US3891652A - Antianginal aryldecahydropyrrolo{8 3,4-f{9 quinolines - Google Patents

Antianginal aryldecahydropyrrolo{8 3,4-f{9 quinolines Download PDF

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Publication number
US3891652A
US3891652A US374593A US37459373A US3891652A US 3891652 A US3891652 A US 3891652A US 374593 A US374593 A US 374593A US 37459373 A US37459373 A US 37459373A US 3891652 A US3891652 A US 3891652A
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United States
Prior art keywords
compounds
aryl
formula
phenyl
decahydro
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Expired - Lifetime
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US374593A
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English (en)
Inventor
Frederic Peter Hauck
Joseph E Sundeen
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ER Squibb and Sons LLC
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ER Squibb and Sons LLC
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Priority to US374593A priority Critical patent/US3891652A/en
Priority to GB2721474A priority patent/GB1477734A/en
Priority to FR7422485A priority patent/FR2350841A1/fr
Priority to JP49074922A priority patent/JPS5040595A/ja
Priority to DE2431201A priority patent/DE2431201A1/de
Priority to US05/549,581 priority patent/US3963724A/en
Application granted granted Critical
Publication of US3891652A publication Critical patent/US3891652A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—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 one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6

Definitions

  • ABSTRACT 4-Ary1-2,3,3a,4,5,6,7,8,9,9b-decahydro-Il-I-pyrrolo- [3,4-f1quinolines, 4-aryl2,3,3a,4,5.7,8,9,9a,9bdecahydro-1-I-l-pyrr0lo[3,4-f]quinolinium salts, intermediates for their preparation and methods for their preparation are disclosed.
  • This invention relates to blood pressure lowering agents, anti-inflammatory agents, antianginal and antiarrhythmic agents of the following general formula wherein Aryl is selected from the group consisting of phenyl, naphthyl, and substituted phenyl or naphthyl, wherein said substituent is selected from the group consisting of lower alkyl, lower alkoxy, di(lower alkyl- )amino, halogen and trifluoromethyl, and R and R are selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, aryl-lower alkyl and aryllower alkenyl, and acid addition salts (la) thereof which have the formula
  • This invention also relates to the useful intermediates of the formulae:
  • the term lower alkyl is intended to mean a straight or branched chain alkyl group of from one to eight carbon atoms.
  • lower alkoxy is intended to mean a straight or branched chain alkyl group of from one to eight carbon atoms linked directly to an oxygen atom.
  • aryl is intended to mean phenyl, naphthyl and substituted phenyl or naphthyl.
  • substituted when applied to aryl or phenyl is intended to encompass one or two substituents which may be alike or different and are selected from the following group: lower alkyl, lower alkoxy, halogen, trifluoromethyl, and di(lower alkyl)amino.
  • acid addition salts is intended to encompass the salts formed upon the addition of an acid to the compounds of this invention.
  • monoor di-salts of this invention may be formed by the addition of such acids as hydrochloric acid, phosphoric acid, sulfuric acid, perchloric acid, acetic acid, citric acid, etc.
  • the preferred acids are those which form pharmaceutically acceptable acid addition salts although other salts may be of use in purifying and storing the compounds of this invention.
  • the salt form is best described by formula la.
  • the compounds of the present invention may exist in a number of isomeric forms such as steroisomeric forms, endo and exo forms, etc. All of these isomers are intended to be within the scope of the present invention.
  • Compounds of the formula VIIl are then added to compounds of the formula VII to give compounds of the formula ll.
  • Compounds of the formula ll are generally converted to compounds of the formula ill utilizing a dehydrating agent, such as ptoluene sulfonic acid or its monohydrate.
  • the dehydration reactions and Diels-Alder reactions are generally carried out from about 15 to about 80 in a lower alkyl anhydride solvent, such as acetic anhydride, for periods of from 1 hour to 24 hours.
  • a lower alkyl anhydride solvent such as acetic anhydride
  • the compounds of formula V are converted into the compounds of this invention by a reduction reaction utilizing LiAll'l in an ethereal solvent, preferably tetrahydrofuran.
  • the compounds of formula I may be converted to their salts by reaction with acids, such as sulfuric acid, perchloric acid, hydrochloric acid, etc.
  • acids such as sulfuric acid, perchloric acid, hydrochloric acid, etc.
  • the resultant compounds are best represented by formula Xl /N A H -B R 2X v
  • the compounds of this invention and their non-toxic pharmaceutically acceptable salts have thus been found to be useful as antiinflammatory, antianginal and anti-arrhythmic agents and to reduce blood pressure in mammals when administered in amounts ranging from about 2 mg. to about 25 mg. per kg. of body weight per day.
  • a preferred dosage regimen for optimum results would be from about l0 mg. to about 20 mg. per kg. of body weight per day, and such dosage units are employed that a total of from about 500 mg. to about 1,000 mg. of active ingredient for a subject of about 70 kg. body weight are administered in a 24 hour period.
  • the compounds of the present invention in the described dosages are intended to be administered orally; however, other routes such as rectally, intraperitoneally, subcutaneously, intramuscularly or intravenously may be employed.
  • the active compounds of the present invention are orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
  • the active compounds of this invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like.
  • Such compositions and preparations should contain at least 0.1 percent of active compound.
  • the percentage in the compositions and preparations may, of course, be varied and may conveniently be between about 5 to about percent or more of the weight of the unit.
  • the amount of active compound in such therapeutically useful compositions of preparations is such that a suitable dosage will be obtained.
  • Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 10 and 200 milligrams of active compound.
  • the tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate, a disintegrating agent such as corn starch, potato starch alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of Wintergreen, or cherry flavoring.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • an excipient such as dicalcium phosphate, a disintegrating agent such as corn starch, potato starch alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the-amounts employed.
  • EXAMPLE 6 6-BenZyl-2,3 ,3a,4,5 ,7,8,9,9a,9b-Decahydro-2-methyl- 4-phenyl-lll-pyrrolo[3,4-f]quinolinium chloride hydrochloride.
  • Example ld Substituting benzylamine for methylamine in the procedure of Example l-c yields the corresponding imide lactam which is then reduced as in Example ld,e to the title compound.
  • Example 1c Substituting aniline for methylamine in the procedure of Example 1c yields the corresponding imide lactam which is then reduced as in Example 1d,e to the title compound.
  • Aryl is selected from the group consisting of phenyl, naphthyl, substituted phenyl and substituted naphthyl, wherein said substituent is selected from the group consisting of lower alkyl, lower alkoxy, di(lower all yl)amino, halogen and trifluoromethyl, and R and R are selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl-lower alkyl and styryl, and acid addition salts thereof having the formula:
  • aryl is selected from the group consisting of phenyl and pmethoxyphenyl and R and R are lower alkyl.
  • aryl is pmethoxyphenyl and R and R are methyl 4.
  • aryl is phenyl and citrate salts.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Hydrogenated Pyridines (AREA)
US374593A 1973-06-28 1973-06-28 Antianginal aryldecahydropyrrolo{8 3,4-f{9 quinolines Expired - Lifetime US3891652A (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US374593A US3891652A (en) 1973-06-28 1973-06-28 Antianginal aryldecahydropyrrolo{8 3,4-f{9 quinolines
GB2721474A GB1477734A (en) 1973-06-28 1974-06-19 Quinolines
FR7422485A FR2350841A1 (fr) 1973-06-28 1974-06-27 Aryldecahydropyrrolo(3,4-f)quinoleines anti-angineuses
JP49074922A JPS5040595A (enExample) 1973-06-28 1974-06-28
DE2431201A DE2431201A1 (de) 1973-06-28 1974-06-28 4-aryldecahydro-1h-pyrrolo eckige klammer auf 3,4-f eckige klammer zu chinolinderivate, verfahren zu ihrer herstellung und arzneimittel
US05/549,581 US3963724A (en) 1973-06-28 1975-02-13 Intermediates useful in the preparation of aryldecahydropyrrolo[3,4-f]quinolines

