological Test Method
[0186] The IC.sub.50 values of the example compounds given above
were determined in the Ussing Chamber assay.
[0187] Ussing Chamber: Mouse kidney M-1 cells were cultivated in
DMEM containing 5% FCS and 5 .mu.M dexamethasone for 10 to 12 days
on polyester transwell filters. Filters were inserted into a
teflon-coated well-plate which fit into the ussing chamber system.
Prior to measurement the medium of M-1 cells was replaced with
Caco-2 transport buffer (Invitrogen, Germany). During measurements,
the Ussing chamber temperature was kept at 37.degree. C. Short
circuit currents (I_sc) were measured in the voltage-clamp mode
with the software package Lab View for data acquisition and
analysis. The transepithelial electrical resistance (TEER) was
determined by the application of voltage steps of .+-.5 mV every 5
sec. Compounds were administered at a final concentration of 3
.mu.M or at increasing concentrations (1-3-10 .mu.M) to the apical
solution. At the end of each experiment the amiloride sensitive
I_SC was measured by adding 3 .mu.M amiloride to the apical
compartment. Results are expressed as inhibition in percent of the
amiloride effect or as IC.sub.50.
[0188] With the example compounds given above, the following
IC.sub.50 values were determined in the Ussing Chamber assay:
TABLE-US-00015 Example 1.01 1.02 1.03 2.01 2.02 2.03 2.04 2.05 2.06
2.07 IC.sub.50 [nM] 10 10 8 1 2 1 3 3 1 3
Permeability in CALU-3 Cells:
[0189] Permeability measurements across polarized, confluent CALU-3
cell monolayers grown on permeable filter supports are used to
provide information on the potential of a compound to pass the lung
epithelium. Apparent permeability coefficients (Papp) of the
compounds across the CALU-3 cell monolayers are measured (pH 7.4,
37.degree. C.) in apical-to-basal (AB) and basal-to-apical (BA)
transport direction. AB permeability (Papp, AB) represents drug
absorption from the lung lumen into the blood and BA permeability
(Papp, BA) drug transport from the blood into the lung lumen mainly
via passive permeability since Calu-3 cells as well as lung
epithelial cells do not express efflux transporters like P-gp,
while uptake transporters may be expressed.
[0190] CALU-3 cells (1-2.times.10.sup.5 cells/1 cm.sup.2 area) are
seeded on filter inserts (Costar transwell polycarbonate filters,
0.4 .mu.m pore size) and cultured (for 10-12 days DMEM) until tight
monolayers are formed. Compounds of interest are dissolved in
appropriate solvent (DMSO, 10 mM stock solution). Stock solutions
are diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM
MgSO4, 1.8 mM CaCl2, 4.17 mM NaHCO3, 1.19 mM Na2HPO4.times.7H2O,
0.41 mM NaH2PO4.times.H2O, 15 mM HEPES, 20 mM glucose, 0.25% BSA,
pH 7.4) to prepare the transport solutions (10 .mu.M compound,
final DMSO<=0.5%). The transport solution (TL) is applied to the
apical or basolateral donor side for measuring A-B or B-A
permeability (3 filter replicates), respectively. The receiver side
contains the same buffer as the donor side. After 30 min of
accommodation, samples are collected at the start t0=0 min and at
the end of the experiment tn=90 min from the donor and at 0, 30,
60, and 90 min also from the receiver chamber. Volume removed is
replenished by HTP-4 buffer. The compound concentration in the
samples is measured by HPLC-MS/MS or scintillation counting. The
permeability coefficient (Papp) and efflux ratio are calculated
according to: Papp [cm/s]=(concentration receiver [nM]*volume
receiver [mL]/time interval [sec])*(1/filter area)*(1/donor
concentration [nM]).
[0191] With example compounds given above, the following
permeability values were determined in the CALU-3 cells assay:
TABLE-US-00016 Example 1.01 1.02 1.03 2.01 2.04 2.05 2.06 Papp, AB
0.8 0.6 0.4 0.2 <0.7 0.4 <1 [10.sup.-6 cm/s] Papp, BA 0.3 0.3
0.1 0.5 0.4 0.1 0.2 [10.sup.-6 cm/s]
Indications
[0192] As has been found, the compounds of formula (I) are
characterized by their wide range of applications in the
therapeutic field. Particular mention should be made of those
applications for which the compounds according to the invention of
formula (I) are preferably suited on account of their
pharmaceutical efficacy as ENaC inhibitors. Examples include
respiratory diseases or complaints, allergic diseases of the
airways, or dry eyes.
