US3699125A - 1,2,3-trisubstituted pyrrolidine derivatives - Google Patents

1,2,3-trisubstituted pyrrolidine derivatives Download PDF

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Publication number
US3699125A
US3699125A US886328A US3699125DA US3699125A US 3699125 A US3699125 A US 3699125A US 886328 A US886328 A US 886328A US 3699125D A US3699125D A US 3699125DA US 3699125 A US3699125 A US 3699125A
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US
United States
Prior art keywords
methyl
pyrrolidine
ylidene
dibenzo
dihydro
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 - Lifetime
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US886328A
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English (en)
Inventor
Suminori Umio
Shizuo Maeno
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Fujisawa Pharmaceutical Co Ltd
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Fujisawa Pharmaceutical Co Ltd
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Filing date
Publication date
Priority claimed from JP179069A external-priority patent/JPS4819631B1/ja
Priority claimed from JP179169A external-priority patent/JPS4819632B1/ja
Priority claimed from JP178869A external-priority patent/JPS4819629B1/ja
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Application granted granted Critical
Publication of US3699125A publication Critical patent/US3699125A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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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
    • C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—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 one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • X and X are same or different hydrogen, halogen, lower alkyl or lower alkoxy; Y is hydroxy or halogen; R and R are hydrogen or R and R are bound together intervening ethylene, oxygen or sulfur; R is lower alkyl; and R is lower alkylene and pharmaceutically acceptable salts thereof.
  • This invention relates to new 1,2,3-trisubstituted pyrrolidine derivatives having gastric secretion inhibiting action or anti-tremorine action.
  • X, and X are same or different hydrogen, halogen, lower alkyl or lower alkoxy; Y is hydroxy or halogen; R and R are hydrogen or R and R are bound together intervening ethylene, oxygen or sulfur; R is lower alkyl; and R is lower alkylene.
  • alkyl, alkoxy or alkylene group is intended to mean group having from one to four carbon atoms in alkyl part and said alkyl part may be straight or branched.
  • Halogen chlorine, bromine, fluorine, etc.
  • Lower alkyl methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.
  • Lower alkylene ethylene, propylene, 2-methylethylene,
  • a basic object of this invention is to embody the compounds [I] and their salts.
  • Another object of this invention is to embody the compounds [I] and their salts having gastric secretion inhibiting action or anti-tremor action.
  • a further object of the invention is to embody the compounds [I] and their salts useful as a gastric secretioninhibiting agent or anti-tremor agent (e.g. antiparkinson agent).
  • a still further object of the invention is to embody a process for preparing the compounds [I] and their salts.
  • the compound of the general Formula I is prepared by reacting the compound of the Formula II;
  • X X R R and R are the same significance as defined above, or the acid salt thereof with a N-substituting agent selected from the group of 1,2-epoxyalkane [III] and the compound of the formula;
  • the starting compound [11] may be prepared, for example, by the following methods. That is, 2-lower alkyl- 3-diphenylmethylenepyrrolidine may be prepared by reducing 2-lower alkyl-3-diphenylmethylene 1 pyrroline, which can be prepared according to the method as described in Japanese patent gazette No. 19454/ 19-64, with sodium boron hydride.
  • the other starting compounds i.e. 2-lower a1kyl-3-( 10,1 l-dihydro-SH-dibenzo [a,d] cycloheptene-S-ylidene)-pyrrolidine,. 2-lower alkyl-3-(xanthene-9- ylidene)pyrrolidine and 2-lower.
  • a1kyl-3-(thioxanthene-9- yliden6)pyrrolidine may be prepared by reducing the corresponding pyrroline compounds, which may be prepared, in the substantially same method as described in the gazette, from each material of -(3-halo-propylidene)- 10,11 dihydro-SH-dibenzo[a,d]cyc1oheptene, 9'-(3-halopropylidene)xanthene and 4,5-dihydrospiro [furan-Z (3H) 9'-9'H-xanthene].
  • the starting compound [II] wherein the benzene ring(s) is (are) substituted with halogen, lower alkyl or lower alkoxy at the optional position(s), may be prepared in the substantially same manner as aforementioned.
  • the reaction is'carried out by treating the starting compound [II] or the acid salt thereof with N-substituting agent selected from the group of 1,2-epoxyalkane [III] and the compound of the formula [IV] preferably in the presence of an basic condensing agent.
