WO1995026335A1 - Nouveaux amides n-arylaliphatiques-n-alkyl-fonctionnalises, procede pour leur preparation et compositions pharmaceutiques en contenant - Google Patents
Nouveaux amides n-arylaliphatiques-n-alkyl-fonctionnalises, procede pour leur preparation et compositions pharmaceutiques en contenant Download PDFInfo
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- WO1995026335A1 WO1995026335A1 PCT/FR1995/000369 FR9500369W WO9526335A1 WO 1995026335 A1 WO1995026335 A1 WO 1995026335A1 FR 9500369 W FR9500369 W FR 9500369W WO 9526335 A1 WO9526335 A1 WO 9526335A1
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- 0 *C1CC*CC1 Chemical compound *C1CC*CC1 0.000 description 8
- KXKCDIMYBHBSQD-UHFFFAOYSA-N C=[Au]CCN(CC1)CCC1(c1ccccc1)O Chemical compound C=[Au]CCN(CC1)CCC1(c1ccccc1)O KXKCDIMYBHBSQD-UHFFFAOYSA-N 0.000 description 1
- ODLMAHJVESYWTB-UHFFFAOYSA-N CCCc1ccccc1 Chemical compound CCCc1ccccc1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
Definitions
- the present invention relates to new N-arylaliphatic-N-alkyl-functionalized amides, a process for their preparation and the pharmaceutical compositions containing them as active principle.
- the present invention relates to a new class of N-arylaliphatic-N-alkyl-functionalized amides for therapeutic use, in pathological phenomena which involve the tachykinin system, for example in a nonlimiting and exclusive manner: pain (D Regoli et al., Life Sciences, 1987, 40, 109-117), allergy and inflammation (JE Morlay et al., Life
- Tachykinins are distributed in both the central nervous system and the peripheral nervous system. Tachykinin receptors have been recognized and are classified into three types: NK 1 , NK 2 , NK 3 .
- Substance P is the endogenous ligand for NK 1 receptors, neurokinin A (NK A ) for NK 2 receptors and neurokinin B (NK B ) for NK 3 receptors.
- NK 1 , NK 2 , NK 3 receptors have been demonstrated in different species.
- CP-96345 J. Med. Chem., 1992, 35, 2591-2600
- RP-68651 Proc. Natl. Acad. Sci. USA , 1991, 88, 10208-10212
- SR 140333 Rel. J. Pharmacol., 1993, 250, 403-413
- SR 48968 For the NK 2 receptor, a selective non-peptide antagonist, SR 48968 has been described in detail (Life Sci., 1992, 50, PL101-PL106).
- NK 3 receptor certain non-peptide compounds have been described as having an affinity for the NK 3 receptor of the rat and guinea pig brain (FASEB J., 1993, 7 (4), A710, 4104); a peptide antagonist [Trp 7 , ⁇ Ala 8 ] NK A , weakly specific for the NK 3 receptor of the rat brain has also been described (J.
- R * represents a hydrogen or an alkyl group optionally substituted by an amino group.
- N-arylaliphatic-N-alkylfunctionalized amides have interesting pharmacological properties, as neurokinin receptor antagonists and are in particular useful for the treatment of any substance P and neurokinin dependent pathology.
- N-arylaliphatic-N-alkylfunctionalized amides having the structure of formula (A) above in which R * represents an alkyl functionalized by a group other than -NH 2 have a very high affinity for neurokinin receptors.
- the present invention relates to compounds of formula:
- - Ar represents a phenyl which is unsubstituted or substituted one or more times by a substituent chosen from: a halogen atom, a hydroxy, a (C 1 -C 4 ) alkoxy, a (C 1 -C 4 ) alkyl, a trifluoromethyl , a methylenedioxy, said substituents being identical or different; a thienyl unsubstituted or substituted by a halogen atom; a benzothienyl unsubstituted or substituted by a halogen atom; naphthyl unsubstituted or substituted by a halogen atom; an indolyl which is unsubstituted or N-substituted by a (C 1 -C 4 ) alkyl or a benzyl; imidazolyl unsubstituted or substituted by a halogen atom; a pyridyl which is
- R 1 represents a ⁇ - (C 1 -C 4 ) alkoxy- (C 2 -C 4 ) alkylene; a ⁇ - (C 1 -C 4 ) alkylcarbonyloxy- (C 2 -C 4 ) alkylene; a ⁇ -benzoyloxy- (C 2 -C 4 ) alkylene; a ⁇ -hydroxy- (C 2 -C 4 ) alkylene; a ⁇ - (C 1 -C 4 ) alkylthio- (C 2 -C 4 ) alkylene; a ⁇ - (C 1 -C 4 ) alkylcarbonyl- (C 2 -C 4 ) alkylene.
- R 8 represents a (C 1 -C 7 ) alkyl or a phenyl
- R 9 and R 10 each independently represent a hydrogen or a (C 1 -C 7 ) alkyl;
- R 10 may also represent a (C 3 -C 7 ) cycloalkyl, a (C 3 - C 7 ) cycloalkylmethyl, a phenyl or a benzyl; or else R 9 and R 10 together with the nitrogen atom to which they are bonded constitute a heterocycle chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine or piperazine which is unsubstituted or substituted for position 4 with a (C 1 -C 4 ) alkyl;
- R 11 represents a hydrogen, a (C 1 -C 7 ) alkyl, a vinyl, a phenyl, a benzyl, a pyridyl or a (C 3 -C 7 ) cycloalkyl unsubstituted or substituted by one or more methyls;
- R 12 represents a hydrogen or a (C 1 -C 7 ) alkyl
- R 13 represents a (C 1 -C 7 ) alkyl or a phenyl
- R 14 represents a (C 1 -C 7 ) alkyl; an amino free or substituted with one or two (C 1 -C 7 ) alkyls; a phenyl which is unsubstituted or substituted one or more times with a substituent chosen from: a halogen atom, a (C 1 -C 7 ) alkyl, a trifluoromethyl, a hydroxy, a (C 1 -C 7 ) alkoxy, a carboxy , a (C 1 -C 7 ) alkoxycarbonyl, a (C 1 -C 7 ) alkylcarbonyloxy, a cyano, a nitro, an amino free or substituted by one or two (C 1 -C 7 ) alkyls, said substituents being identical or different.
