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WO1992014465A1 - Utilisation de derives anneles d'acide tetrahydropyridinacetique pour le traitement de maladies neurologiques - Google Patents

Utilisation de derives anneles d'acide tetrahydropyridinacetique pour le traitement de maladies neurologiques Download PDF

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Publication number
WO1992014465A1
WO1992014465A1 PCT/EP1992/000263 EP9200263W WO9214465A1 WO 1992014465 A1 WO1992014465 A1 WO 1992014465A1 EP 9200263 W EP9200263 W EP 9200263W WO 9214465 A1 WO9214465 A1 WO 9214465A1
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Prior art keywords
alkyl
hydrogen
phenyl
group
substituted
Prior art date
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Ceased
Application number
PCT/EP1992/000263
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German (de)
English (en)
Inventor
Walter Lösel
Otto Roos
Dietrich Arndts
Günter Schingnitz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim GmbH
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim GmbH
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Filing date
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Publication of WO1992014465A1 publication Critical patent/WO1992014465A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines

Definitions

  • the invention relates to the use of fused tetrahydropyridine acetic acid derivatives for the treatment of neurological diseases.
  • German patent application P 38 27 727.1 describes fused tetrahydropyridine acetic acid derivatives as compounds with cardioprotective activity.
  • the present invention relates to
  • the invention relates to the use of a compound of the general formula I,
  • A represents a benzo, thieno or indolo radical
  • R is hydrogen, (C 1 -C 4 ) alkyl, halogen (F, Cl,
  • Methanesulfonamido, or two adjacent substituents R together are -O-CH 2 -O- or -O-CH 2 -CH 2 -O-; m represents 1, 2 or 3 when A is a benzo or indole radical and 1 or 2 when A is a thieno radical; R 5 is hydrogen, (C 1 -C 10 ) alkyl, phenyl,
  • R 7 and R 8 are independent of one another
  • R 7 is hydrogen and R 8 is phenyl
  • Piperazinyl ring optionally by methyl, unsubstituted phenyl, mono- or
  • Phenyl (C 1 -C 4 ) alkyl may be N-substituted; and when R 4 and R 6 together form the group
  • (d) denotes branched or unbranched alkyl having 1-12 carbon atoms, where the alkyl can be substituted by hydroxy
  • A is an indole radical, R, m and R 5 are as defined above,
  • R 4 represents (C 1 -C 4 ) alkyl; R 6 is hydroxy, (C 1 -C 4 ) alkoxy or a
  • R and m are as defined above, R 4 is hydrogen,
  • R 5 is hydrogen, (C 1 -C 10 ) alkyl
  • R 6 is hydroxy, (C 1 -C 4 ) alkoxy or a
  • -NR 7 R 8 group the -NR 7 R 8 group being as defined above; or their pharmaceutically acceptable salt with an inorganic or organic acid for the treatment of neurological diseases.
  • A represents a benzo, thieno or indolo radical
  • R denotes hydrogen, (C 1 -C 4 ) alkyl, halogen (F, Cl, Br, J), hydroxy, (C 1 -C 4 ) alkoxy, amino, methylthio, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R together - Are O-CH 2 -O- or -O-CH 2 -CH 2 -O-; m means 1, 2 or 3 when A is a benzo- or
  • R 4 represents hydrogen or (C 1 -C 4 ) alkyl
  • R 5 is hydrogen, (C 1 -C 10 ) alkyl, phenyl
