US3668208A - Hexahydro imidazoquinolines - Google Patents

Hexahydro imidazoquinolines Download PDF

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Publication number
US3668208A
US3668208A US11308A US3668208DA US3668208A US 3668208 A US3668208 A US 3668208A US 11308 A US11308 A US 11308A US 3668208D A US3668208D A US 3668208DA US 3668208 A US3668208 A US 3668208A
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Prior art keywords
methyl
hexahydroimidazo
nitro
carbon atoms
alkyl
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Expired - Lifetime
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US11308A
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English (en)
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Charles A R Baxter
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Pfizer Corp Belgium
Pfizer Corp SRL
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Pfizer Corp Belgium
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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

Definitions

  • ABSIRACT A series of novel substituted hexahydro imidazoquinoline [52] U.S.Cl. ..260/283 S, 260/268 C, 260/283 CN, compounds have been prepared from the corresponding 2.
  • novel substituted hexahydro imidazoquinoline compounds are extremely useful when employed in the field of drug therapy as anti-schistosomal agents.
  • the novel compounds of this invention are all selected from the group consisting of substituted l,2,3,3a,4,5-hexahydroimidazo-[ l,5-a]-quinline bases of the formula:
  • R is a member selected from the group consisting of alkyl having from one to six carbon atoms, hydroxyalkyl having from two to six carbon atoms, alkoxyalkyl having from two to six carbon atoms in the oxyalkyl moiety and from one to six carbon atoms in the alkyl moiety, alkanoyloxyalkyl having from two to six carbon atoms in the oxyalkyl moiety and from two to six carbon atoms in the alkanoyl moiety, cycloalkyl having from three to six carbon atoms and phenylalkyl having up to three carbon atoms in the alkyl moiety; R is a member selected from the group consisting of methyl, formyl, hydroxymethyl, alkoxymethyl having from one to six carbon atoms in the alkyl moiety and alkanoyloxymethyl having from two to six carbon atoms in the alkanoyl moiety;
  • R is methyl, hydroxymethyl, or ethoxymethyl
  • R is nitro or chloro
  • R is hydrogen
  • R is hydrogen or methyl
  • R is hydrogen, methyl, ethyl, phenyl, nitrophenyl or thienyl.
  • Typical member compounds of the preferred class include such 2-(lower alkyl)-7-methyl (or hydroxymethyl)-8-nitro (or chloro)- 1,2,3,3a,4,5-hexahydroimidazo-[ l,5-a]-quinolines as 2- isopropyl-7-methyl-8-nitrol ,2,3 ,3a,4,5-hexahydroimidazo-[ l ,S-al-quinoline, 1 ,7-dimethyl-2-isopropyl-8-nitrol ,2,3,3a,4,5-hexahydroimidazo-[ l,5-a]-quinoline, 2- isopropyl7-hydroxymethyl-8-nitrol ,2,3 ,3a,4,5-hexahydroimidazo-[ l ,S-aI-quinoline, l-ethyl-2-isopropyl-7- methyl-S-nitrol ,2,3,3a,4,5hexahydroimidazo-[ l ,5-a
  • an appropriately substituted 2-aminomethyl-1,2,3,4-tetrahydroquinoline (see British Pat. No. 1,166,538) is treated with an aldehyde of the formula li -CHO, where R; is defined as aforesaid.
  • This particular reaction is normally carried out in the presence of a suitable solvent for the aldehyde, e.g., water or ethanol, or it may be carried out in the absence of a solvent by merely suspending the tetrahydroquinoline compound in the liquid aldehyde.
  • the reaction is conducted at a temperature that is in the range of from about 0 C. to about C. for a period of about 15 minutes to about four hours.
  • N-oxide derivatives of the compounds of this invention i.e., N-oxide derivatives of the aforementioned novel substituted hexahydro imidazoquinolines, may be prepared by simply using well-known synthetic methods to efiect such a conversion from the parent compound, e.g., oxidation via 30 percent hydrogen peroxide or benzoyl peroxide, etc.
  • the esters of those compounds containing free hydroxyl groups are also prepared by conventional means.
  • substituted hexahydro imidazoquinoline compounds of this invention all possess asymmetric carbon atoms at positions 1 and 3a of the imidazoquinoline fused ring system, they may exist in separated dand l-optically active forms, as well as in racemic dl-mixtures necessarily produced by the present synthetic methods as hereinbefore described.
  • the invention contemplates the d, land racemic forms within its scope.
  • the acids which are used-to prepare the pharmaceuticallyacceptable acid addition salts of the aforementioned hexahydro imidazoquinoline base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, saccharate, methanesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1- methylene-bis-2-hydroxy-3-naphthoate) salts.
  • non-toxic acid addition salts i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate, phosphat
  • the compounds of the invention can be administered alone, but will generally be administered in conjunction with a pharmaceutical carrier.
