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GB646198A - Improvements in or relating to the preparation of antispasmodic agents - Google Patents

Improvements in or relating to the preparation of antispasmodic agents

Info

Publication number
GB646198A
GB646198A GB2255/47A GB225547A GB646198A GB 646198 A GB646198 A GB 646198A GB 2255/47 A GB2255/47 A GB 2255/47A GB 225547 A GB225547 A GB 225547A GB 646198 A GB646198 A GB 646198A
Authority
GB
United Kingdom
Prior art keywords
phenyl
methyl
piperidino
cyclohexyl
dimethylamino
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
GB2255/47A
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.)
Winthrop Stearns Inc
Original Assignee
Winthrop Stearns Inc
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
Application filed by Winthrop Stearns Inc filed Critical Winthrop Stearns Inc
Publication of GB646198A publication Critical patent/GB646198A/en
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Compounds of the formula R1R2C(OH)-Y-NR3R4, where R1 is aryl, cycloalkyl or heterocyclic, R2 is aryl or cycloalkyl (but R1 and R2 are not both aryl), Y is an a : b -alkylene group and R3 and R4 are alkyl groups which may form a heterocyclic ring with the nitrogen atom, are prepared by reacting a ketone R1-CO-Y-NR3R4 with an organo-metallic compound R2M, where M is an alkali metal or halomagnesium, and hydrolysing the resulting complex. The reactants are mixed at a temperature around 0 DEG C., the mixture warmed to room temperature or higher and then treated with a strong acid around 0 DEG C. The products may be converted into salts, especially water-soluble non-toxic salts such as sulphates, phosphates, citrates, tartrates, sulphamates, hydrochlorides and hydrobromides. The products are antispasmodic agents having a high musculotropic action but little neurotropic action. Examples show the preparation of the following 1 - phenyl - 1 - cyclohexyl - 1 - propanols: - 3 - N - piperidino, 2 - methyl - 3 - N-piperidino -, 2 - ethyl - 3 - N - piperidino -, 3-dimethylamino-, and 3-di-n-butylamino-, and also of 1 - phenyl - 1 - (2 - thienyl) - 2 - methyl-3 - N - piperidino - 1 - propanol and 1 - (2-thienyl) - 1 - cyclohexyl - 2 - methyl - 3 - di-ethylamino - 1 - propanol. Specified radicals for R1 are phenyl, naphthyl, furyl, thienyl, pyridyl, cyclohexyl and cyclopentyl, and for R2 are phenyl, naphthyl, cyclohexyl and cyclopentyl; these may carry alkyl, alkoxy, halogen or amino-substituents, as for example methylcyclohexyl and veratryl. The heterocyclic ring formed by R3, R4 and the nitrogen atom may be that of morpholine, pyrrolidine, piperazine or thiomorpholine in addition to piperidine mentioned above. M may be sodium, potassium, lithium or bromo-magnesium. Specification 307,304, [Class 2 (iii)], is referred to. Amino-ketones of the above formula can be obtained by (1) the Mannich reaction, e.g. a -(diethylaminomethyl) - 2 - propiothienone from ethyl 2-thienyl ketone, formaldehyde and di-ethylamine hydrochloride; (2) reaction of b -(tertiary-amino)-acyl halides with aromatic compounds, e.g. b -dimethylamino-butyric acid is converted into its acid chloride hydrochloride with thionyl chloride, and this is condensed with benzene in the presence of aluminium chloride to give b -dimethylamino-butyrophenone; (3) addition of amines of a : b -unsaturated ketones, e.g. piperidine and crotonophenone give b -piperidino-butyrophenone. The Specification as open to inspection under Sect. 91 refers to the production of compounds R1R2C(OH)-Y-NR3R4, where R1 and R2 may both be aryl, R2 may be heterocyclic, R3 and R4 may be cycloalkyl, and R4 may be hydrogen or benzyl, in addition to the groups defined above. These compounds may be prepared as defined above, and in the case where R4 is hydrogen, they may be obtained by catalytic hydrogenation of the corresponding compound where R4 is benzyl (see below). Examples show the preparation of 1 : 1-diphenyl - 3 - piperidino - 1 - propanol and the 2 - methyl derivative and 1 : 1 - diphenyl - 2-methyl - 3 - diethylamino - 1 - propanol. The following 1 : 1-diphenyl-1-propanols are mentioned: 2 - methyl - 3 - morpholino -, 2 - ethyl-3 - piperidino -, 3 - methylamino -, 3 - methyl-3 - dimethylamino -, 3 : 3 - dimethyl - 3 - di-ethylamino - and 2 - ethyl - 3 - thiamorpholino-, and also the following 1-propanols: 1-phenyl-1 - p - anisyl - 3 - dimethylamino -, 1 - phenyl-1 - cyclohexyl - 2 - 2 - dimethyl - 3 - piperidino-, 1 - phenyl - 1 - a - naphthyl - 2 - methyl - 2-morpholino -, 1 - phenyl - 1 - p - xenyl - 2-methyl - 3 - morpholino-, 1 - phenyl - 1 - p-tolyl - 2 - methyl - 3 - morpholino -, 1 - phenyl-1 - o - tolyl - 2 - methyl - 3 - morpholino -, 1-b - naphthyl - 1 - cyclohexyl - 3 - dimethylamino -, 1 - veratryl - 1 - cyclohexyl - 3 - di-ethylamino -, 1 : 1 - dicyclohexyl - 3 - piperidino -, 1 - a - furyl - 1 - cyclohexyl - 3 - di-methylamino - and 1 - b - pyridyl - 1 - cyclohexyl-3-dimethylamino. Amino-ketones of the above formula where R4 is hydrogen can be prepared by the Mannich reaction, e.g. b -methylamino-propiophenone from acetophenone, formaldehyde and methylamine hydrochloride, or from b -alkyl-benzylamino-acid halides as in method (2) above, the benzyl group being removed, e.g. by catalytic hydrogenation, before or after reaction of the ketone with the organometallic compound. Amines of the formula R1R2CH-Y-NR3R4 are obtained from the amino-propanols by (1) reduction with phosphorus and hydrogen iodide; (2) dehydration to an unsaturated amine with acetic anhydride, benzoyl chloride, hydrochloric acid in acetic acid, or sulphuric acid, and catalytic hydrogenation of the product, or (3) replacing the hydroxyl group by a halogen with acetyl chloride, thionyl chloride or phosphorus tribromide, and reductively clearing the product, e.g. by catalytic hydrogenation. The production of the following 1-cyclohexyl-propanes is mentioned: 1-phenyl-2 - butyl - 3 - dibutylamino -, 1 - phenyl - 3-methylamino -, 1 - b - naphthyl - 3 - dimethylamino -, 1 - phenyl - 2 : 2 - dimethyl - 3 - piperidino -, 1 - (2 - thienyl) - 2 - methyl - 3 - diethylamino -, 1 - a - furyl - 3 - dimethylamino - and 1 - veratryl - 3 - diethylamino-. This subject-matter does not appear in the Specification as accepted.
GB2255/47A 1946-02-28 1947-01-24 Improvements in or relating to the preparation of antispasmodic agents Expired GB646198A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US646198XA 1946-02-28 1946-02-28

