EP0477184A1 - Inhibiteurs de la mono-amine oxydase, leur procede de preparation et leur utilisation en therapeutique - Google Patents

Inhibiteurs de la mono-amine oxydase, leur procede de preparation et leur utilisation en therapeutique

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Publication number
EP0477184A1
EP0477184A1 EP19900906244 EP90906244A EP0477184A1 EP 0477184 A1 EP0477184 A1 EP 0477184A1 EP 19900906244 EP19900906244 EP 19900906244 EP 90906244 A EP90906244 A EP 90906244A EP 0477184 A1 EP0477184 A1 EP 0477184A1
Authority
EP
European Patent Office
Prior art keywords
group
formula
indicated above
compound
single bond
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP19900906244
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German (de)
English (en)
French (fr)
Inventor
Patrice Renaut
François Bellamy
Thierry Boucher
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Fournier Industrie et Sante SAS
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Fournier Industrie et Sante SAS
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Publication of EP0477184A1 publication Critical patent/EP0477184A1/fr
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/32—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups bound to acyclic carbon atoms and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/20—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/50—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
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    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
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    • C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups

Definitions

  • Monoamine oxidase inhibitors process for their preparation and their use in therapy
  • the present invention relates to novel monoamine oxidase inhibitors. It also relates to their use in therapy and their preparation process.
  • the products according to the invention act on the central nervous system as inhibitors of monoamine oxidase A (abbreviated MAOA-A) and / or B (abbreviated MAOI-B) and are useful in particular in the treatment of pathologies linked to degenerative processes and certain depressive states, alone or in combination with biogenic monoamine precursors.
  • MAOA-A monoamine oxidase A
  • MAOI-B monoamine oxidase A
  • Monoinamine oxidase inhibitors are now proposed which are different from the antihypertensive compounds described in DE-A-2534339 (i) by their structure and (ii) by their therapeutic utility as as inhibitors of monoamine oxidase A and / or B which is a completely different therapeutic area from hypertension.
  • the compounds of formula Io below are targeted.
  • - R represents a halogen atom, a C 1 -C 4 alkoxy group, a cyano group, a nitro group or a trifluoromethyl group
  • X represents a group - (CH 2 ) 2 O- or a group -CH 2 O-,
  • a group NR 1 R 2 (where R 1 and R 2 , identical or different, each represent the hydrogen atom, a C 1 -C 4 alkyl group, a group - (CH 2 ) v -CH 2 OH where v is equal to 1, 2 or 3, R 1 and R 2 , considered together, can form with the nitrogen atom to which they are linked an N-heterocyclic group of 5 to 7 vertices capable of contain a second heteroatom chosen from N, O and S) and Y represents
  • halogen is meant fluorine, chlorine and bromine atoms and preferably chlorine and fluorine atoms.
  • C 1 -C 4 alkoxy group is meant a group of formula C t H 2t + 1 O where t can take the integer values 1 to 4 and where the part C t H 2t + 1 is linear or branched.
  • the preferred alkoxy group is the methoxy group.
  • C 1 -C 4 alkyl group is meant a group of formula C t H 2t + 1 , linear or branched, where t can take the integer values 1 to 4.
  • the preferred alkyl group is the methyl group.
  • R 1 and R 2 form with the nitrogen atom to which they are linked a heterocyclic group
  • the morpholinyl group and the piperidinyl group are preferred.
  • the other heterocyclic NR 1 R 2 groups which are suitable according to the invention, mention may in particular be made of pyrrolidinyl, thiomorpholinyl, piperazinyl, 4- (2-hydroxyethyl) piperazinyl, 4- (4-chlorophenyl) piperazinyl and hexamethyleneimino groups.
  • the products according to formula (Io) where Z represents a group NR 1 R 2 can be salified by mineral or organic acids.
  • the mineral acids hydrochloric acid is preferred.
  • the organic acids fumaric acid, maleic acid, methanesulfonic acid, oxalic acid and citric acid are preferred.
  • X represents the group CH 2 O
  • Y represents a single bond
  • n 0, 1, 2 or 3
  • p 1
  • Z represents a group NR 1 R 2 and R
  • R 1 and R 2 have the meanings indicated above
  • X represents the group CH 2 O
  • Y represents the oxygen atom
  • Z represents a group NR 1 R 2 and R
  • R 1 and R 2 have the meanings indicated above
  • 3) X represents the group (CH 2 ) 2 O
  • Y represents a single bond
  • X represents the group CH 2 O
  • Y represents the group CONH
  • n 2
  • p 1
  • Z represents a group NR 1 R 2 and R
  • R 1 and R 2 have the meanings indicated above
  • X represents the group CH 2 O
  • Y represents the group CONH
  • n 2
  • p 0,
  • Z represents a group OR 3 and R and R 3 have the meanings indicated above,
  • X represents the group CH 2 O
  • Y represents the group NHCO
  • n 2
  • p 0,
  • Z represents a group NR 1 R 2 and R
  • R 1 and R 2 have the meanings indicated above
  • X represents the group CH 2 O
  • Y represents the group NHCO
  • n 2
  • p 0,
  • Z represents a group OR 3 and R and R 3 have the meanings indicated above,