- - T represents a direct bond; a hydroxymethylene group; an (C 1 -C 4 ) alkoxymethylene group; a (C 1 -C 5 ) alkylene group; vinylene; an oxygen atom; a group -NR 7 - in which R 7 represents a hydrogen or a (C 1 - C 4 ) alkyl;
- - Z represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group
- R 2 represents a phenyl which is unsubstituted or substituted one or more times by a substituent chosen from: a halogen atom, a hydroxy, a (C 1 -C 4 ) alkoxy, a (C 1 -C 4 ) alkyl, trifluoromethyl, methylenedioxy, said substituents being identical or different; pyridyl; thienyl; pyrimidyl; imidazolyl unsubstituted or substituted by a (C 1 -C 4 ) alkyl;
- R 2 is as defined above; i 3 - either a group
- - X 1 represents a hydrogen; a (C 1 -C 7 ) alkyl; formyl; a (C 1 - C 7 ) alkylcarbonyl; a cyano; a group - (CH 2 ) q -OH; a (C 1 -C 7 ) alkyl-O- (CH 2 ) q - group; a group R 15 COO- (CH 2 ) q -; a (C 1 -C 7 ) alkyl-NHCOO- (CH 2 ) q - group; a group -NR 16 R 17 ; a group -CH 2 -NR 18 R 19 ; a group -CH 2 - CH 2 -NR 18 R 19 ; a group - (CH 2 ) q -NR 3 COR 4 ; a group - (CH 2 ) q - NR 3 COOR 20 ; a group - (CH 2 ) q -NR 3 SO 2 R 21
- R 3 represents a hydrogen or a (C 1 -C 4 ) alkyl
- R 4 represents a hydrogen; a (C 1 -C 7 ) alkyl; a (C 3 -C 7 ) cycloalkyl which is unsubstituted or substituted by one or more methyls; phenyl; pyridyl; vinyl; benzyl;
- R 3 and R 4 together represents a group - (CH 2 ) t -;
- - 1 is three or four; - R 15 represents a hydrogen; a (C 1 -C 7 ) alkyl; a (C 3 -C 7 ) cycloalkyl which is unsubstituted or substituted by one or more methyls; phenyl; pyridyl;
- R 17 each independently represent a hydrogen or a (C 1 - C 7 ) alkyl; R 17 may also represent a (C 3 -C 7 ) cycloalkylmethyl, a benzyl or a phenyl; or alternatively R 16 and R 17 together with the nitrogen atom to which they are linked constitute a heterocycle chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine or piperazine which is unsubstituted or substituted in position 4 with a (C 1 -C 4 ) alkyl;
- R 18 and R 19 each independently represent a hydrogen or a (C 1 - C 7 ) alkyl; R 19 may also represent a (C 3 -C 7 ) cycloalkylmethyl or a benzyl;
- R 20 represents a (C 1 -C 7 ) alkyl or a phenyl
- R 21 represents a (C 1 -C 7 ) alkyl; an amino free or substituted with one or two (C 1 -C 7 ) alkyls; a phenyl which is unsubstituted or substituted one or more times with a substituent chosen from: a halogen atom, a (C 1 -C 7 ) alkyl, a trifluoromethyl, a hydroxy, a (C 1 -C 7 ) alkoxy, a carboxy , a (C 1 - C 7 ) alkoxycarbonyl, a (C 1 -C 7 ) alkylcarbonyloxy, a cyano, a nitro, an amino free or substituted by one or two (C 1 -C 7 ) alkyls, said substituents being identical or different ;
- R 22 and R 23 each independently represent a hydrogen or a (C 1 -
- R 23 may also represent a (C 3 -C 7 ) cycloalkyl, a (C 3 - C 7 ) cycloalkylmethyl, a hydroxy, a (C 1 -C 4 ) alkoxy, a benzyl or a phenyl;
- R 22 and R 23 together with the nitrogen atom to which they are linked constitute a heterocycle chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine or unsubstituted or substituted piperazine in position 4 with a (C 1 -C 4 ) alkyl;
- - X 2 represents an oxygen atom; a sulfur atom; sulfinyl; a
- - p is one, two or three; - R 5 and R 6 each independently represent a hydrogen or a (C 1 - C 4 ) alkyl; or else R 5 and R 6 together with the nitrogen atom to which they are linked constitute a heterocycle chosen from pyrrolidine, piperidine or morpholine;
- R 24 represents a (C 1 -C 4 ) alkyl
- X 3 , X 4 , X 5 together and with the nitrogen atom to which they are bonded form an azabicyclic or azatricyclic system containing from 5 to 9 carbon atoms, unsubstituted or substituted by a phenyl or a benzyl;
- - X 6 represents an oxygen atom; a sulfur atom; a group -NR 27 in which R 27 represents a hydrogen or a (C 1 -C 3 ) alkyl;
- R 25 represents a hydrogen; a (C 1 -C 6 ) alkyl; a (C 3 -C 6 ) alkenyl in which a vinyl carbon atom is not linked to the nitrogen atom; 2-hydroxyethyl; a (C 3 -C 7 ) cycloalkyl; a phenyl which is unsubstituted or substituted one or more times with a substituent chosen from: a halogen atom, a trifluoromethyl, a (C 1 -C 4 ) alkyl, a (C 1 -C 4 ) alkoxy, a nitro, an amino , hydroxy, said substituents being the same or different; a 6-membered heteroaryl containing one or two nitrogen atoms as a heteroatom, said heteroaryl being unsubstituted or substituted one or more times by a substituent chosen from: a halogen atom, a trifluoromethyl, a (C 1 - C 4 )
- R 26 represents a hydrogen; a phenyl which is unsubstituted or substituted one or more times with a substituent chosen from: a halogen atom, a trifluoromethyl, a (C 1 -C 4 ) alkyl, a (C 1 -C 4 ) alkoxy, a nitro, an amino , hydroxy, said substituents being the same or different; a (C 1 -C 6 ) alkyl unsubstituted or substituted by hydroxy and / or by one, two or three fluorine atoms; a (C 3 -C 6 ) cycloalkyl; a (C 1 -C 5 ) alkoxy (only when X 6 represents an oxygen atom); a (C 3 -C 6 ) cycloalkyloxy (only when X 6 represents an oxygen atom); a group -NR 28 R 29 containing from zero to seven carbon atoms; and R 26 being other than a (C 1 -
- R 25 and R 26 together constitute a divalent hydrocarbon group L in which position 1 is linked to the carbon atom carrying the substituent X 6 , the divalent hydrocarbon group L being chosen from: a trimethylene, a cis-propenylene , tetramethylene, cis-butenylene, cis-but-3-enylene, cis, cis- butadienylene, pentamethylene or cis-pentenylene, said divalent hydrocarbon group L being unsubstituted or substituted by one or two methyls;
- R 28 and R 29 each independently represent a hydrogen, a (C 1 - C 5 ) alkyl or a (C 3 -C 6 ) cycloalkyl; or else R 28 and R 29 together with the nitrogen atom to which they are bonded constitute a heterocycle chosen from: pyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) or unsubstituted or substituted piperazine in position 4 with methyl or ethyl;
- - X 7 represents a (C 1 -C 6 ) alkyl or a (C 3 -C 8 ) cycloalkyl, said alkyl and cycloalkyl groups being unsubstituted or substituted by one or more substituents chosen from: a halogen atom; a (C 3 -C 6 ) cycloalkyl; a cyano; a nitro; hydroxy; a (C 1 -C 4 ) alkoxy; formyloxy; a (C 1 - C 4 ) alkylcarbonyloxy; arylcarbonyl; heteroarylcarbonyl; an oxo; an imino unsubstituted or substituted on the nitrogen atom with a (C 1 -C 6 ) alkyl, a (C 3 -C 6 ) cycloalkyl, a formyl, a (C 1 -C 4 ) alkylcarbonyl or an arylcarbonyl;
- R30 and R31 each independently represent a hydrogen, a (C 1 - C 5 ) alkyl or a (C 3 -C 6 ) cycloalkyl; or else R 30 and R 31 together with the nitrogen atom to which they are bonded constitute a heterocycle chosen from: pyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) or unsubstituted or substituted piperazine in position 4 with methyl or ethyl;
- R 32 represents a hydrogen or a (C 1 -C 4 ) alkyl
- - X 8 represents an oxygen atom; a sulfur atom; a group -NR 34 ; a group -CHR 39 ; - R 34 represents a hydrogen or a (C 1 -C 4 ) alkyl; or R 34 together with R 36 constitute an ethylene group or a trimethylene group;
- R 35 and R 36 each independently represent a hydrogen, a (C 1 - C 5 ) alkyl or a (C 3 -C 6 ) cycloalkyl; or alternatively R 35 and R 36 together with the nitrogen atom to which they are linked constitute a heterocycle chosen from: pyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) or unsubstituted or substituted piperazine in position 4 with methyl or ethyl; or R 35 represents a hydrogen or a (C 1 -C 4 ) alkyl and R 36 together with R 34 constitute an ethylene group or a trimethylene group;
- R 37 and R 38 each independently represent a (C 1 -C 3 ) alkyl
- - R 39 represents a cyano; a nitro; a group -SO 2 R 40 .
- R 40 represents a (C 1 -C 4 ) alkyl or a phenyl
- X 7 represents a cyclic group or when a substituent of X 7 is a cyclic group or contains a cyclic group, said cyclic groups can also be substituted on a carbon atom by one or more (C 1 -C 3 ) alkyls; and when a substituent of X 7 contains an aryl group or a heteroaryl group, said aryl or heteroaryl groups may also be substituted one or more times by a substituent chosen from: a halogen atom, a (C 1 -C 4 ) alkyl, a (C 1 - C 4 ) alkoxy, a cyano, a trifluoromethyl, a nitro, said substituents being identical or different;
- - X 9 and X 10 each represent hydrogen; or X 9 represents hydrogen and X 10 represents hydroxy;
- the radical Z can also represent a bicyclic aromatic group such as 1- or 2-naphthyl; 1-, 2-, 3-, 4-, 5-, 6-, 7-indenyl, one or more bonds of which may be hydrogenated, said groups possibly being unsubstituted or optionally containing one or more substituents such as: the alkyl group , phenyl, cyano, hydroxyalkyl, hydroxy, oxo, alkylcarbonylamino and alkoxycarbonyl, thioalkyl, halogen, alkoxy, trifluoromethyl, in which the alkyls and alkoxy are C 1 -C 4 .
- a bicyclic aromatic group such as 1- or 2-naphthyl; 1-, 2-, 3-, 4-, 5-, 6-, 7-indenyl, one or more bonds of which may be hydrogenated, said groups possibly being unsubstituted or optionally containing one or more substituents such as: the alkyl group , phenyl
- the radical Z can also be a pyridyl, thiadiazolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl, group.
