US2901478A - Phenothiazine compounds - Google Patents

Phenothiazine compounds Download PDF

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Publication number
US2901478A
US2901478A US639208A US63920857A US2901478A US 2901478 A US2901478 A US 2901478A US 639208 A US639208 A US 639208A US 63920857 A US63920857 A US 63920857A US 2901478 A US2901478 A US 2901478A
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melting point
piperidyl
phenothiazine
compounds
boiling point
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US639208A
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Schuler Wilhelm Alfons
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Chemische Fabrik Promonta GmbH
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Chemische Fabrik Promonta GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the compounds of this invention may readily be prepared by reacting a compound having the formula with a compound having the formula A Y-Ofi ⁇ N-R1 ⁇ B/ III wherein R R A and B are as above defined, and Y is halogen.
  • the reaction is carried out in the presence of a basic condensing agent such as sodamide, lithium amide, sodium, sodium alcoholate, sodium hydride, and the like, and in the presence of an inert solvent such as benzene, toluene, xylene, cyclohexane, tetralin, decalin, and the like.
  • a basic condensing agent such as sodamide, lithium amide, sodium, sodium alcoholate, sodium hydride, and the like
  • an inert solvent such as benzene, toluene, xylene, cyclohexane, tetralin, decalin, and the like.
  • EXAMPLE 1 10-(1-ethyl-3-piperidyl) phenothiazine hydrochloride A mixture of 0.25 mole of phenothiazine and 0.31 mole of lithium amide in 250 ml. of tetralin is heated at -175 C. for about two hours, then 0.25 mole of lethyl-3-bromopiperidine in- 150 ml. of tetralin is added over a period of two hours at -175" C. After the addition has been completed, heating is continued at 170-175 C. for three to four hours. After cooling, the product is extracted with aqueous acetic acid and the organic layer is removed.
  • the aqueous layer is made strongly alkaline with sodium hydroxide and the organic base is extracted with ether.
  • the ether is removed, yielding 10-(l-ethyl-3-piperidyl)phenothiazine which distills at 220-225 C./2-3 mm.
  • the hydrochloride is prepared by heating the free base in aqueous hydrochloric acid and allowing the resulting liquid to cool, whereupon the desired substance is obtained, M.P. 230-231 C.
  • l0-(l-n-butyl-3-piperidyl)phenothiazine Boiling point 235-240 C./2-3 mm.; the hydrochloride is hygroscopic, and the melting point thereof cannot be determined.
  • a piperidyl substituted phenothiazine compound selected from the group consisting of compounds of the formula wherein R is lower alkyl and R is selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, and the non-toxic acid addition salts thereof.

