Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1992-01-24
2003-04-08
Travers, Russell (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S452000, C514S602000
Reexamination Certificate
active
06545040
ABSTRACT:
BACKGROUND OF THE INVENTION
In U.S. Pat. No. 4,654,362 there are described 2,2′-iminobisethanol derivatives having &bgr; adrenergic blocking properties. It now has been found that a certain class of isomers of said bisethanol derivatives potentiate the activity of blood pressure reducing agents.
DESCRIPTION OF THE INVENTION
The present invention is concerned with a group of compounds capable of potentiating the effects of blood pressure reducing agents, said compounds being represented by the formula
or the pharmaceutically acceptable acid addition salts thereof, wherein
R
1
and R
2
each independently are hydrogen or C
1-6
alkyl;
R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
and R
10
each independently are hydrogen, halo, C
1-6
alkyl, C
1-6
alkyloxy, hydroxy, cyano, carboxy or C
1-6
alkyloxycarbonyl; or two vicinal radicals of R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
and R
10
taken together may form a —CH═CH—CH═CH— or —(CH
2
)
4
— radical.
As used in the foregoing definitions the term halo is generic to fluoro, chloro, bromo and iodo; the term “C
1-6
alkyl” defines straight and branch chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl and the like.
The descriptors R and S as used in the above formula (I) indicate the absolute configuration at the respective carbon atoms. The carbon atom bearing R
1
has the R configuration, whereas the carbon atoms bearing the hydroxy functions and the carbon atoms bearing R
2
have the S configuration.
Preferred compounds of formula (I) are those wherein R
3
, R
4
, R
6
, R
7
, R
8
, and R
10
are hydrogen.
Particularly preferred are those preferred compounds wherein R
5
and R
9
are hydrogen or halo, particularly fluoro.
The most preferred compound is [2R,&agr;S,2′S,&agr;S]-&agr;,&agr;′-[iminobismethylene]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] or a pharmaceutically acceptable acid addition salt thereof.
The compounds of formula (I) can be prepared following the procedures described in U.S. Pat. No. 4,654,362. Some particular ways of obtaining the compounds of formula (I) will be described hereinafter in some more detail.
The compounds of formula (I) can be prepared by reacting an oxirane of formula (II-a) or (II-b) with an amine of formula (III-a) or (III-b).
In (III-a) and (III-b), P is either hydrogen or an appropriate protecting group, for example an allyl group, or in particular P may be a benzyl group. Or, a reagent P—NH
2
may be reacted with (II-a) and (II-b) in a one-pot procedure. The above described reactions to prepare a compound of formula (I) may be conducted in a reaction-inert solvent such as, for example, an aromatic hydrocarbon, e.g. benzene or methylbenzene; an alkanol, e.g. methanol, ethanol, propanol; a ketone, e.g. 2-propanone, 4-methyl-2-pentanone; an ether, e.g. 1,4-dioxane, tetrahydrofuran, 1,1′-oxybisethane; a dipolar aprotic solvent, e.g. N,N-dimethylformamide or N,N-dimethylacetamide and the like solvents. In certain instances, in order to increase the reaction rate, it may be appropriate to heat the reaction mixture.
If in the above reactions P is other than hydrogen, the N-protected derivatives of formula (I) are obtained wherefrom the compounds of formula (I) themselves can be obtained by a deprotection reaction. For example, where P is allyl, by reaction with an appropriate noble metal compound such as PdCl
2
or Rh[P(C
6
H
5
)
3
]Cl, or where P is benzyl, by a catalytic hydrogenation procedure, e.g. palladium or platinum on charcoal in a suitable solvent such as an ether, e.g. 1,4-dioxane, tetrahydrofuran, an alkanol, e.g. methanol, ethanol, an alkoxyalkanol, e.g. methoxyethanol and the like.
The intermediates of formula (II-a) or (III-b) are obtained by the reaction of the amine P-KH
2
with (II-b) or (II-a) or, by reacting a reagent P
2
NH, for example dibenzylamine, with (II-b) or (II-a) and subsequently selectively removing one of the P-groups, e.g. when P is benzyl by a catalytic hydrogenation procedure using one equivalent hydrogen. The afore described reactions to prepare (III-a) or (III-b) are conducted following the same procedures as described hereinabove for the preparation of the compounds (I).
The starting materials (II-a) are obtained by an oxirane formation reaction from an aldehyde of formula (IV-a), e.g. by reaction of the latter with a trimethylsulfoxonium halide, or from an ethylene of formula (V-a) by reaction of the latter with a peroxide, e.g. a haloperbenzoic acid. In the same way, the intermediate (II-b) is obtained from the corresponding S-isomers (IV-b) or (V-b). The oxiranes of formula (IV-a-1) obtained in the aforementioned oxirane-formation reaction are separated in their stereoisomers, e.g. by HPLC or selective crystallization.
The compounds of formula (IV-a), (IV-b), (V-a) or (V-b) are obtained by a suitable separation procedure, i.e. by HPLC, or by a reduction reaction of the corresponding optically active racemic acids whereas (IV-a) or (IV-b) can be converted to (V-a) or (V-b) by a Wittig reaction. The said corresponding optically active acids in turn can be obtained by conventional separation techniques, i.e. by salt or amide formation with an optically active reagent and a selective crystallization procedure or a HPLC separation.
The compounds of formula (I) have basic properties and, consequently, they may be converted to their therapeutically active non-toxic acid addition salt forms by treatment with appropriate acids, such as, for example, inorganic acids, such as hydrohalic acid, e.g. hydrochloric, hydrobromic and the like, and sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propane-tricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.
Conversely, the salt form can be converted by treatment with alkali into the free base form.
The compounds of formula (I) with the exception of (RSSS)-&agr;,&agr;′-[iminobis(methylene)bis(3,4-dihydro-2H-1-benzopyran-2-methanol] ethanedioate(1:1) are deemed to be novel compounds and constitute in an additional feature to the present invention.
The compounds of formula (I) and the pharmaceutically acceptable acid addition salts thereof potentiate the activity of blood pressure reducing agents. In particular they potentiate the reduction of the blood pressure and of the heart rate.
As blood pressure reducing agents of which the activity is potentiated there may be mentioned agents having adrenergic and/or vasodilating activity. In particular such agents may be the compounds mentioned in U.S. Pat. Nos. 3,663,607 and 3,836,671, in particular atenolol; U.S. Pat. Nos. 3,337,628 and 3,520,919, in particular propranolol; U.S. Pat. No. 3,873,600, in particular metoprolol; U.S. Pat. No. 3,511,836, in particular prazosin; U.S. Pat. No. 2,484,029, in particular hydralazine; U.S. Pat. No. 2,928,829 in particular guanethidine; U.S. Pat. No. 2,503,059, in particular phentolamine; U.S. Pat. No. 3,261,859, in particular verapamil; U.S. Pat. No. 3,485,847 in particular nifedipine; U.S. Pat. No. 3,910,924, in particular carteolol; German Pat. Nos. 2,458,624 and 2,458,625, in particular celiprolol. A particular group of blood pressure reducing compounds are the compounds of U.S. Pat. No. 4,654,362 other than the compounds of formula (I) and in particular the enantiomers of the compounds of formula (I), i.e. the SRRR-isomers. A particular compound is [2S,&agr;R,2′R,&agr;′R]-&agr;,&agr;′-[iminobismethylene]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol. These groups of active ingredients are listed w
Van Lommen Guy Rosalia Eugene
Xhonneux Raymond Mathieu
Janssen Pharmaceutica N.V.
Travers Russell
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