  • N-substituting agent selected from the group of 1,2-epoxyalkane [III] and the compound of the formula [IV] preferably in the presence of an basic condensing agent.
  • the acid salt of the starting compound [II] are the salts with a mineral acid (e.g. hydrochloric acid, sulfuric acid, etc.) and with an organic acid (e.g. acetic acid, oxalic acid, maleic acid, picric acid, etc.).
  • Examples of the reagent, 1,2-epoxyalklane [III] include epoxyethane, 1,2-epoxypropane, 1,2-epoxybutane and the like.
  • examples of an acidic residue represented by the symbol Z are as follows: halogen (e.g. chlorine, bromine, iodine, etc.); sulfuric acid residue; and sulfonic acid residue (e.g. methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, etc.) and the like, provided that when Z is an acid residue of hydrohalogenic acid, i.e. halogen, the halogen should be higher in reactivity than that in the symbol Y. Thereaction is usually carried out in an inert solvent,
  • the solvent when the N-substituting agent itself is liquid and can be also employed as a solvent accordingly.
  • the solvent are frequently used methanol, ethanol, acetone, chloroform, dioxane, n-hexane, benzene, toluene, xylene, N,N-dimethyl formamide, etc., and the other inert solvents.
  • the reaction may be preferably carried out in the presence of a basic condensing agent such as an alkalimetal (e.g. sodium, potassium, lithium) and an alkaline earth metal (e.g. calcium) and their hydroxide (e.g. sodiumhydroxide, potassium hydroxide), amide (e.g. sodium amide), alkoxide (e.g. sodium ethoxide), carbonate (e.g.. sodium carbonate, potassium carbonate), and bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate); and an organic tertiary amine (e.g. pyridine, triethylamine, picoline, N-methylmorphorine).
  • a basic condensing agent such as an alkalimetal (e.g. sodium, potassium, lithium) and an alkaline earth metal (e.g. calcium) and their hydroxide (e.g. sodiumhydroxide, potassium hydroxide), amide (e.g. sodium amide), alkoxide (e.g. sodium
  • the reaction temperature varies according to the kinds of the starting compound [II], the N-substituting agent, the condensing agent and the solvent to be used, and is nonlimitative, but the reaction is usually etfected under warming or heating around the boiling point of the solvent to be used.
  • the pyrrolinium compound [V] to be used as the starting materials in this procedure may be prepared, for example, by reacting the corresponding pyrroline 'compounds, which can be prepared according to the method as described before, with a N-substituted agent of the formula: Z'R -OH wherein Z' and R are the same significance as defined above.
  • the reaction is conducted by reducing the pyrrolinium compound [V] in a solvent.
  • the reduction method of this procedure there may be used any conventional methods which are generally employed for the reduction of an immonium salt, for example, the reduction method using alkali boron hydride (e.g. lithium, sodium or potassium boron hydride), alkali metal hydride (e.g. lithium aluminum hydride) and. the like; the reduction method using a metal (e.g. iron, zinc, tin, etc.) and an acid (e.g. hydrochloric acid, sulfuricacid, acetic acid, etc.); the catalytic reduction method using metallic catalyst (e.g. platinium oxide, palladium-carbon, Raney-nickel, etc.); and so forth.
  • the reaction temperature and the solvent to be employed in this reaction are optionally selected depending on the reduction methods as described above.
  • the reaction may he usually conducted in a solvent such as water, methanol, ethanol, dioxane, tetrahydrofuran and the like, at room temperature or under heating; in case of the reduction using alkalimetal aluminum hydride, it may be under substantially anhydrous condition in an inert solvent (e.g. ether, tetrahydrofuran, dioxane, etc.) at room temperature or under heating; in case of the catalytic reduction, it may be in a solvent such as methanol, ethanol, dioxane, ether, water, benzene, acetic acid, etc. under warming or heating; and in case of the reduction using an acid and a metal, it may be at the room temperature and the acid can be used as a solvent, too.
  • a solvent such as water, methanol, ethanol, dioxane, tetrahydrofuran and the like
  • an inert solvent e.g. ether, tetrahydrofuran,
  • the said compound can be halogenated with a halogenating agent thereby to provide the compound [I] wherein Y is halogen as shown by the following scheme:
  • the reaction is effected by treating the compound [I] with a halogenating agent.
  • halogenating agent there may be exemplified hydrogen halide (e.g. hydrogen chloride, hydrogen bromide, hydrogen iodide, etc.), alkalimetal halide (e.g. sodium bromide, potassium bromide, potassium iodide, sodium iodide, etc.), thionylhalide (e.g. thionylchloride, thionylbromide, etc.), phosphorus halide (e.g. phosphorus trichloride, phosphorus tribromide, phosphorus triiodide, phosphorus pentachloride, phosphorus pentabromide, 0 etc.), phosphorus oxyhalide (e.g.
  • phosphorus oxychloride phosphorus, oxybromide, etc.