  • -NR 7 R 8 group means in which R 7 and R 8 independently of one another
  • (d) mean branched or unbranched alkyl having 1-12 carbon atoms, where the alkyl can be substituted by
  • R 7 is hydrogen and R 8 is phenyl
  • Piperazinyl ring can optionally be N-substituted by methyl, unsubstituted phenyl, mono- or di (C 1 -C 4 ) alkoxyphenyl, pyrimidinyl or phenyl (C 1 -C 4 ) alkyl; or their pharmaceutically acceptable salt with an inorganic or organic acid for the treatment of neurological diseases.
  • the invention further relates to the use of a compound of the general formula Ib
  • A means an indole residue
  • R, m and R 5 are as defined above,
  • R 4 represents hydrogen
  • R 5 is hydrogen, (C 1 -C 10 ) alkyl
  • R 6 is hydroxy, (C 1 -C 4 ) alkoxy or a
  • -NR 7 R 8 group is as defined above; or their pharmaceutically acceptable salt with an inorganic or organic acid for the treatment of neurological diseases.
  • the invention further relates to the use of a compound of the general formula Ic,
  • inorganic or organic acid for the treatment of neurological diseases.
  • R is hydrogen, hydroxy, (C 1 -C 4 ) alkoxy or
  • Is methylthio preferably is methoxy; especially where R is methoxy and m 2 and the substituents R are in positions 6 and 7; -) R 4 is hydrogen or methyl;
  • R 5 is hydrogen, (C 1 -C 5 ) alkyl, phenyl,
  • R 5 is hydrogen, (C 1 -C 5 ) alkyl,
  • Phenyl, phenethyl or methoxy is preferred
  • R 6 is hydroxy or ethoxy, or
  • R 6 is an NR 7 R 8 group, wherein
  • R 7 and R 8 are (C 1 -C 5 ) alkyl, or
  • R 7 is hydrogen and R 8 is aikenyl or alkynyl with 3 carbon atoms, preferably
  • R 7 is hydrogen and R 8 is alkyl with 1-8
  • Is carbon atoms and the alkyl can be substituted by hydroxy, methoxy, dimethylamino, furyl, pyridyl, pyrrolidinyl, morpholino, phenyl or penyl which is 1 to 3 times substituted by hydroxy or methoxy; or -) R 7 and R 8 together with the nitrogen atom
  • R 6 is a -NR 7 R 8 group in which
  • R 7 is hydrogen, methyl or ethyl and R 8
  • Thienyl can be substituted; or -) R 7 and R 8 together with the nitrogen atom
  • R 4 is hydrogen and / or R 5 is hydrogen or
  • R 6 is the -NR 7 R 8 group in which R 7
  • R is hydrogen, hydroxy, (C 1 -C 4 ) alkoxy or
  • R 5 is hydrogen, (C 1 -C 5 ) alkyl, phenyl,
  • R 5 is hydrogen, (C 1 -C 5 ) alkyl, phenyl,
  • R 8 is alkyl with 1 to 3 carbon atoms and
  • the alkyl can be substituted by hydroxy, methoxy, dimethylamino, furyl pyridyl,
  • R 8 is methyl or ethyl, which is replaced by morpholino
  • Alzheimer's disease suitable and especially in the
  • hypoxia tolerance test When testing the viability of animals in a closed chamber (hypoxia tolerance test), which with a gas mixture consisting of 96.5% nitrogen and
  • Treatments can be used.
  • Neuronal cells from fetal rat brains preparation according to HW Müller and W. Seifert, Proc. Natl. Acad. Sei. USA 81: 1248-1252, 1984; J. Neurosci. Res. 8: 195-204, 1982; and Müller and Seifert in "Methods for Serum Free Culture of Neuronal and Lymphoid Cells," p. 67-77, AR Liss Inc., 150 Fifth Ave., New York, NY 10011, 1984) became the direct neural attack of the
  • Receptor agonists eg EAA, the chemotactic peptide fMLP, leukotrienes, PAF, endothelin, etc.
  • This influx described by TJ Hallam and TJ Rink (Tips 10: 8-10, 1989) as "receptor mediated Ca 2+ entry (RMCE)", is characterized by classic