[0193] Particular mention should be made of the prevention and
treatment of diseases of the airways and of the lung which are
accompanied by increased mucus production, inflammation and/or
obstructive diseases of the airways. Examples include acute,
allergic or chronic bronchitis, chronic obstructive bronchitis
(COPD), coughing, pulmonary emphysema, allergic or non-allergic
rhinitis or sinusitis, chronic rhinitis or sinusitis, asthma,
alveolitis, Farmer's disease, hyperreactive airways, infectious
bronchitis or pneumonitis, paediatric asthma, bronchiectases,
pulmonary fibrosis, ARDS (acute adult respiratory distress
syndrome), bronchial oedema, pulmonary oedema, bronchitis,
pneumonia or interstitial pneumonia triggered by various causes,
such as aspiration, inhalation of toxic gases, or bronchitis,
pneumonia or interstitial pneumonia as a result of heart failure,
irradiation, chemotherapy, cystic fibrosis or mucoviscidosis, or
alpha1-antitrypsin deficiency.
[0194] Particularly preferably the present invention relates to the
use of compounds of formula (I) for preparing a pharmaceutical
composition for the treatment of inflammatory or obstructive
diseases of the upper and lower respiratory tract including the
lungs, such as for example allergic rhinitis, chronic rhinitis,
bronchiectasis, cystic fibrosis, COPD, chronic bronchitis, chronic
sinusitis and asthma.
[0195] It is most preferable to use the compounds of formula (I)
for the treatment of inflammatory and obstructive diseases such as
COPD, chronic bronchitis, chronic sinusitis, asthma, cystic
fibrosis, particularly COPD, chronic bronchitis, asthma and cystic
fibrosis.
[0196] The actual pharmaceutically effective amount or therapeutic
dosage will of course depend on factors known by those skilled in
the art such as age and weight of the patient, route of
administration and severity of disease. In any case the combination
will be administered at dosages and in a manner which allows a
pharmaceutically effective amount to be delivered based upon
patient's unique condition.
Combinations
[0197] The compounds of formula (I) may be used on their own or in
conjunction with other active substances of formula (I) according
to the invention. If desired the compounds of formula (I) may also
be used in combination with other pharmacologically active
substances.
[0198] Therefore the invention further relates to medicament
combinations which preferably contain, besides one or more
compounds of formula (I) or a salt thereof, as further active
substances, one or more compounds selected from among the
categories of further ENaC inhibitors, betamimetics,
anticholinergics, corticosteroids, PDE4-inhibitors,
LTD4-antagonists, EGFR-inhibitors, dopamine agonists,
H1-antihistamines, PAF-antagonists, MAP-kinase inhibitors,
MPR4-Inhibitors, iNOS-Inhibitors, SYK-Inhibitors, corrections of
the cystic fibrosis transmembrane regulator (CFTR) and CFTR
potentiators, or double or triple combinations thereof.
Formulations
[0199] Suitable forms for administration are for example inhalable
powders or aerosols. The content of the pharmaceutically effective
compound(s) in each case should be in the range from 0.2 to 50 wt
%, preferably 0.5 to 25 wt % of the total composition, i.e. in
amounts which are sufficient to achieve the dosage range specified
hereinafter.
[0200] Administered by inhalation the active substance combination
may be given as a powder, as an aqueous or aqueous-ethanolic
solution or using a propellant gas formulation.
[0201] Preferably, therefore, pharmaceutical formulations are
characterised in that they contain one or more compounds of formula
(I) according to the preferred embodiments above.
[0202] It is also preferred if the compounds of formula (I) are
administered by inhalation, particularly preferably if they are
administered once or twice a day. For this purpose, the compounds
of formula (I) have to be made available in forms suitable for
inhalation. Inhalable preparations include inhalable powders,
propellant-containing metered-dose aerosols or propellant-free
inhalable solutions, which are optionally present in admixture with
conventional physiologically acceptable excipients.
[0203] Within the scope of the present invention, the term
propellant-free inhalable solutions also include concentrates or
sterile ready-to-use inhalable solutions. The preparations which
may be used according to the invention are described in more detail
in the next part of the specification.
Inhalable Powders
[0204] If the active substances of formula (I) are present in
admixture with physiologically acceptable excipients, the following
physiologically acceptable excipients may be used to prepare the
inhalable powders according to the invention: monosaccharides (e.g.
glucose or arabinose), disaccharides (e.g. lactose, saccharose,
maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols
(e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride,
calcium carbonate) or mixtures of these excipients with one
another. Preferably, mono- or disaccharides are used, while the use
of lactose or glucose is preferred, particularly, but not
exclusively, in the form of their hydrates. For the purposes of the
invention, lactose is the particularly preferred excipient, while
lactose monohydrate is most particularly preferred. Methods of
preparing the inhalable powders according to the invention by
grinding and micronising and by finally mixing the components
together are known from the prior art.
