EP0000306A1 - Substituierte Hexahydro-benzopyrano(3,2-c)pyridine, Verfahren zu ihrer Herstellung und diese enthaltende Medikamente - Google Patents

Substituierte Hexahydro-benzopyrano(3,2-c)pyridine, Verfahren zu ihrer Herstellung und diese enthaltende Medikamente Download PDF

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Publication number
EP0000306A1
EP0000306A1 EP78400025A EP78400025A EP0000306A1 EP 0000306 A1 EP0000306 A1 EP 0000306A1 EP 78400025 A EP78400025 A EP 78400025A EP 78400025 A EP78400025 A EP 78400025A EP 0000306 A1 EP0000306 A1 EP 0000306A1
Authority
EP
European Patent Office
Prior art keywords
benzopyrano
hexahydro
mole
pyridine
lactam
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.)
Granted
Application number
EP78400025A
Other languages
English (en)
French (fr)
Other versions
EP0000306B1 (de
Inventor
Philippe Briet
Jean-Jacques Berthelon
Jean-Claude Depin
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.)
Merck Sante SAS
Original Assignee
LIPHA SAS
LIPHA Liyonnaise Industrielle Pharmaceutique
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from FR7719360A external-priority patent/FR2395270A1/fr
Priority claimed from FR7816376A external-priority patent/FR2427336A2/fr
Application filed by LIPHA SAS, LIPHA Liyonnaise Industrielle Pharmaceutique filed Critical LIPHA SAS
Publication of EP0000306A1 publication Critical patent/EP0000306A1/de
Application granted granted Critical
Publication of EP0000306B1 publication Critical patent/EP0000306B1/de
Expired legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/14—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 6 and unsubstituted in position 7
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/12—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 3 and unsubstituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7