  • HL60 cells and neuron cells are confirmed.
  • % H % inhibition of the transmembrane Ca 2+ current, which is determined by a uniform (10 -5 M) concentration of
  • Test substances is effected. The is inhibited
  • A is a benzo radical
  • R is hydrogen, hydroxy, methoxy or methylthio
  • R means or two adjacent substituents R together are -O-CH 2 -O-; m represents 1, 2 or 3; R 4 represents hydrogen or methyl; R 5 is hydrogen, (C 1 -C 5 ) alkyl, phenyl,
  • R 6 represents the -NR 7 R 8 group, therein a) R 7 and R 8 independently of one another
  • R 7 is hydrogen and R 8 is aikenyl or alkynyl
  • A is a benzo radical
  • Positions 6 and 7 are, where the two R are independently methoxy, methylthio or
  • R 4 represents hydrogen or methyl
  • R 5 (C 2 -C 5 ) alkyl or phenyl (C 1 -C 5 ) alkyl
  • R 6 represents ethoxy or an NR 7 R 8 group, where
  • R 7 is hydrogen and R 8 is alkyl with 4-8
  • Is dimethoxyphenyl or R 8 is phenyl or fluorophenyl; respectively the
  • A is a benzo radical, m is 2 and the two substituents R in the
  • Positions 6 and 7 are, either either R being methoxy or one
  • R 4 is hydrogen or methyl
  • R 5 is (C 2 -C 8 ) alkyl or phenethyl
  • R 6 is ethoxy or the group NR 7 R 8 , wherein
  • R 7 is hydrogen and R 8
  • Phenyl, dimethoxyphenyl, furyl, dimethylamino or hydroxy is substituted
  • R 5 is C 4 or C 5 alkyl or phenethyl
  • R 6 is ethoxy or the group NR 7 R 8 , wherein
  • R 7 and R 8 are butyl or
  • R 7 is hydrogen and R 8 is phenyl
  • R 6 is ethoxy or the group NR 7 R 8 , wherein
  • R 7 and R 8 are butyl or
  • R 7 is hydrogen and R 8 is phenyl
  • R 4 is hydrogen
  • R 5 is butyl or phenethyl
  • R 6 is the NR7R8 group, wherein
  • R 7 and R 8 are butyl or
  • R 7 is hydrogen and R 8 is phenyl
  • R 5 is (CH 2 ) 3 CH 3 and R 6 is ethoxy or -NH (CH 2 ) 4 CH 3 and the
  • R 5 is (CH 2 ) 3 CH 3 and R 6 NHCH (CH 3 ) (CH 2 ) 3 CH (CH 3 ) 2 or
  • R 5 is C 6 H 5 (CH 2 ) 2 and
  • alkyl groups mentioned in the definitions above can be either straight-chain or branched.
  • the active ingredients are suitable for use in pharmaceuticals for oral or parenteral administration.
  • the main forms of medicine used are tablets,
  • Single dose to these dosage forms is between 1.0 and 200 mg, preferably 20 and 50 mg per 75 kg
  • Body weight Depending on the severity of the case, 1 to 3 single doses should generally be administered daily.
  • Formula I can be carried out by processes known per se.
  • R 5 and R 6 are as defined above, can be made by the corresponding compound of
  • This method is preferably applied to compounds of the formula II in which R 4 is hydrogen.
  • Ammonium salt transferred e.g. by reacting with
  • the reduction is preferably carried out in a solvent such as, for example, methanol or ethanol at room temperature or, if appropriate, at elevated temperatures
  • A represents a benzo, thieno or indolo radical
  • R is hydrogen, (C 1 -C 4 ) alkyl, halogen (F, Cl, Br,
  • R 9 represents hydrogen or (C 1 -C 4 ) alkyl
  • R 5 is hydrogen, (C 1 -C 10 ) alkyl, phenyl,
  • (d) means branched or unbranched alkyl having 1-12 carbon atoms, where the alkyl can be substituted by
  • N-benzylpiperidyl means.
