U.S. patent application number 09/732453 was filed with the patent office on 2001-04-19 for use of substituted amidino compounds in the treatment of chronic obstructive pulmonary disease.
Invention is credited to Fujimoto, Roger A., Marshall, Paul J..
Application Number | 20010000341 09/732453 |
Document ID | / |
Family ID | 22341609 |
Filed Date | 2001-04-19 |
United States Patent
Application |
20010000341 |
Kind Code |
A1 |
Marshall, Paul J. ; et
al. |
April 19, 2001 |
Use of substituted amidino compounds in the treatment of chronic
obstructive pulmonary disease
Abstract
Use in medicaments for the treatment of chronic obstructive
pulmonary disease of compounds of formula 1 wherein the
C(.dbd.NH)--NHR.sub.3 group may be in tautomeric or isomeric form,
or a pharmaceutically acceptable salt thereof, in which: R.sub.1 is
amino which is mono- or disubstituted by a substituent selected
from an aliphatic hydrocarbon radical, an araliphatic hydrocarbon
radical, an aromatic radical, and a cycloaliphatic hydrocarbon
radical or is amino which is disubstituted by a divalent aliphatic
hydrocarbon radical or a said radical interrupted by oxygen;
R.sub.2 is hydrogen, halogen, trifluoromethyl, an aliphatic
hydrocarbon radical, hydroxy or is hydroxy which is etherified by
an aliphatic, araliphatic or aromatic alcohol or by an aliphatic
alcohol which is substituted by carboxy, by esterified carboxy or
by amidated carboxy or which is esterified by an aliphatic or
araliphatic carboxylic acid; R.sub.3 is hydrogen or an acyl radical
which is derived from an organic carbonic acid, an organic
carboxylic acid, a sulfonic acid, or a carbamic acid; X.sub.1 and
X.sub.3, independently or one another, are oxygen (--O--) or
sulphur (--S--); and X.sub.2 is a divalent aliphatic hydrocarbon
radical which may be interrupted by an aromatic radical; wherein
the phenyl rings of formula I may be, independently or one another,
further substituted by one or more substituents selected from
halogen, trifluoromethyl, an aliphatic hydrocarbon radical,
hydroxy, and hydroxy which is etherified by an aliphatic alcohol or
which is esterified by an aliphatic or araliphatic carboxylic acid;
wherein aryl in the above definitions may be, independently of one
another, further substituted by one or more substituents selected
from halogen, trifluoromethyl, an aliphatic hydrocarbon radical,
hydroxy, and hydroxy which is etherified by an aliphatic alcohol or
which is esterified by an aliphatic or araliphatic carboxylic acid;
wherein a cycloaliphatic hydrocarbon radical may be substituted by
an aliphatic radical.
Inventors: |
Marshall, Paul J.;
(Flanders, NJ) ; Fujimoto, Roger A.; (Morristown,
NJ) |
Correspondence
Address: |
THOMAS HOXIE
NOVARTIS CORPORATION
PATENT AND TRADEMARK DEPT
564 MORRIS AVENUE
SUMMIT
NJ
079011027
|
Family ID: |
22341609 |
Appl. No.: |
09/732453 |
Filed: |
December 7, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09732453 |
Dec 7, 2000 |
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09435943 |
Nov 9, 1999 |
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09435943 |
Nov 9, 1999 |
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09210634 |
Dec 11, 1998 |
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09210634 |
Dec 11, 1998 |
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08989367 |
Dec 12, 1997 |
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60112002 |
Dec 12, 1997 |
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Current U.S.
Class: |
514/613 |
Current CPC
Class: |
A61K 31/166 20130101;
A61P 11/00 20180101 |
Class at
Publication: |
514/613 |
International
Class: |
A61K 031/47 |
Claims
What is claimed is:
1. A method for the treatment of chronic obstructive pulmonary
disease which comprises administering to a mammal in need of such
treatment an effective amount of a pharmacologically active
compound of formula 7wherein the C(.dbd.NH)--NHR.sub.3 group may be
in tautomeric or isomeric form; or a pharmaceutically acceptable
salt thereof, in which: R.sub.1 is amino which is mono- or
disubstituted by a substituent selected from an aliphatic
hydrocarbon radical, an araliphatic hydrocarbon radical, an
aromatic radical, and a cycloaliphatic hydrocarbon radical or is
amino which is disubstituted by a divalent aliphatic hydrocarbon
radical or a said radical interrupted by oxygen; R.sub.2 is
hydrogen, halogen, trifluoromethyl, an aliphatic hydrocarbon
radical, hydroxy or is hydroxy which is etherified by an aliphatic,
araliphatic or aromatic alcohol or by an aliphatic alcohol which is
substituted by carboxy, by esterified carboxy or by amidated
carboxy or which is esterified by an aliphatic or araliphatic
carboxylic acid; R.sub.3 is hydrogen or an acyl radical which is
derived from an organic carbonic acid, an organic carboxylic acid,
a sulfonic acid, or a carbamic acid; X.sub.1 and X.sub.3,
independently of one another, are oxygen (--O--) or sulphur
(--S--); and X.sub.2 is a divalent aliphatic hydrocarbon radical
which may be interrupted by an aromatic radical; wherein the phenyl
rings of formula I may be, independently of one another, further
substituted by one or more substituents selected from halogen,
trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, and
hydroxy which is etherified by an aliphatic alcohol or which is
esterified by an aliphatic or araliphatic carboxylic acid; wherein
aryl in the above definitions may be, independently of one another,
further substituted by one or more substituents selected from
halogen, trifluoromethyl, an aliphatic hydrocarbon radical,
hydroxy, and hydroxy which is etherified by an aliphatic alcohol or
which is esterified by an aliphatic or araliphatic carboxylic acid;
wherein a cycloaliphatic hydrocarbon radical may be substituted by
an aliphatic radical.
2. A method according to claim 1, in which: R.sub.1 is amino which
is mono- or disubstituted by a substituent selected from lower
alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl,
phenyl-lower alkenyl, phenyl-lower alkynyl, phenyl, napthyl,
indanyl, fluorenyl, cycloalkyl, and cycloalkenyl, cycloalkyl and
cycloalkenyl each being unsubstituted or mono- or polysubstituted
by lower alkyl, or is amino which is disubstituted by lower
alkylene; R.sub.2 is hydrogen, halogen, trifluoromethyl, lower
alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, lower
alkenyloxy, phenyl-lower alkoxy, phenoxy, lower alkoxy substituted
by carboxy, lower alkoxycarbonyl, aminocarbonyl or mono- or
di-lower alkylaminocarbonyl, lower alkanoyloxy, lower alkenoyloxy
or phenyl-lower alkanyloxy; R.sub.3 is hydrogen, alkoxycarbonyl or
alkenyloxycarbonyl, each of which is unsubstituted or substituted
by phenyl, naphthyl, indanyl or fluorenyl, or is
cycloalkoxycarbonyl being unsubstituted or mono- or polysubstituted
by lower alkyl, or is lower alkanoyl or phenyl-lower alkanoyl, or
is benzoyl, naphthoyl, indanoyl or fluorenoyl, or is
C.sub.1-C.sub.7-alkanes- ulfonyl,
phenyl-C.sub.1-C.sub.7alkanesulfonyl, C.sub.3-C.sub.7-cycloalkane-
sulfonyl, or phenylsulfonyl, or is aminocarbonyl which is
substituted by lower alkyl, phenyl-lower alkyl or phenyl; X.sub.1
and X.sub.3, independently of one another, are O or S; and X.sub.2
is lower alkylene, lower alkylene-phenylene-lower alkylene or lower
alkylene-naphthylene-low- er alkylene; wherein the phenyl rings of
formula I may be, independently of one another, substituted by one
or more substituents selected from halogen, trifluoromethyl, lower
alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, lower
alkenyloxy, phenyl-lower alkoxy, lower alkanoyloxy, lower
alkenoyloxy and phenyl-lower alkanoyloxy; wherein the aromatic
radicals in the above definitions may be, independently of one
another, substituted by one or more substituents selected from
halogen, trifluoromethyl, lower alkyl, lower alkenyl, lower
alkynyl, hydroxy, lower alkoxy, lower alkenyloxy, phenyl-lower
alkoxy, lower alkanoyloxy, lower alkenoyloxy and phenyl-lower
alkanoyloxy.