Publications (1)

Publication Number Publication Date
GB646198A true GB646198A (en) 1950-11-15

Family

ID=22057174

Family Applications (1)

Application Number Title Priority Date Filing Date
GB2255/47A Expired GB646198A (en) 1946-02-28 1947-01-24 Improvements in or relating to the preparation of antispasmodic agents

Country Status (3)

Country Link
DE (1) DE871899C (en)
FR (1) FR941465A (en)
GB (1) GB646198A (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2759926A (en) * 1953-01-30 1956-08-21 Basf Ag Substituted amino phenylcycloalkenyl propanols
DE1003209B (en) * 1953-03-24 1957-02-28 Basf Ag Process for the production of spasmolytically effective basic carbinols
DE1005067B (en) * 1953-03-14 1957-03-28 Knoll Ag Process for the preparation of bicyclically substituted aminopropanols
DE1183090B (en) * 1958-01-31 1964-12-10 Colgate Palmolive Co Process for the preparation of 1,4-disubstituted piperazines and their hydrochlorides

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1194424B (en) * 1961-11-10 1965-06-10 Degussa Process for the preparation of basic thiophene derivatives
DE1219038B (en) * 1962-12-08 1966-06-16 Degussa Process for the preparation of thiophene compounds

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2759926A (en) * 1953-01-30 1956-08-21 Basf Ag Substituted amino phenylcycloalkenyl propanols
DE1005067B (en) * 1953-03-14 1957-03-28 Knoll Ag Process for the preparation of bicyclically substituted aminopropanols
DE1003209B (en) * 1953-03-24 1957-02-28 Basf Ag Process for the production of spasmolytically effective basic carbinols
DE1183090B (en) * 1958-01-31 1964-12-10 Colgate Palmolive Co Process for the preparation of 1,4-disubstituted piperazines and their hydrochlorides

Also Published As

Publication number Publication date
DE871899C (en) 1953-03-26
FR941465A (en) 1949-01-12

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