- J 1 represents: i 1 - either a group
- R 2 represents a phenyl which is unsubstituted or substituted one or more times by a substituent chosen from: a halogen atom, a hydroxy, a (C 1 -C 4 ) alkoxy, a (C 1 -C 4 ) alkyl, trifluoromethyl, said substituents being the same or different; pyridyl; thienyl; pyrimidyl; imidazolyl unsubstituted or substituted by C 1 -C 4 alkyl;
- - X 1 represents a hydrogen; hydroxy; a (C 1 -C 4 ) alkoxy; a (C 1 - C 6 ) alkyl carbonyloxy; benzoyloxy; carboxy; a (C 1 -C 4 ) alkoxycarbonyl; an amino; a group -NR3COR4; a cyano; a group -CH 2 NH 2 ; a group - CH 2 NR 3 COR 4 ; a group -CH 2 OH; a group -CH 2 -O-Alk in which Alk represents a C 1 -C 4 alkyl; a group -CH 2 -O-COR 15 ;
- R 4 represents a (C 1 -C 7 ) alkyl; a (C 3 -C 7 ) cycloalkyl which is unsubstituted or substituted by one or more methyls; phenyl; pyridyl;
- R 15 represents R 4 ;
- - R 3 is as defined above; - p is one, two or three;
- R 5 and R 6 each independently represent a hydrogen or a (C 1 - C 4 ) alkyl
- R 5 and R 6 together with the nitrogen atom to which they are linked constitute a heterocycle chosen from pyrrolidine, piperidine or morpholine;
- R 2 is as defined above
- X 3 , X 4 , X 5 together and with the nitrogen atom to which they are bonded form an azabicyclic or azatricyclic system containing from 5 to 9 carbon atoms, unsubstituted or substituted by a phenyl or a benzyl;
- - Ar represents a phenyl which is unsubstituted or substituted one or more times by a substituent chosen from: a halogen atom, a hydroxy, a (C 1 -C 4 ) alkoxy, a
- (C 1 -C 4 ) alkyl trifluoromethyl, said substituents being identical or different; thienyl; benzothienyl; naphthyl; an indolyl which is unsubstituted or N-substituted by a (C 1 -C 4 ) alkyl or a benzyl;
- R 7 represents a hydrogen or a (C 1 -C 4 ) alkyl
- a phenyl unsubstituted or substituted one or more times by a substituent chosen from: a halogen atom; trifluoromethyl; a cyano; hydroxy; a nitro; amino unsubstituted or substituted once or twice with C 1 -C 4 alkyl; a benzylamino; carboxy; a (C 1 -C 10 ) alkyl; a (C 3 -C 8 ) cycloalkyl which is unsubstituted or substituted one or more times with methyl; a (C 1 -C 10 ) alkoxy; a
- R 1 cannot represent an ⁇ - (C 1 -C 4 ) alkoxy
- - Q represents a (C 1 -C 6 ) alkyl or a benzyl; said substituent being either in an axial position or in an equatorial position;
- the compounds of formula (I) according to the invention include both the racemates, the optically pure isomers, as well as the axial and equatorial isomers when in the compound of formula (I), Am represents Am4 or Amio ⁇
- the anions A are those normally used to salify the quaternary ammonium ions, preferably the chloride, bromide, iodide, hydrogen sulfate, methanesulfonate, paratoluenesulfonate, acetate, benzenesulfonate ions.
- the pharmaceutically acceptable anions are used, for example chloride, methanesulfonate or benzenesulfonate.
- alkyl groups or the alkoxy groups are straight or branched;
- halogen atom means a chlorine, bromine, fluorine or iodine atom.
- aryl a phenyl radical or a carbocyclic, bicyclic, orthocondensed, C 9 -C 10 radical and in which at least one of the ring nuclei is aromatic
- heteroaryl is meant either a five or six-membered monocyclic aromatic heterocycle containing from one to four heteroatoms, said heteroatoms being chosen from an oxygen atom, a sulfur atom or a nitrogen atom, and said heterocycle being linked by a carbon atom of the ring, an aromatic heterocycle bicyclic ortho-condensed from eight to ten members containing from one to four heteroatoms as defined above.
- the radical Z represents a phenyl which is unsubstituted or substituted one or more times by a halogen atom, more particularly a chlorine, fluorine or iodine atom, a trifluoromethyl, a (C 1 -C 4 ) alkyl, hydroxy, (C 1 -C 4 ) alkoxy; naphthyl unsubstituted or substituted one or more times with a halogen, a trifluoromethyl, a (C 1 -C 4 ) alkyl, a hydroxy, a (C 1 -C 4 ) alkoxy; pyridyl; thienyl; indolyl; quinolyl; benzothienyl; an imidazolyl.
- a halogen atom more particularly a chlorine, fluorine or iodine atom, a trifluoromethyl, a (C 1 -C 4 ) alkyl, hydroxy, (C 1
- the substituent Ar is preferably a phenyl group advantageously substituted by two chlorine atoms or two fluorine atoms, more particularly in positions 3 and 4.
- R 25 is hydrogen, a (C 1 -C 6 ) alkyl, a (C 3 -C 7 ) cycloalkyl, preferably cyclohexyl, a C 3 -C 4 2-alken-1-yl, preferably allyl and R 26 is hydrogen, a (C 1 -C 6 ) alkyl, a (C 1 -C 4 ) alkylamino, preferably methylamino, a phenyl group, or, only when R 25 is other than hydrogen, R 26 is a di (C 1 -C 6 ) alkylamino, preferably dimethylamino, or alternatively, R 25 and R 26 , represent, together, a 1,3-propylene, 1,4-butylene or cis, cis-1,4-butadienylene group. Consequently, the compounds of formula (I) in which
- either X 6 is oxygen, R 26 is a (C 1 -C 4 ) alkyl, a trifluoromethyl or a phenyl and R 25 is a (C 1 -C 6 ) alkyl, in particular ethyl; or .
- either X 6 is oxygen, R 25 is allyl, cyclohexyl and R 26 is methyl; or
- R 1 represents a 2-hydroxyethyl group or a 2-acetoxyethyl group or a 2-methoxyethyl group or a 2-benzoyloxyethyl group or a 2-benzyloxyethyl group or a ⁇ -R 8 NHCOO- (C 2 -C 4 ) alkylene group ;
- - Ar represents a 3,4-dichlorophenyl or a 3,4-difluorophenyl
- X 7 is advantageously an alkyl group substituted by a hydroxy, oxo, hydroxyimino, (C 1 -C 4 ) alkoxyimino, (C 1 -C 4 ) alkanoyloxy, (C 1 -C 4 ) group. alkanoylamino, (C 1 -C 4 ) alkoxy or, at the same time, by an oxo group and a hydroxy group or (C 1 -C 4 ) alkoxy.
- - Am represents Am 6 in which: X 7 is 1-hydroxypropyl, 1-hydroxyethyl, 1-hydroxybutyl, 2-hydroxybut-2-yl, 4-hydroxyhept-4-yl, 2-hydroxyethyl, 1-hydroxyiminopropyl (sin- or anti-), 1-methoxyiminopropyl (sin- or anti-), 2-acetoxyethyl, 2-acetamidoethyl, carboxy or ethoxycarbonyl;
- R 1 represents a 2-hydroxyethyl group or a 2-acetoxyethyl group or a 2-methoxyethyl group or a 2-benzoyloxyethyl group or a 2-benzyloxyethyl group or a ⁇ -R 8 NHCOO- (C 2 -C 4 ) alkylene group ;
- - Ar represents a 3,4-dichlorophenyl or a 3,4-difluorophenyl
- X 10 is advantageously hydroxy and X 11 is phenyl (X 9 being hydrogen) or X 10 and X 9 are hydrogen and X 11 is a pyridyl group substituted by a halogen, in particular chlorine or fluorine , or by a cyano, trifluoromethyl, hydroxy group (C 1 -C 5 ) alkoxy, in particular methoxy or ethoxy, (C 1 -C 5 ) alkanoyloxy, in particular acetoxy, amino, methylamino, diethylamino, acetamido, imidazolin-2-yl , carboxy, methoxycarbonyl, benzyloxycarbonyl, ethoxycarbonyl, carbamoyl, N, N-dimethylcarbamoyl, pyrrolidinocarbonyl, Nmethylcarbamoyl, methylthio, methylsulfinyl, (C 1 -
- R 1 represents a 2-hydroxyethyl group or a 2-acetoxyethyl group or a 2-methoxyethyl group or a 2-benzoyloxyethyl group or a 2-benzyloxyethyl group or a ⁇ -R 8 NHCOO- (C 2 -C 4 ) alkylene group ;
- - Ar represents a 3,4-dichlorophenyl or a 3,4-difluorophenyl
- Another group of preferred compounds of the invention consists of the compounds of formula (I) in which Ar, R 1 , T, Z and m are as defined above for (I) and Am is the group Amg.