  • alkanesulfonyl halide e.g. methanesulfonylchloride, ethanesulfonylbromide, methanesulfonylbromide, etc.
  • phosgen e.g. phosgen and the like.
  • the halogenating reaction is conducted with a hydrogen halide or metalhalide
  • the reaction may be carried out in the presence of sulfuric acid, phosphoric acid, zinc halide, or the like.
  • reaction may be also carried out in an inert solvent.
  • solvent examples of the said solvent are chloroform, tetrahydrofuran, etc.
  • reaction temperature There is no limitation to the reaction temperature. However, it is usually decided in accordance with the kinds of the compound [I] and the halogenating agent to be used.
  • the acid salts of thus prepared compound [I] are produced by causing the pyrrolidine base to react with an acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, citric acid, tartaric acid and lactic acid.
  • an acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, citric acid, tartaric acid and lactic acid.
  • the quarternary ammonium salts are obtained by reacting thus prepared compound [I] with an aliphatic or aromatic agent such as methyl chloride, methyl bromide, methyl iodide, dimethyl sulfate, methyl benzene sulfonate, methyl p-toluene sulfonate, ethyl bromide, propyl bromide and benzyl chloride.
  • an aliphatic or aromatic agent such as methyl chloride, methyl bromide, methyl iodide, dimethyl sulfate, methyl benzene sulfonate, methyl p-toluene sulfonate, ethyl bromide, propyl bromide and benzyl chloride.
  • Guinea pig ileum was placed in the organ bath filled with Tyrodes solution. Drugs were studied for their antagonism with acetylcholine (0.2 #QJIHL).
  • chorda tympani was stimulated electrically.
  • the drops of saliva from the Whartons duct was counted. Drugs were tested for their inhibitory action of these salivary secretions.
  • Dogs were anesthetized with morphine-urethane, and the spontaneous motility of the jejunal portion was recorded using balloon-transducer system. The amplitude of each wave was chosen to investigate dose-response relationship.
  • mice of 1GB. strain ranging from 4 to 6 Weeks of age and Weighing between 23 g. and 32 g., were subcutaneously given the test compound in varying doses. Thirty minutes thereafter, each animal was given 10 mg. per kg. of tremorme dihydrochloride intraperitoneally. Any tremor observed Within 30 minutes was noted. The EDm values to inhibit tremor was determined by the Lichfield-Wilcoxon method.
  • Anti-acetylcholine potency was measured by Magnus method using the isolated intestines of guinea pigs.
  • the ED value to inhibit acetylcholine contraction was deterrmned by graphing the mean potency at each dose level from an inhibitory potency of the test compound against contraction induced by acetylcholine.
  • the same test as aforementioned was conducted on atropine to determine the equipotent ratio of the test compound with respect to atropine.
  • the anti-histamine potency was determined by using the ISO- lated small intestines of guinea pigs according to the Mag-nus method.
  • the EDw value, at which histamine contraction was inhibited, was determined by graphing the mean potency at each dose level from an inhibitory potency of the test compound against contraction induced by histamine. The same test as aforementioned was conducted on dophene hydramme to determine the equipotent ratio of the test compound with respect to diphene hydrarm'nc.
  • the compounds [I] canbe administered by the conventional methods, the conventional types of unit dosages or with the conventional pharmaceutical carriers to produce a gastric secretion inhibiting or anti-tremor in human beings and animals.
  • they can be used in the form of pharmaceutical preparation, which contain them in admixture with a pharmaceutical organic or inorganic carrier material suitable for enteral, parenteral or local application.
  • Oral administration by the use of tablets, capsules or in liquid form such as suspensions, solution or emulsion is particularly advantageous.
  • the conventional binding and disintegrating agents used in therapeutic unit dosages can be employed.
  • binding agents there can be mentioned glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate and talc.
  • disintegrating agents there can be mentioned corn starch, keratin, colloidal silica and potato starch.
  • the conventional liquid carriers can be used.
  • Y is hydroxy or halogen
  • R and R bound together are ethylene
  • R is lower alkyl
  • R is lower alkylene and their pharmaceutically acceptable salts.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
US886328A 1969-01-09 1969-12-18 1,2,3-trisubstituted pyrrolidine derivatives Expired - Lifetime US3699125A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP179069A JPS4819631B1 (enrdf_load_stackoverflow) 1969-01-09 1969-01-09
JP179169A JPS4819632B1 (enrdf_load_stackoverflow) 1969-01-09 1969-01-09
JP178869A JPS4819629B1 (enrdf_load_stackoverflow) 1969-01-09 1969-01-09

