Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-09
2001-04-10
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S314000, C514S329000, C546S223000
Reexamination Certificate
active
06214846
ABSTRACT:
This invention relates to piperidine derivatives and their use as tachykinin antagonists, and in particular as neurokinin-1 receptor antagonists.
We have now found a class of piperidine derivatives which are potent receptor antagonists of tachykinins, especially of the neurokinin-1 (substance P) receptor. In addition, the compounds of the present invention exhibit a high level of hepatic stability as measured by, for example, conventional liver microsome analysis.
Furthermore, by virtue of their unique cyclopropyl ether moiety, the compounds of the present invention possess a high degree of oral bioavailability together with high affinity for the human NK
1
receptor.
NK
1
antagonist piperidine derivatives are disclosed in International Patent Publicatioin No. WO-A-9300331.
The present invention provides the compounds of the formula (I):
wherein
R
1
represents a fluoroC
1-2
alkoxy group; and
R
2
represents a hydrogen or halogen atom or a C
1-4
alkyl, C
1-4
alkoxy, fluoroC
1-4
alkyl or fluoroC
1-4
alkoxy group; or a pharmaceutically acceptable salt thereof.
When any variable occurs more than one time in formula (I) or in any substituent, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term “alkyl” or “alkoxy” as a group or part of a group means that the group is straight or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
As used herein, the terms “fluoroC
1-4
alkyl” and fluoroC
1-4
alkoxy” means a C
1-4
alkyl or C
1-4
alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Similarly, the term “fluoroC
1-2
alkoxy” means a methoxy or ethoxy group in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Particularly preferred are fluoroC
1-2
alkyl and fluoroC
1-2
alkoxy groups, for example, CF
3
, CH
2
CH
2
F, CH
2
CHF
2
, CH
2
CF
3
, OCF
3
, OCH
2
CH
2
F, OCH
2
CHF
2
or OCH
2
CF
3
, and most especially CF
3
, OCF
3
, OCHF
2
and OCH
2
CF
3
.
Particularly preferred compounds of formula (I) are those wherein R
1
represents OCF
3
, OCHF
2
, OCH
2
F or OCH
2
CF
3
. Most especially, R
1
represents OCF
3
.
Further preferred compounds of formula (I) are those wherein R
2
represents a hydrogen, fluorine or chlorine atom or a methyl, methoxy or trifluoromethoxy group. Especially preferred are those compounds of formula (I) wherein R
2
is a hydrogen atom, a 4-fluorine atom or a 3-trifluoromethoxy group. Most especially, R
2
is a hydrogen atom or a 4-fluorine atom.
A particularly preferred compound of the present invention is the compound of formula (Ia)
or a salt thereof, especially a pharmaceutically acceptable acid addition salt thereof. Most aptly the compounds of the formula (I) and (Ia) are the (2S,3S) stereoisomer.
Specific compounds of the present invention include:
N-{[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]methyl}-2-phenylpiperidin-3-amine;
(2S,3S)-N-{[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]methyl}-2-phenylpiperidin-3-amine;
N-{[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]methyl}-2-(4-fluorophenyl)piperidin-3-amine;
or a pharmaceutically acceptable salt thereof.
In a further aspect of the present invention, the compounds of formula (I) may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.
For use in medicine, the salts of the compounds of formula (I) will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.
The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.
The compounds according to the invention have at least two asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. The 2S,3S stereoisomer is particularly preferred.
The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier or excipient.
Preferably the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Chang Ceila
Merck Sharp & Dohme Limited
Rose David L.
Thies J. Eric
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