  • the carrier is normally selected with regard to the intended route of administration, as well as standard pharmaceutical practice.
  • these compounds may be administered orally in the form of tablets containing excipients such as starch or milk sugar (lactose), or in cap sules either alone or on admixture with excipients, or else in the fonn of elixirs or suspensions containing flavoring or coloring agents, etc.
  • a sterile aqueous solution of a water-soluble salt e.g., the methanesulfonate salt
  • a water-soluble salt e.g., the methanesulfonate salt
  • the activity of the compounds of the present invention has been determined by a technique which depends on the movement of adult sehistosomes from their normal sites in the mesenteric veins to the veins within the liver, as effected by chemotherapeutically-active compounds. This technique has been described in detail in the Journal of Tropical Medicine & Hygiene, Vol 71, pp. 139-145 (June, 1968). In the present case, white mice of 3-4 weeks age were infected percutaneously with 120 cercariae of Schistosoma manroni (East African strain). Eight weeks after infection, the compound to be assessed was administered orally or intraperitoneally at a basic dosage of 25 mg./kg.
  • mice were perfused post mortem to recover the worms separately from the mesenteric veins, as well as from the hepatic portal vein and from the veins within the liver. The proportional movement of worms from the portal and mesenteric veins to the veins within the liver formed the basis for the assessment.
  • EXAMPLE 11 A solution of acetaldehyde (2.5 ml.) in absolute ethanol ml.) was added to a solution of 2-isopropylaminomethyl-6- methyl-7-nitro-1,2,3,4-tetrahydroquino1ine 1.0 g.) in absolute ethanol (30 ml.). The slightly exothermic reaction mixture was then allowed to stand at room temperature (25 C.) for 2 hours, after which time the solution was concentrated in vacuo. The resulting orange oil was dissolved in hot petroleum ether (b.p.
  • the alcohol was then removed by means of evaporation under reduced pressure, and the crude product so obtained was subsequently dissolved in benzene and chromatographed on a neutral alumina column, using benzene as the eluent.
  • the first 25 ml. of eluent was shown by thin-layer paper chromatographic analysis to contain benzaldehyde and a compound which was not the original starting material.
  • the benzaldehyde was removed (and recovered) by distillation in vacuo (b.p. 65C./ 18 mm. Hg.) and the residue dissolved in hot petroleum ether (b.p. 60-80 C.).
  • reaction solution was then evaporated to dryness while under reduced pressure to give 1-methyl-2-isopropyl-7-ethoxymethyl-8-nitro-1,2,3,3a,4,'5-hexahydroimidazo-[ l,5-a]-quinoline as an orange solid, which was subsequently recrystallized from ethanol to yield 1.6 g. of product, m.p. l03-105C. Anal.
  • N0 H CH Z-thienyl No: II H I1-CuH13 0 N02 11 H CH3 CHQCHQOH CH3 Bl C2H5 H CaH5CH2 n-CuHnOH CHaOH CN n-CoHm H S-iuryl.
  • the other N-oxide compounds of this invention are each similarly formed by merely employing the appropriate substituted l,2,3,3a,4,5-hexahydroimidazo-[ l ,5-a]- quinoline base as starting material in the above reaction procedure, in place of the particular quinoline base compound used previously.
  • a hexahydro imidazoquinoline compound selected from the group consisting of substituted l,2,3,3a,4,5hexahydroimidazo-[ l,5-a]-quinoline bases of the formula:
  • R is alkyl having from one to six carbon atoms
  • R is a member selected from the group consisting of methyl and hydroxymethyl
  • R is a member selected from the group consisting of nitro and chlorine
  • R is hydrogen
  • R is a member selected from the group consisting of hydrogen and methyl
  • R is a member selected from the group consisting of hydrogen, alkyl having from one to six carbon atoms, phenyl, nitrophenyl and thienyl.
  • R is alkyl having from one to six carbon atoms, R, is methyl, R, is nitro, and R,, R, and R, are each hydrogen.
  • R is alkyl having from one to six carbon atoms, R, and R, are each methyl, R is chlorine, and R and R are each hydrogen.
  • R is alkyl having from one to six carbon atoms, R, is hydroxymethyl, R, is nitro, and R,, R, and R, are each hydrogen.
  • R, and R are each alkyl having from one to six carbon atoms, R, is methyl, R is nitro, and R and R, are each hydrogen.
  • R is alkyl having from one to six carbon atoms, R, is methyl, R is nitro, R, and R are each hydrogen, and R,, is phenyl.
  • R is alkyl having from one to six carbon atoms, R, is methyl, R is nitro, R, and R, are each hydrogen and R is thienyl.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US11308A 1969-02-19 1970-02-13 Hexahydro imidazoquinolines Expired - Lifetime US3668208A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB8882/69A GB1278272A (en) 1969-02-19 1969-02-19 Substituted hexahydro-imidazoquinolines