3. A method according to claim 1, in which: R.sub.1 is amino which
is mono- or disubstituted by a substituent selected from
C.sub.1-C.sub.7-alkyl, phenyl-C.sub.1-C.sub.7-alkyl, phenyl and
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl being
unsubstituted or mono- or polysubstituted by C.sub.1-C.sub.7alkyl,
or is amino which is disubstituted by C.sub.3-C.sub.6-alkylene;
R.sub.2 is hydrogen, hydroxy, C.sub.1-C.sub.7-alkoxy,
C.sub.1-C.sub.7-alkoxy substituted by carboxy or lower
alkoxycarbonyl or phenyl-C.sub.1-C.sub.4 alkoxy; R.sub.3 is
hydrogen, C.sub.1-C.sub.12-alkoxy-carbonyl,
C.sub.2-C.sub.5-alkanoyl, phenyl-C.sub.2-C.sub.5-alkanoyl, benzoyl
which is unsubstituted or substituted by halogen, trifluoromethyl,
C.sub.1-C.sub.7-alkyl, or C.sub.1-C.sub.7alkoxy,
C.sub.3-C.sub.6-cycloalk- ylcarbonyl which is unsubstituted or
substituted by C.sub.1-C.sub.7-alkyl, or is benzoyl, naphthoyl,
indanoyl or fluorenoyl, or is C.sub.1-C.sub.7alkanesulfonyl,
phenyl-C.sub.1-C.sub.7alkanesulfonyl,
C.sub.3-C.sub.7-cycloalkanesulfonyl, or phenylsulfonyl, or is
aminocarbonyl which is substituted by C.sub.1-C.sub.7-alkyl,
phenyl-C.sub.1-C.sub.7-alkyl or phenyl; X.sub.1 and X.sub.3 each
are --O--, or furthermore are, independently of one another, --O--
or --S--; and X.sub.2 is C.sub.2-C.sub.7-alkylene or
C.sub.2-C.sub.4-alkylene-pheny- lene-C.sub.2-C.sub.4-alkylene;
wherein the phenyl rings of formula I may be unsubstituted or,
furthermore, independently of one another, substituted by one or
more substituents selected from halogen, trifluoromethyl,
C.sub.1-C.sub.7-alkyl, and C.sub.1-C.sub.7-alkoxy; wherein phenyl
in the above definitions is unsubstituted or, furthermore,
independently of one another, substituted by one or more
substituents selected from halogen, trifluoromethyl,
C.sub.1-C.sub.7-alkyl, and C.sub.1-C.sub.7-alkoxy.
4. A method according to claim 1, in which --CO--R.sub.1 is located
in position 4 (para) or 3 or 5 (meta) of the corresponding phenyl
ring with respect to --X.sub.1--; R.sub.2-- is located in position
2 (ortho) or 3 (meta) of the corresponding phenyl ring with respect
to --X.sub.1--; and --C(.dbd.NH)--NHR.sub.3 is located in position
4 (para) of the corresponding phenyl ring with respect to
--X.sub.3--.
5. A method according to claim 1, in which the compound of formula
I is of formula IA 8wherein the C(.dbd.NH)--NHR.sub.3 group may be
in tautomeric or isomeric form, and in which: R.sub.1 is
di-C.sub.1-C.sub.4-alkylamino, C.sub.1-C.sub.4alkyl-(phenyl)amino,
C.sub.1-C.sub.4alkyl-(phenyl-C.sub.1-- C.sub.4-alkyl)amino,
di-C.sub.3-C.sub.6-cycloalkylamino, which is unsubstituted or
substituted by C.sub.1-C.sub.4-alkyl, or 1-piperidino substituted
by C.sub.1-C.sub.4-alkyl; R.sub.2 is hydrogen,
C.sub.1-C.sub.4-alkoxy or C.sub.1-C.sub.4-alkoxy which is
substituted by carboxy, lower alkoxycarbonyl, aminocarbonyl or by
mono- or di-lower alkylaminocarbonyl; R.sub.3 is hydrogen,
C.sub.1-C.sub.12-alkoxycarbonyl,
phenyl-C.sub.1-C.sub.4-alkoxycarbonyl, C.sub.2-C.sub.5-alkanoyl,
benzoyl which is unsubstituted or substituted by halogen,
trifluoromethyl, C.sub.1-C.sub.4-alkyl or by
C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-cycloalkylcarbonyl which is
unsubstituted or substituted by C.sub.1-C.sub.4-alkyl; X.sub.1 and
X.sub.3 are --O--; X.sub.2 is C.sub.4-C.sub.7-alkylene; wherein the
phenyl rings of formula IA may be unsubstituted or, furthermore,
independently of one another, substituted by one or more
substituents selected from halogen, trifluoromethyl,
C.sub.1-C.sub.4-alkyl, and C.sub.1-C.sub.4-alkoxy.
6. A method according to claim 5, in which: R.sub.1 is
di-C.sub.1-C.sub.4-alkylamino,
C.sub.1-C.sub.4-alkyl-(phenyl)-amino,
C.sub.1-C.sub.4-alkyl-(phenyl-C.sub.1-C.sub.4-alkyl)amino,
di-C.sub.3-C.sub.6-cycloalkylamino, which is unsubstituted or
substituted by C.sub.1-C.sub.4-alkyl, or 1-piperidino substituted
by C.sub.1-C.sub.4-alkyl; R.sub.2 is hydrogen,
C.sub.1-C.sub.4-alkoxy or C.sub.1-C.sub.4-alkoxy substituted by
C.sub.1-C.sub.4-alkoxycarbonyl; R.sub.3 is hydrogen; or R.sub.3 is
lower alkanoyl; X.sub.1 and X.sub.3 are --O--; and X.sub.2 is
C.sub.4-C.sub.7-alkylene.
7. A method according to claim 5, in which: R.sub.1 is
di-C.sub.1-C.sub.4-alkylamino; R.sub.2 is hydrogen,
C.sub.1-C.sub.4-alkoxy or C.sub.1-C.sub.4-alkoxy substituted by
C.sub.1-C.sub.4-alkoxycarbonyl or by aminocarbonyl; R.sub.3 is
C.sub.1-C.sub.12-alkoxycarbonyl,
phenyl-C.sub.1-C.sub.4-alkoxycarbonyl, C.sub.2-C.sub.5-alkanoyl,
benzoyl which is unsubstituted or substituted by halogen,
trifluoromethyl, C.sub.1-C.sub.4-alkyl, or C.sub.1-C.sub.4-alkoxy,
C.sub.3-C.sub.6-cycloalkylcarbonyl which is unsubstituted or
substituted by C.sub.1-C.sub.4-alkyl; X.sub.1 and X.sub.3 are
--O--; and X.sub.2 is C.sub.4-C.sub.7-alkylene.
8. A method according to claim 5, in which: R.sub.1 is
di-C.sub.1-C.sub.4-alkylamino; R.sub.2 is hydrogen,
C.sub.1-C.sub.4-alkoxy or C.sub.1-C.sub.4-alkoxy substituted by
C.sub.1-C.sub.4-alkoxycarbonyl or by aminocarbonyl; R.sub.3 is
hydrogen or C.sub.1-C.sub.4-alkanoyl; X.sub.1 and X.sub.3 are
--O--; and X.sub.2 is C.sub.4-C.sub.7-alkylene.
9. A method according to claim 5, in which R.sub.1 is
di-isopropylamino, R.sub.2 is methoxy, R.sub.3 is hydrogen, X.sub.1
and X.sub.3 are --O-- and X.sub.2 is pentylene.
10. A method according to claim 1, in which the compound of formula
I is of formula IB 9wherein the C(.dbd.NH)--NHR.sub.3 group may be
in tautomeric or isomeric form, and in which: R.sub.1 is
di-C.sub.1-C.sub.4-alkylamino, C.sub.1-C.sub.4alkyl-(phenyl)amino,
C.sub.1-C.sub.4-alkyl-(phenyl-C.sub.1-C.sub.4-alkyl)amino,
di-C.sub.3-C.sub.6-cycloalkylamino, which is unsubstituted or
substituted by C.sub.1-C.sub.4-alkyl, or 1-piperidino substituted
by C.sub.1-C.sub.4-alkyl; R.sub.2 is hydroxy or
C.sub.1-C.sub.4-alkoxy which is substituted by carboxy, lower
alkoxycarbonyl, aminocarbonyl or by mono- or di-lower
alkylaminocarbonyl; R.sub.3 is hydrogen,
C.sub.1-C.sub.12-alkoxycarbonyl,
phenyl-C.sub.1-C.sub.4-alkoxycarbonyl, C.sub.2-C.sub.5-alkanoyl,
benzoyl which is unsubstituted or substituted by halogen,
trifluoromethyl, C.sub.1-C.sub.4-alkyl, or C.sub.1-C.sub.4-alkoxy,
C.sub.3-C.sub.6-cycloalkylcarbonyl which is unsubstituted or
substituted by C.sub.1-C.sub.4-alkyl; X.sub.1 and X.sub.3 are
--O--; and X.sub.2 is C.sub.4-C.sub.7-alkylene; wherein the phenyl
rings of formula IB may be unsubstituted or, furthermore,
independently of one another, substituted by one or more
substituents selected from halogen, trifluoromethyl,
C.sub.1-C.sub.4-alkyl, and C.sub.1-C.sub.4-alkoxy.
11. A method according to claim 10, in which: R.sub.1 is
di-C.sub.1-C.sub.4-alkylamino,
C.sub.1-C.sub.4-alkyl-(phenyl)-amino,
C.sub.1-C.sub.4alkyl-(phenyl-C.sub.1-C.sub.4-alkyl)-amino,
di-C.sub.3-C.sub.6-cycloalkylamino, which is unsubstituted or
substituted by C.sub.1-C.sub.4-alkyl, or 1-piperidino substituted
by C.sub.1-C.sub.4-alkyl; R.sub.2 is hydroxy or
C.sub.1-C.sub.4-alkoxy substituted by
C.sub.1-C.sub.4-alkoxycarbonyl, or by aminocarbonyl; R.sub.3 is
hydrogen; or R.sub.3 is C.sub.2-C.sub.5-alkanoyl; X.sub.1 and
X.sub.3 are --O--; and X.sub.2 is C.sub.4-C.sub.7-alkylene.