- the particularly preferred compounds are those of formula (I) in which both:
- - Am represents an Am 8 group
- R 1 represents a 2-hydroxyethyl group or a 2-acetoxyethyl group or a 2-methoxyethyl group or a 2-benzoyloxyethyl group or a 2-benzyloxyethyl group or a ⁇ -R 8 NHCOO- (C 2 -C 4 ) alkylene group ;
- - Ar represents a 3,4-dichlorophenyl or a 3,4-difluorophenyl
- the particularly preferred compounds are those of formula (I) in which both:
- - Am represents an Am 9 group
- R 1 represents a 2-hydroxyethyl group or a 2-acetoxyethyl group or a 2-methoxyethyl group or a 2-benzoyloxyethyl group or a 2-benzyloxyethyl group or a ⁇ -R 8 NHCOO- (C 2 -C 4 ) alkylene group ;
- - Ar represents a 3,4-dichlorophenyl or a 3,4-difluorophenyl
- R 2 , x and X 1 are as defined above.
- the particularly preferred compounds are those of formula (I) in which both:
- - Z represents a phenyl
- - Ar represents a 3,4-dichlorophenyl or a 3,4-difluorophenyl.
- - Z represents a 3-isopropoxyphenyl
- - Ar represents a 3,4-dichlorophenyl or a 3,4-difluorophenyl
- quaternary ammonium salts which are particularly preferred according to the present invention are those of formula (I) in which both:
- - Q is as defined above and is in the axial position
- - Z represents a 3-isopropoxyphenyl group
- - Ar represents a 3,4-dichlorophenyl or a 3,4-difluorophenyl
- a - A ⁇ represents an anion, preferably a pharmaceutically acceptable anion.
- Another group of preferred compounds of the invention consists of the compounds of formula (I) in which Ar, R 1 , T, Z and m are as defined above and Am is the group Am 3 .
- the particularly preferred compounds are those of formula (I) in which both:
- - Am represents a radical (d) or (1) as defined above for the radical Am 3 ⁇ , with A ⁇ representing an anion, preferably a pharmaceutically acceptable anion;
- - Z represents a 3-isopropoxyphenyl group
- - Ar represents a 3,4-dichlorophenyl or a 3,4-difluorophenyl
- the present invention relates to a process for the preparation of the compounds of formula (I) and their salts, characterized in that:
- R ' 1 represents a ⁇ - (C 1 -C 4 ) alkoxy- (C 2 -C 4 ) alkylene, a ⁇ -hydroxy- ( C 2 -C 4 ) alkylene, a ⁇ - (C 1 -C 4 ) alkylthio- (C 2 -C 4 ) alkylene, a ⁇ - (C 1 - C 4 ) alkylcarbonyl- (C 2 -C 4 ) alkylene, a ⁇ -carboxy (C 2 -C 4 ) aIkylène, a ⁇ - (C 1 -
- T represents a direct bond, a hydroxymethylene group, a (C 1 - C4) alkoxymethylene group, a (C 1 -C 5 ) alkylene group or a vinylene
- T represents a direct bond, a hydroxymethylene group, a (C 1 -C 4 ) alkoxymethylene group, a (C 1 -C 5 ) alkylene group or a vinylene
- R " 1 represents a ⁇ - (C 1 -C 4 ) alkylcarbonyloxy- (C 2 -C 4 ) alkylene, a ⁇ -benzoyloxy (C 2 - C 4 ) alkylene, a ⁇ -benzyloxy- (C2 ⁇ C4) alkylene, a ⁇ -formyloxy- (C 2 -C 4 ) alkylene, a ⁇ -R 8 NHCOO- (C 2 -C 4 ) alkylene, a ⁇ - R 11 CONR 12 - (C 2 -C 4 ) alkylene, a ⁇ -R 13 OCONR 12 - (C 2 -C 4 ) alkylene, a ⁇ -R 9 R 10 NCONR 12 - (C 2 -C 4 ) alkylene, a ⁇ -R 14 SO 2 NR 12 - (C 2 -C 4 ) alkylene or optionally
- step 1) the compound thus obtained is hydrolyzed in step 1) or in step 2), to obtain the alcohol of formula:
- R 2 is as defined for (I);
- R 2 is as defined for (I);
- R 2 and x are as defined for (I) and X ' 1 represents either X 1 as defined for (I) or a precursor of Xi, it being understood that when X' 1 contains a hydroxy or an amino, these groups can be protected;
- R 2 and X 2 are as defined for (I);
- R 1 and m are as defined above, it being understood that when A m 'contains a hydroxyl or an amino, these groups can be protected, and / or when R 1 represents a ⁇ -hydroxy group (C 2 - C 4 ) alkylene, hydroxyl can be protected, with one of the compounds (III), (IV), (V) or (VI) as defined above, and 2 ′) after optional deprotection of the hydroxyl groups or of the amino groups, the product obtained is optionally transformed into one of its salts with a mineral or organic acid or into one of its quaternary ammonium salts.
- R ' 1 is different from a ⁇ - (C 1 -C 4 ) alkoxy (C 2 -C 4 ) alkylene, are new and are part of the invention.
- R 1 is different from a ⁇ - (C 1 -C 4 ) alkoxy- (C 2 -C 4 ) alkylene or a ⁇ -alkylcarbonyloxy- (C 2 -C 4 ) alkylene, are new and are part of the invention.
- R 1 is different from a ⁇ - (C 1 -C 4 ) alkoxy (C 2 -C 4 ) alkylene or from a ⁇ - (C 1 -C 4 ) alkylcarbonyloxy (C 2 -C 4 ) alkylene, are new and are part of the invention.
- This protection can be carried out using conventional protective groups, such as those described in Protective Groups in Organic Chemistry, J.F.W. McOmie, Ed. Plénum Press, 1973 and in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wutts, Ed. John Wiley and Sons, 1991. Removal of the protecting groups can be accomplished at a convenient later stage using methods known to those skilled in the art which do not affect the rest of the molecule concerned.
- O-protecting groups optionally used to obtain a compound of formula (I) in which R 1 represents a ⁇ -hydroxy (C 2 -C 4 ) alkylene and / or Xi contains a hydroxy are the well-known conventional O-protecting groups those skilled in the art such as, for example, tetrahydropyran-2-yl, acetyl or benzoyl.
- N-protective groups optionally used to obtain a compound of formula (I) in which X 1 contains an amino are the conventional N-protective groups well known to those skilled in the art such as, for example, the trityl group, methoxytrityl, tert-butoxycarbonyl or benzyloxycarbonyl.
- the compound of formula (I) obtained represents the final product in which R 1 represents a ⁇ -acetoxy (C 2 -C 4 ) alkylene and / or X 1 contains an acetoxy or R 1 represents a ⁇ -benzoyloxy (C 2 -C 4 ) alkylene and / or X 1 contains a benzoyloxy.
- step 1) or in step 1 ' as the functional derivative of acid (III), the acid itself is used, suitably activated for example by 1,3-dicylohexylcarbodiimide or by benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (dimethylamino) phosphonium (BOP), or one of the functional derivatives which react with amines, for example an anhydride, a mixed anhydride, acid chloride, or an activated ester, such as paranitrophenyl ester.
- 1,3-dicylohexylcarbodiimide or by benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (dimethylamino) phosphonium (BOP), or one of the functional derivatives which react with amines, for example an anhydride, a mixed anhydride, acid chloride, or an activated ester
- the reaction is carried out in a solvent such as dichloromethane, at a temperature between 0oC and room temperature and in the presence of a base such as triethylamine.
- a solvent such as dichloromethane
- the reaction is carried out in a solvent such as toluene or 1,2-dichloroethane, at a temperature between 80 and 110 ° C and in the presence of a base such than triethylamine.
- a solvent such as toluene or 1,2-dichloroethane
- step 2 optionally the compound thus obtained is subjected to a subsequent treatment to prepare a compound of formula (VII 'bis) by transformation of the group R' 1 into R " 1 or optionally when R ' 1 represents a ⁇ - hydroxy- (C 2 -C 4 ) alkylene, the hydroxyl is protected.
