Neurokinin antagonists

Details Neurokinin antagonists Neurokinin antagonists

2001-10-16

2003-12-16

Kifle, Bruce (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S274000, C514S315000, C514S317000, C514S321000, C514S326000, C544S096000, C544S097000, C544S311000, C546S192000, C546S195000, C546S196000, C546S197000, C546S207000, C546S208000, C546S210000, C546S213000

Reexamination Certificate

active

06664253

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to new compounds of formula I,
wherein the groups Ar, R
1
, R
2
, R
3
, R
4
and X have the meanings given in the claims and specification, processes for preparing them as well as their use as pharmaceutical compositions, and the pharmaceutically acceptable salts thereof, processes for preparing them and pharmaceutical compositions containing these compounds. The compounds are valuable neurokinin (tachykinin) antagonists.
BACKGROUND OF THE INVENTION
The compounds of formula I are partly covered by the broad general formula of International Patent Application WO96/32386. However, this does not disclose any compounds in which the amide group is substituted with a 2-phenyl-ethyl group and the piperidyl group in the 4 position is substituted with a substituted urethane or urea group. The compounds described in this international patent application are neurokinin antagonists with a broad spectrum of activity.
The problem of the present invention is to provide new neurokinin antagonists with an enhanced activity. This problem is now solved according to the invention by the preparation of the new compounds of formula I.
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly it has been found that the activity of the new NK
1
receptor antagonists of formula I is dramatically increased compared with the known compounds.
The invention therefore relates to new compounds of formula I
or the pharmaceutically acceptable salts thereof,
wherein
R
1
denotes C
1
-C
6
-alkyl or Ar
2
,
R
2
denotes hydrogen, C
1
-C
6
-alkyl or C
3
-C
6
-cycloalkylmethyl, or
R
1
and R
2
taken together denote a C
2
-C
3
-alkylenediyl group optionally substituted by one or two oxo groups (=O),
X denotes O or NR
5
,
Ar
1
and Ar
2
independently of one another denote unsubstituted phenyl or phenyl which is 1- to 5-substituted by halogen, hydroxy, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-fluoroalkyl, C
1
-C
4
-fluoroalkoxy or —OCH
2
O—;
R
3
denotes 2-phenyl-ethyl, wherein the phenyl group may be substituted by 1 to 3 substituents, while the substituents, independently of one another, are selected from among halogen, hydroxy, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-fluoroalkyl, C
1
-C
4
-fluoroalkoxy;
R
4
denotes hydrogen, C
1
-C
4
-alkyl, C
3
-C
8
-cycloalkyl, CH
2
COOH, —CH
2
C(O)NH
2
, —OH or phenyl-C
1
-C
4
-alkyl; and
R
5
denotes hydrogen or C
1
-C
6
-alkyl.
In the foregoing and in what is to follow, the terms “alkyl” and “alkoxy” as used with reference to the groups R
1
, R
2
, R
3
, R
4
or the substituents of Ar
1
or Ar
2
denote straight-chain or branched, saturated hydrocarbon groups with up to 6 carbon atoms, preferably 1 to 4 carbon atoms, particularly methyl, ethyl, n-propyl, 1-propyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy or i-propoxy.
In the foregoing and in what is to follow, the terms “fluoroalkyl” and “fluoroalkoxy” as used with reference to the group R
3
or the substituents of Ar denote straight-chain or branched, fluorine-substituted hydrocarbon groups with up to 4 carbon atoms and up to 9 fluorine atoms, preferably 1 or 2 carbon atoms and up to 5 fluorine atoms, particularly trifluoroethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy or 2-fluoroethoxy.
The compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have substance P-antagonistic properties. They are useful for treating and preventing neurokinin-mediated illnesses and additionally have a dramatically increased effect.
Compounds of general formula I may have acid groups, mainly carboxyl groups, and/or basic groups such as, for example, amino functions. Compounds of general formula I may therefore be in the form of internal salts, salts with pharmaceutically useable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or organic acids (such as for example maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or salts with pharmaceutically useable bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as, for example, diethylamine, triethylamine, triethanolamine etc.
The compounds according to the invention may occur as racemates, or they may be obtained as pure enantiomers, i.e. in the (R)- or (S)-form. Compounds which occur as racemates or as the (S)-form are preferred.
The compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have substance P-antagonistic properties. They are useful for treating and preventing neurokinin-mediated illnesses:
Treatment or prevention of inflammatory and allergic complaints of the airways, such as asthma, chronic bronchitis, hyperreactive airways, emphysema, rhinitis, COPD, pulmonary hypertension, cystic fibrosis, coughs;
of the eyes, such as conjunctivitis and iritis,
of the skin, such as dermatitis in contact eczema, neurodermatitis, pruritus, urticaria, psoriasis, sunburn, burns, insect bites, rosacea, itching, sensitive or hypersensitive skin, of the gastrointestinal tract, such as gastric and duodenal ulcers, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable colon, Hirschsprung's disease, motility problems;
of the joints or bones, such as rheumatoid arthritis, reactive arthritis, arthrosis, osteoporosis and Reiter's syndrome; of the bladder, such as irritable bladder, incontinence, urinary urgency, urethritis, colic and cystitis.
Also for the treatment of diseases of the central nervous system such as dementia, Alzheimer's disease, schizophrenia, psychoses, anxiety states, alcohol or drug dependency, sexual dysfunctions, eating disorders, depression, headaches (e.g. migraine or tension headaches), epilepsy; Parkinson's disease, stroke,
treatment of Herpes zoster as well as postherpetic pain, tumours, collagenoses, a dysfunction of the deferent urinary tracts, haemorrhoid, nausea and vomiting, triggered for example by radiation or cytostatic therapy or motion, and painful conditions of all kinds.
The invention therefore also relates to the use of the compounds of formula I as curative agents and pharmaceutical preparations which contain these compounds. They are preferably used on humans. The compounds according to the invention may be given intravenously, subcutaneously, intramuscularly, intraperitoneally, intranasally, by inhalation, transdermally, optionally assisted by iontophoresis or enhancers known from the literature, and by oral route.
For parenteral administration the compounds of formula I or their physiologically acceptable salts, may be put into solution, suspension or emulsion, possibly with substances conventionally used for this purpose such as solubilisers, emulsifiers or other adjuvants. Suitable solvents include, for example: water, physiological saline solutions or alcohols, e.g. ethanol, propanediol or glycerol, sugar solutions such as glucose or mannitol solutions or a mixture of various solvents.
In addition, the compounds may be administered by the use of implants, e.g. of polylactide, polyglycolide or polyhydroxybutyric acid or intranasal preparations.
Compounds of formula I, wherein R
4
denotes C
1
-C
4
-alkyl, particularly methyl, are preferred.
Also preferred are compounds of formula I wherein Ar is unsubstituted phenyl or 2,3-methylenedioxyphenyl, particularly unsubstituted phenyl.
Preferred compounds of formula I are those wherein R
3
denotes 2-phenylethyl, wherein the phenyl group may be substituted by 1 to 3 substituents, wherein the substituents are selected independently of one another from among halogen, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, particularly wherein R
3
is 2-(3,5-bis-trifluoromethylphenyl)-ethyl.
Particularly preferred compounds of formula I are those wherein the group —NR
3
R
4
is
In a preferred aspect the invention relates to compounds of formula I, wherein
R
1
denotes a C
1
-C
3
-alkyl, particularly methyl, phenyl or C
1
-

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