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US374593A US3891652A (en) 1973-06-28 1973-06-28 Antianginal aryldecahydropyrrolo{8 3,4-f{9 quinolines

Related Child Applications (1)

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US05/549,581 Division US3963724A (en) 1973-06-28 1975-02-13 Intermediates useful in the preparation of aryldecahydropyrrolo[3,4-f]quinolines

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US3891652A true US3891652A (en) 1975-06-24

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US (1) US3891652A (enExample)
JP (1) JPS5040595A (enExample)
DE (1) DE2431201A1 (enExample)
FR (1) FR2350841A1 (enExample)
GB (1) GB1477734A (enExample)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4235909A (en) * 1979-04-19 1980-11-25 Eli Lilly And Company Octahydro-2H-pyrrolo[3,4-g]quinolines
US4282362A (en) * 1979-04-19 1981-08-04 Eli Lilly And Company Octahydro-2H-pyrrolo[3,4-g]quinolines
US4311844A (en) * 1980-04-18 1982-01-19 Eli Lilly And Company Octahydro-2H-pyrrolo[3,4,-g]quinolines

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE895842A (fr) * 1982-02-12 1983-08-08 Sandoz Sa Nouveaux alcaloides ergopeptidiques, leur preparation et leur utilisation comme medicaments
JP2005222832A (ja) * 2004-02-06 2005-08-18 Sumitomo Electric Ind Ltd ケーブルの製造方法及び製造装置

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
luhan et al., Chem. Abstracts, Vol. 77, Abst. No. 152419w (1972). *
Wagner-Jauregg et al., Helv. Chim. Acta Vol. 56, pgs. 440 to 449, (Jan. 31, 1973, copy received POSL 4/27/73). *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4235909A (en) * 1979-04-19 1980-11-25 Eli Lilly And Company Octahydro-2H-pyrrolo[3,4-g]quinolines
US4282362A (en) * 1979-04-19 1981-08-04 Eli Lilly And Company Octahydro-2H-pyrrolo[3,4-g]quinolines
US4311844A (en) * 1980-04-18 1982-01-19 Eli Lilly And Company Octahydro-2H-pyrrolo[3,4,-g]quinolines

Also Published As

Publication number Publication date
FR2350841A1 (fr) 1977-12-09
DE2431201A1 (de) 1975-01-16
FR2350841B1 (enExample) 1978-12-29
GB1477734A (en) 1977-06-22
JPS5040595A (enExample) 1975-04-14

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