  • the reduction can be carried out with NaBH 4 in glacial acetic acid, possibly with the addition of a solvent (based on C. Djerassi, HJ Monteiro, A. Walser, LH Durham J. Am. Chem. Soc. 88, (1966) 1792).
  • a compound of general formula Ic is dissolved in glacial acetic acid and with cooling and stirring
  • the reaction time is very largely determined by the length of the radical R 5 and is between 1 and 15 hours at room temperature.
  • the response times take in order
  • R 5 H ⁇ CH 3 - ⁇ C 2 H 5 ⁇ C 4 H 9 ⁇ C 5 H 11 ....
  • reaction temperature is largely uncritical and can be between 5 ° C and the boiling point of
  • Reaction mixture lie.
  • the implementation is ice cooling in one
  • Glacial acetic acid and a suitable, inert solvent are used, for example THF, dioxane, ethanol etc.
  • the reaction in glacial acetic acid is preferred.
  • the starting compounds (Ic) are dissolved in glacial acetic acid. While stirring and cooling to 5 ° C., the finely powdered NaBH 4 (4 ⁇ 10-fold excess) is introduced in portions. When the reaction has ended, water is carefully added, the mixture is made alkaline with dilute NaOH and extracted with CH 2 Cl 2 .
  • the starting compounds (Ic) are dissolved in glacial acetic acid. While stirring and cooling to 5 ° C., the finely powdered NaBH 4 (4 ⁇ 10-fold excess) is introduced in portions. When the reaction has ended, water is carefully added, the mixture is made alkaline with dilute NaOH and extracted with CH 2 Cl 2 .
  • a compound of the general formula Ia in which R 6 is hydroxy or (C 1 -C 4 ) alkoxy can be converted into the corresponding amide in which
  • R 6 is the group NR 7 R 8 .
  • reactive carboxylic acid derivatives are: acid halides,
  • Acid azides or mixed acid anhydrides e.g. with an aromatic or aliphatic
  • Carboxylic acid alkyl carbonic acid or
  • Dialkylphosphoric acid etc.
  • acid amides e.g. with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole, etc.
  • active esters e.g. cyanomethyl, methoxymethyl, vinyl, propargyl or
  • the amide formation is generally carried out in an inert solvent such as dioxane, acetonitrile, dimethylformamide or a mixture of one or more of these solvents, if appropriate in the presence of an organic or inorganic base as an acid scavenger.
  • an inert solvent such as dioxane, acetonitrile, dimethylformamide or a mixture of one or more of these solvents, if appropriate in the presence of an organic or inorganic base as an acid scavenger.
  • the reaction temperature can, depending on
  • R 4 is hydrogen, can be converted by N-alkylation into the corresponding compound of the formula Ia, in which R 4 (C 1 -C 4 ) alkyl
  • alkylating agents are suitable for N-alkylation insofar as they have sufficient reactivity, e.g. active alkyl esters, such as dialkyl sulfate,
  • Alkyl fluorosulfonates or alkyl halides such as alkyl bromides or alkyl iodides.
  • the reaction takes place at temperatures up to the boiling point of the reaction mixture.
  • Alkyl stands for
  • aminoalkylation can also follow
  • Formalin solution treated in the presence of formic acid at reflux temperature. The time varies between 3 and 18 hours. This
  • reaction is particularly suitable for compounds (I) in which R 6 is not NH 2 or NHR 8 .
  • R 6 is not NH 2 or NHR 8 .
  • Racemate separation e.g. Column chromatography.
  • the free base of the general formula Ia is converted into its acid addition salts in a manner known per se.