Publications (1)

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US3699125A true US3699125A (en) 1972-10-17

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US (1) US3699125A (enrdf_load_stackoverflow)
BE (1) BE744014A (enrdf_load_stackoverflow)
CA (1) CA971569A (enrdf_load_stackoverflow)
CH (2) CH527184A (enrdf_load_stackoverflow)
DE (1) DE2000463A1 (enrdf_load_stackoverflow)
FR (1) FR2034459B1 (enrdf_load_stackoverflow)
GB (1) GB1259400A (enrdf_load_stackoverflow)
NL (1) NL7000277A (enrdf_load_stackoverflow)
SE (1) SE366308B (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3992409A (en) * 1975-06-18 1976-11-16 Fujisawa Pharmaceutical Co., Ltd. 1-Alkanesulfonyloxyalkyl-2-alkyl-3-diphenylmethylenepyrrolidines

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3992409A (en) * 1975-06-18 1976-11-16 Fujisawa Pharmaceutical Co., Ltd. 1-Alkanesulfonyloxyalkyl-2-alkyl-3-diphenylmethylenepyrrolidines

Also Published As

Publication number Publication date
NL7000277A (enrdf_load_stackoverflow) 1970-07-13
FR2034459B1 (enrdf_load_stackoverflow) 1974-08-30
CH528505A (de) 1972-09-30
DE2000463A1 (de) 1970-12-10
CA971569A (en) 1975-07-22
BE744014A (fr) 1970-06-15
SE366308B (enrdf_load_stackoverflow) 1974-04-22
GB1259400A (enrdf_load_stackoverflow) 1972-01-05
FR2034459A1 (enrdf_load_stackoverflow) 1970-12-11
CH527184A (de) 1972-08-31

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