Description

United States Patent PHENOTHIAZINE COR/[POUNDS Wilhelm Alfons Schuler, Bad Hamburg vor der Hohe, Germany, assignor to Chemische Fabrik Promonta, G.m.b.H.
No Drawing. Application February 11, 1957 Serial No. 639,208
6 Claims. (Cl. 260-243) wherein R denotes lower alkyl, R denotes hydrogen, halogen, lower alkyl or lower alkoxy. A denotes methylene or ethylene, B denotes ethylene or propylene, the sum of the number of carbon atoms contained in the radicals A and B being four. Also included in this invention are the nontoxic acid addition salts of the compounds having the above structural formula.
It is an object of this invention to provide compounds which generally depress the vital body functions such as the blood pressure and the pulse and breathing rates. Further, these compounds potentiate the physiological action of narcotics-a property which renders them extremely valuable in surgery.
The compounds of this invention may readily be prepared by reacting a compound having the formula with a compound having the formula A Y-Ofi \N-R1 \B/ III wherein R R A and B are as above defined, and Y is halogen.
The reaction is carried out in the presence of a basic condensing agent such as sodamide, lithium amide, sodium, sodium alcoholate, sodium hydride, and the like, and in the presence of an inert solvent such as benzene, toluene, xylene, cyclohexane, tetralin, decalin, and the like. The free bases obtained by the reaction described above, are converted to nontoxic acid addition salts thereof with inorganic acids or organic acids, in the usual manner.
The following example will serve to illustrate this invention:
EXAMPLE 1 10-(1-ethyl-3-piperidyl) phenothiazine hydrochloride A mixture of 0.25 mole of phenothiazine and 0.31 mole of lithium amide in 250 ml. of tetralin is heated at -175 C. for about two hours, then 0.25 mole of lethyl-3-bromopiperidine in- 150 ml. of tetralin is added over a period of two hours at -175" C. After the addition has been completed, heating is continued at 170-175 C. for three to four hours. After cooling, the product is extracted with aqueous acetic acid and the organic layer is removed. The aqueous layer is made strongly alkaline with sodium hydroxide and the organic base is extracted with ether. The ether is removed, yielding 10-(l-ethyl-3-piperidyl)phenothiazine which distills at 220-225 C./2-3 mm. The hydrochloride is prepared by heating the free base in aqueous hydrochloric acid and allowing the resulting liquid to cool, whereupon the desired substance is obtained, M.P. 230-231 C.
In a corresponding manner, the following compounds were prepared:
10-(1-methyl-4-piperidyl)phenothiazine: Boiling point.
196 C./2-3 mm.; melting point of hydrochloride 244-246 C.
10-( l-methyl-3 -piperidyl) -2-chlorophenothiazine: Boiling point 191/ 0.1 mm.; melting point of hydrochloride 203-206" C.
10( 1-methyl-3 -piperidyl -4-chlorophenothiazine: Boiling point 187-189 C./0.l8 mm.; melting point of picrate 181-183 C. (dec); melting point of hydrochloride 227-230 C. (dec).
10-(1-n-propyl-3-piperidyl)-2-methylphenothiazine: Boiling point -178 C./0.075 mm.; melting point of picrate l69-l71 C.; melting point of oxalate 178- C.
10-( l-n-propyl-3piperidyl) -3-methylphenothiazine: Boiling point 178-179 C./0.10 mm.; melting point of picrate 153-154 C.; melting point of oxalate 164- 166 C.
10( 1-n-propyl-3 -piperidyl) -4-methylphenothiazine: Boiling point 174-175 C./0.l mm.; melting point of picrate 141-143 C. (dec); melting point of oxalate 180-182 C. (dec).
10 (l propyl 3 piperidyl) 2 methoxyphenothiazine: Boiling point 208-210 C./0.4 mm.; melting point of picrate 168-171 C.
10-(l-methyl-3-piperidyl)-3-methoxyphenothiazine: Boiling point -186 C./0.06 mm.; melting point of picrate l94-196 C. (dec).
10-( 1-methyl-4-piperidyl) -2-chlorophenothiazine: Boiling point 198-200 C./2-3 mm.; hydrochloride is bygroscopic, and the melting point thereof could not be determined.
l0( 1-methyl-4-piperidyl) -4-chloropl1enothiazine: Boiling point 194-198 C./ 0.3 mm.; melting point of picrate 180-182" C. (dec); melting point of oxalate 217- 220 C. (dec).
10( 1-methyl-3 -piperidyl phenothiazine:
of hydrochloride 236-238 C.
l0-(l-n-butyl-3-piperidyl)phenothiazine: Boiling point 235-240 C./2-3 mm.; the hydrochloride is hygroscopic, and the melting point thereof cannot be determined.
Melting point Since certain changes may be made in the compounds above described without departing from the scope of this invention, it is intended that all matter contained in the above description shall be interpreted as illustrative, and not in a limiting sense.
I claim:
1. A piperidyl substituted phenothiazine compound selected from the group consisting of compounds of the formula wherein R is lower alkyl and R is selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, and the non-toxic acid addition salts thereof.
References Cited in the file of this patent UNITED STATES PATENTS Robinson et al. Mar. 25, 1952 Schuler Mar. 5, 1957 OTHER REFERENCES Nieschulz et aL: Arzneimittel Forsch, vol. 4, Apr. 1954, pp. 232, 233, 234 and 241.
Viaud: J. Pharm. Pharmacol, vol. 6 (1954), pp. 361 and 364.

Claims (1)