Publications (1)

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US3668208A true US3668208A (en) 1972-06-06

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US (1) US3668208A (enExample)
JP (1) JPS5016796B1 (enExample)
CH (1) CH521979A (enExample)
DE (1) DE2007345A1 (enExample)
FR (1) FR2034556B1 (enExample)
GB (1) GB1278272A (enExample)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3887566A (en) * 1971-02-11 1975-06-03 Aspro Nicholas Ltd 2,3-Dihydroimidazo-isoquinolines
US3901897A (en) * 1972-10-05 1975-08-26 Squibb & Sons Inc 1,2,3,4,4a,5,6,7-octahydro-7-aryl-isoquinolines and derivatives thereof
US3917610A (en) * 1972-06-30 1975-11-04 Chinoin Gyogyszer Es Vegyeszet Amino-imidazo and amino-pyrazolo-isoquinolines and process for the preparation thereof
US4075343A (en) * 1976-09-13 1978-02-21 Pfizer Inc. Anti-allergenic 5-alkoxyimidazo[1,2-A]quinoline-2-carboxylic acids and derivatives thereof
US4097598A (en) * 1976-08-06 1978-06-27 Pfizer Inc. Quaternary salts as hypoglycemic agents
US5594140A (en) * 1993-11-19 1997-01-14 The Upjohn Company Imidazo[1,5-A]quinolines for treatment of anxiety and sleep disorders
US20080151580A1 (en) * 1997-01-24 2008-06-26 Schlecht Martin F High efficiency power converter
CN117700413A (zh) * 2024-02-05 2024-03-15 湖南工程学院 一种六氢咪唑并[2,1-a]异喹啉衍生物及其合成方法

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5227199U (enExample) * 1975-08-19 1977-02-25
FR2624861B1 (fr) * 1987-12-21 1990-06-01 Delalande Sa Carbamates tricycliques, leur procede de preparation et leur application en therapeutique