Propellant-Containing Inhalable Aerosols
[0205] The propellant-containing inhalable aerosols which may be
used according to the invention may contain a compound of formula
(I) dissolved in the propellant gas or in dispersed form. The
propellant gases which may be used to prepare the inhalation
aerosols according to the invention are known from the prior art.
Suitable propellant gases are selected from among hydrocarbons such
as n-propane, n-butane or isobutane and halohydrocarbons such as
preferably fluorinated derivatives of methane, ethane, propane,
butane, cyclopropane or cyclobutane. The propellant gases mentioned
above may be used on their own or in mixtures thereof. Particularly
preferred propellant gases are fluorinated alkane derivatives
selected from TG134a (1,1,1,2-tetrafluoroethane), TG227
(1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof. The
propellant-driven inhalation aerosols used within the scope of the
use according to the invention may also contain other ingredients
such as co-solvents, stabilisers, surfactants, antioxidants,
lubricants and pH adjusters. All these ingredients are known in the
art.
Propellant-Free Inhalable Solutions
[0206] The compounds of formula (I) according to the invention are
preferably used to prepare propellant-free inhalable solutions and
inhalable suspensions. Solvents used for this purpose include
aqueous or alcoholic, preferably ethanolic solutions. The solvent
may be water on its own or a mixture of water and ethanol. The
solutions or suspensions are adjusted to a pH of 3 to 7 using
suitable acids. The pH may be adjusted using acids selected from
inorganic or organic acids. Examples of particularly suitable
inorganic acids include hydrochloric acid, hydrobromic acid, nitric
acid, sulphuric acid and/or phosphoric acid. Examples of
particularly suitable organic acids include ascorbic acid, citric
acid, malic acid, tartaric acid, maleic acid, succinic acid,
fumaric acid, acetic acid, formic acid and/or propionic acid etc.
Preferred inorganic acids are hydrochloric and sulphuric acids. It
is also possible to use the acids which have already formed an acid
addition salt with one of the active substances. Of the organic
acids, ascorbic acid, fumaric acid and citric acid are preferred.
If desired, mixtures of the above acids may also be used,
particularly in the case of acids which have other properties in
addition to their acidifying qualities, e.g. as flavourings,
antioxidants or complexing agents, such as citric acid or ascorbic
acid, for example. According to the invention, it is particularly
preferred to use hydrochloric acid to adjust the pH.
[0207] Co-solvents and/or other excipients may be added to the
propellant-free inhalable solutions used for the purpose according
to the invention. Preferred co-solvents are those which contain
hydroxyl groups or other polar groups, e.g. alcohols--particularly
isopropyl alcohol, glycols--particularly propyleneglycol,
polyethyleneglycol, polypropyleneglycol, glycolether, glycerol,
polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The
terms excipients and additives in this context denote any
pharmacologically acceptable substance which is not an active
substance but which can be formulated with the active substance or
substances in the pharmacologically suitable solvent in order to
improve the qualitative properties of the active substance
formulation. Preferably, these substances have no pharmacological
effect or, in connection with the desired therapy, no appreciable
or at least no undesirable pharmacological effect. The excipients
and additives include, for example, surfactants such as soya
lecithin, oleic acid, sorbitan esters, such as polysorbates,
polyvinylpyrrolidone, other stabilisers, complexing agents,
antioxidants and/or preservatives which guarantee or prolong the
shelf life of the finished pharmaceutical formulation, flavourings,
vitamins and/or other additives known in the art. The additives
also include pharmacologically acceptable salts such as sodium
chloride as isotonic agents. The preferred excipients include
antioxidants such as ascorbic acid, for example, provided that it
has not already been used to adjust the pH, vitamin A, vitamin E,
tocopherols and similar vitamins or provitamins occurring in the
human body. Preservatives may be used to protect the formulation
from contamination with pathogens. Suitable preservatives are those
which are known in the art, particularly cetyl pyridinium chloride,
benzalkonium chloride or benzoic acid or benzoates such as sodium
benzoate in the concentration known from the prior art.
[0208] For the treatment forms described above, ready-to-use packs
of a medicament for the treatment of respiratory complaints are
provided, containing an enclosed description including for example
the words respiratory disease, COPD or asthma, a compound according
to the invention and one or more combination partners selected from
those described above.
* * * * *
References