- R ' 1 represents a ⁇ -hydroxy- (C 2 -C 4 ) alkylene
- optionally an O-acylation reaction is carried out according to methods known to those skilled in the art, to obtain a compound of formula (VII 'bis) in which R " 1 represents a ⁇ - (C 1 -C 4 ) alkylcarbonyloxy- (C 2 -C 4 ) alkylene or a ⁇ -benzoyloxy- (C 2 -C 4 ) alkylene.
- R 11 represents a hydrogen or respectively a (C 1 -C 7 ) alkyl, a vinyl, a phenyl, a benzyl, a pyridyl or an optionally substituted (C 3 -C 7 ) cycloalkyl, reacting the formic acid in acetic anhydride or respectively an appropriate anhydride of formula (R 11 CO) 2 or an appropriate acid chloride of formula R 11 COCl in the presence of a base such as triethylamine, on a intermediate compound of formula (VII ′ bis) in which R " 1 represents a ⁇ -HNR 12 - (C 2 -C 4 ) alkylene.
- the compounds of formula (VIF bis) are prepared in which R " 1 represents a ⁇ -R 9 R 10 NCONR 12 - (C 2 -C 4 ) alkylene wherein R 9 represents a (C 1 -C 7 ) alkyl.
- R 14 SO 2 CI By the action of a sulfonyl chloride of formula R 14 SO 2 CI, the compounds of formula (VIF bis) are prepared in which R " 1 represents a ⁇ -R 14 SO 2 NR 12 - (C 2 -C 4 ) alkylene .
- An intermediate compound of formula (VIF bis) in which R " 1 represents a ⁇ -HNR 12 - (C 2 -C 4 ) alkylene can be prepared by following the various steps of the process described in SCHEME 2.
- the sulfonate (IX) is then prepared to replace it with a cyclic secondary amine of formula (X) or (XI) or (XXIII) or (XXIV) or (XXV) or (XXVI) or with a cyclic tertiary amine of formula ( XII) or by a compound of formula (XXVII).
- the product obtained can either represent the final product, or have one or more protecting groups.
- the O-protecting groups and / or the N-protecting groups are optionally hydrolyzed according to the usual methods.
- step 1 an alcohol of formula (VIII) is subjected to oxidation to obtain an aldehyde of formula (XXVIII), it being understood that when R 1 represents a ⁇ -hydroxy- (C 2 -C 4 ) alkylene and / or when T represents a hydroxymethylene group, the hydroxyls are protected
- the oxidation reaction is carried out using, for example, oxalyl chloride, dimethyl sulfoxide and triethylamine in a solvent such as dichloromethane and at a temperature between -78oC and room temperature or by using the hexamethylenetetramine-Brome complex according to the method described in J. Chem. Research (S),
- step 2 a compound of formula (X), (XI), (XXIII), (XXIV), (XXV), (XXVI) or (XXVII) is reacted with an aldehyde of formula (XXVIII) in the presence of an acid such as acetic acid to form in situ an intermediate imine which is reduced chemically using for example sodium cyanoborohydride or catalytically using hydrogen and a catalyst such as palladium on carbon or Raney nickel ®. are finally obtained after deprotection of any hydroxyl or amino groups, or optional conversion of X '1 X 1, the compounds (I) of the invention.
- step l an alcohol of formula (VIII) is transformed into a halogen derivative of formula (XXIX) according to the methods described by March. J. in” Advanced Organic Chemistry “, 3rd ed., John Wiley & Sons, New York, pp 382-384 (1985).
- the compound of formula (XXIX) is reacted in step 2 ′) with a compound of formula (X), (XI), (XII), (XXIII), (XXIV), (XXV), (XXVI) or (XXVII) in the presence or absence of a base.
- a base is chosen from organic bases such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine or from carbonates or alkali metal bicarbonates such as potassium carbonate, sodium carbonate or sodium bicarbonate.
- the reaction is carried out in a solvent such as dichloromethane, toluene, N, N- dimethylformamide or isopropanol.
- Am 6 , Am 7 , Am 8 or Am 9 is obtained in the form of a free base, the salification is carried out by treatment with the chosen acid in an organic solvent.
- the free base dissolved for example in an alcohol such as isopropanol or in an ether such as diethyl ether with a solution of the chosen acid in the same solvent, the corresponding salt is obtained which is isolated according to classical techniques.
- hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, Foxalate, maleate, fumarate, 2-naphthalene sulfonate, benzenesulfonate are prepared.
- the compounds of formula (I) in which Am represents Am 1 , Am 2 , Am 5 , Am 6 , Am 7 , Am 8 or Am 9 can be isolated in the form of one of their salts, for example the hydrochloride, or the oxalate; in this case, if necessary, the free base can be prepared by neutralizing said salt with an inorganic or organic base, such as sodium hydroxide or triethylamine or with an alkali carbonate or bicarbonate, such as carbonate or sodium or potassium bicarbonate.
- an inorganic or organic base such as sodium hydroxide or triethylamine
- an alkali carbonate or bicarbonate such as carbonate or sodium or potassium bicarbonate.
- (XII) and the compound of formula (IX) can be exchanged, in situ or after isolation of the compound of formula (I) in which Am represents a group Am 3 in which A ⁇ is the ion YSO 3 ⁇ , by another anion A ⁇ , according to conventional methods, for example by exchange in solution with a saturated solution of sodium chloride or with a hydrochloric acid solution when A ⁇ represents a chloride anion or by exchange of the anion by elution of the compound ( I) on an ion exchange resin, for example Amberlite IRA68 ® or Duolite A375 ® .
- Amberlite IRA68 ® Amberlite IRA68 ® or Duolite A375 ®
- the quaternary ammonium salts formed with the piperidine nitrogen are prepared by reaction of the free bases of the compounds of formula (I) in which Am represents Ami or Am 5 For which the other amino functions, optionally present are N-protected by a usual N-protecting group, such as for example tert-butoxycarbonyl, with an excess of alkylating agent of formula:
- A is as defined above for (I), preferably a chloride or an iodide and Q is as defined above for (I) and the reaction mixture is heated in a solvent, for example dichloromethane, chloroform, l acetone or acetonitrile, at a temperature between room temperature and reflux for one to several hours to obtain, after treatment according to the usual methods and after possible deprotection, a mixture of the axial and equatorial isomers of the quaternary ammonium salts.
- a solvent for example dichloromethane, chloroform, l acetone or acetonitrile
- A is iodide that can be exchanged for another anion or a pharmacologically acceptable anion, for example a chloride, by elution of the compound (I) on an ion exchange resin, e.g., Amberlite IRA68 ® or Duolite A375 ® .
- an ion exchange resin e.g., Amberlite IRA68 ® or Duolite A375 ® .
- the isomers are separated according to the usual methods, for example by chromatography or by recrystallization.
- N-oxide derivatives optionally formed with the nitrogen indicated by ⁇ of a compound of formula (I) when Am represents a group Am 5 are prepared by oxidation of the nitrogen atom indicated by ⁇ of a compound of formula (I) using the usual methods such as the action of hydrogen peroxide in methanol or the action of peracetic acid or metachloroperbenzoic acid in an inert solvent such as dichloromethane or tetrahydrofuran.
- the reduction of the nitriles of formula (XIV) is carried out by hydrogenation in an alkanol such as ethanol, in the presence of a catalyst such as for example nickel of
- R ′ 1 represents a ⁇ -alkoxycarbonyl (C 2 -C 4 ) alkylene
- famine (XV) is reacted with a ⁇ -halo (C 2 -C 4 ) alkylene carboxylic acid ( C 1 -C 4 ) alkyl such as for example ethyl 3-bromopropionate, ethyl 4-bromobutyrate or ethyl 5-bromovalerate.
- nitriles of formula (XIV) are prepared from commercial or known nitriles of formula:
- E and m are as defined above and G is a halogen atom, for example bromine.
- the synthesis of the nitriles of formula (XIV) where E is a tetrahydropyran-2-yl group is carried out starting from a tetrahydropyranyloxy derivative obtained by reaction between an alkanol of formula Br- (CH 2 ) m -OH and the 3,4-dihydro-2H-pyrane to yield the compound:
- nitriles of formula (XVIII) are synthesized according to known methods by reacting with chlorinated derivatives of formula:
- the chlorinated derivative (XX) is prepared by the action of a chlorinating reagent such as for example thionyl chloride on the hydroxyl derivative of formula:
- the piperidines of formula (X) are known or prepared by known methods, such as those described in EP-A-0428434, EP-A-0474561, EP-A-0515240 and EP-A-559438.
