Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-05-04
2003-04-15
Low, Christopher S. F. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C562S445000, C562S575000
Reexamination Certificate
active
06548480
ABSTRACT:
The present invention relates to phosphonic acid derivatives useful in the treatment of cardiovascular diseases and, more particularly, it relates to phosphonic acid derivatives useful in the treatment of cardiovascular diseases as metallopeptidase inhibitors. The pharmacologic interest towards the study of metallopeptidase inhibitory molecules derives from the role that said enzymes exert on the level of the cardiocirculatory system.
It is well-known in fact that compounds with angiotensin converting enzyme (ACE) inhibitory activity are mainly useful in the treatment of hypertension, of heart failure and of post-infarct in that they inhibit the formation of angiotensin II, a substance which increases the blood pressure.
Compounds with endothelin converting enzyme (ECE) inhibitory activity are useful as anti-vasoconstrictors in that they inhibit the formation of endothelin, a 21 amino acid peptide with vasoconstrictor activity.
Instead, compounds with inhibitory activity of the neutral endopeptidase (NEP) enzyme, also called enkephalinase, are useful as vasodilators and diuretics in that the NEP enzyme is responsible for the inactivation, not only of endogenous enkephahne, but also of some natriuretic factors among which, for instance, the atrial natriuretic factor (ANF), a vasodilating hormone secreted by heart.
Therefore, even exerting their action on the cardiovascular system with different mechanisms of action, the compounds with metallopeptidase inhibitory activity are generally used, alone or in combination, in the treatment of hypertension, renal failure, congestive heart failure and post-infarct.
In the U.S. Pat. No. 4,432,972 (E.R. Squibb & Sons, Inc.) phosphorylated derivatives of amino acids such as, in particular, phosphonamidates endowed with ACE-inhibitory and enkephahnase-inhibitory activity were described.
Said compounds were described as useful hypotensive and analgesic agents. In the European patent application No. 0518299 (Takeda Chemical Industries, Ltd) some phosphonic acid derivatives, endowed with ECE-inhibitory activity, usefull in the treatment of hypertension, of cardiac or cerebrovascular diseases and of renal diseases were described.
Now we have found phosphonic acid derivatives which are endowed with inhibitory activity on the angiotensin converting enzyme as well as on the neutral endopeptidase enzyme (dual ACE/NEP-inhibitory activity) which renders them particularly useful in the cardiovascular therapy.
Therefore object of the present invention are the compounds of formula
wherein
R is a straight or branched C
1
-C
6
alkyl group optionally substituted with one or more fluorine atoms, an aryl or arylalkyl group with from 1 to 6 carbon atoms in the alkyl moiety wherein the aryl is a phenyl 1-naphthyl, 2-naphthyl group or a 5 or 6 membered aromatic heterocycle with 1 or 2 heteroatoms selected among nitrogen, oxygen and sulphur, optionally substituted with one or more substituents, the same or different, selected among halogen atoms, hydroxy groups, alkyl, alkoxy, alkythio, alkylsulphonyl or alkoxycarbonyl groups with from 1 to 3 carbon atoms in the alkyl moiety, carboxy groups, aminocarbonyl groups, acylamino groups, aminosulphonyl groups, mono- or di-alkylaminocarbonyl groups with from 1 to 3 carbon atoms in the alkyl moiety;
R
1
and R
2
, the same or different, represent a hydrogen atom or a straight or branched C
1
-C
4
alkyl group;
R
3
is a straight or branched C
1
-C
6
alkyl group or an arylalkyl group with from 1 to 6 carbon atoms in the alkyl moiety wherein the aryl is a phenyl, 1-naphthyl 2-naphthyl group or a 5 or 6 membered aromatic heterocycle with one or two heteroatoms selected among nitrogen, oxygen and sulphur, optionally substituted as indicated for R;
R
4
is a 5 or 6 membered aromatic heterocyclic group with one or two heteroatoms selected among nitrogen, oxygen and sulphur, optionally substituted with a 5 or 6 membered aromatic heterocyclic group with one or two heteroatoms selected among nitrogen, oxygen and sulphur or with a phenyl group, or it is a phenyl group substituted with a 5 or 6 membered aromatic heterocyclic group with one or two heteroatoms selected among nitrogen, oxygen and sulphur, being the phenyl and the heterocyclic groups optionally substituted with one or more substituents, the same or different, selected among halogen atoms, alkyl alkoxy, alkylthio or alkoxycarbonyl groups with from 1 to 3 carbon atoms in the alkyl moiety;
X is a single bond or an —O—CONH— or —CONH— group;
the carbon atoms marked with an asterisk are asymmetric carbon atoms;
and pharmaceutically acceptable salts thereof;
provided that R
4
is not an imidazolyl or indolyl group.