12. A method according to claim 10, in which: R.sub.1 is
di-C.sub.1-C.sub.4-alkylamino; R.sub.2 is hydroxy or
C.sub.1-C.sub.4-alkoxycarbonylmethoxy, or aminocarbonylmethoxy;
R.sub.3 is hydrogen or C.sub.2-C.sub.5-alkanoyl; X.sub.1 and
X.sub.3 are --O--; and X.sub.2 is C.sub.4-C.sub.7-alkylene.
13. A method according to claim 10, in which R.sub.1 is
di-isopropylamino, R.sub.2 is hydroxy, R.sub.3 is hydrogen, X.sub.1
and X.sub.3 are --O-- and X.sub.2 is pentylene.
14. A method according to claim 1, in which the compound of formula
I or salt thereof is administered in combination with a
pharmaceutically acceptable carrier.
15. A method according to claim 1, in which the disease is chronic
bronchitis.
16. A method according to claim 9, in which the compound of formula
I or salt thereof is administered in combination with a
pharmaceutically acceptable carrier.
17. A method according to claim 9, in which the disease is chronic
bronchitis.
18. A method according to claim 13, in which the compound of
formula I or salt thereof is administered in combination with a
pharmaceutically acceptable carrier.
19. A method according to claim 13, in which the disease is chronic
bronchitis.
20. A medicament suitable for pulmonary administration comprising a
compound of formula I as specified in claim 1, or a
pharmaceutically acceptable salt thereof, or a mixture of said
compound or salt with a pharmaceutically acceptable carrier
therefor, the compound, salt or mixture being in inhalable
form.
21. A medicament suitable for pulmonary administration comprising a
compound of formula IA as specified in claim 14, or a
pharmaceutically acceptable salt thereof, or a mixture of said
compound or salt with a pharmaceutically acceptable carrier
therefor, the compound, salt or mixture being in inhalable
form.
22. A compound of formula IB as defined in claim 13 in the form of
the maleate salt thereof.
Description
1. This invention relates to the use of organic compounds,
particularly substituted amidino compounds, in the treatment of
chronic obstructive respiratory diseases, particularly chronic
obstructive pulmonary disease (COPD), including emphysema, cystic
fibrosis and, especially, chronic bronchitis.
2. COPD is one of the major causes of death and disability in the
USA and Europe and there are no effective therapies currently
available which prevent progression of the disease. The most common
causal mechanism is cigarette smoking, which leads to chronic
bronchitis. About 15% of smokers develop progressive airflow
limitation, which is largely due to emphysema.
3. The invention provides, in one aspect, the use, for the
preparation of a medicament for the treatment of chronic
obstructive pulmonary disease, of a pharmacologically active
compound of formula 2
4. wherein the C(.dbd.NH)--NHR.sub.3 group may be in tautomeric or
isomeric form, or a pharmaceutically acceptable salt thereof, in
which:
5. R.sub.1 is amino which is mono- or disubstituted by a
substituent selected from an aliphatic hydrocarbon radical, an
araliphatic hydrocarbon radical, an aromatic radical, and a
cycloaliphatic hydrocarbon radical or is amino which is
disubstituted by a divalent aliphatic hydrocarbon radical or a said
radical interrupted by oxygen;
6. R.sub.2 is hydrogen, halogen, trifluoromethyl, an aliphatic
hydrocarbon radical, hydroxy or is hydroxy which is etherified by
an aliphatic, araliphatic or aromatic alcohol or by an aliphatic
alcohol which is substituted by carboxy, by esterified carboxy or
by amidated carboxy or which is esterified by an aliphatic or
araliphatic carboxylic acid;
7. R.sub.3 is hydrogen or an acyl radical which is derived from an
organic carbonic acid, an organic carboxylic acid, a sulfonic acid,
or a carbamic acid;
8. X.sub.1 and X.sub.3, independently of one another, are oxygen
(--O--) or sulphur (--S--); and X.sub.2 is a divalent aliphatic
hydrocarbon radical which may be interrupted by an aromatic
radical;
9. wherein the phenyl rings of formula I may be, independently of
one another, further substituted by one or more substituents
selected from halogen, trifluoromethyl, an aliphatic hydrocarbon
radical, hydroxy, and hydroxy which is etherified by an aliphatic
alcohol or which is esterified by an aliphatic or araliphatic
carboxylic acid;
10. wherein aryl in the above definitions may be, independently of
one another, further substituted by one or more substituents
selected from halogen, trifluoromethyl, an aliphatic hydrocarbon
radical, hydroxy, and hydroxy which is etherified by an aliphatic
alcohol or which is esterified by an aliphatic or araliphatic
carboxylic acid;
11. wherein a cycloaliphatic hydrocarbon radical may be substituted
by an aliphatic radical.
12. In another aspect, the invention provides pharmacologically
active compounds of formula I and pharmaceutically acceptable salts
thereof for use in the treatment of chronic obstructive pulmonary
disease.
13. In a further aspect, the invention provides a method for the
treatment of chronic obstructive pulmonary disease which comprises
administering to a mammal in need of such treatment an effective
amount of a pharmacologically active compound of formula I, or a
pharmaceutically acceptable salt thereof, as hereinbefore
defined.
14. The compounds of formula I wherein the C(.dbd.NH)--NHR.sub.3
group is in tautomeric or isomeric form are represented by formula
I.sup.1 3
15. wherein R.sub.1, R.sub.2, R.sub.3, X.sub.1, X.sub.2 and X.sub.3
have the meanings as defined for formula I.
16. As compounds of formula I have a basic centre, they can thus
form acid addition salts, especially pharmaceutically acceptable
salts. These are formed, for example, with inorganic acids, such as
mineral acids, for example sulfuric acid, a phosphoric or
hydrohalic acid, or with organic carboxylic acids, such as
(C.sub.1-C.sub.4)-alkanecarboxylic acids which, for example, are
unsubstituted or substituted by halogen, for example acetic acid,
such as saturated or unsaturated dicarboxylic acids, for example
oxalic, malonic, succinic, maleic, fumaric, phthalic or
terephthalic acid, such as hydroxycarboxylic acids, for example
ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as
amino acids, for example aspartic or glutamic acid, benzoic acid or
with organic sulfonic acids, such as (C.sub.1-C.sub.4)-alkane- or
arylsulfonic acids which are unsubstituted or substituted, for
example, by halogen, for example methane- or toluenesulfonic acid.
Preferred are salts formed with hydrochloric acid, methanesulfonic
acid and maleic acid, especially maleic acid.
17. The general definitions used below have, if not defined
differently, the following meanings:
18. An aliphatic hydrocarbon radical is, for example, lower alkyl,
lower alkenyl and secondarily lower alkynyl.
19. An araliphatic hydrocarbon radical is, for example, optionally
substituted phenyl-lower alkyl and secondarily phenyl-lower alkenyl
and phenyl-lower alkynyl.
20. A cycloaliphatic hydrocarbon radical is, for example,
cycloalkyl and secondarily cycloalkenyl, which is unsubstituted or
mono- or polysubstituted, for example, disubstituted, by lower
alkyl.
21. A divalent aliphatic hydrocarbon radical is, for example, lower
alkylene.
22. A divalent aliphatic radical interrupted by oxygen is, for
example, lower alkylene interrupted by oxygen, e.g.
ethylene-O-ethylene.
23. A divalent aliphatic hydrocarbon radical which is interrupted
by an aromatic radical is, for example, lower
alkylene-phenylene-lower alkylene or lower
alkylene-naphthylene-lower alkylene.
24. An aliphatic alcohol is, for example, a lower alkanol or lower
alkenol, and an araliphatic alcohol is, for example, a phenyl-lower
alkanol, for example benzyl alcohol.
25. Hydroxy which is etherified by an aliphatic or araliphatic
alcohol is, for example, lower alkoxy or lower alkenyloxy and
phenyl-lower alkoxy.
26. Hydroxy etherified by an aliphatic alcohol substituted by
carboxy, esterified carboxy or amidated carboxy is, for example,
lower alkoxy substituted by carboxy, by lower alkoxycarbonyl, by
aryl-lower alkoxycarbonyl, by aminocarbonyl or by mono-or di-lower
alkylaminocarbonyl.
27. An aliphatic carboxylic acid is, for example, a lower alkanoic
or lower alkenoic acid, and an araliphatic carboxylic acid is, for
example, a phenyl-lower alkanoic acid.
28. Hydroxy which is esterified by an aliphatic or araliphatic
carboxylic acid is, for example, lower alkanoyloxy, lower
alkenoyloxy or phenyl-lower alkanoyloxy.