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3253986A (en) * 1963-07-04 1966-05-31 Parke Davis & Co Antiparasitic compositions and use thereof
US3329620A (en) * 1963-04-01 1967-07-04 Hooker Chemical Corp Novel phosphorus sulfide product and method for its manufacture
US3393195A (en) * 1964-02-06 1968-07-16 Merck Ag E 1, 2, 3, 6, 7, 11b-hexahydro-4h-pyrazino-2, 1-a-isoquinolines
US3454579A (en) * 1967-08-17 1969-07-08 American Cyanamid Co Imidazo(1,5-a)quinolin-1-one and thione derivatives
GB1166538A (en) * 1967-06-10 1969-10-08 Pfizer Ltd Substituted Tetrahydroquinolines
US3557120A (en) * 1969-05-21 1971-01-19 Sterling Drug Inc Hexahydroimidazoisoquinolines
US3565902A (en) * 1967-09-15 1971-02-23 American Cyanamid Co 1,2-dihydro-3h-imidazo(1,5-a)indol-3-ones and 3-thiones

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3329620A (en) * 1963-04-01 1967-07-04 Hooker Chemical Corp Novel phosphorus sulfide product and method for its manufacture
US3253986A (en) * 1963-07-04 1966-05-31 Parke Davis & Co Antiparasitic compositions and use thereof
US3393195A (en) * 1964-02-06 1968-07-16 Merck Ag E 1, 2, 3, 6, 7, 11b-hexahydro-4h-pyrazino-2, 1-a-isoquinolines
GB1166538A (en) * 1967-06-10 1969-10-08 Pfizer Ltd Substituted Tetrahydroquinolines
US3454579A (en) * 1967-08-17 1969-07-08 American Cyanamid Co Imidazo(1,5-a)quinolin-1-one and thione derivatives
US3565902A (en) * 1967-09-15 1971-02-23 American Cyanamid Co 1,2-dihydro-3h-imidazo(1,5-a)indol-3-ones and 3-thiones
US3557120A (en) * 1969-05-21 1971-01-19 Sterling Drug Inc Hexahydroimidazoisoquinolines

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3887566A (en) * 1971-02-11 1975-06-03 Aspro Nicholas Ltd 2,3-Dihydroimidazo-isoquinolines
US3917610A (en) * 1972-06-30 1975-11-04 Chinoin Gyogyszer Es Vegyeszet Amino-imidazo and amino-pyrazolo-isoquinolines and process for the preparation thereof
US3901897A (en) * 1972-10-05 1975-08-26 Squibb & Sons Inc 1,2,3,4,4a,5,6,7-octahydro-7-aryl-isoquinolines and derivatives thereof
US4097598A (en) * 1976-08-06 1978-06-27 Pfizer Inc. Quaternary salts as hypoglycemic agents
US4075343A (en) * 1976-09-13 1978-02-21 Pfizer Inc. Anti-allergenic 5-alkoxyimidazo[1,2-A]quinoline-2-carboxylic acids and derivatives thereof
US5594140A (en) * 1993-11-19 1997-01-14 The Upjohn Company Imidazo[1,5-A]quinolines for treatment of anxiety and sleep disorders
USRE35840E (en) * 1993-11-19 1998-07-07 Pharmacia & Upjohn Company Imidazo 1,5-a!quinolines for treatment of anxiety and sleep disorders
US20080151580A1 (en) * 1997-01-24 2008-06-26 Schlecht Martin F High efficiency power converter
CN117700413A (zh) * 2024-02-05 2024-03-15 湖南工程学院 一种六氢咪唑并[2,1-a]异喹啉衍生物及其合成方法

Also Published As

Publication number Publication date
FR2034556B1 (enExample) 1974-04-12
JPS5016796B1 (enExample) 1975-06-16
CH521979A (fr) 1972-04-30
DE2007345A1 (de) 1970-09-17
FR2034556A1 (enExample) 1970-12-11
GB1278272A (en) 1972-06-21

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