The compounds of formula I contain at least two asymmetric carbon atoms and can thus exist in the form of stereoisomers.
Therefore, object of the present invention are the compounds of formula I in the form of stereoisomeric mixture as well as in the form of single stereoisomers.
The compounds of formula I object of the present invention are endowed with a dual ACE/NEP-inhibitory activity and are useful in the treatment of cardiovascular diseases.
In the present description, unless otherwise specified, with the term alkyl group we intend a straight or branched alkyl such as methyl, ethyl, n.propyl, isopropyl, n.butyl, sec-butyl tert-butyl isobutyl n.pentyl 2-pentyl, 3-pentyl, isopentyl, tert-pentyl n.hexyl and isohexyl; with the term alkoxy group we intend a straight or branched alkoxy such as methoxy, ethoxy, n.propoxy and isopropoxy; with the term halogen atom we intend a fluorine, chlorine, bromine or iodine atom; with the term acyl we intend an acyl group deriving from an aliphatic or aromatic carboxylic acid such as acetic, propionic, butyric and benzoic acid; with the term aryl we intend an aromatic group such as phenyl, 1-naphthyl, 2-naphthyl or a 5 or 6 membered heterocyclic group containing 1 or 2 heteroatoms selected among nitrogen, oxygen and sulphur such as thiazole, isoxazole, oxazole, isothiazole, pyrazole, imidazole, thiophene, pyrrole, pyridine, pyrimidine, pyrazine and furan, optionally benzocondensed.
Examples of pharmaceutically acceptable salts of the compounds of formula I are the salts with alkali or alkali-earth metals and the salts with pharmaceutically acceptable organic bases.
Preferred compounds of formula I are the compounds wherein R
4
represents a phenyl group substituted in position 4 with a heterocyclic group.
Particularly preferred, in this class, are the compounds of formula I wherein R
1
and R
2
represent a hydrogen atom and R
3
represents a straight or branched C
1
-C
4
alkyl group.
Preferred examples of pharmaceutically acceptable salts of the compounds of formula I are the salts with alkali metals such as sodium, lithium and potassium.
Specific examples of preferred compounds of formula I, object of the present invention, are:
N-(N′-propylphosphonyl-leucyl)-[4-(2-furyl)]-phenylalanine;
N-(N′-propylphosphonyl-leucyl)-[4-(3-furyl)]-phenylalanine;
N-(N′-propylphosphonyl-leucyl)-[4-(2-thienyl)]-phenylalanine;
N-(N′-propylphosphonyl-leucyl)-[4-(3-thienyl)]-phenylalanine;
N-(N′-propylphosphonyl-leucyl)-[4-(N″-methyl-2-pyrrolyl)]-phenylalanine;
N-(N′-propylphosphonyl-leucyl)-[4-(N″-methyl-3-pyrrolyl)]-phenylalanne;
N-(N′-propylphosphonyl-leucyl)-[4-(2-thiazolyl)]-phenylalanine;
N-(N′-propylphosphonyl-leucyl)-[4-(2-pyridyl)]-phenylalanine;
N-(N′-propylphosphonyl-leucyl)-[4-(3-pyridyl)]-phenylalanine;
N-(N′-propylphosphonyl-leucyl)-(4-pyrazinyl)-phenylalanine;
N-(N′-propylphosphonyl-leucyl)-[4-(5-pyrmidinyl)]-phenylalanine;
N-(N′-propylphosphonyl-valyl)-[4-(2-furyl)]-phenylalaine;
N-(N′-propyhphosphonyl-valyl)-[4-(3-furyl)]-phenylalanine;
N-(N′-propyhphosphonyl-valyl)-[4-(2-thienyl)]-phenylalanine;
N-(N′-propylphosphonyl-valyl)-[4-(3-thienyl)]-phenylalanine;
N-(N′-propylphosphonyl-valy
Botta Daniela
Norcini Gabriele
Santangelo Francesco
Arent Fox Kintner & Plotkin & Kahn, PLLC
Low Christopher S. F.
Lukton David
Zambon Group S.p.A.
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