US3686311A - Basic {60 -nortricyclyl-(3)-benzyl ether, and the salts thereof - Google Patents

Basic {60 -nortricyclyl-(3)-benzyl ether, and the salts thereof Download PDF

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Publication number
US3686311A
US3686311A US857272A US3686311DA US3686311A US 3686311 A US3686311 A US 3686311A US 857272 A US857272 A US 857272A US 3686311D A US3686311D A US 3686311DA US 3686311 A US3686311 A US 3686311A
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United States
Prior art keywords
ether
benzyl
compound
nortricyclyl
hydrochloride
Prior art date
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Expired - Lifetime
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US857272A
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English (en)
Inventor
Herbert Arnold
Norbert Brock
Engelbert Kuhas
Dieter Lenke
Hans Pohle
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Asta Medica GmbH
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Asta Werke AG Chemische Fabrik
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

Definitions

  • R is a lower alkyl group having from one to four carbon atoms, and the acid addition salts, quaternary ammonium salts and N-oxides thereof, have valuable properties, in particular as therapeutically active compounds.
  • Acid addition salts of the compounds of formula I are in particular those of pharmacologically acceptable acids.
  • Quaternary salts of the compounds of formula I are in particular those deriving from alkyl halides, in particular chlorides and bromides, and alkyl sulfates having one or two carbon atoms in the alkyl group.
  • R is hydrogen, fluorine, chlorine or bromine or the methyl
  • R is hydrogen, the methyl or ethinyl group, -alk is the methylene or the ethylene group, and R R and R,, which may be identical or different from each other, represent methyl or ethyl groups.
  • Preferred acid addition salts are those deriving from hydrochloric, sulphuric, phosphoric, acetic, glycolic, lactic, malic, succinic, tartaric, citric, benzoic, B- hydroxy-napthoic and embonic acid. Particularly preferred are the hydrochlorides.
  • the compounds of the general formula I and the acid addition and quaternary salts and N-oxides thereof are effective as spasmolytics and, as long as they represent tertiary amines, antiallerg'ics, antidepressives and tremor inhibitors.
  • the compounds have been tested locally on the small intestine of guinea-pigs according to N. BROCK, D. LORENZ and H. BARTLING, Arch. exp. Path. Pharmakol. 215, (1952), pgs. 512 to 524.
  • the tested compounds have been applied intravenously.
  • the effective dose DE has been determined as that dose which reduces for 75 percent spasms caused by administration of Neostigrnine or barium chloride.
  • the compounds A and B according to the present invention are myotrop-spasmolytically three to four times more effective (BaCl spasm).
  • the neurotrop-spasmolytical effectiveness of B corresponds to that of the known compound E while compound A is four times more effective (Neostigmine spasm).
  • the further known comparative test compounds Avacan and Papaverine have been less effective than compounds A, B and E.
  • the tested quaternary ammonium compounds are characterized by a particularly high spasmolytic activity.
  • compound F according to the present invention has been more effective for 32 percent and compound G according to the present invention has been effective 93 percent more effective than the known comparative test compound ciclonium bromide.
  • compound G With respect to the spasm caused by barium chloride, compound G has been twice as effective and compound F has been 25 percent more effective than ciclonium bromide.
  • Compound G according to the present invention has been more effective than the further known comparative test compound methanteline bromide both with respect to the musculotropand the neurotrop-spasmolytic effectiveness.
  • the neurotrop-spasmolytic effectiveness of compound F according to the present invention also has been significantly higher than that of the known compound methantelinc bromide.
  • the conversion of the compounds of formula I into the corresponding N-oxides is effected by subjecting the compounds of formula 1 to reaction with hydrogenperoxide or with a peroxy acid such as peroxy acetic or benzoic acid.
  • a peroxy acid such as peroxy acetic or benzoic acid.
  • the preferred acid binding agents are metallic sodium, sodium hydride, sodium amide, sodium oxide, sodium or potassium hydroxyde or sodium or potassiurn alcoholates.
  • the reaction is carried out in a suitable inert organic solvent such as benzene, toluene or xylene.
  • a suitable inert organic solvent such as benzene, toluene or xylene.
  • the reactions are carried out at anor illustrate the EXAMPLE 1
  • B-Diethylamino ethyl [a-nortricyclyl-(B )-benzyl] ether 200 g. of a-nortricyclyl-(3)-benzyl alcohol are added with stirring to a suspension of 49 g. of sodium amide in 1,200 ml. of toluene. After standing for 10 minutes, the reaction mixture is heated to boiling and 170 g. of B- diethylaminoethyl chloride are added thereto slowly. The reaction mixture then is refluxed with stirring for 2 hours.
  • the above obtained base is dissolved in anhydrous ether and a little less than the theoretical amount of hydrogen chloride dissolved in anhydrous ether is added thereto with stirring.
  • the precipitated hydrochloride is filtered off with suction and recrystallized from ethyl acetate.
  • ndrtrlcyclyl-(w-benzyl] gthosulfate F.P.: 117 at 101.
  • the above components are passed through a stainless steel sieve having a mesh width of 1 mm. and are mixed thoroughly for 30 minutes.
  • the resulting product is pressed without previous granulation to kernels weighing 90 mg. and having diameter of 6 mm. and a radius of dishing of 5 mm.
  • EXAMPLE 27 Injection solution containing 10 mg. of active principle per 2 ml. of solution.
  • bidistilled water filled up to 1.00 ml.
  • bidistilled water filled up to The compounds are dissolved in the bidistilled water useful for injection purpose without warming, passed through a sterile Seitz-EKS-filter under aseptic conditions and in a nitrogen atmosphere and are filled in white 1 or, respectively, 2 ml. ampoules.
  • the active compounds sieved to a grain-size of p. are suspended homogeneously in the molten Witepsol and are poured to suppositories weighing 2.0 g. each at a temperature not exceeding 42 C.
  • the compounds and preparations herein above described are particularly useful as spasmolyties and, as long as the active compounds are tertiary amines, as antiallergics, antidepressives, and tremor inhibitors.
  • the treatment of spasm is effected by administering to persons suffering therefrom a pharmaceutical preparation of a compound of the general formula I, in particular a quaternary ammonium salt thereof and in particular orally in a dose of about 5 to about 20 mg. with persons suffering from the other symptoms (allergy, depression, tremors) the dose ranges from about 20 to about 50 mg. one to three times a day both for parenteral and oral administration, i.e., the total daily dose ranges from 20 to mg. The treatment in continued until the symptoms have disappeared.
  • a tablet containing 10 mg. of compound G of Table 2 has been administered orally to a person suffering from spasms of the intestines. About 20 minutes after the administration the pains caused by the spasms disappeared. The same amount of the same compound has been administered to a person suffering from a dyskinesia of the bile-duct. The pains caused by the spasms disappeared 20 minutes after the administration of the tablet. Still another patient suffering from spasms of the intestinal tract after ileo-colectomia obtained a dragee according to Example 26 b containing the compound G of Table 2; the spastic pains disappeared with 30 minutes; no undesirable side effects have been observed.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US857272A 1968-09-06 1969-08-21 Basic {60 -nortricyclyl-(3)-benzyl ether, and the salts thereof Expired - Lifetime US3686311A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19681793364 DE1793364A1 (de) 1968-09-06 1968-09-06 Basische alpha-Nortricyclyl-(3)-benzyl-aether,ihre quartaeren Salze und N-Oxide und pharmazeutische Produkte hieraus