29. An acyl radical which is derived from an organic carboxylic
acid is, for example, lower alkanoyl, phenyl-lower alkanoyl or
unsubstituted or substituted aroyl, such as benzoyl, naphthoyl,
indanoyl or fluorenoyl, or heteroaroyl such as pyridylcarbonyl,
thienylcarbonyl, pyrrolylcarbonyl, furanylcarbonyl and
imidazolylcarbonyl.
30. An acyl radical which is derived form an organic carbonic acid
is, for example, alkoxycarbonyl or alkenyloxycarbonyl which in each
case are unsubstituted or substituted by an aromatic radical or is
cycloalkoxycarbonyl which unsubstituted or substituted by lower
alkyl.
31. An acyl radical which is derived from a sulfonic acid is, for
example, alkanesulfonyl, arylalkanesulfonyl, cycloalkanesulfonyl or
arylsulfonyl.
32. An acyl radical which is derived from a carbamic acid is, for
example, amino-carbonyl which is substituted by alkyl, arylalkyl or
aryl.
33. An aromatic radical is, for example, unsubstituted or
substituted such as monosubstituted or polysubstituted, for
example, disubstituted or secondarily trisubstituted carbocyclic
aryl, such as phenyl, naphthyl, indanyl or fluorenyl, or
heterocyclic aryl, such as pyridyl, thienyl, pyrrolyl, furanyl, and
imidazolyl.
34. Aryl represents preferably monocarbocyclic aryl, advantageously
optionally substituted phenyl, such being phenyl or phenyl
substituted by e.g. lower alkyl, lower alkoxy, halogen or
trifluoromethyl.
35. The phenyl rings of formulae I and I.sup.1 as well as aromatic
radicals referred to before and hereafter are generally
unsubstituted or further substituted such as monosubstituted or
polysubstituted, for example disubstituted or secondarily
trisubstituted, in particular, for example, by a substituent
selected from the group consisting of halogen, trifluoromethyl,
lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy,
lower alkenyloxy, phenyl-lower alkoxy, lower alkanoyloxy, lower
alkenoyloxy, and phenyl-lower alkanoyloxy. Preferably, the phenyl
rings of formula I and I.sup.1 do not exhibit any additional
substitutent.
36. Preferred positions of the following structural elements in the
corresponding phenyl ring in formula I are: positions 4 (para) or 5
(meta) for --CO--R.sub.1, position 2 (ortho) or 3 (meta) for
R.sub.2, and position 4 (para) for --C(.dbd.NH)--NHR.sub.3 grouping
and both tautomeric and isomeric forms are encompassed by the
instant invention.
37. The term "substituted by one or more substituents" refers
preferably to one, two or three such substituents, advantageously
one or two.
38. The expression "lower" means that corresponding groups and
compounds in each case contain in particular not more than 7,
preferably not more than 4, carbon atoms.
39. Halogen is, in particular, fluorine, chlorine or bromine, and
furthermore includes iodine.
40. Lower alkyl is, in particular, C.sub.1-C.sub.7-alkyl and is,
for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl and furthermore includes corresponding
pentyl, hexyl and heptyl radicals. C.sub.1-C.sub.4-alkyl is
preferred.
41. Lower alkenyl is, in particular, C.sub.3-C.sub.7-alkenyl and
is, for example, 2-propenyl or 1-, 2- or 3-butenyl.
C.sub.3-C.sub.5-Alkenyl is preferred.
42. Lower alkynyl is, in particular, C.sub.3-C.sub.7-alkynyl and is
preferably propargyl.
43. Phenyl-lower alkyl is, in particular,
phenyl-C.sub.1-C.sub.4-alkyl and is preferably benzyl, 1- and
2-phenethyl, while phenyl-lower alkenyl and phenyl-lower alkynyl
are, in particular, phenyl-C.sub.2-C.sub.5alkenyl and -alkynyl, in
particular 2-phenyl-vinyl, 3-phenylallyl and 3-phenylpropargyl.
44. Cycloalkyl is, in particular, C.sub.3-C.sub.7-cycloalkyl and
is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
and cycloheptyl. Cyclopentyl and cyclohexyl are preferred.
45. Cycloalkenyl is, in particular, C.sub.3-C.sub.7-cycloalkenyl
and is preferably cyclopent-2- or -3-enyl, or cyclohex-2- and
-3-en-yl.
46. Lower alkylene e.g. in amino which is disubstituted by lower
alkylene is, in particular, C.sub.2-C.sub.6-alkylene and is, for
example, butylene, pentylene, or 2,6-hexylene. Preferred is
C.sub.4-C.sub.5-alkylene, especially pentylene.
47. Lower alkylene X.sub.2 is, in particular,
C.sub.2-C.sub.8-alkylene, preferably straight-chain, and is, for
example, ethylene, propylene, butylene, pentylene, hexylene,
heptylene and also octylene. C.sub.4-C.sub.7-Alkylene is preferred,
especially pentylene and also butylene, hexylene or heptylene.
48. Lower alkylene which is interrupted by a phenyl radical
(X.sub.2) is, in particular, lower alkylene-phenylene-lower
alkylene or lower alkylene-napthylene-lower alkylene such as
C.sub.2-C.sub.4-alkylene-pheny- lene-C.sub.2-C.sub.4-alkylene or
C.sub.2-C.sub.4-alkylene-napthylene-C.sub- .2-C.sub.4-alkylene,
preferably straight-chain, and is, for example,
methylene-phenylene-methylene, 1,2-ethylene-phenylene-1,2-ethylene,
such as 1,2-ethylene-1,4-phenylene-1,2-ethylene,
1,3-propylene-phenylene-1,3-p- ropylene, such as
1,3-propylene-1,4-phenylene-1,3-propylene, or
butylene-phenylene-butylene radicals, also a corresponding
1,2-ethylene-napthylene-1,2-ethylene radical.
49. C.sub.2-C.sub.4-alkylene-phenylene-C.sub.2-C.sub.4-alkylene or
C.sub.2-C.sub.3-alkylene-napthylene-C.sub.2-C.sub.3-alkylene is
preferred, especially 1,2-ethylene-1,4-phenylene-1,2-ethylene.
50. Lower alkoxy is, in particular, C.sub.1-C.sub.7-alkoxy and is,
for example, methoxy, ethoxy, n-propyloxy, isopropyloxy,
n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy and
furthermore includes corresponding pentyloxy, hexyloxy and
heptyloxy radicals. C.sub.1-C.sub.4-Alkoxy is preferred.
51. Lower alkenyloxy is, in particular, C.sub.3-C.sub.7-alkenyloxy
and is, for example, allyloxy or but-2-en- or but-3-enyloxy.
C.sub.3-C.sub.5-Alkenyloxy is preferred.
52. Phenyl-lower alkoxy is, in particular,
phenyl-C.sub.1-C.sub.4-alkoxy, such as benzyloxy, 1- or
2-phenylethoxy, or 1-, 2- or 3-phenylpropyloxy.
53. Lower alkanoyloxy is, in particular,
C.sub.2-C.sub.8-alkanoyloxy, in particular,
C.sub.2-C.sub.5-alkanoyloxy, such as acetyloxy, propionyloxy or
pivaloyloxy.
54. Lower alkenoyloxy is, in particular,
C.sub.3-C.sub.8-alkenoyloxy, in particular,
C.sub.3-C.sub.5-alkenoyloxy, such as propenoyloxy.
55. Phenyl-lower alkanoyloxy is, in particular,
phenyl-C.sub.2-C.sub.8-alk- anoyloxy, in particular,
phenyl-C.sub.2-C.sub.5-alkanoyloxy, such as phenylacetyloxy,
phenylpropionloxy or phenylpivaloyloxy.
56. Alkoxycarbonyl is, in particular,
C.sub.2-C.sub.12-alkoxycarbonyl and is, for example, methoxy-,
ethoxy-, propyloxy-pivaloxy or oxtyloxy-carbonyl.
C.sub.2-C.sub.9-Alkoxycarbonyl is preferred.
57. Alkenyloxycarbonyl is, in particular,
C.sub.3-C.sub.12-alkenyloxycarbo- nyl, for example,
allyloxycarbonyl. Preferred is C.sub.3-C.sub.5-alkenylox-
ycarbonyl.
58. Cycloalkyloxycarbonyl is, in particular,
C.sub.3-C.sub.7-cycloalkyloxy- carbonyl, preferred is
cyclopentyloxycarbonyl or cyclohexyloxycarbonyl.
59. Alkanesulfonyl is, in particular, C.sub.1-C.sub.7alkanesulfonyl
and is, for example, methane-, ethane-, n-propane- or
isopropanesulfonyl. C.sub.1-C.sub.4-Alkanesulfonyl is
preferred.
60. Arylalkanesulfonyl is, in particular,
phenyl-C.sub.1-C.sub.7alkanesulf- onyl, for example, benzyl- or 1-
and 2-phenylethan-sulfonyl. Phenyl-C.sub.1-C.sub.4-alkane-sulfonyl
is preferred.
61. Cycloalkanesulfonyl is, in particular,
C.sub.3-C.sub.7-cycloalkanesulf- onyl, preferred is
cyclopentanesulfonyl or cyclohexanesulfonyl.