- J'i represents a group in which IL, is a pyrid-2-yl, x is zero and X ', is hydroxyl
- the compounds of formula (X) in which X ′ 1 is an amino are then prepared.
- R 4 COOH By the action of a functional derivative of an acid R 4 COOH, the compounds of formula (X) in which X ' 1 is the group R 4 CONR 3 - are prepared.
- the compounds of formula (X) are prepared in which X ′ 1 is the group -NR 3 COOR 20 .
- a sulfonyl chloride CISO 2 R 21 the compounds of formula (X) are prepared in which X ′ 1 is the group -NR 3 SO 2 R 21 .
- a chloride of carbamoyl R 22 R 23 NCOCI the compounds of formula (X) are prepared in which X ′ 1 is the group -NR 3 CONR 22 R 2 3.
- a compound of formula (X) is prepared in which X ′ 1 represents a group -NR 16 R 17 in which R 16 and R 17 together with the nitrogen atom to which they are linked constitute a heterocycle, by application or adaptation of Bruylants reaction
- a compound of formula (X) is prepared in which X ′ 1 represents a group
- a compound of formula (X) in which X ' 1 represents a group -NR 16 R 17 in which Rig represents a hydrogen and R 17 represents a (C 1 -C 7 ) alkyl, or respectively (C 3 -C 7 ) cycloalkylmethyl or a benzyl can be carried out a reduction of a compound of formula (X) in which X ' 1 represents a group - (CH 2 ) q -NR 3 COR 4 in which q is zero, R 3 represents l hydrogen and R4 represents a hydrogen or a (C 1 -C 6 ) alkyl, or respectively a (C 3 -C 7 ) cycloalkyl or a phenyl.
- the reaction is carried out by means of a reducing agent such as aluminum and lithium hydride in a solvent such as tetrahydrofuran at the reflux temperature of the solvent.
- the compounds of formula (X) can be prepared in which X ′ 1 represents a group -NR 16 R 17 in which R 16 represents a (C 1 -C 4 ) alkyl and R 17 represents a (C 1 - C 7 ) alkyl, or respectively a (C 3 -C 7 ) cycloalkylmethyl or a benzyl from a compound of formula (X) in which X ' 1 represents a group - (CH 2 ) q -NR 3 COR 4 in which q is zero, R 3 represents a (C 1 -C 4 ) alkyl and R 4 represents a hydrogen or a (C 1 -C 6 ) alkyl, or respectively a (C 3 -C 7 ) cycloalkyl or a phenyl.
- the compounds of formula (X) in which X ′ 1 represents a group -NR 16 R 17 in which R 16 represents a (C 5 -C 7 ) alkyl can be
- X ′ 1 represents a group -CH 2 -NR 18 R 19 or respectively -CH 2 CH 2 NR 18 R 19 in which R 18 represents a hydrogen or a (C 1 -C 4 ) alkyl and R 19 represents a (C 1 -C 7 ) alkyl, a (C 3 -C 7 ) cycloalkylmethyl or a benzyl starting from a compound of formula (X) in which X ' 1 represents a group - (CH 2 ) q -NR 3 COR 4 in which q is respectively 1 or 2, R 3 represents a hydrogen or a (C 1 -C 4 ) alkyl and R 4 represents a hydrogen, a (C 1 -C 6 ) alkyl, a (C 3 -C 7 ) cycloalkyl or a phenyl.
- X ′ 1 represents a group -CH 2 NR 18 R 19 or -CH 2 CH 2 NR 18 R 19 in which R 18 represents a (C 5 -C 7 ) alkyl.
- a compound of formula (X) is prepared in which X ′ 1 represents a group - (CH 2 ) q -NR 3 COR 4 in which R 3 and R 4 together represent a group - (CH 2 ) 3 - or - (CH 2 ) 4 - by application or adaptation of the method described in J. Med. Chem., 1985, 28, 46-50.
- a compound of formula (X) is prepared in which X ′ 1 represents a group
- a compound of formula (X) in which X ' 1 represents a carboxy can be prepared by hydrolysis of a compound of formula (X) in which X' 1 represents a cyano according to methods known to those skilled in the art.
- a compound of formula (X) in which X ′ 1 represents a carboxymethyl can be prepared according to the method described in Chem. Ber., 1975, 108, 3475-3482.
- a compound of formula (X) in which X ′ 1 represents a (C 1 -C 7 ) alkoxycarbonyl or respectively a (C 1 -C 7 ) alkoxycarbonylmethyl can be prepared from a compound of formula (X) in which X ' 1 represents a carboxy or a carboxymethyl respectively, by esterification reaction according to methods well known to those skilled in the art.
- x is. one and X ' 1 represents a (C 1 -C 7 ) alkoxycarbonyl, a 4- (C 1 -C 7 ) alkoxycarbonylpiperidine is reacted with a benzyl halide optionally substituted in the presence of a base such as hydride sodium, potassium tert-butoxide or sodium diisopropylamide in a solvent such than tetrahydrofuran, N, N-dimethylformamide or dimethyl sulfoxide, at a temperature between -78oC and room temperature. After a deprotection step, the compound of formula (X) expected is obtained.
- a base such as hydride sodium, potassium tert-butoxide or sodium diisopropylamide
- solvent such than tetrahydrofuran, N, N-dimethylformamide or dimethyl sulfoxide
- the piperazines of formula (XI) are known or prepared by known methods, such as those described in EP-A-0474561.
- the piperidines of formula (XXIII) are known or prepared by known methods, such as those described in WO 94/10146.
- the piperidines of formula (XXIV) are known or prepared by known methods, such as those described in EP-A-0625509.
- the piperidines of formula (XXV) are known or prepared by known methods, such as those described in EP-A-0630887.
- the piperidines of formula (XXVI) are known or prepared by known methods, such as those described in WO 94/26735.
- T represents a hydroxymethylene group, C 1 -C 4 alkoxymethylene
- the compounds of formula (I) above also include those in which one or more hydrogen or carbon atoms have been replaced by their radioactive isotope, for example tritium, carbon-14 or iodine-125.
- radioactive isotope for example tritium, carbon-14 or iodine-125.
- Substance P either Neurokinin A or Neurokinin B inhibit the binding of these to their receptors with an inhibition constant (Ki) between 10 -8 M and 10 -10 M in the various biochemical tests carried out .
- the compounds of the present invention are in particular active principles of pharmaceutical compositions, the toxicity of which is compatible with their use as medicaments.
- the compounds of formula (I) above can be used at daily doses of 0.01 to 100 mg per kg of body weight of the mammal to be treated, preferably at daily doses of 0.1 to 50 mg / kg.
- the dose may preferably vary from 0.5 to 4000 mg per day, more particularly from 2.5 to 1000 mg per day depending on the age of the subject to be treated or the type of treatment: prophylactic or curative .
- the compounds of formula (I) are generally administered in dosage units.
- Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient.
- the present invention relates to pharmaceutical compositions containing, as active principle, a compound of formula (I).
- the active ingredients can be administered in unit administration forms, as a mixture with conventional pharmaceutical carriers, animals and humans.
- Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, aerosols, implants, forms subcutaneous, intramuscular, intravenous, intranasal or intraocular administration and forms of rectal administration.
- the main active principle is mixed with a pharmaceutical vehicle such as silica, gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
- a pharmaceutical vehicle such as silica, gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
- the tablets can be coated with sucrose, various polymers or other suitable materials or else they can be treated so that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.
- a preparation in capsules is obtained by mixing the active principle with a diluent such as a glycol or a glycerol ester and by incorporating the mixture obtained in soft or hard capsules.
- a diluent such as a glycol or a glycerol ester
- a preparation in the form of a syrup or elixir may contain the active principle together with a sweetener, preferably calorie-free, methylparaben and propylparaben as an antiseptic, as well as a flavoring agent and an appropriate color.
- a sweetener preferably calorie-free, methylparaben and propylparaben as an antiseptic, as well as a flavoring agent and an appropriate color.
- the water-dispersible powders or granules may contain the active principle in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or taste.
- Suppositories are used for rectal administration which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols.
- aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol.
- an aerosol containing, for example, sorbitan trioleate or oleic acid, as well as trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane or any other biologically compatible propellant is used; one can also use a system comprising the active principle, alone or associated with an excipient, in powder form.
- the active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.
- each dosage unit the active principle of formula (I) is present in the quantities adapted to the daily doses envisaged.
