P-thienylbenzylamides as agonists of angiotensin-(1-7)...

Details P-thienylbenzylamides as agonists of angiotensin-(1-7)... P-thienylbenzylamides as agonists of angiotensin-(1-7)...

2002-03-13

2003-03-25

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S069000

Reexamination Certificate

active

06538144

ABSTRACT:

The invention relates to p-thienylbenzylamides of formula (I)
in which R(1), R(2), R(3), R(4), R(5), R(6) and X have the meanings given below. The compounds of formula (I) are potent agonists of angiotensin-(1-7) receptors. As a result of the stimulation of these receptors, which is elicited by the compounds of formula (I), and the production and release of the vasorelaxing and cardioprotective messengers cyclic guanosine monophosphate (cGMP) and nitrogen monoxide (NO) associated with endothelial cells, the compounds of formula (I) are suitable as pharmaceutically active compounds for treating and preventing hypertension; cardiac hypertrophy; cardiac insufficiency; coronary heart diseases, such as angina pectoris; and endothelial dysfunction or endothelial damage, for example, as a consequence of atherosclerotic processes or in association with diabetes mellitus.
PCT application WO-0068226 describes 1-(p-thienylbenzyl)imidazoles as agonists of angiotensin-(1-7) receptors for the treatment and/or prophylaxis of hypertension, cardiac hypertrophy, cardiac insufficiency and endothelial dysfunction or endothelial damage.
In view of the multifarious possibilities for using angiotensin (ANG)-(1-7) receptor agonists as pharmaceuticals, and the demands for such properties, there is a need for further ANG-(1-7) receptor agonists which exhibit favorable activity and selectivity (i.e., a good pharmacodynamic or pharmacokinetic profile).
It has been found, surprisingly, that p-thienylbenzylamides of formula (I) have a pronounced effect on angiotensin-(1-7) receptors and mimic the biological effect of the effector hormone angiotensin-(1-7).
One part of the subject-matter of the invention consequently relates to compounds of formula (I)
in which the indicated radicals have the following meanings:
R(1) is chosen from among
1. (C
1
-C
5
)-alkyl, unsubstituted or substituted by a radical chosen from among NH
2
, halogen, O—(C
1
-C
3
)-alkyl, CO—O—(C
1
-C
3
)-alkyl and CO
2
H;
2. (C
3
-C
8
)-cycloalkyl;
3. (C
1
-C
3
)-alkyl-(C
3
-C
8
)-cycloalkyl;
4. (C
6
-C
10
)-aryl, unsubstituted or substituted by a radical chosen from halogen and O—(C
1
-C
3
)-alkyl;
5. (C
1
-C
3
)-alkyl-(C
6
-C
10
)-aryl, where the aryl radical is unsubstituted or substituted by a radical chosen from halogen and O—(C
1
-C
3
)-alkyl;
6. (C
1
-C
5
)-heteroaryl; and
7. (C
1
-C
3
)-alkyl-(C
1
-C
5
)-heteroaryl;
R(2) is chosen from among
1. hydrogen;
2. (C
1
-C
6
)-alkyl, unsubstituted or substituted by a radical chosen from halogen and O—(C
1
-C
3
)-alkyl;
3. (C
3
-C
8
)-cycloalkyl;
4. (C
1
-C
3
)-alkyl-(C
3
-C
8
)-cycloalkyl;
5. (C
6
-C
10
)-aryl, unsubstituted or substituted by a radical chosen from among halogen, O—(C
1
-C
3
)-alkyl and CO—O—(C
1
-C
3
)-alkyl; and
6. (C
1
-C
3
)-alkyl-(C
6
-C
10
)-aryl, unsubstituted or substituted by a radical chosen from halogen and O—(C
1
-C
3
)-alkyl;
R(3) is chosen from among
1. hydrogen;
2. COOH; and
3. COO—(C
1
-C
4
)-alkyl;
R(4) is chosen from among
1. hydrogen;
2. halogen; and
3. (C
1
-C
4
)-alkyl;
R(5) is chosen from among
1. hydrogen, and
2. (C
1
-C
6
)-alkyl;
R(6) is chosen from among
1. hydrogen;
2. (C
1
-C
6
)-alkyl;
3. (C
1
-C
3
)-alkyl-(C
3
-C
8
)-cycloalkyl; and
4. (C
2
-C
6
)-alkenyl;
X is chosen from among
1. oxygen, and
2. NH;
in all the stereoisomeric forms thereof, and mixtures thereof in all ratios, and the physiologically tolerated salts thereof.
Unless otherwise indicated, the term alkyl encompasses straight-chain or branched saturated hydrocarbon radicals. This also applies to substituents which are derived therefrom, such as alkoxy or the radicals SO
2
NHCOO-alkyl and SO
2
NHCONH-alkyl. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-hexyl, isohexyl and n-heptyl. Examples of alkoxy radicals include methoxy, ethoxy and propoxy, such as n-propoxy and isopropoxy.