  • X represents the group CH 2 O
  • Y represents a single bond
  • n 1, 2, 3
  • p 0,
  • Z represents a group OR 3 and R and R 3 have the meanings indicated above,
  • X represents the group CH 2 O
  • Y represents a single bond
  • n 2
  • p 1
  • Z represents a group OR 3 and R and R 3 have the meanings indicated above
  • X represents the group CH 2 O
  • Y represents a single bond
  • n 3
  • p 0,
  • Z represents a group NR 1 R 2 and R
  • R 1 and R 2 have the meanings indicated above.
  • a therapeutic composition is recommended, characterized in that it contains, in association with a physiologically acceptable excipient, at least one compound chosen from the group consisting of:
  • R represents a halogen atom, a C i -C 4 alkoxy group, a cyano group, a nitro group or a trifluoromethyl group,
  • X represents a group - (CH 2 ) 2 O- or a group -CH 2 O- - Z represents
  • a group NR 1 R 2 (where R 1 and R 2 , identical or different, each represent the hydrogen atom, a C1-C4 alkyl group, a group - (CH 2 ) v -CH 2 OH where v is equal to 1, 2 or 3, R 1 and R 2 , considered together, which can form with the nitrogen atom to which they are linked an N- heterocyclic group of ⁇ with 7 vertices capable of co-containing a second chosen heteroatom among N, 0 and S) and Y represents
  • the compounds of formula I can be prepared according to methods known per se by application of conventional reaction mechanisms. According to the invention, it is recommended to prepare the compounds of formula I in the following manner:
  • L represents a labile group, such as for example the chlorine atom or the mesyl group, for example according to a reaction of WILLIAMSON
  • n, R 1 and R 2 have the meanings indicated above
  • c) if necessary, protection of the amino group is carried out, in particular by means of diterbutyldicarbonate to obtain a phenol of formula: (XVIII) where na has the meaning indicated above and where R ' 1 and R' 2 have the meanings indicated above or can represent a protective group such as for example t-butyloxycarbonate, d) the phenol of formula XVIII is subjected to a substitution nucleophile with a benzyl chloride of formula: where R has the meaning indicated above, for example according to a WILLIAMSON reaction to obtain an ether of formula:
  • R 1 and R 2 have the meanings indicated above, a) an amine of formula is subjected:
  • A represents a halogen atom, an OH group or a single bond
  • the isolated organic phase is washed with water, using a saturated aqueous NaCl solution and then using an aqueous solution of potassium hydrogen sulfate, dried over magnesium sulfate, filtered and then evaporated under reduced pressure. 7.17 g are obtained (yield ⁇ 100%) of the expected product which melts at 86-87oC after washing with hexane.
  • N- (1,1-dimethylethoxycarbonyl) -N-methyl-4- [(3-chlorophenyl) methoxy] - ⁇ -methyl-benzenebutamine Has a suspension of 0.95 g (0.0396 mol) of NaH in 200 cm 3 of dimethylformamide at - 25oC under an argon atmosphere are successively added a solution of 7.1 g (0.0242 mole) of N- (1,1-dimethylethoxycarbonyl) - N- (methyl) - (4-hydroxy) - ⁇ -methyl-benzenebutanamine obtained in preparation XXXXIV in 70 cm 3 of dimethylformamide then after 2 hours of stirring at - 10oC, 10 minutes at room temperature and after having lowered the temperature to around - 25oC, a solution of 4.28 g (0.026 mole) of 3-chlorobenzyl chloride in 10 cm 3 of dimethylformamide.
  • a mixture of 6.5 g (0.0277 mole) of 4 - [(3-chlorophenyl) methoxy] -phenol obtained in preparation L, of 5.36 g (0.039 mole) of potassium carbonate, of 0.8 g of sodium iodide and 5.53 g (0.059 mole) of chloroacetone in acetone is brought to reflux under nitrogen for 2 days.
  • the precipitate formed is filtered, the mother liquors are evaporated and the residue obtained is dissolved in ether.
  • the organic phase obtained is washed with IN sodium hydroxide solution, then with water, dried over magnesium sulphate and evaporated under reduced pressure.
  • a suspension of 2.76 g (0.01 mol) of 4 - [(3-chlorophenyl) methoxy] -benzoic acid methyl ester obtained in preparation LVI in 5 ml of 2-aminoethylamine under nitrogen is brought to 130oC for 5 hours then the reaction medium obtained is poured into water.
  • the precipitate formed is filtered and dried, then partitioned between a solution of IN hydrochloric acid, methanol and ethyl acetate.
  • the isolated organic phase is extracted many times with a 1N hydrochloric acid solution, then the acid aqueous phases are made basic by adding sodium hydroxide and then extracted with ethyl acetate.
  • the combined organic phases are dried and evaporated under reduced pressure.
  • the inhibitory effect of all the products tested is determined after different preincubation times at 37oC between the product and the enzyme, in particular 60 minutes.
  • the inhibitory power is given by the IC 50 (concentration in mole / 1 of product which inhibits by 50% the control activity).
  • the products according to the invention are useful in therapy. They can be used alone or in combination with precursors of biogenic monoamines, such as tryptophan, 1-dopa or phenylalanine, as well as in combination with physiologically acceptable excipients, in particular in certain depressive states and in pathologies linked to degenerative processes due to the environment or to age, such as Parkinson's disease and senile dementia and senile preeminence.
  • biogenic monoamines such as tryptophan, 1-dopa or phenylalanine