  • Acids suitable for salt formation are:
  • hydrochloric acid for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, oxalic acid, malonic acid, succinic acid, maleic acid,
  • Fumaric acid lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, cinnamic acid, ascorbic acid or methanesulfonic acid.
  • the compounds of the formula II or Ib can be prepared by processes known per se, preferably by that in the German
  • Patent application P 37 18 570.5 described method In the presence of a condensing agent, a
  • R, m, R 5 and R 6 are as defined above and Ar is phenyl, 2- or 3-indolyl or 2- or 3-thienyl, are cyclized to the corresponding compounds II and Ib.
  • R 4 is hydrogen or (C 1 -C 4 ) alkyl.
  • Strong Lewis acids such as e.g. Phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride,
  • Tin tetrachloride but also inorganic acids, e.g. Polyphosphoric acid, sulfuric acid, fluorosulfonic acid and hydrofluoric acid, or mixtures of
  • Condensing agents such as a mixture of
  • Phosphorus oxychloride and phosphorus pentachloride or a mixture of phosphorus pentoxide and (C 1 -C 4 )
  • Alkylsulfonic acid for example with a P 2 O 5 content of approx. 10 percent by weight.
  • the cyclization can be carried out in the presence or absence of a solvent. All inert solvents are suitable, provided they are one
  • benzene alkylbenzenes (e.g. toluene, xylene), chlorobenzenes, chloroform, acetonitrile, decalin.
  • alkylbenzenes e.g. toluene, xylene
  • chlorobenzenes chloroform
  • acetonitrile decalin.
  • condensing agent for example phosphorus oxychloride in acetonitrile or a
  • the cyclization is preferably carried out with
  • Phosphorus oxychloride in acetonitrile or in difficult cases with a mixture of phosphorus pentoxide and (C 1 -C 4 ) alkyl sulfonic acid (preferably methanesulfonic acid).
  • a mixture of phosphorus pentoxide and (C 1 -C 4 ) alkyl sulfonic acid preferably methanesulfonic acid.
  • Temperature range preferably with heating or heating to 50 ° C to about the boiling point of
  • Reaction mixture can be carried out.
  • the required reaction time depends on
  • the compounds of general formula Ic can be prepared by a corresponding
  • R 6 represents the group -NHR 8 and R, m, R 5 and R 8 as in the desired one
  • R 9 represents hydrogen or (C 1 -C 3 ) alkyl.
  • the compounds of the general formulas Ib and Ic can be subjected to aftertreatments which are analogous to the aftertreatments described for the compounds of the general formula Ia.
  • (C 1 -C 4 ) alkyl means can also be prepared
  • R 4 is hydrogen, is converted into its quaternary ammonium salt (for example by reaction with (C 1 -C 4 ) alkyl iodide) and then with a base (for example
  • Alkali Alkali
  • reaction product is purified on Al 2 O 3 activity level III (eluent CCl 4 ) and into the hydrochloride
  • Diastereomer 1 mp 94-96 ° C (ethyl acetate / ligroin)
  • Diastereomer 2 mp. 75-78 ° C (ethyl acetate / ligroin)
  • 1 coated tablet contains:
  • Corn starch is made with a 10% aqueous solution
  • Cores obtained are coated in the usual way with a shell, which is by means of an aqueous
  • Active ingredient and magnesium stearate are combined with a
  • the active ingredient, milk sugar and corn starch are first mixed in a mixer and then in one