Publications (1)

Publication Number Publication Date
US3686311A true US3686311A (en) 1972-08-22

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US857272A Expired - Lifetime US3686311A (en) 1968-09-06 1969-08-21 Basic {60 -nortricyclyl-(3)-benzyl ether, and the salts thereof

Country Status (13)

Country Link
US (1) US3686311A (enrdf_load_stackoverflow)
AT (1) AT296249B (enrdf_load_stackoverflow)
BE (1) BE738449A (enrdf_load_stackoverflow)
BR (1) BR6912200D0 (enrdf_load_stackoverflow)
CH (1) CH545767A (enrdf_load_stackoverflow)
DE (1) DE1793364A1 (enrdf_load_stackoverflow)
ES (1) ES370977A1 (enrdf_load_stackoverflow)
FR (1) FR2017501A1 (enrdf_load_stackoverflow)
GB (1) GB1240943A (enrdf_load_stackoverflow)
IL (1) IL32882A0 (enrdf_load_stackoverflow)
LU (1) LU59333A1 (enrdf_load_stackoverflow)
NL (1) NL6913584A (enrdf_load_stackoverflow)
OA (1) OA03379A (enrdf_load_stackoverflow)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4065501A (en) * 1974-03-22 1977-12-27 Asta-Werke Aktiengesellschaft Basic enol ether and acid addition salts thereof
US4124716A (en) * 1974-03-22 1978-11-07 Asta-Werke Aktiengesellschaft Process for the treatment of spasmodic conditions in humans

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004045220A1 (de) * 2004-09-17 2006-04-06 Riemser Arzneimittel Ag Neue Arzneimittel

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2812327A (en) * 1954-04-14 1957-11-05 Thomae Gmbh Dr K Basic ethers of carbinols substituted by endocyclic groups, and a process of making same
US2914561A (en) * 1957-08-06 1959-11-24 Wm S Merrell Co Amine derivatives of triphenylethylene
US2971001A (en) * 1959-10-21 1961-02-07 Wm S Merrell Co Quaternary salts of triphenylethanols, -ethylenes, and -ethanes

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1102156B (de) * 1959-02-27 1961-03-16 Bayer Ag Verfahren zur Herstellung von basisch substituierten Estern der Hydracrylsaeure

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2812327A (en) * 1954-04-14 1957-11-05 Thomae Gmbh Dr K Basic ethers of carbinols substituted by endocyclic groups, and a process of making same
US2914561A (en) * 1957-08-06 1959-11-24 Wm S Merrell Co Amine derivatives of triphenylethylene
US2971001A (en) * 1959-10-21 1961-02-07 Wm S Merrell Co Quaternary salts of triphenylethanols, -ethylenes, and -ethanes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Burger, Medicinal Chemistry , 2nd Ed., pages 38, 42 and 82 83 (1960) *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4065501A (en) * 1974-03-22 1977-12-27 Asta-Werke Aktiengesellschaft Basic enol ether and acid addition salts thereof
US4124716A (en) * 1974-03-22 1978-11-07 Asta-Werke Aktiengesellschaft Process for the treatment of spasmodic conditions in humans

Also Published As

Publication number Publication date
IL32882A0 (en) 1970-01-29
SU375844A3 (enrdf_load_stackoverflow) 1973-03-23
AT296249B (de) 1972-02-10
CH545767A (enrdf_load_stackoverflow) 1974-02-15
NL6913584A (enrdf_load_stackoverflow) 1970-03-10
BR6912200D0 (pt) 1973-05-10
GB1240943A (en) 1971-07-28
DE1793364A1 (de) 1972-01-27
BE738449A (enrdf_load_stackoverflow) 1970-02-16
FR2017501A1 (enrdf_load_stackoverflow) 1970-05-22
ES370977A1 (es) 1972-01-01
OA03379A (fr) 1970-12-15
LU59333A1 (enrdf_load_stackoverflow) 1970-01-06

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