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP19900906244 1989-03-30 1990-03-28 Inhibiteurs de la mono-amine oxydase, leur procede de preparation et leur utilisation en therapeutique Withdrawn EP0477184A1 (fr)

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FR8904139 1989-03-30
FR8904139A FR2645019A1 (zh) 1989-03-30 1989-03-30

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US5495046A (en) * 1991-01-04 1996-02-27 Taisho Pharmaceutical Co., Ltd. Alkoxyphenylalkylamine derivatives
US5380755A (en) * 1992-07-24 1995-01-10 The Du Pont Merck Pharmaceutical Company Alkyl and alkylbenzyl ethers of substituted hydroquinones
EP0870758B1 (en) * 1995-06-14 2001-02-21 Taisho Pharmaceutical Co. Ltd Optically active substituted phenylalkylamine derivatives
US6900354B2 (en) * 2002-07-15 2005-05-31 Hoffman-La Roche Inc. 3-phenyl-propionamido, 3-phenyl-acrylamido and 3-phenyl-propynamido derivatives
AU2004283452A1 (en) 2003-10-23 2005-05-06 F. Hoffmann-La Roche Ag Benzazepine derivatives as MAO-B inhibitors

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DE1125434B (de) * 1959-06-11 1962-03-15 Eprova Ag Verfahren zur Herstellung basischer Amide
US4051173A (en) * 1974-04-02 1977-09-27 Merck Patent Gesellschaft Mit Beschrankter Haftung Phenoxyalkanol derivatives
US4329367A (en) * 1974-08-05 1982-05-11 Ciba-Geigy Corporation 1-(Aralkoxyphenyl)-2-(bis-arylalkylamino)-alkanes
EP0002408A1 (fr) * 1977-11-26 1979-06-13 SOCIETE DE RECHERCHES INDUSTRIELLES S.O.R.I. Société anonyme dite: Nouveaux composés phénoxy-alcanols substitués, leur procédé de préparation et leur application en thérapeutique
ZA782420B (en) * 1978-04-27 1979-04-25 Ciba Geigy Ag 1-(aralkoxyphenyl)-2-(bisarylalkylamino)-alkanes
DE2820612A1 (de) * 1978-05-11 1979-11-15 Ciba Geigy Ag Verfahren zur herstellung des neuen l-1- eckige klammer auf 4-(3-trifluoromethyl-benzyloxy)-phenyl eckige klammer zu -2-(3,3-diphenylpropylamino)-propans
DE2842759A1 (de) * 1978-09-30 1980-04-10 Merck Patent Gmbh Basische aether, diese enthaltende pharmazeutische zubereitungen und verfahren zu ihrer herstellung
AU542420B2 (en) * 1980-02-07 1985-02-21 Richardson-Merrell Inc. Anti-rhinovirus agents
US4393061A (en) * 1982-06-21 1983-07-12 Stiefel Laboratories, Inc. Anesthetic-antipruritic morpholine compounds, compositions and use
FR2626877B1 (fr) * 1988-02-05 1991-04-05 Delalande Sa Ethers alkyliques ou benzyliques du phenol, leurs procedes de preparation et leur application en therapeutique

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Title
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WO1990011997A2 (fr) 1990-10-18
WO1990011997A3 (fr) 1990-11-15
CA2050590A1 (fr) 1990-10-01

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