62. Naphthyl is 1- or 2-naphthyl.
63. Indanyl is, for example, 1-, 2-, 3- or 4-indanyl.
64. Fluorenyl is, for example, 1-, 2-, 3-, 4- or 5-fluorenyl.
65. Lower alkanoyl is, in particular, C.sub.1-C.sub.7-alkanoyl and
is, for example, formyl, acetyl, propionyl, butyryl, isobutyryl or
pivavolyl. C.sub.2-C.sub.5-Alkanoyl is preferred.
66. Phenyl-lower alkanoyl is, in particular,
phenyl-C.sub.2-C.sub.7-alkano- yl and is, for example, phenylacetyl
or 2- or 3-phenylpropionyl. Phenyl-C.sub.2-C.sub.4-alkanoyl is
preferred.
67. Substituted aroyl represents aroyl, such as benzoyl, which is
substituted e.g. by lower alkoxy, lower alkyl, hydroxy,
hydroxymethyl or by acyloxymethyl (such as lower alkanoyloxymethyl
or benzoyloxymethyl.
68. Naphthoyl is 1- or 2-naphthoyl.
69. Indanoyl is, for example, 1-, 2-, 3- or 4-indanoyl.
70. Fluorenoyl is, for example, 1-, 2-, 3- 4- or 5-fluorenoyl.
71. Esterified carboxyl represents preferably lower alkoxycarbonyl
or aryl-lower alkoxycarbonyl.
72. Amidated carboxyl represents preferably aminocarbonyl, mono- or
di-lower alkylaminocarbonyl, (mono-aryl-mono-lower
alkyl)aminocarbonyl, mono- or di-(aryl-lower alkyl)aminocarbonyl or
(mono-aryl-lower alkyl-mono-lower alkyl)aminocarbonyl.
73. The invention relates preferably to the use of compounds of
formula I and pharmaceutically acceptable salts thereof, in
which:
74. R.sub.1 is amino which is mono- or disubstituted by a
substituent selected from lower alkyl, lower alkenyl, lower
alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl, phenyl-lower
alkynyl, phenyl, napthyl, indanyl, fluorenyl, cycloalkyl, and
cycloalkenyl, cycloalkyl and cycloalkenyl each being unsubstituted
or mono- or polysubstituted by lower alkyl, or is amino which is
disubstituted by lower alkylene;
75. R.sub.2 is hydrogen, halogen, trifluoromethyl, lower alkyl,
lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, lower
alkenyloxy, phenyl-lower alkoxy, phenoxy, lower alkoxy substituted
by carboxy, lower alkoxycarbonyl, aminocarbonyl or mono- or
di-lower alkylaminocarbonyl, lower alkanoyloxy, lower alkenoyloxy
or phenyl-lower alkanyloxy;
76. R.sub.3 is hydrogen, alkoxycarbonyl or alkenyloxycarbonyl, each
of which is unsubstituted or substituted by phenyl, naphthyl,
indanyl or fluorenyl, or is cycloalkoxycarbonyl being unsubstituted
or mono- or polysubstituted by lower alkyl, or is lower alkanoyl or
phenyl-lower alkanoyl, or is benzoyl, naphthoyl, indanoyl or
fluorenoyl, or is C.sub.1-C.sub.7-alkanesulfonyl,
phenyl-C.sub.1-C.sub.7alkanesulfonyl,
C.sub.3-C.sub.7-cycloalkanesulfonyl, or phenylsulfonyl, or is
aminocarbonyl which is substituted by lower alkyl, phenyl-lower
alkyl or phenyl;
77. X.sub.1 and X.sub.3, independently of one another, are O or
S;
78. X.sub.2 is lower alkylene, lower alkylene-phenylene-lower
alkylene or lower alkylene-naphthylene-lower alkylene;
79. wherein the phenyl rings of formula I may be, independently of
one another, substituted by one or more substituents selected from
halogen, trifluoromethyl, lower alkyl, lower alkenyl, lower
alkynyl, hydroxy, lower alkoxy, lower alkenyloxy, phenyl-lower
alkoxy, lower alkanoyloxy, lower alkenoyloxy and phenyl-lower
alkanoyloxy;
80. wherein the aromatic radicals in the above definitions may be,
independently of one another, substituted by one or more
substituents selected from halogen, trifluoromethyl, lower alkyl,
lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, lower
alkenyloxy, phenyl-lower alkoxy, lower alkanoyloxy, lower
alkenoyloxy and phenyl-lower alkanoyloxy.
81. The invention especially relates to the use of compounds of
formula I and pharmaceutically acceptable salts thereof, in
which:
82. R.sub.1 is amino which is mono- or disubstituted by a
substituent selected from C.sub.1-C.sub.7-alkyl,
phenyl-C.sub.1-C.sub.7-alkyl, phenyl and
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl being
unsubstituted or mono- or polysubstituted by C.sub.1-C.sub.7alkyl,
or is amino which is disubstituted by C.sub.3-C.sub.6-alkylene;
83. R.sub.2 is hydrogen, hydroxy, C.sub.1-C.sub.7-alkoxy,
C.sub.1-C.sub.7-alkoxy substituted by carboxy or lower
alkoxycarbonyl or phenyl-C.sub.1-C.sub.4 alkoxy;
84. R.sub.3 is hydrogen, C.sub.1-C.sub.12-alkoxy-carbonyl,
C.sub.2-C.sub.5-alkanoyl, phenyl-C.sub.2-C.sub.5-alkanoyl, benzoyl
which is unsubstituted or substituted by halogen, trifluoromethyl,
C.sub.1-C.sub.7-alkyl, or C.sub.1-C.sub.7 alkoxy,
C.sub.3-C.sub.6-cycloal- kylcarbonyl which is unsubstituted or
substituted by C.sub.1-C.sub.7-alkyl, or is benzoyl, naphthoyl,
indanoyl or fluorenoyl, or is C.sub.1-C.sub.7alkanesulfonyl,
phenyl-C.sub.1-C.sub.7alkanesulfonyl- ,
C.sub.3-C.sub.7-cycloalkanesulfonyl, or phenylsulfonyl, or is
aminocarbonyl which is substituted by C.sub.1-C.sub.7-alkyl,
phenyl-C.sub.1-C.sub.7-alkyl or phenyl;
85. X.sub.1 and X.sub.3 each are --O--, or furthermore are,
independently of one another, --O-- or --S--;
86. X.sub.2 is C.sub.2-C.sub.7-alkylene or
C.sub.2-C.sub.4-alkylene-phenyl- ene-C.sub.2-C.sub.4-alkylene;
87. wherein the phenyl rings of formula I may be unsubstituted or,
furthermore, independently of one another, substituted by one or
more substituents selected from halogen, trifluoromethyl,
C.sub.1-C.sub.7-alkyl, and C.sub.1-C.sub.7-alkoxy;
88. wherein phenyl in the above definitions is unsubstituted or,
furthermore, independently of one another, substituted by one or
more substituents selected from halogen, trifluoromethyl,
C.sub.1-C.sub.7-alkyl, and C.sub.1-C.sub.7-alkoxy.
89. The invention especially relates to the use of compounds of
formula I and pharmaceutically acceptable salts thereof, in which
--CO--R.sub.1 is located in position 4 (para) or 3 or 5 (meta) of
the corresponding phenyl ring with respect to --X.sub.1--;
R.sub.2-- is located in position 2 (ortho) or 3 (meta) of the
corresponding phenyl ring with respect to --X.sub.1--; and
--C(.dbd.NH)--NHR.sub.3 is located in position 4 (para) of the
corresponding phenyl ring with respect to --X.sub.3--.
90. The invention especially relates to the use of compounds of
formula IA 4
91. wherein the C(.dbd.NH)--NHR.sub.3 group may be in tautomeric or
isomeric form, and pharmaceutically acceptable salts thereof, in
which:
92. R.sub.1 is di-C.sub.1-C.sub.4-alkylamino, such as di-ethylamino
or di-isopropylamino, C.sub.1-C.sub.4alkyl-(phenyl)amino, such as
phenyl-isopropyl-amino,
C.sub.1-C.sub.4alkyl-(phenyl-C.sub.1-C.sub.4-alky- l)-amino, such
as methyl-benzyl-amino, di-C.sub.3-C.sub.6-cycloalkylamino, such as
di-cyclohexylamino, which is unsubstituted or substituted by
C.sub.1-C.sub.4-alkyl, or 1-piperidino substituted by
C.sub.1-C.sub.4-alkyl, such as 2-methyl-1-piperidino;
93. R.sub.2 is hydrogen, C.sub.1-C.sub.4-alkoxy such as methoxy or
C.sub.1-C.sub.4-alkoxy which is substituted by carboxy, lower
alkoxycarbonyl, aminocarbonyl or by mono- or di-lower
alkylaminocarbonyl;
94. R.sub.3 is hydrogen, C.sub.1-C.sub.12-alkoxycarbonyl, such as
methoxycarbonyl or octyloxycarbonyl,
phenyl-C.sub.1-C.sub.4-alkoxycarbony- l, such as benzyloxycarbonyl,
C.sub.2-C.sub.5-alkanoyl, such as acetyl, benzoyl which is
unsubstituted or substituted by halogen, trifluoromethyl,
C.sub.1-C.sub.4-alkyl or by C.sub.1-C.sub.4-alkoxy, such as
3,4-dimethoxybenzoyl, C.sub.3-C.sub.6-cycloalkylcarbonyl which is
unsubstituted or substituted by C.sub.1-C.sub.4-alkyl, such as
2-isopropyl-5-methyl-cyclohexylcarbonyl;
95. X.sub.1 and X.sub.3 are --O--;
96. X.sub.2 is C.sub.4-C.sub.7-alkylene, such as pentylene;
97. wherein the phenyl rings of formula IA may be unsubstituted or,
furthermore, independently of one another, substituted by one or
more substituents selected from halogen, trifluoromethyl,
C.sub.1-C.sub.4-alkyl, and C.sub.1-C.sub.4-alkoxy.