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

On utilise un composé répondant à la formule générale (I), ou ses sels pharmaceutiquement acceptables avec un acide anorganique ou organique, pour traiter des maladies neurologiques. Dans la formule générale (I), A représente un reste benzo, thièno ou indolo; U et V représentent chacun un hydrogène ou, lorsque A désigne un reste indolo, ils représentent ensemble une liaison; alors que R4 et R6 représentent des groupes indépendants ou forment ensemble un groupe répondant à la formule (a).
PCT/EP1992/000263 1991-02-13 1992-02-06 Utilisation de derives anneles d'acide tetrahydropyridinacetique pour le traitement de maladies neurologiques Ceased WO1992014465A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4104257A DE4104257A1 (de) 1991-02-13 1991-02-13 Verwendung von anellierten tetrahydropyridinessigsaeurederivaten fuer die behandlung neurologischer erkrankungen
DEP4104257.3 1991-02-13

Publications (1)

Publication Number Publication Date
WO1992014465A1 true WO1992014465A1 (fr) 1992-09-03

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PCT/EP1992/000263 Ceased WO1992014465A1 (fr) 1991-02-13 1992-02-06 Utilisation de derives anneles d'acide tetrahydropyridinacetique pour le traitement de maladies neurologiques

Country Status (6)

Country Link
AU (1) AU1199092A (fr)
DE (1) DE4104257A1 (fr)
IE (1) IE920451A1 (fr)
IL (1) IL100927A0 (fr)
WO (1) WO1992014465A1 (fr)
ZA (1) ZA921039B (fr)

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US6395897B1 (en) 1999-03-02 2002-05-28 Boehringer Ingelheim Pharmaceuticals, Inc. Nitrile compounds useful as reversible inhibitors of #9 cathepsin 5
US6756372B2 (en) 1999-09-13 2004-06-29 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cysteine proteases
JP2012517984A (ja) * 2009-02-16 2012-08-09 アボット ゲーエムベーハー ウント カンパニー カーゲー 複素環式化合物、これらを含む医薬組成物およびグリシントランスポーター１の阻害剤としてのこれらの使用
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US10927124B2 (en) 2016-07-29 2021-02-23 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof

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FR2724384B1 (fr) * 1994-09-14 1999-04-16 Cemaf Nouveaux derives de la 3,4-dihydro beta-carboline agonistes de la melatonine, leur procede de preparation et leur utilisation a titre de medicament
WO2000056304A2 (fr) * 1999-03-24 2000-09-28 Harbor Branch Oceanographic Institution, Inc. Utilisation de manzamines en tant qu'anti-inflammatoires
IL162310A0 (en) * 2001-12-19 2005-11-20 Lundbeck & Co As H 3,4-Dihydro-1h-isoquinoloin-2-yl-derivatives
DK3252057T3 (da) 2009-12-04 2024-06-17 Sunovion Pharmaceuticals Inc Multicykliske forbindelser og fremgangsmåder til anvendelse deraf
CN110678205B (zh) 2017-02-16 2023-05-23 桑诺维恩药品公司 治疗精神分裂症的方法
JP7453148B2 (ja) 2018-02-16 2024-03-19 サノビオン ファーマシューティカルズ インク 塩、結晶形態、およびその製造方法
MX2022012833A (es) 2020-04-14 2022-11-07 Sunovion Pharmaceuticals Inc (s)-(4,5-dihidro-7h-tieno[2,3-c]piran-7-il)-n-metilmetanamina para tratar trastornos neurologicos y psiquiatricos.

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3021331A (en) * 1959-07-20 1962-02-13 Pfizer & Co C Azabenzopyridocolines
EP0021857A1 (fr) * 1979-04-26 1981-01-07 Synthelabo Dérivés de l'indole, leur préparation et medicaments les contenant
EP0288048A2 (fr) * 1987-04-24 1988-10-26 Boehringer Ingelheim Kg Dérivés de benzo- et thiéno-3,4-dihydropyridine, procédés pour leur préparation et médicaments les contenant
DE3827727A1 (de) * 1988-08-16 1990-02-22 Boehringer Ingelheim Kg Anellierte tetrahydropyridinessigsaeurederivate, verfahren zu deren herstellung und verwendung solcher verbindungen zur kardioprotektion
EP0364996A2 (fr) * 1988-10-21 1990-04-25 G.D. Searle & Co. Composés phosphono-hydroisoquinoline utiles pour réduire les lésions neurotoxiques
EP0421436A2 (fr) * 1989-10-03 1991-04-10 Warner-Lambert Company Carboxytétrahydroisoquinoléines substituées et leur dérivés ayant une activité pharmaceutique
JPH03109385A (ja) * 1989-09-22 1991-05-09 Fujisawa Pharmaceut Co Ltd 新規３環性アミン化合物およびその塩類

