EP0000306B1 - Hexahydro benzopyrano (3,2-c) pyridines substituées, leur procédé de préparation et médicament les contenant - Google Patents

Hexahydro benzopyrano (3,2-c) pyridines substituées, leur procédé de préparation et médicament les contenant Download PDF

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Publication number
EP0000306B1
EP0000306B1 EP78400025A EP78400025A EP0000306B1 EP 0000306 B1 EP0000306 B1 EP 0000306B1 EP 78400025 A EP78400025 A EP 78400025A EP 78400025 A EP78400025 A EP 78400025A EP 0000306 B1 EP0000306 B1 EP 0000306B1
Authority
EP
European Patent Office
Prior art keywords
benzopyrano
hexahydro
pyridine
lactam
amino
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.)
Expired
Application number
EP78400025A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP0000306A1 (fr
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 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 Liyonnaise Industrielle Pharmaceutique filed Critical LIPHA Liyonnaise Industrielle Pharmaceutique
Publication of EP0000306A1 publication Critical patent/EP0000306A1/fr
Application granted granted Critical
Publication of EP0000306B1 publication Critical patent/EP0000306B1/fr
Expired legal-status Critical Current

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    • 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.
  • R is hydrogen or a saturated or unsaturated, linear or branched lower alkyl radical, aralkyl, acyl, dialkylaminoalkyl, alkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, aryl, benzyloxycarbonyl, ethoxalyl and ethoxycarbonylmethyl;
  • R 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 s 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 @ series.
  • the transition from the compounds of the @ series to the corresponding compounds of the @ series is achievable by treating with hot hydrochloric acid the said compound of the @ series.
  • R is hydrogen
  • R benzyl
  • halo coumarin ethyl carboxylate-3 synthetic intermediates such as fluoro-6, chloro-5 and chloro-7 ethyl coumarin carboxylate-3 are new.
  • the new substituted hexahydro benzopyrano [3,2-C] pyridines have remarkable properties which make them useful drugs in depressive states and mental disorders. This mood-modifying activity can be determined by standardized tests well known to specialists. Thus, the compounds of the invention have been found to be potent inhibitors of reserpine ptosis.
  • Table 1 lists the effective doses 50 (ED.50) obtained for some products and those obtained for standard substances well known to specialists, such as Imipramine [N- (3-dimethylaminopropyl) iminodibenzyl hydrochloride] and Amitripthyline [(dimethylamino-3) propylidene hydrochloride) -5 dibenzo (a, d) cycloheptadiene-1,4].
  • Imipramine N- (3-dimethylaminopropyl) iminodibenzyl hydrochloride
  • Amitripthyline (dimethylamino-3) propylidene hydrochloride) -5 dibenzo (a, d) cycloheptadiene-1,4].
  • LD 50 oral lethal doses 50
  • the medicament containing as active principle 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.
  • the lactam is obtained from the acid [amino-4a hexahydro-1,2,3,4,4a, 10a, [10H] (benzopyrano) (3,2-C) ( pyridine)] yl-10 acetic in the form of a white solid, melting at 212 ° C.
  • Weight obtained 20 g (Yield: 80%)
  • IR vc o : 1680 cm- 1 .
  • Mp G 206-208 ° C
  • IR ⁇ c o : 1680 cm- 1 .

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 Hexahydro benzopyrano (3,2-c) pyridines substituées, leur procédé de préparation et médicament les contenant Expired EP0000306B1 (fr)

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 EP0000306A1 (fr) 1979-01-10
EP0000306B1 true EP0000306B1 (fr) 1980-05-28

Family

ID=26220098

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78400025A Expired EP0000306B1 (fr) 1977-06-24 1978-06-19 Hexahydro benzopyrano (3,2-c) pyridines substituées, leur procédé de préparation et médicament les contenant

Country Status (22)

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

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006523674A (ja) * 2003-04-18 2006-10-19 ファルマシア・アンド・アップジョン・カンパニー・エルエルシー 慢性閉塞性肺疾患（ｃｏｐｄ）のための組合せ治療法
SG185102A1 (en) 2010-04-30 2012-12-28 Basf Se Polyether polyols, process for preparing polyether polyols and their use for producing polyurethanes
EP2691383B1 (en) * 2011-03-30 2015-01-21 3M Innovative Properties Company Fluorogenic or fluorophoric compounds and uses thereof
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

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3549641A (en) * 1966-06-28 1970-12-22 Warner Lambert Pharmaceutical Pyrano pyridines and process for their production
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

Also Published As

Publication number Publication date
YU143878A (en) 1982-10-31
IL54953A (en) 1984-06-29
ES471060A1 (es) 1979-01-01
DE2860016D1 (en) 1980-10-16
NO782184L (no) 1978-12-28
IL54953A0 (en) 1978-08-31
HU177341B (en) 1981-09-28
YU40338B (en) 1985-12-31
EP0000306A1 (fr) 1979-01-10
IN151192B (no) 1983-03-05
IE46999B1 (en) 1983-11-30
MX5090E (es) 1983-03-15
IT7824705A0 (it) 1978-06-19
JPS633866B2 (no) 1988-01-26
CA1098519A (fr) 1981-03-31
NO150205B (no) 1984-05-28
AT356662B (de) 1980-05-12
NO150205C (no) 1984-09-05
DK158311C (da) 1990-10-08
DK158311B (da) 1990-04-30
IE781239L (en) 1978-12-24
AR225732A1 (es) 1982-04-30
DD137441A5 (de) 1979-09-05
US4201783A (en) 1980-05-06
IT1097257B (it) 1985-08-31
SU931108A3 (ru) 1982-05-23
AU519417B2 (en) 1981-12-03
ATA464478A (de) 1979-10-15
JPS5412399A (en) 1979-01-30
DK281978A (da) 1978-12-25
AU3746378A (en) 1980-01-03
NZ187629A (en) 1981-03-16
CS207624B2 (en) 1981-08-31

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