- each dosage unit is suitably adjusted according to the dosage and the type of administration intended, for example tablets, capsules and the like, sachets, ampoules, syrups and the like, drops so that such a dosage unit contains 0.5 to 1000 mg of active ingredient, preferably 2.5 to 250 mg to be administered one to four times a day.
- the present invention relates to the use of the products of formula (I) for the preparation of medicaments intended to treat physiological disorders associated with an excess of tachykinins, in particular of Substance
- inflammations such as chronic obstructive respiratory diseases, asthma, allergies, rhinitis, coughs, bronchitis, hypersensitivity for example to pollens and mites, rheumatoid arthritis, osteoarthritis, psoriasis, colitis ulcers, Crohn's disease, inflammation of the intestines (irritable colon), prostatitis, neurological bladder, cystitis, urethritis, nephritis,
- rheumatoid arthritis for example rheumatoid arthritis, psoriasis, Crohn's disease, diabetes, lupus,
- neurodegenerative diseases of the central nervous system of the neuropsychiatric or neurological type such as anxiety, depression, psychosis, schizophrenia, mania, dementia, epilepsy, Parkinson's disease, Alzheimer's disease, drugs -dependence, Down syndrome and Huntington's chorea as well as neurodegenerative diseases,
- - diseases of the cardiovascular system such as hypertension, vascular aspects of migraine, edema, thrombosis, angina pectoris and vascular spasms.
- the present invention also includes a method for treating said conditions at the doses indicated above.
- Silica H 60 H silica gel sold by Merck (DARMSTAD)
- the residue is chromatographed on silica, eluting with toluene. 15 g of the expected product are obtained, which product is used as it is in the next step.
- This compound is prepared by the action of phenyllithium on 1-benzylpiperidin-4-one according to the process described in EP-A-474561.
- This compound is obtained according to the Ritter reaction by adding acetonitrile to the compound prepared in step A according to the process described in EP-A-474561.
- a suspension of 1.3 g of lithium aluminum hydride in 50 ml of THF is heated to 60 ° C. and a solution of 6 g of the compound obtained in the previous step in 50 ml of THF is added dropwise .
- the mixture is heated for 3 hours at reflux and then after cooling, the reaction mixture is hydrolyzed by adding 1 ml of water, then 1 ml of 3N NaOH and 3 ml of water.
- the mineral salts are filtered and the filtrate is evaporated under vacuum. 4.5 g of the expected product are obtained, which product is used as it is in the next step.
- a suspension of 1.5 g of aluminum and lithium hydride in 30 ml of THF is heated to reflux and a solution of 7.5 g of the compound obtained in the preceding step in 40 ml of THF is added dropwise. . It is left for 3 hours at reflux with stirring then, after cooling, the reaction mixture is hydrolyzed by adding 1 ml of water. The mineral salts are filtered and the filtrate is evaporated under vacuum. The residue is chromatographed on silica, eluting with a DCM / MeOH mixture (100 / 1.5; v / v). 4.1 g of the expected product are obtained, which product is used as it is in the next step.
- a suspension of 1.7 g of lithium aluminum hydride in 60 ml of THF is heated to 60 ° C. and a solution of 16 g of the compound obtained in the previous step in 40 ml of THF is added dropwise .
- the mixture is left to reflux for 4 hours then, after cooling, the reaction mixture is hydrolyzed by adding 2 ml of water, then 2 ml of 3N NaOH and 6 ml of water.
- the mineral salts are filtered and the filtrate is evaporated under vacuum. The residue is chromatographed on silica, eluting with the mixture
- a mixture of 14 g of the compound obtained in Preparation 2 is cooled to 0oC, 5.94 g of triethylamine in 100 ml of DCM and 6.69 g of ethyloxalyl chloride is added. The mixture is left stirring for 30 minutes while allowing the temperature to rise to RT and then evaporates under vacuum. The residue is taken up in ether, washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica, eluting with the mixture DCM / MeOH (100/1; v / v). 16.5 g of the expected product are obtained, which product is used as it is in the next step.
- a suspension of 6.3 g of lithium aluminum hydride in 180 ml of THF is heated to reflux and a solution of 16.5 g of the compound obtained in the preceding step is added dropwise in 100 ml of THF.
- the mixture is left under reflux for 18 hours, then after cooling, the reaction mixture is hydrolyzed by adding 6 ml of water, then 6 ml of 4N NaOH and 18 ml of water.
- the mineral salts are filtered through Celite ® and the filtrate is evaporated under vacuum.
- the residue is taken up in DCM, dried over sodium sulfate and the solvent is evaporated under vacuum.
- the residue is chromatographed on silica, eluting with a DCM / MeOH mixture (95/5; v / v). 5.5 g of the expected product are obtained, which product is used as it is in the next step.
- a mixture of 0.4 g of the compound obtained in the preceding step, 0.155 g of 4-hydroxy-4-phenylpiperidine, 0.4 g of potassium carbonate in 1.5 ml of DMF is heated at 60 ° C. for 4 hours. 1.5 ml of acetonitrile. After cooling, the reaction mixture is poured into an ice / water mixture, extracted with AcOEt, the organic phase is washed with water, with a saturated solution of sodium chloride, dried over sodium sulfate and the solvent evaporated under vacuum. . The residue is chromatographed on silica H, eluting with a DCM / MeOH mixture (100/1; v / v).
- step C of EXAMPLE 3 To a solution of 1.3 g of the compound obtained in step C of EXAMPLE 3 in 10 ml of 1,2-dichloroethane is added dropwise a solution of 0.332 g of phenyl isocyanate in 5 ml of 1 , 2-dichloroethane and heats at 40oC for 18 hours. The residue is concentrated under vacuum and the residue is chromatographed on silica H, eluting with a DCM / MeOH mixture (100/1; v / v). 1.3 g of the expected product are obtained.
- This compound is prepared according to the procedure described in step C of EXAMPLE 7 from 1.1 g of the compound obtained in the previous step, 0.336 g of triethylamine in 10 ml of DCM and 0.28 g of methanesulfonyl chloride in 10 ml of DCM. 1.08 g of the expected product are obtained.
