Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-22
2001-03-06
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S241000, C514S242000, C514S063000, C514S252030, C514S256000, C514S322000, C544S107000, C544S180000, C544S182000, C544S238000, C544S364000, C544S333000, C544S215000, C544S129000, C544S130000, C546S199000, C546S184000
Reexamination Certificate
active
06197769
ABSTRACT:
The present invention relates to an indazole amide compound possessing a serotoninergic action, a method for preparing thereof and the pharmaceutical compositions containing the same.
Amongst the numerous known families of serotonin receptors, the 5HT
4
receptors have only recently been identified in the urinary bladder, smooth and cardiac muscle and specific areas of the central nervous system. Compounds possessing agonistic, partially agonistic and antagonistic actions against such receptors are of potential interest in pharmacological treatment of disorders of gastrointestinal motility, disorders of the central nervous system, urinary incontinence and cardiac arrhythmia. The action of such compounds in fact takes place by mimicking or antagonising the ability of serotonin to stimulate intestinal motility by activation of the enteric neurons, to modulate important cerebral processes such as training, memory and anxiety, to induce relaxation of the urinary bladder and to increase frequency of atrial contraction.
A family of indazole amide compounds has now been found which possess affinity with 5HT
4
receptors and which act as antagonists of serotonin.
It is therefore a first object of the present invention to provide an indazole amide compound having the general formula:
wherein
R
6
is selected from the group comprising, C
3-7
cycloalkyl, heterocyclic ring having from 5 to 6 members where 1 to 4 members are heteroatoms, the same or different from each other, selected from the group comprising N, O and S, dimethylamino C
1-3
alkyl, methoxy C
1-3
alkyl, N-phenyl amide, aminosulphonylmethyl, dihydroxy C
2-3
alkyl, aryl substituted by hydroxy; acid addition salts thereof with pharmaceutically acceptable organic and inorganic acids and pharmaceutically acceptable quaternary salts thereof.
Preferred examples of aryl are phenyl, naphthyl and biphenyl.
Preferred examples of heterocyclic rings are thienyl, furanyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furazanyl, pyrroilnyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, morpholinyl, triazinyl, thiazolyl, tetrazolyl and thiadiazolyl. Typical examples of R
6
are cyclopropyl, cyclohexyl, pyridinyl, tetrazolyl, morpholinyl, methoxymethyl, methoxypropyl, hydroxyphenyl, dimethylaminomethyl and aminosulphonylmethyl.
It is a second object of the present invention to provide a process for preparing a compound of the formula (I), acid addition salts thereof with pharmaceutically acceptable organic and inorganic acids and pharmaceutically acceptable quaternary salts thereof, comprising:
a) acylating a 4-aminomethyl piperidine of the formula:
wherein
P is a suitable protecting group;
by means of a 1-alkyl-indazole-3-carboxylic acid halide of the formula:
wherein
X is halogen,
to give a compound of the formula:
b) de-protecting a compound of the formula (IV) to give a compound of the formula:
c) alkylating a compound of the formula (V) with a compound of the formula (VI) to give a compound of the formula (I) according to the following reaction scheme:
wherein
R
6
has the above mentioned meanings, and
Y is halogen,
d) optionally forming an acid addition salt of an indazole amide compound of the formula (I) with a pharmaceutically acceptable organic or inorganic acid, or a pharmaceutically acceptable quaternary salt of an indazole amide compound of the formula (1).
Typical examples of protecting groups (P) are benzyloxycarbonyl, benzyl, terbutoxycarbonyl and trimethylsilylethoxycarbonyl.
Step a) is preferably carried out by reacting a compound of the formula (II) with a compound of the formula (III) in which X is chlorine, in the presence of a suitable diluent and at a temperature of from 0 to 140° C. for a period of time of from 0.5 to 20 hours.
Preferably the diluent is aprotic, polar or apolar. Still more preferably, it is aprotic apolar. Examples of suitable aprotic apolar diluents are aromatic hydrocarbons such as, for example, benzene, toluene and xylenes. Examples of suitable aprotic polar diluents are dimethylformamide and dimethylsulphoxide.
Still more preferably, the reaction is performed at a temperature of from 15 to 40° C. for a period of time of from 1 to 14 hours.
In turn, step (b) is carried out according to techniques known to the person skilled in the art of the protecting group (Theodora W. Greene and Peter G. M. Wuts, “Protective groups in organic synthesis”, pp. 309-406, John Wiley & Sons, Inc., N.Y., 1991). In the case of benzyl and benzyloxycarbonyl, the deprotection of the protecting group is preferably carried out by catalytic hydrogenation. An example of a suitable catalyst is palladium on activated carbon.
Preferably the deprotection is carried out by hydrogenation in the presence of a suitable diluent such as, for example, a low aliphatic alcohol, a low aliphatic acid and mixtures thereof. An example of a preferred diluent is an ethyl alcohol/acetic acid mixture.
Step c) is preferably performed with a compound of the formula (VI), in which Y is chlorine or bromine in the presence of a suitable acceptor of acids such as, for example, alkali carbonates and bicarbonates, low trialkylamines and a suitable diluent such as, for example, aromatic hydrocarbons, dimethylformamide and aliphatic low alcohols.
Typical examples of preferred organic and inorganic acids for forming addition salts of the present invention (step d) are oxalic, maleic, tartaric, methanesulphonic, sulphuric, phosphoric acid, hydrogen bromide and hydrogen chloride.
Methyl iodide is a typical example of a preferred compound forming a pharmaceutically acceptable quaternary salt of the invention.
The preparation of the above mentioned salts comprises addition (step d) of a pharmaceutically acceptable organic or inorganic acid, or of methyl iodide to an indazole amide compound of the formula (I) obtained in step c).
The intermediates of formula (IV) and (V) are new. They are therefore a further object of the present invention.
Alternatively, indazole amide compound of the formula (I) can be prepared by acylation of a suitable 4-aminomethyl piperidine with a compound of the formula (III).
Typical examples of pathological conditions which might benefit from treatment with a pharmaceutical composition according to this invention are all the pathologies which are responsive to treatment with antagonists of 5-HT
4
receptor such as, for example, gastrointestinal disorders associated with high intestinal motility, such as IBS (irritable bowel syndrome), urinary incontinence, and cardiac arrhythmias such as atrial fibrillation.
Preferably, the pharmaceutical compositions of the present invention will be prepared in suitable dosage forms comprising an effective dose of at least one compound of the formula (I) or a pharmaceutically acceptable addition salt thereof or a quaternary salt thereof and at least one pharmaceutically acceptable inert ingredient.
Examples of suitable dosage forms are tablets, capsules, coated tablets, granules, solutions and syrups for oral administration; creams, ointments and medicated adhesive strips for topical administration; suppositories for rectal administration and sterile solutions for injectable, aerosol or ophthalmic administration.
The dosage forms may also contain other conventional ingredients such as stabilizing agents, preservatives, surfactants, buffers, salts for adjusting the osmotic pressure, emulsifiers, sweeteners, coloring agents, flavoring agents, and the like.
When required by particular therapies, the pharmaceutical composition of the present invention may contain other pharmacologically active ingredients whose concomitant administration is therapeutically useful.
The amount of the compound of formula (I) or of a pharmaceutically acceptable salt thereof may vary within a wide range depending on known factors such as, for example, the type of disease to be treated, the severity of the disease, the patient's body weight, the dosage form, the chosen route of administration, the number of dosage forms administered pe
Alisi Alessandra
Brufani Mario
Cazzolla Nicola
Giannangeli Marilena
Pinza Mario
Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.p.A.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Ramsuer Robert W.
Wright Sonya
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