Definitions

  • the present invention relates to substituted hexahydro benzopyrano [3,2-C] pyridines,
  • Hexahydro benzopyrano [3,2-C] pyridines have been found represented by the formula: in which R is hydrogen or a saturated or unsaturated, linear or branched lower alkyl radical, aralkyl, acyl, dialkylaminoalkyl, alkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl or aryl; R 1 is hydrogen, halogen or a lower alkoxy radical; R 2 is hydrogen or halogen; R 3 is hydrogen, halogen, lower alkyl, alkoxy, nitro, amino or forms naphthalene with R 4 and the benzene ring; R 4 is hydrogen, halogen or forms naphthalene with R 3 and the benzene ring; R is hydrogen, a lower alkyl or arylalkyl radical.
  • the polycyclic structure of the compounds suggests for a given compound the existence of several stereoisomers. Examination in thin layer chromatography of the reaction products reveals the existence of two stereoisomers A and B. Recrystallization from an adequate solvent is sufficient to isolate in the pure state the majority stereoisomer of the crude reaction product. The minority stereoisomer can be obtained by concentration of the mother liquors. It is possible to transform the minority stereoisomer by acid treatment into the majority stereoisomer.
  • Decarboxylation by heating in sodium hydrogen carbonate makes it possible to isolate the compounds belonging to the B series.
  • the transition from the compounds of the B series to the corresponding compounds of the A series is achievable by treating with hot hydrochloric acid the said compound of the B series.
  • R is hydrogen
  • R benzyl
  • R 1 or R 2 or R 3 or R 4 is a halogen
  • R benzyl with benzyl chloroformate and to hydrolyze the carbonate obtained by hydrobromic acid in order to be able to access the compounds where R is H when R 1 or R 2 or R 3 or R 4 is a halogen. It is then convenient to replace this hydrogen with a saturated or unsaturated, linear or branched, aralkyl, dialkylaminoalkyl alkyl radical.
  • halo coumarin ethyl carboxylate-3 synthetic intermediates such as fluero-6, chloro-5 and chloro-7 ethyl coumarin carboxylate-3 are new and as such fall within the scope of the invention.
  • the new hexahydro benzopyrano [3,2-C] pyridines substitutedea have excellent properties which make them drugs used in depressive states and peychic disorders This mood-modifying activity can be determined by standardized tests well known to specialists.
  • the compounds of the invention have been found to be potent inhibitors of reserpine ptosis.
  • LD 50 oral lethal doses 50
  • the medicament containing as active ingredient a compound of the invention, associated with an acceptable pharmaceutical vehicle or excipient, is presented in a form suitable for oral or parenteral administration.
  • the dosage forms are unitary such as tablets, capsules, capsules, ampoules ... These dosage forms contain from 0.05 to 100 mg of active substance and allow daily administration of 1 to 200 mg.
  • Weight regain Improved mood and social inclusion.
  • Weight gain Improved mood and sleep. Decreased anxiety. Improvement of hypochondriac disorders.
  • Severe hypochondriac depressive syndrome Associated treatments MEPRONIZINE. Dosage and duration of treatment: 10 mg / day for 20 days
  • the patient is less concerned with his body. Reduction of washing rites. Improvement of social behavior.
  • the solid obtained is drained, which is in the form of a cream product, melting at 228 ° C. It is recrystallized from 10 liters of isopropanol. 2.083 kg (yield 70%) of lactam of [amino-4a, 2-methyl-hexahydro-1, 2, 3, 4a, 10a [10 H] (benzopyrano) (3,2-C) (pyridine) is obtained.
  • Lactam of amino-4a-dimethyl-2, 8 hexahydro-1, 2, 3. 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C (pyridine) yl-10 acetic (formula 7) C 16 H 20 N 2 O 2 PM 272.3 4
  • Example 5.1 Prepared according to Example 5.1 from 60 g (0.258 mole) of methyl 6-coumarin-3 ethyl carboxylate, 29.6 g (0.258 mole ) of N-methyl piperidone-4, 39.9 g (0.516 mol) of ammonium acetate and 2 liters of ethanol. After recrystallization from acetone-ethanol, 39.3 g of lactam are obtained.
  • Lactam of the acid [amino-4a n-propyl-2 hexahydro-1,2, 3, 4. 4a. 10a [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl -10 acetic (formula 12) C 17 H 22 N 2 O 2 , PM 286.38 It is brought to 10 hours at 80 ° C a solution of 15 g (0.061 mole) of the product of Example 4 in 300 ml of dimethylformamide with 7.9 g (0.064 mole) of propyl bromide and 9.1 g (0.66 mole) of potassium carbonate. The insoluble material is filtered, the solvent is evaporated under vacuum. We purify in ethyl acetate.
  • Lactam of acid [amino-4a, chloro-6, methyl-2 hexahydro-1, 2, 3 4, 4a, 10a, [10 H] (benzopyrano (3.2-C) pyridine) -yl -10 acetic (formula 23) C 15 H 17 ClN 2 O 2 PM 292.77
  • Example 5.1 Prepared according to Example 5.1 from 12 g (0.048 mole) of chloro-8, coumarin-3, ethyl carboxylate, 5.5 g (0.048 mole) of N-methylpiperidone-4, 7.4 g (0.096 mole) of ammonium acetate and 140 ml of ethanol.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Psychiatry (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Saccharide Compounds (AREA)
EP78400025A 1977-06-24 1978-06-19 Substituierte Hexahydro-benzopyrano(3,2-c)pyridine, Verfahren zu ihrer Herstellung und diese enthaltende Medikamente Expired EP0000306B1 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
FR7719360 1977-06-24
FR7719360A FR2395270A1 (fr) 1977-06-24 1977-06-24 Hexahydro benzopyrano (3,2-c) pyridines substituees, utilisables notamment comme medicaments
FR7816376 1978-06-01
FR7816376A FR2427336A2 (fr) 1978-06-01 1978-06-01 Hexahydro benzopyrano (3,2-c) pyridines substituees utilisables notamment comme medicament

Publications (2)

Publication Number Publication Date
EP0000306A1 true EP0000306A1 (de) 1979-01-10
EP0000306B1 EP0000306B1 (de) 1980-05-28

Family

ID=26220098

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78400025A Expired EP0000306B1 (de) 1977-06-24 1978-06-19 Substituierte Hexahydro-benzopyrano(3,2-c)pyridine, Verfahren zu ihrer Herstellung und diese enthaltende Medikamente

