Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-12-07
2002-04-30
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S618000, C514S620000, C514S621000, C514S622000
Reexamination Certificate
active
06380259
ABSTRACT:
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.
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.
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
wherein the C(═NH)—NHR
3
group may be in tautomeric or isomeric form, or a pharmaceutically acceptable salt thereof, in which:
R
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
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
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
1
and X
3
, independently of one another, are oxygen (—O—) or sulphur (—S—); and X
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.
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.
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.
The compounds of formula I wherein the C(═NH)—NHR
3
group is in tautomeric or isomeric form are represented by formula I
1
wherein R
1
, R
2
, R
3
, X
1
, X
2
and X
3
have the meanings as defined for formula I.
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
1
-C
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
1
-C
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.
The general definitions used below have, if not defined differently, the following meanings:
An aliphatic hydrocarbon radical is, for example, lower alkyl, lower alkenyl and secondarily lower alkynyl.
An araliphatic hydrocarbon radical is, for example, optionally substituted phenyl-lower alkyl and secondarily phenyl-lower alkenyl and phenyl-lower alkynyl.
A cycloaliphatic hydrocarbon radical is, for example, cycloalkyl and secondarily cycloalkenyl, which is unsubstituted or mono- or polysubstituted, for example, disubstituted, by lower alkyl.
A divalent aliphatic hydrocarbon radical is, for example, lower alkylene.
A divalent aliphatic radical interrupted by oxygen is, for example, lower alkylene interrupted by oxygen, e.g. ethylene-O-ethylene.
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.
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.
Hydroxy which is etherified by an aliphatic or araliphatic alcohol is, for example, lower alkoxy or lower alkenyloxy and phenyl-lower alkoxy.
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.
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.
Hydroxy which is esterified by an aliphatic or araliphatic carboxylic acid is, for example, lower alkanoyloxy, lower alkenoyloxy or phenyl-lower alkanoyloxy.
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.
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.
An acyl radical which is derived from a sulfonic acid is, for example, alkanesulfonyl, arylalkanesulfonyl, cycloalkanesulfonyl or arylsulfonyl.
An acyl radical which is derived from a carbamic acid is, for example, amino-carbonyl which is substituted by alkyl, arylalkyl or aryl.
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.
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.
The phenyl rings of formulae I and I
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 consis
Fujimoto Roger A.
Marshall Paul J.
Loeschorn Carol A.
Novartis AG
Reamer James H.
LandOfFree
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