Alkenyl denotes singly or multiply unsaturated hydrocarbon radicals in which the double bonds can be present in any arbitrary position. Examples of alkenyl radicals include vinyl, prop-2-enyl (allyl), prop-1-enyl and butenyl.
Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Halogen denotes fluorine, chlorine, bromine or iodine, and in one embodiment, the halogen is chlorine or fluorine.
Examples of aryl radicals include phenyl and naphthyl (1- or 2-naphthyl).
In substituted aryl radicals,.the substituents can be located in any positions in relation to each other.
Heteroaryl is understood as meaning radicals of monocyclic 5-membered or 6-membered aromatic ring systems. They can be regarded as being radicals which are derived from cyclopentadienyl and phenyl by the replacement of one or two CH groups and/or CH
2
groups with S, O, N or NH (or N carrying a substituent, such as N—CH
3
), in connection with which the aromatic ring system is preserved or an aromatic ring system is formed. In addition to the one, two, three or four ring heteroatoms, they may contain one, two, three, four or five ring carbon atoms ((C
1
-C
5
)-heteroaryl). Examples of suitable heteroaryls include furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl and pyrimidyl. A heteroaryl radical can be bonded by way of any suitable carbon atom.
In one embodiment,
R(1) is
1. (C
1
-C
5
)-alkyl, such as methyl; or
2. (C
1
-C
5
)-alkyl, substituted by a radical chosen from CO—O—(C
1
-C
3
)-alkyl and CO
2
H; such as carboxypropionyl and methoxycarbonylpropionyl; or
3. (C
1
-C
3
)-alkyl-(C
3
-C
8
)-cycloalkyl, such as cyclohexylmethyl; or
4. (C
6
-C
10
)-aryl, such as phenyl; or
5. (C
1
-C
5
)-heteroaryl, such as furanoyl.
R(2) is
1. hydrogen; or
2. (C
1
-C
6
)-alkyl, such as isopropyl; or
3. (C
1
-C
6
)-alkyl, substituted by O—(C
1
-C
3
)-alkyl, such as methoxymethylene; or
4. (C
3
-C
8
)-cycloalkyl, such as cyclopropyl and cyclohexyl; or
5. (C
6
-C
10
)-aryl, such as phenyl.
R(3) is
1. COOH; or
2. COO—(C
1
-C
4
)-alkyl, such as methoxycarbonyl and ethoxycarbonyl.
R(4) is hydrogen.
R(5) is (C
1
-C
6
)-alkyl, such as isobutyl.
R(6) is (C
1
-C
6
)-alkyl, such as methyl, ethyl or butyl.
The present invention encompasses all the stereoisomeric forms of the compounds of formula (I). In the compounds of formula (I) which contain centers of asymmetry, all these centers can, independently of each other, have the S or R configuration. The invention includes all the possible enantiomers and diastereomers, as well as mixtures of two or more diastereomeric forms, for example mixtures composed of enantiomers and/or diastereomers, in all ratios. When a cis/trans isomerism is present, both the cis and the trans form, and mixtures of these forms in all ratios, are part of the subject-matter of the invention. The invention also encompasses all the tautomeric forms of the compounds of formula (I).
Physiologically tolerated salts of compounds of formula (I) are understood as being both their inorganic salts and their organic salts, as described in Remington's Pharmaceutical Sciences (A. R. Gennard, Editor, Mack Publishing Co, Easton Pa., 17th edition, pages 14-18, 1985). Because of their physiological and chemical stability and solubility, useful salts include, inter alia, sodium, potassium, calcium, magnesium and ammonium salts for acidic groups. Reactions of compounds of formula (I) with bases for the purpose of preparing the salts are, in general, carried out in accordance with customary procedures in a solvent or diluent.
The present invention furthermore encompasses solvates of compounds of formula (I), for example, hydrates or adducts with alcohols; and also derivatives of the compounds of formula (I), such as esters; and prodrugs and active metabolites.
In another embodiment, the compounds of formula (I) include those in which
R(1) is chosen from among
1. (C
1
-C
5
)-alkyl, unsubstituted or substituted by a radical chosen from among NH
2
, halogen, O—(C
1
-C
3
)-alkyl, CO—O—(C
1
-C
3
)-alkyl and CO
2
H;
2. (C
3
-C
6
)-cycloalkyl;
3. (C
1
-C
3
)-alkyl-(C
3
-C
6
)-cycl

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