Country Status (22)

Country Link
US (1) US4201783A (de)
EP (1) EP0000306B1 (de)
JP (1) JPS5412399A (de)
AR (1) AR225732A1 (de)
AT (1) AT356662B (de)
AU (1) AU519417B2 (de)
CA (1) CA1098519A (de)
CS (1) CS207624B2 (de)
DD (1) DD137441A5 (de)
DE (1) DE2860016D1 (de)
DK (1) DK158311C (de)
ES (1) ES471060A1 (de)
HU (1) HU177341B (de)
IE (1) IE46999B1 (de)
IL (1) IL54953A (de)
IN (1) IN151192B (de)
IT (1) IT1097257B (de)
MX (1) MX5090E (de)
NO (1) NO150205C (de)
NZ (1) NZ187629A (de)
SU (1) SU931108A3 (de)
YU (1) YU40338B (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011135027A1 (de) 2010-04-30 2011-11-03 Basf Se Polyetherpolyole, verfahren zur herstellung von polyetherpolyolen, sowie deren verwendung zur herstellung von polyurethanen

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2522666A1 (en) * 2003-04-18 2004-10-28 Pharmacia & Upjohn Company Llc Combination therapies for chronic obstructive pulmonary disease (copd)
JP6425538B2 (ja) * 2011-03-30 2018-11-21 スリーエム イノベイティブ プロパティズ カンパニー 蛍光性化合物又は発蛍光団化合物、並びにこれらの使用法
JP7209475B2 (ja) 2018-04-09 2023-01-20 日産自動車株式会社 電池の製造方法
CN111617254B (zh) * 2020-07-02 2022-04-26 中国人民解放军军事科学院军事医学研究院 降低mysm1含量或活性的物质在治疗抑郁症中的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR7143M (de) * 1966-06-28 1969-07-28

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3673194A (en) * 1970-05-04 1972-06-27 American Cyanamid Co DERIVATIVES OF 1,4,4a,9b-TETRAHYDRO-8,9b-DIMETHYL-2-PHENYL-1,4-ETHANOBENZOFURO {8 3,2-C{9 PYRIDINE-3(2H), 10-DIONE
US4033968A (en) * 1976-04-14 1977-07-05 Merck & Co., Inc. Diazatetracyclododecanes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR7143M (de) * 1966-06-28 1969-07-28

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011135027A1 (de) 2010-04-30 2011-11-03 Basf Se Polyetherpolyole, verfahren zur herstellung von polyetherpolyolen, sowie deren verwendung zur herstellung von polyurethanen

Also Published As

Publication number Publication date
JPS5412399A (en) 1979-01-30
ES471060A1 (es) 1979-01-01
DK158311C (da) 1990-10-08
NO150205C (no) 1984-09-05
IL54953A (en) 1984-06-29
AR225732A1 (es) 1982-04-30
YU40338B (en) 1985-12-31
US4201783A (en) 1980-05-06
EP0000306B1 (de) 1980-05-28
JPS633866B2 (de) 1988-01-26
IT7824705A0 (it) 1978-06-19
IT1097257B (it) 1985-08-31
AU3746378A (en) 1980-01-03
DK158311B (da) 1990-04-30
AU519417B2 (en) 1981-12-03
AT356662B (de) 1980-05-12
IN151192B (de) 1983-03-05
IL54953A0 (en) 1978-08-31
HU177341B (en) 1981-09-28
MX5090E (es) 1983-03-15
DE2860016D1 (en) 1980-10-16
DK281978A (da) 1978-12-25
NO150205B (no) 1984-05-28
DD137441A5 (de) 1979-09-05
IE781239L (en) 1978-12-24
YU143878A (en) 1982-10-31
CS207624B2 (en) 1981-08-31
NO782184L (no) 1978-12-28
ATA464478A (de) 1979-10-15
SU931108A3 (ru) 1982-05-23
IE46999B1 (en) 1983-11-30
CA1098519A (fr) 1981-03-31
NZ187629A (en) 1981-03-16

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