Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-08
2003-02-18
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S319000
Reexamination Certificate
active
06521631
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field
The present invention relates to heterocyclic sulfonamides, methods for their manufacture, and their use as medicaments, especially for treating chronic heart failure.
2. Description
Sulfonamides are known inhibitors of endothelin receptors. See, for example, EP 0 713 875. There is a need for endothelin receptor inhibitors that have high antagonistic potency and achieve high plasma levels following oral administration.
SUMMARY OF THE INVENTION
The subject invention provides compounds of formula:
wherein
R
1
is pyridyl, pyridyl substituted with lower alkyl, pyridyl substituted with lower alkenyl, thiazolyl, thiazolyl substituted with lower alkyl, or thiazolyl substituted with lower alkenyl;
and pharmaceutically usable salts of such compounds.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to by construed as limiting.
The present invention relates to compounds of the formula (I)
wherein
R
1
is a heterocyclic residue selected from pyridyl and thiazolyl, where said heterocyclic residue may optionally be substituted with lower alkyl or lower alkenyl;
and pharmaceutically acceptable salts thereof.
The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier and/or adjuvant.
Furthermore the present invention relates to the use of such compounds for the preparation of medicaments for the treatment or prophylaxis of disorders which are associated with abnormal vascular tone and endothelial dysfunction.
The present invention also relates to processes for the preparation of the compounds of formula (I).
In addition, the present invention relates to a method for the prophylactic and/or therapeutic treatment of disorders that are associated with abnormal vascular tone and endothelial dysfunction, which method comprises administering a compound of formula (I) to a human being or an animal.
The sulfonamides of the present invention are inhibitors of endothelin receptors. They can accordingly be used for the treatment of disorders which are associated with abnormal vascular tone and endothelial dysfunction. EP 0 713 875 discloses sulfonamide compounds as endothelin receptor inhibitors. However, the compounds of the present invention have a high antagonistic potency in vitro and show unexpectedly high plasma levels following oral administration.
Unless otherwise indicated the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term “lower alkyl” refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon radical of one to seven carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.
The term “lower alkenyl” refers to a lower alkyl group containing one or more double bond(s) in the alkylene chain.
The term “pharmaceutically acceptable salts” embraces salts of the compounds of formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non-toxic to living organisms. It also includes salts with inorganic or organic bases such as alkali salts like sodium and potassium salts, alkaline earth metal salts like calcium and magnesium salts, N-methyl-D-glutamine salts and salts with amino acids like arginine, lysine and the like.
More particularly, the present invention relates to compounds of the above formula (I), wherein
R
1
is a heterocyclic residue selected from pyridyl and thiazolyl, where said heterocyclic residue may optionally be substituted with lower alkyl or lower alkenyl. The term “lower alkyl” preferably means methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl or t-butyl, more preferably methyl, ethyl or isopropyl, still more preferably methyl or isopropyl, most preferably methyl. The term “lower alkenyl” preferably means vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl or 3-butenyl, more preferably vinyl, 1-propenyl, allyl and isopropenyl, most preferably isopropenyl.
Preferred heterocyclic residues in R
1
are 2-pyridyl and 2-thiazolyl, most preferred is 2-pyridyl. In a preferred embodiment, the heterocyclic residues in R
1
are substituted with lower alkyl or lower alkenyl, with lower alkyl being preferred.
Particularly preferred residues R
1
are 5-methyl-pyridine-2-yl, 5-isopropyl-pyridine-2-yl, 5-isopropenyl-pyridine-2-yl and 5-methyl-thiazol-2-yl. More preferred are 5-methyl-pyridine-2-yl, 5-isopropyl-pyridine-2-yl and 5-isopropenyl-pyridine-2-yl. Still more preferred are 5-methyl-pyridine-2-yl and 5-isopropyl-pyridine-2-yl. Most preferred is 5-methyl-pyridine-2-yl.
Particularly preferred compounds of formula (I) are 5-methyl-pyridine-2-sulfonic acid[6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]- amide, 5-isopropyl-pyridine-2-sulfonic acid[6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide, 5-isopropenyl-pyridine-2-sulfonic acid[6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide and 5-methyl-thiazole-2-sulfonic acid[6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]- amide.
More particularly preferred compounds of formula (I) are 5-methyl-pyridine-2-sulfonic acid[6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide and 5-isopropyl-pyridine-2-sulfonic acid[6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide, most preferred is 5-methyl-pyridine-2-sulfonic acid[6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]- amide.
The compounds of formula (I) can be prepared in analogy to known processes or processes described below and summarized in the following schemes 1 and 2:
4,6-Dichloro-5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidine (described in EP 0 799 209) can be transformed to the intermediate of formula (III)—according to scheme 1—on reaction with an appropriate sulfonamide of formula (II), wherein R
1
is as defined in claim
1
, in a suited solvent such as DMSO or DMF at room temperature or at elevated temperature and in the presence of a suited base such as potassium carbonate.
The corresponding sulfonamides can also be applied in above reaction in form of their re-formed sodium or potassium salts.
Compounds of formula (III) can be further transformed to compounds of formula (I) by treatment with sodium methylate in a solvent such as methanol.
The heterocyclic sulfonamides of formula (II) are either already known in the literature, prepared in a manner analogous to established procedures and/or can be derived from corresponding mercapto derivatives in analogy to a known reaction sequence comprising oxidation with Cl
2
in an acidic aqueous medium, such as diluted aqueous HCl, to yield the corresponding sulfonyl chlorides which can be transformed with liquid ammonia or aqueous ammonium hydroxide to the sulfonamides. The corresponding sodium or potassium salts can be obtained on treatment with sodium or potassium alkoxide in an appropriate solvent such as methanol.
Alternatively, compounds of formula (I) can be prepared—according to scheme 2—starting from 4-[4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-1-oxide (preparation described in EP 0 799 209) in a reaction sequence analogous to that of scheme 1, to give compounds of formula (V).
Pyridine-N-oxide reduction of compounds of formula (V) can be accomplished with a reagent system such as TiCl
4
/NaI in analogy to a method described in Chem. Ber. 123, 647 (1990), or with a trialkylsilyl chloride (for example, t-butyldimethylsilyl chloride) in the presence of a suited
Breu Volker
Coassolo Philippe
Neidhart Werner
Roux Sébastien
Weiss Peter
Ford John M.
Hoffmann-La Roche Inc.
Johnston George W.
Rocha-Tramaloni Patricia S.
Smith Lyman H.
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