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3021331A (en) * 1959-07-20 1962-02-13 Pfizer & Co C Azabenzopyridocolines
EP0021857A1 (fr) * 1979-04-26 1981-01-07 Synthelabo Dérivés de l'indole, leur préparation et medicaments les contenant
EP0288048A2 (fr) * 1987-04-24 1988-10-26 Boehringer Ingelheim Kg Dérivés de benzo- et thiéno-3,4-dihydropyridine, procédés pour leur préparation et médicaments les contenant
DE3827727A1 (de) * 1988-08-16 1990-02-22 Boehringer Ingelheim Kg Anellierte tetrahydropyridinessigsaeurederivate, verfahren zu deren herstellung und verwendung solcher verbindungen zur kardioprotektion
EP0364996A2 (fr) * 1988-10-21 1990-04-25 G.D. Searle & Co. Composés phosphono-hydroisoquinoline utiles pour réduire les lésions neurotoxiques
JPH03109385A (ja) * 1989-09-22 1991-05-09 Fujisawa Pharmaceut Co Ltd 新規３環性アミン化合物およびその塩類
EP0421436A2 (fr) * 1989-10-03 1991-04-10 Warner-Lambert Company Carboxytétrahydroisoquinoléines substituées et leur dérivés ayant une activité pharmaceutique

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Arzneimittel Forschung/Drug-Research, Band 37, Nr. 7, 1987, T. KUWAHARA et al.: "Preventive effects of the cerebral circulation improver 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-4- 4-(2-methoxyphenyl)-1-piperazinylÜmethyl isoquinoline on stroke symptoms in stroke-prone spontaneously hypertensive rats", Seiten 778-782, siehe das ganze Dokument *
Journal of Medicinal and Pharmaceutical Chemistry, Band 3, Nr. 3, 1961, J.G. LOMBARDINO et al.: "Azabenzoquinolizines with tranquillizing activity", Seiten 505-517, siehe das ganze Dokument (in der Anmeldung erw{hnt) *
Patent Abstracts of Japan, Band 15, Nr. 297 (C-854)[4825], 29. Juli 1991, & JP,A,3109385 (FUJISAWA PHARMACEUT. CO., LTD) 9. Mai 1991, siehe die ganze Zusammenfassung *

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US6608057B2 (en) 1999-03-02 2003-08-19 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cathepsin S
US6730671B2 (en) 1999-03-02 2004-05-04 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cathespin S
US6395897B1 (en) 1999-03-02 2002-05-28 Boehringer Ingelheim Pharmaceuticals, Inc. Nitrile compounds useful as reversible inhibitors of #9 cathepsin 5
US7279472B2 (en) 1999-09-13 2007-10-09 Boehringer Ingelheim Pharmaceuticals Inc. Compounds useful as reversible inhibitors of cysteine proteases
US6756372B2 (en) 1999-09-13 2004-06-29 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cysteine proteases
US6982272B2 (en) 1999-09-13 2006-01-03 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cysteine proteases
US7056915B2 (en) 1999-09-13 2006-06-06 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cysteine proteases
US7265132B2 (en) 1999-09-13 2007-09-04 Boehringer Ingelheim Pharmaceuticals Inc. Compounds useful as reversible inhibitors of cysteine proteases
US6858623B2 (en) 2000-09-08 2005-02-22 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cysteine proteases
JP2012517984A (ja) * 2009-02-16 2012-08-09 アボット ゲーエムベーハー ウント カンパニー カーゲー 複素環式化合物、これらを含む医薬組成物およびグリシントランスポーター１の阻害剤としてのこれらの使用
US10927124B2 (en) 2016-07-29 2021-02-23 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11958862B2 (en) 2016-07-29 2024-04-16 Sumitomo Pharma America, Inc. Compounds and compositions and uses thereof
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US11491133B2 (en) 2017-08-02 2022-11-08 Sunovion Pharmaceuticals Inc. Heteroaryl-isochroman compounds and uses thereof
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof

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IE920451A1 (en) 1992-08-12

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