98. The invention especially relates to the use of compounds of
formula IA and pharmaceutically acceptable salts thereof, in
which:
99. R.sub.1 is di-C.sub.1-C.sub.4-alkylamino, such as di-ethylamino
or di-isopropylamino, C.sub.1-C.sub.4-alkyl-(phenyl)-amino, such as
phenyl-isopropyl-amino,
C.sub.1-C.sub.4-alkyl-(phenyl-C.sub.1-C.sub.4-alk- yl)-amino, such
as methyl-benzyl-amino, di-C.sub.3-C.sub.6-cycloalkylamino- , such
as di-cyclohexylamino which is unsubstituted or substituted by
C.sub.1-C.sub.4-alkyl, or 1-piperidino substituted by
C.sub.1-C.sub.4-alkyl, such as 2-methyl-1-piperidino;
100. R.sub.2 is hydrogen, C.sub.1-C.sub.4-alkoxy such as methoxy or
C.sub.1-C.sub.4-alkoxy which is substituted by carboxy, lower
alkoxycarbonyl, aminocarbonyl or mono- or di-lower
alkylaminocarbonyl;
101. R.sub.3 is C.sub.1-C.sub.4alkanesulfonyl, such as methane-,
ethane- or isopropanesulfonyl,
phenyl-C.sub.1-C.sub.4-alkanesulfonyl, such as benzylsulfonyl,
C.sub.3-C.sub.7-cycloalkane-sulfonyl, such as cyclohexanesulfonyl,
or phenylsulfonyl, or is aminocarbonyl which is substituted by
C.sub.1-C.sub.4-alkyl, phenyl-C.sub.1-C.sub.4-alkyl or phenyl;
102. X.sub.1 and X.sub.3 are --O--;
103. X.sub.2 is C.sub.4-C.sub.7-alkylene, such as pentylene.
104. The invention especially relates to the use of compounds of
formula IA and pharmaceutically acceptable salts thereof, in
which:
105. R.sub.1 is di-C.sub.1-C.sub.4-alkylamino, such as
di-ethylamino or di-isopropylamino,
C.sub.1-C.sub.4-alkyl-(phenyl)-amino, such as
phenyl-isopropyl-amino,
C.sub.1-C.sub.4-alkyl-(phenyl-C.sub.1-C.sub.4-alk- yl)-amino, such
as methyl-benzyl-amino, di-C.sub.3-C.sub.6-cycloalkylamino- , such
as di-cyclohexylamino which is unsubstituted or substituted by
C.sub.1-C.sub.4-alkyl, or 1-piperidino substituted by
C.sub.1-C.sub.4-alkyl, such as 2-methyl-1-piperidino;
106. R.sub.2 is hydrogen, C.sub.1-C.sub.4-alkoxy such as methoxy or
C.sub.1-C.sub.4-alkoxy substituted by
C.sub.1-C.sub.4-alkoxycarbonyl, such as ethoxycarbonylmethyl, or by
aminocarbonyl;
107. R.sub.3 is hydrogen; or R.sub.3 is lower alkanoyl, such as
acetyl;
108. X.sub.1 and X.sub.3 are --O--;
109. X.sub.2 is C.sub.4-C.sub.7-alkylene, such as pentylene.
110. The invention further especially relates to the use of
compounds of formula IA and pharmaceutically acceptable salts
thereof, in which;
111. R.sub.1 is di-C.sub.1-C.sub.4-alkylamino, such as
di-isopropylamino;
112. R.sub.2 is hydrogen, C.sub.1-C.sub.4-alkoxy such as methoxy or
C.sub.1-C.sub.4-alkoxy substituted by
C.sub.1-C.sub.4-alkoxycarbonyl or by aminocarbonyl
113. R.sub.3 is C.sub.1-C.sub.12-alkoxycarbonyl, such as
methoxycarbonyl or octyloxycarbonyl,
phenyl-C.sub.1-C.sub.4-alkoxycarbonyl, such as benzyloxycarbonyl,
C.sub.2-C.sub.5-alkanoyl, such as acetyl, benzoyl which is
unsubstituted or substituted by halogen, trifluoromethyl,
C.sub.1-C.sub.4-alkyl, or C.sub.1-C.sub.4-alkoxy, such as
3,4-dimethoxybenzoyl, C.sub.3-C.sub.6-cycloalkylcarbonyl which is
unsubstituted or substituted by C.sub.-C.sub.4-alkyl, such as
2-isopropyl-5-methyl-cyclohexycarbonyl;
114. X.sub.1 and X.sub.3 are --O--;
115. X.sub.2 is C.sub.4-C.sub.7-alkylene, especially pentylene.
116. The invention further especially relates to the use of
compounds of formula IA and pharmaceutically acceptable salts
thereof, in which:
117. R.sub.1 is di-C.sub.1-C.sub.4-alkylamino, such as
di-ethylamino or di-isopropylamino;
118. R.sub.2 is hydrogen, C.sub.1-C.sub.4-alkoxy such as methoxy or
C.sub.1-C.sub.4-alkoxy substituted by
C.sub.1-C.sub.4-alkoxycarbonyl such as ethoxycarbonyl or by
aminocarbonyl,
119. R.sub.3 is hydrogen or C.sub.1-C.sub.4-alkanoyl, such as
acetyl;
120. X.sub.1 and X.sub.3 are --O--;
121. X.sub.2 is C.sub.4-C.sub.7-alkylene, especially pentylene.
122. The invention also particularly relates to the use of
compounds of formula IB 5
123. wherein the C(.dbd.NH)--NHR.sub.3 group may be in tautomeric
or isomeric form, and pharmaceutically acceptable salts thereof, in
which:
124. R.sub.1 is di-C.sub.1-C.sub.4-alkylamino, such as
di-ethylamino or di-isopropylamino,
C.sub.1-C.sub.4alkyl-(phenyl)amino, such as phenyl-isopropyl-amino,
C.sub.1-C.sub.4-alkyl-(phenyl-C.sub.1-C.sub.4-alk- yl)-amino, such
as methyl-benzyl-amino, di-C.sub.3-C.sub.6-cycloalkylamino- , such
as di-cyclohexylamino, which is unsubstituted or substituted by
C.sub.1-C.sub.4-alkyl, or 1-piperidino substituted by
C.sub.1-C.sub.4-alkyl, such as 2-methyl-1-piperidino;
125. R.sub.2 is hydroxy or C.sub.1-C.sub.4-alkoxy which is
substituted by carboxy, lower alkoxycarbonyl, aminocarbonyl or by
mono- or di-lower alkylaminocarbonyl;
126. R.sub.3 is hydrogen, C.sub.1-C.sub.12-alkoxycarbonyl, such as
methoxycarbonyl or octyloxycarbonyl,
phenyl-C.sub.1-C.sub.4-alkoxycarbony- l, such as benzyloxycarbonyl,
C.sub.2-C.sub.5-alkanoyl, such as acetyl, benzoyl which is
unsubstituted or substituted by halogen, trifluoromethyl,
C.sub.1-C.sub.4-alkyl, or C.sub.1-C.sub.4-alkoxy, such as
3,4-dimethoxybenzoyl, C.sub.3-C.sub.6-cycloalkylcarbonyl which is
unsubstituted or substituted by C.sub.1-C.sub.4-alkyl, such as
2-isopropyl-5-methyl-cyclohexylcarbonyl;
127. X.sub.1 and X.sub.3 are --O--;
128. X.sub.2 is C.sub.4-C.sub.7-alkylene, such as pentylene;
129. wherein the phenyl rings of formula IB may be unsubstituted
or, furthermore, independently of one another, substituted by one
or more substituents selected from halogen, trifluoromethyl,
C.sub.1-C.sub.4-alkyl, and C.sub.1-C.sub.4-alkoxy.