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Abstract
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Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU21422/95A AU2142295A (en) | 1994-03-25 | 1995-03-24 | Novel n-arylaliphatic-n-alkyl-functionalised amides, method for their prepation and pharmaceutical compositions containing same |
JP7525003A JPH08511277A (ja) | 1994-03-25 | 1995-03-24 | n−アリール脂肪族−n−アルキルで機能化された新規なアミド、これらを製造する方法及びこれらが存在する薬学的組成物 |
EP95914415A EP0700382A1 (fr) | 1994-03-25 | 1995-03-24 | Nouveaux amides n-arylaliphatiques-n-alkyl-fonctionnalises, procede pour leur preparation et compositions pharmaceutiques en contenant |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9403560A FR2717802B1 (fr) | 1994-03-25 | 1994-03-25 | Nouveaux composés aromatiques, procédé pour leur préparation et compositions pharmaceutiques en contenant. |
FR94/03560 | 1994-03-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995026335A1 true WO1995026335A1 (fr) | 1995-10-05 |
Family
ID=9461451
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR1995/000369 WO1995026335A1 (fr) | 1994-03-25 | 1995-03-24 | Nouveaux amides n-arylaliphatiques-n-alkyl-fonctionnalises, procede pour leur preparation et compositions pharmaceutiques en contenant |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0700382A1 (fr) |
JP (1) | JPH08511277A (fr) |
AU (1) | AU2142295A (fr) |
FR (1) | FR2717802B1 (fr) |
HU (1) | HUT73226A (fr) |
WO (1) | WO1995026335A1 (fr) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996032386A1 (fr) * | 1995-04-14 | 1996-10-17 | Boehringer Ingelheim Kg | Derives d'arylglycinamides, procede de fabrication et compositions pharmaceutiques contenant ces composes |
WO1996039386A1 (fr) * | 1995-06-06 | 1996-12-12 | Schering Corporation | Derives de piperidine utilises en tant qu'antagonistes de la neurokinine |
US5710155A (en) * | 1995-04-14 | 1998-01-20 | Boehringer Ingelheim Kg | Arylglycinamide derivatives, processes for the manufacture thereof and pharmaceutical compositions containing these compounds |
WO1998035663A1 (fr) * | 1997-02-17 | 1998-08-20 | Sanofi-Synthelabo | Formulations pharmaceutiques presentees sous forme seche pour l'administration orale d'un compose ammonium quaternaire cyclique |
US6413959B1 (en) | 1995-04-14 | 2002-07-02 | Boehringer Ingelheim Kg | Method of treating depression with arylglycinamide derivatives |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5688960A (en) * | 1995-05-02 | 1997-11-18 | Schering Corporation | Substituted oximes, hydrazones and olefins useful as neurokinin antagonists |
US5696267A (en) * | 1995-05-02 | 1997-12-09 | Schering Corporation | Substituted oximes, hydrazones and olefins as neurokinin antagonists |
US5789422A (en) * | 1996-10-28 | 1998-08-04 | Schering Corporation | Substituted arylalkylamines as neurokinin antagonists |
FR2761901B1 (fr) | 1997-04-10 | 1999-05-14 | Valeo | Procede de realisation d'un dispositif de filtration et dispositif de filtration en particulier pour l'aeration et/ou la climatisation de locaux ou de vehicules |
US6063926A (en) * | 1998-11-18 | 2000-05-16 | Schering Corporation | Substituted oximes as neurokinin antagonists |
MXPA03008484A (es) | 2001-03-21 | 2003-12-08 | Pharmacopeia Inc | Compuestos de arilo y biarilo que tienen actividad moduladora de hormona concentradora de melanina. |
JP4280073B2 (ja) | 2001-04-12 | 2009-06-17 | ファーマコペイア ドラッグ ディスカバリー, インコーポレイテッド | Mchアンタゴニストとして使用されるアリールピペリジンおよびビアリールピペリジン |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0428434A2 (fr) * | 1989-11-06 | 1991-05-22 | Sanofi | Composés aromatiques aminés et leurs énantiomères, procédé pour leur préparation et compositions pharmaceutiques les contenant |
EP0474561A1 (fr) * | 1990-09-05 | 1992-03-11 | Sanofi | Arylalkylamines, procédé pour leur préparation et compositions pharmaceutiques les contenant |
EP0515240A1 (fr) * | 1991-05-03 | 1992-11-25 | Sanofi | Nouveaux composés N-alkylènepipéridino et leurs énantiomères, procédé pour leur préparation et compositions pharmaceutiques les contenant |
EP0559538A1 (fr) * | 1992-03-03 | 1993-09-08 | Sanofi | Sels quaternaires de pipéridines 4-substitués, leur préparation et compositions pharmaceutiques les contenant |
EP0591040A1 (fr) * | 1992-09-30 | 1994-04-06 | Sanofi | Amides basiques quaternaires comme tachykinines antagonistes |
WO1994010146A1 (fr) * | 1992-11-03 | 1994-05-11 | Zeneca Limited | Derives de la piperidine 4-carboxoamido, produits intermediaires et utilisation comme antagonistes de la neurokinine |
WO1994026735A1 (fr) * | 1993-05-06 | 1994-11-24 | Merrell Dow Pharmaceuticals Inc. | Pyrrolidin-3-yl-alkyl-piperidines substituees utiles comme antagonistes de la tachykinine |
EP0630887A1 (fr) * | 1993-05-24 | 1994-12-28 | Zeneca Limited | Pipéridines-4-aryl-substituées comme antagonistes des récepteurs de neurokinine |
-
1994
- 1994-03-25 FR FR9403560A patent/FR2717802B1/fr not_active Expired - Fee Related
-
1995
- 1995-03-24 AU AU21422/95A patent/AU2142295A/en not_active Abandoned
- 1995-03-24 JP JP7525003A patent/JPH08511277A/ja active Pending
- 1995-03-24 WO PCT/FR1995/000369 patent/WO1995026335A1/fr not_active Application Discontinuation
- 1995-03-24 EP EP95914415A patent/EP0700382A1/fr not_active Withdrawn
- 1995-03-24 HU HU9503366A patent/HUT73226A/hu unknown
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0428434A2 (fr) * | 1989-11-06 | 1991-05-22 | Sanofi | Composés aromatiques aminés et leurs énantiomères, procédé pour leur préparation et compositions pharmaceutiques les contenant |
EP0474561A1 (fr) * | 1990-09-05 | 1992-03-11 | Sanofi | Arylalkylamines, procédé pour leur préparation et compositions pharmaceutiques les contenant |
EP0515240A1 (fr) * | 1991-05-03 | 1992-11-25 | Sanofi | Nouveaux composés N-alkylènepipéridino et leurs énantiomères, procédé pour leur préparation et compositions pharmaceutiques les contenant |
EP0559538A1 (fr) * | 1992-03-03 | 1993-09-08 | Sanofi | Sels quaternaires de pipéridines 4-substitués, leur préparation et compositions pharmaceutiques les contenant |
EP0591040A1 (fr) * | 1992-09-30 | 1994-04-06 | Sanofi | Amides basiques quaternaires comme tachykinines antagonistes |
WO1994010146A1 (fr) * | 1992-11-03 | 1994-05-11 | Zeneca Limited | Derives de la piperidine 4-carboxoamido, produits intermediaires et utilisation comme antagonistes de la neurokinine |
WO1994026735A1 (fr) * | 1993-05-06 | 1994-11-24 | Merrell Dow Pharmaceuticals Inc. | Pyrrolidin-3-yl-alkyl-piperidines substituees utiles comme antagonistes de la tachykinine |
EP0630887A1 (fr) * | 1993-05-24 | 1994-12-28 | Zeneca Limited | Pipéridines-4-aryl-substituées comme antagonistes des récepteurs de neurokinine |
Non-Patent Citations (1)
Title |
---|
CARLO ALBERTO MAGGI ET AL.: "Tachykinin receptors and tachykinin receptors antagonists", J. AUTON. PHARMACOL., vol. 13, 1993, pages 13 - 93 * |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996032386A1 (fr) * | 1995-04-14 | 1996-10-17 | Boehringer Ingelheim Kg | Derives d'arylglycinamides, procede de fabrication et compositions pharmaceutiques contenant ces composes |
US5710155A (en) * | 1995-04-14 | 1998-01-20 | Boehringer Ingelheim Kg | Arylglycinamide derivatives, processes for the manufacture thereof and pharmaceutical compositions containing these compounds |
AU706209B2 (en) * | 1995-04-14 | 1999-06-10 | Boehringer Ingelheim International Gmbh | New arylglycinamide derivatives, processes for the manufacture thereof and pharmaceutical compositions containing these compounds |
US6124296A (en) * | 1995-04-14 | 2000-09-26 | Boehringer Ingelheim Kg | Arylglycinamide derivatives, methods of producing these substances and pharmaceutical compositions containing such compounds |
US6251909B1 (en) | 1995-04-14 | 2001-06-26 | Boehringer Ingelheim Kg | Arylglycinamide derivatives, methods of producing these substances and pharmaceutical compositions containing such compounds |
US6294556B1 (en) | 1995-04-14 | 2001-09-25 | Boehringer Ingelheim Kg | Arylglycinamide derivatives, methods of producing these substances and pharmaceutical compositions containing such compounds |
US6303601B2 (en) | 1995-04-14 | 2001-10-16 | Boehringer Ingelheim Kg | Arylgycinamide derivatives, methods of producing these substances and pharmaceutical compositions containing such compounds |
US6413959B1 (en) | 1995-04-14 | 2002-07-02 | Boehringer Ingelheim Kg | Method of treating depression with arylglycinamide derivatives |
WO1996039386A1 (fr) * | 1995-06-06 | 1996-12-12 | Schering Corporation | Derives de piperidine utilises en tant qu'antagonistes de la neurokinine |
WO1998035663A1 (fr) * | 1997-02-17 | 1998-08-20 | Sanofi-Synthelabo | Formulations pharmaceutiques presentees sous forme seche pour l'administration orale d'un compose ammonium quaternaire cyclique |
FR2759585A1 (fr) * | 1997-02-17 | 1998-08-21 | Sanofi Sa | Formulations pharmaceutiques presentees sous forme seche pour l'administration orale d'un compose ammonium quaternaire cyclique |
US6303626B1 (en) | 1997-02-17 | 2001-10-16 | Sanofi-Synthelabo | Pharmaceutical formulations in dry form for the oral administration of a cyclic quaternary ammonium compound |
Also Published As
Publication number | Publication date |
---|---|
FR2717802A1 (fr) | 1995-09-29 |
HU9503366D0 (en) | 1996-02-28 |
JPH08511277A (ja) | 1996-11-26 |
EP0700382A1 (fr) | 1996-03-13 |
HUT73226A (en) | 1996-07-29 |
FR2717802B1 (fr) | 1996-06-21 |
AU2142295A (en) | 1995-10-17 |
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