130. The invention especially relates to the use of compounds of
formula IB and pharmaceutically acceptable salts thereof, in
which:
131. R.sub.1 is di-C.sub.1-C.sub.4-alkylamino, such as
di-ethylamino or di-isopropylamino,
C.sub.1-C.sub.4-alkyl-(phenyl)-amino, such as
phenyl-isopropyl-amino,
C.sub.1-C.sub.4-alkyl-(phenyl-C.sub.1-C.sub.4-alk- yl)-amino, such
as methyl-benzyl-amino, di-C.sub.3-C.sub.6-cycloalkylamino- , such
as di-cyclohexylamino, which is unsubstituted or substituted by
C.sub.1-C.sub.4-alkyl, or 1-piperidino substituted by
C.sub.1-C.sub.4-alkyl, such as 2-methyl-1-piperidino;
132. R.sub.2 is hydroxy or C.sub.1-C.sub.4-alkoxy which is
substituted by carboxy, lower alkoxycarbonyl, aminocarbonyl or
mono- or di-lower alkylaminocarbonyl;
133. R.sub.3 is C.sub.1-C.sub.4alkanesulfonyl, such as methane-,
ethane- or isopropanesulfonyl,
phenyl-C.sub.1-C.sub.4-alkanesulfonyl, such as benzylsulfonyl,
C.sub.3-C.sub.7-cycloalkane-sulfonyl, such as cyclohexanesulfonyl,
or phenylsulfonyl, or is aminocarbonyl which is substituted by
C.sub.1-C.sub.4-alkyl, phenyl-C.sub.1-C.sub.4-alkyl or phenyl;
134. X.sub.1 and X.sub.3 are --O--;
135. X.sub.2 is C.sub.4-C.sub.7-alkylene, such as pentylene.
136. The invention especially relates to the use of compounds of
formula IB and pharmaceutically acceptable salts thereof, in
which:
137. R.sub.1 is di-C.sub.1-C.sub.4-alkylamino, such as
di-ethylamino or di-isopropylamino,
C.sub.1-C.sub.4-alkyl-(phenyl)-amino, such as
phenyl-isopropyl-amino,
C.sub.1-C.sub.4alkyl-(phenyl-C.sub.1-C.sub.4-alky- l)-amino, such
as methyl-benzyl-amino, di-C.sub.3-C.sub.6-cycloalkylamino, such as
di-cyclohexylamino, which is unsubstituted or substituted by
C.sub.1-C.sub.4-alkyl, or 1-piperidino substituted by
C.sub.1-C.sub.4-alkyl, such as 2-methyl-1-piperidino;
138. R.sub.2 is hydroxy or C.sub.1-C.sub.4-alkoxy substituted by
C.sub.1-C.sub.4-alkoxycarbonyl, such as ethoxycarbonylmethoxy or by
aminocarbonyl, such as carbamoylmethoxy;
139. R.sub.3 is hydrogen; or R.sub.3 is C.sub.2-C.sub.5-alkanoyl,
such as acetyl;
140. X.sub.1 and X.sub.3 are --O--;
141. X.sub.2 is C.sub.4-C.sub.7-alkylene, such as pentylene.
142. The invention further especially relates to the use of
compounds of formula IB and pharmaceutically acceptable salts
thereof, in which:
143. R.sub.1 is di-C.sub.1-C.sub.4-alkylamino, such as
di-ethylamino or di-isopropylamino;
144. R.sub.2 is hydroxy or C.sub.1-C.sub.4-alkoxycarbonylmethoxy,
such as ethoxycarbonylmethoxy, or aminocarbonylmethoxy;
145. R.sub.3 is hydrogen or C.sub.2-C.sub.5-alkanoyl, such as
acetyl;
146. X.sub.1 and X.sub.3 are --O--;
147. X.sub.2 is C.sub.4-C.sub.7-alkylene, especially pentylene.
148. Specific especially preferred compounds are those described in
WO 94/11341, EP 0518819, U.S. Pat. No. 5,451,700 and U.S. Pat. No.
5,488,160, particularly the Examples of those publications.
149. The invention relates particularly to the use of a compound of
formula IA and pharmaceutically acceptable salts thereof in which
R.sub.1 is di-isopropylamino, R.sub.2 is methoxy, R.sub.3 is
hydrogen, X.sub.1 and X.sub.3 are --O-- and X.sub.2 is pentylene
and a compound of formula IB and pharmaceutically acceptable salts
thereof in which R.sub.1 is di-isopropylamino, R.sub.2 is hydroxy,
R.sub.3 is hydrogen, X.sub.1 and X.sub.3 are --O-- and X.sub.2 is
pentylene, especially the maleate salts of said compounds.
150. Compounds of formula I and their salts where R.sub.2 is
hydroxy etherified by an aliphatic alcohol which is substituted by
carboxy, esterified carboxy or amidated carboxy and their
preparation are described in WO 94/11341. Other compounds of
formula I and their salts and their preparation are described in EP
0518819, U.S. Pat. No. 5,451,700 and U.S. Pat. No. 5,488,160.
151. Compounds of formula IB may also be prepared by catalytic
hydrogenation of a compound of formula 6
152. where R.sub.1, R.sub.2, R.sub.3, X.sub.1, X.sub.2 and X.sub.3
are as defined in formula IB, to reduce the indicated hydroxyimino
group to imino, for example using palladium-carbon as the catalyst
in a mixture of ethanol and acetic acid when the compound of
formula IB is isolated as the acetate salt which may be converted
if desired into other salts such as the maleate salt or into the
free amidine using known procedures.
153. Compounds of formula II may be prepared as described in U.S.
Pat. No. 5,455,274.
154. The maleate (2-butenedioate) salt of the compound of formula
IB in which R.sub.1 is di-isopropylamino, R.sub.2 is hydroxy,
R.sub.3 is hydrogen, X.sub.1 and X.sub.3 are --O-- and X.sub.2 is
pentylene is novel per se. This salt,
4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2-hydroxy-N-
,N-bis(1-methylethyl)benzamide (Z)-2-butenedioate may be prepared
as described in the Example hereinafter.
155. The compounds of formula I may be prepared in the form of one
of the possible isomers or mixtures thereof, for example, as
substantially pure geometric (cis or trans) isomers, optical
isomers (antipodes), racemates, or mixtures thereof.
156. Any resulting mixtures of isomers can be separated on the
basis of the physico-chemical differences of the constituents, into
the pure geometric or optical isomers, diastereoisomers, racemates,
for example by chromatography and/or fractional
crystallization.
157. Any resulting racemates of final products or intermediates can
be resolved into the optical antipodes by known methods, e.g. by
separation of the diastereoisomeric salts thereof, obtained with an
optically active acid or base, and liberating the optically active
acidic or basic compound. Racemic amidines (wherein R.sub.3
represents hydrogen) can thus be resolved into their optical
antipodes e.g. by fractional crystallization of a salt formed with
an optically active acid.
158. In view of the close relationship between the free compounds
and the compounds in the form of their salts, whenever a compound
is referred to in this context, a corresponding salt is also
intended, provided such is possible or appropriate under the
circumstances.
159. The compounds, including their salts, can also be used in the
form of their hydrates, or include other solvents used for their
crystallization.
160. The compounds of formula I and their salts can be administered
enterally, such as orally or rectally, by the pulmonary route, e.g.
by inhalation, transdermally and parenterally to mammals, including
man, in an effective amount alone or in combination with one or
more pharmaceutically acceptable carriers.
161. The active compound may be administered in a composition
containing, for example, from about 0.1% to about 95%, such as from
about 1% to about 80%, from about 10% to about 80% or, preferably
from about 20% to about 60%, of the active compound. Examples of
pharmaceutical compositions for enteral or parenteral
administration are those in dose-unit forms such as coated tablets,
tablets, capsules or suppositories, as well as ampoules. These are
prepared in a manner known per se, for example using conventional
mixing, granulating, coating, dissolving or freeze-drying
processes. Thus, pharmaceutical products for oral use can be
obtained by combining the active compound with solid excipients,
where appropriate granulating a mixture which is obtained, and
processing the mixture or granules, if desired or necessary, after
addition of suitable auxiliaries to tablets or cores of coated
tablets.
162. Preferred compositions for enteral or parenteral
administration are tablets and gelatin capsules comprising the
active ingredient together with a) diluents, e.g. lactose,
dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b)
lubricants, e.g. silica, talcum, stearic acid, its magnesium or
calcium salt and/or polyethyleneglycol; for tablets also c) binders
e.g. magnesium aluminum silicate, starch paste, gelatin,
tragacanth, methylcellulose, sodium carboxymethylcellulose and or
polyvinylpyrrolidone; if desired d) disintegrants, e.g. starches,
agar, alginic acid or its sodium salt, or effervescent mixtures;
and/or e) absorbants, colorants, flavors and sweeteners. Injectable
compositions are preferably aqueous isotonic solutions or
suspensions, and suppositories are advantageously prepared from
fatty emulsions or suspensions. Said compositions may be sterilized
and/or contain adjuvants, such as preserving, stabilizing, wetting
or emulsifying agents, solution promoters, salts for regulating the
osmotic pressure and/or buffers. Cores of coated tablets are
provided with suitable, optionally enteric, coatings, using, inter
alia, concentrated sugar solutions which optionally contain gum
arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or
titanium dioxide, lacquer solutions in suitable organic solvents or
solvent mixtures or, for the preparation of enteric coatings,
solutions of suitable cellulose products such as acetyl cellulose
phthalate or hydroxypropylmethylcellulo- se phthalate. Colorants or
pigments can be added to the tablets or coatings of coated tablets,
for example, to identify or to indicate various doses of active
compound. In addition, they may also contain other therapeutically
valuable substances. Said compositions are prepared according to
conventional mixing, granulating or coating methods, respectively,
and contain about 0.1 to 75%, preferably about 1 to 50%, of the
active ingredient.
163. A medicament, i.e. a pharmaceutical composition, suitable for
pulmonary administration may comprise a compound of formula I or a
pharmaceutically acceptable salt thereof, as hereinbefore defined,
optionally in admixture with a pharmaceutically acceptable carrier
therefor, the compound or mixture being in inhalable form. For
example, the medicament may be in the form of an aerosol, which can
be prepared in accordance with well-known procedures, or in finely
divided particulate form comprising, for example, the active
ingredient in finely divided form together with a carrier such as
finely divided lactose. Such medicaments may be administered using
an inhaler device suitable for the inhalable form, such devices
being well-known in the art.
164. An aerosol composition suitable for use in the method of the
invention may comprise a compound of formula I or a
pharmaceutically acceptable salt thereof in solution, or dispersed,
in a propellant, which may be chosen from any of the propellants
known in the art, such as fluorocarbons. The concentration of the
active ingredient in the propellant may be up to about 5% by
weight, for example 0.1 to 5%, 0.1 to 3%, 0.1 to 2%, 0.2 to 2%, 0.5
to 2% or 1 to 2% by weight.
165. An inhalable medicament in finely divided particulate form may
comprise a compound of formula I or pharmaceutically acceptable
salt thereof alone or together with a finely divided solid carrier
such as glucose, lactose, mannitol, sorbitol, ribose, mannose,
arabinose, saccharose, galactose, fructose or xylose. In such a
medicament, the compound of formula I or salt thereof suitably has
a median particle size of up to 10 microns, preferably up to 5
microns, especially up to 3 microns. Suitably, at least 70%,
preferably at least 80%, of the particles present in such a
particulate medicament have a median particle size of up to 10
microns, preferably up to 5 microns, especially up to 3
microns.
166. In accordance with the foregoing, the invention also provides
a pharmaceutical composition comprising as active ingredient a
compound of formula I, or a pharmaceutically acceptable salt
thereof, as hereinbefore defined, for use in the treatment of
chronic obstructive pulmonary disease.
167. In conjunction with another active ingredient, a compound of
formula I or a pharmaceutically acceptable salt thereof may be
administered either simultaneously, before or after the other
active ingredient, either separately by the same or different route
of administration or together in the same pharmaceutical
formulation.
168. The dosage of active compound administered is dependent on the
species of warm-blooded animal (mammal), the body weight, age and
individual condition, and on the form of administration. A unit
dosage for oral administration to a mammal of about 70 kg may
contain e.g. between about 1 and about 1000 mg/kg per day of the
active ingredient.
169. The effect of compounds of formula I or their pharmaceutically
acceptable salts in the treatment of chronic obstructive pulmonary
disease can be tested in a murine model of pulmonary neutrophilia
induced by lipopolysaccharide via intranasal instillation.
Bacterial lipopolysaccharide (LPS) is a macromolecular cell surface
antigen of bacteria which, when applied in vivo triggers a network
of inflammatory responses. The main characteristics of this
LPS-induced lung inflammation model, macrophage activation, tumour
necrosis factor-.alpha. (TNF-.alpha.) production and neutrophil
infiltration and activation, are features of chronic obstructive
pulmonary disease. This model causes pulmonary inflammation as an
acute injury which occurs after 2 to 4 hours in the airway lumen,
where all the inflammatory parameters can be assessed by
bronchoalveolar lavage (BAL).
170. The compound under test is dissolved in dimethyl sulfoxide
(DMSO) and to the resulting solution is added sterile phosphate
buffered saline (PBS) (50 .mu.l). The final concentration of DMSO
is 2%. Female Balb/C mice (20-25 g) are treated intranasally, under
Halothane/oxygen/nitrous oxide anaesthesia, with the PBS DMSO
diluent containing the compound under test at a suitable dose
(0.1-30 mg/kg) or with diluent alone and, 30 minutes later, with
0.3 mg/kg of LPS (Salmonella Typhosa, Sigma). The animals are
housed in plastic cages in an air conditioned room at 24.degree. C.
Food and water are available ad libitum. 3 hours after intranasal
administration of LPS, terminal anaesthesia is induced with
pentobarbitone sodium (60 mg/kg, i.p.), the abdominal cavity is
opened and the animals are exsanguinated by withdrawal of blood
from a major blood vessel.
171. The trachea is cannulated and bronchoalveolar lavage (BAL) is
performed by injecting 4 times 0.3 ml of PBS into the lung via the
trachea. The fluid is then immediately withdrawn and the cell
suspension stored on ice. Total cell count is measured and cytospin
preparation (Shandon Scientific Ltd, Cheshire, UK) prepared. Cells
are stained with Dif-Quick (Baxter Dade AG, Dudingen, Switzerland)
and a differential count of 200 cells performed using standard
morphological criteria. The remaining lavage fluids are centrifuged
at 1200 rpm for 10 minutes, the supernatant is aliquoted and stored
at -80.degree. C.
172. BAL myeloperoxidase (MPO) activity is measured on fresh BAL
supernatant using a 96 well plate format colorometric assay. 50
.mu.l of the samples, in duplicate, are mixed with 100 .mu.l of the
substrate buffer for 5 minutes at room temperature (sodium
phosphate 50 mM, pH 6.0 containing 0.5% hexadecyltrimethylammonium
bromide, 0.167 nM o-dianisidine dihydrochloride and 0.4 mM
H.sub.2O.sub.2). The reaction is stopped with 100 .mu.l of 5%
sodium azide in distilled water and the optical density (OD) read
at 450 nm. Results are expressed as U/ml using a standard curve
established with human leukocyte myeloperoxidase (Sigma).
173. The inhibitory effect of the compound under test on lung
inflammation is shown by the reduced neutrophil count and/or
reduced MPO activity obtained after administration of the compound
compared with that obtained after administration of diluent
alone.
174. In a modification of the above procedure, the compound under
test (or diluent alone for comparative purposes) is intranasally
administered a second time at the same dosage, 6 hours after
administration of LPS and the terminal anaesthesia is carried out
18 hours after the second administration. Another modification of
the above procedure which can be used is described by Goncalves de
Moraes et al, 1996 British Journal of Pharmacology, 117,
1792-1796.
EXAMPLE
175.
4-[5-[4-(amino(hydroxyimino)methyl)phenoxy]pentoxy]-2-hydroxy-N,N-bis-
(1-methylethyl)benzamide prepared as described in U.S. Pat. No.
5,455,274 (100.76 g), 370 mL of acetic acid, and 800 mL of ethanol
are gently shaken and warmed to 50-52.degree. C. to form a slightly
yellow solution. 10% palladium-carbon (13.2 g) is added and the
mixture is hydrogenated at 60 psi at a temperature 52-54.degree. C.
for 24 hours. The hot reaction mixture is filtered through a celite
and the filter cake is washed twice with 75 mL of 2:1
ethanol/acetic acid. The solvents are then removed in vacuo at
75.degree. C. Toluene (200 mL) is added to the residue and the
solvents are evaporated in vacuo. This is repeated a second time to
remove trace amounts of acetic acid and ethanol. To the residue is
added 10 g of activated charcoal and 50 mL of 2-propanol, and the
mixture is heated to 75.degree. C. The slurry is filtered hot and
washed twice with 50 mL of 2-propanol.
4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2-hydroxy-
-N,N-bis(1-methylethyl)benzamide monoacetate is crystallized from
2-propanol as the product, m.p. 197-199.degree. C.
176. CHN calculated for C.sub.27H.sub.38N.sub.3O.sub.6
1 Theory: % C: 64.78 % H: 7.65 % N: 8.40 Found: % C: 64.80 % H:
8.10 % N: 8.13
177.
4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2-hydroxy-N,N-bis(1-methyl-
ethyl)benzamide monoacetate (75.24 g) is suspended in 550 mL of
anhydrous ethanol (550 mL) and stirred under a nitrogen atmosphere
and heated to 75.degree. C. A solution of 34.82 g of maleic acid in
75 mL of water is heated to 75.degree. C. and rapidly added to the
mixture. Then 7 g of activated carbon is added, and the black
slurry is heated to 80.degree. C. and filtered through a celite
layer. The filter-cake is washed with ethanol/water (85 mL/15 mL),
and cooled overnight to room temperature. The reaction mixture is
cooled to 3.about.5.degree. C. for 2 hours and
4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2-hydroxy-N,N-bis(1-methylethy-
l)benzamide (Z)-2-butenedioate (1:1) is collected as white
crystals, m.p. 212.degree. C.
178. CHN calculated for C.sub.29H.sub.39N.sub.3O.sub.8
2 Theory: % C: 62.46 % H: 7.05 % N: 7.54 Found: % C: 62.20 % H:
6.92 % N: 7.38
* * * * *