1. A PIPERIDYL SUBSTITUTED A PHENOTHIAZINE COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA
US639208A 1957-02-11 1957-02-11 Phenothiazine compounds Expired - Lifetime US2901478A (en)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3239514A (en) * 1956-04-18 1966-03-08 Sandoz Ltd Phenothiazine derivatives substituted by a monovalent sulfur function in 3-position
WO2002057244A1 (en) * 2001-01-19 2002-07-25 Cytokinetics, Inc. Phenothiazine kinesin inhibitors
US20030054038A1 (en) * 2001-06-22 2003-03-20 Crew Marshall D. Pharmaceutical compositions of drugs and neutralized acidic polymers
US20050009860A1 (en) * 2003-06-27 2005-01-13 Carson John R. Tricyclic delta-opioid modulators
US20060030585A1 (en) * 2004-08-05 2006-02-09 Scott Dax Tricyclic delta-opioid modulators
US20060135524A1 (en) * 2004-12-22 2006-06-22 Carson John R Tricyclic delta-opioid modulators
US20060135522A1 (en) * 2004-12-22 2006-06-22 Carson John R Tricyclic delta-opioid modulators
US20060135763A1 (en) * 2004-12-22 2006-06-22 Coats Steve J Tricyclic delta-opioid modulators
US20060148823A1 (en) * 2005-01-06 2006-07-06 Coats Steven J Tricyclic delta-opioid modulators
US20060287297A1 (en) * 2005-06-16 2006-12-21 Decorte Bart Tricyclic opioid modulators

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2590125A (en) * 1952-03-25 Quaternary-ammonium alkyl
US2784185A (en) * 1953-03-27 1957-03-05 Promonta Chem Fab Phenothiazine compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2590125A (en) * 1952-03-25 Quaternary-ammonium alkyl
US2784185A (en) * 1953-03-27 1957-03-05 Promonta Chem Fab Phenothiazine compounds

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3239514A (en) * 1956-04-18 1966-03-08 Sandoz Ltd Phenothiazine derivatives substituted by a monovalent sulfur function in 3-position
WO2002057244A1 (en) * 2001-01-19 2002-07-25 Cytokinetics, Inc. Phenothiazine kinesin inhibitors
US20040132719A1 (en) * 2001-01-19 2004-07-08 Finer Jeffrey T Phenothiazine kinesin inhibitors
US20060014736A1 (en) * 2001-01-19 2006-01-19 Cytokinetics, Inc. Phenothiazine kinesin inhibitors
US6992082B2 (en) 2001-01-19 2006-01-31 Cytokinetics, Inc. Phenothiazine kinesin inhibitors
US7119089B2 (en) 2001-01-19 2006-10-10 Cytokinetics, Inc. Phenothiazine kinesin inhibitors
US20060204577A1 (en) * 2001-06-22 2006-09-14 Crew Marshall D Pharmaceutical Compositions of Drugs and Neutralized Acidic Polymers
US20030054038A1 (en) * 2001-06-22 2003-03-20 Crew Marshall D. Pharmaceutical compositions of drugs and neutralized acidic polymers
US8147872B2 (en) 2001-06-22 2012-04-03 Bend Reseach, Inc. Pharmaceutical compositions of drugs and neutralized acidic polymers
US20060003011A1 (en) * 2001-06-22 2006-01-05 Pfizer Inc Pharmaceutical compositions of drugs and neutralized acidic polymers
US8173142B2 (en) 2001-06-22 2012-05-08 Bend Research, Inc. Pharmaceutical compositions of drugs and neutralized acidic polymers
US8350041B2 (en) 2003-06-27 2013-01-08 Janssen Pharmaceutica, Nv Tricyclic δ-opioid modulators
US20050009860A1 (en) * 2003-06-27 2005-01-13 Carson John R. Tricyclic delta-opioid modulators
US7982042B2 (en) 2003-06-27 2011-07-19 Janseen Pharmacautica NV Thiozanthene derivatives as delta-opioid modulators
US7589103B2 (en) 2003-06-27 2009-09-15 Janssen Pharmaceutica N.V. Tricyclic-bridged piperidinylidene derivatives as 8-opioid modulators
US8106207B2 (en) 2003-06-27 2012-01-31 Janssen Pharmaceutica, Nv Tricyclic δ-opioid modulators
US20090291979A1 (en) * 2004-08-05 2009-11-26 Scott Dax Tricyclic-bridged piperidinylidene derivatives as delta opioid modulators
US20060030585A1 (en) * 2004-08-05 2006-02-09 Scott Dax Tricyclic delta-opioid modulators
US7553850B2 (en) 2004-08-05 2009-06-30 Janssen Pharmaceutica Nv Tricyclic-bridged piperidinylidene derivatives as δ-opioid modulators
US20060135524A1 (en) * 2004-12-22 2006-06-22 Carson John R Tricyclic delta-opioid modulators
US20080306111A1 (en) * 2004-12-22 2008-12-11 Carson John R Tricyclic delta- opioid modulators
US7439239B2 (en) 2004-12-22 2008-10-21 Janssen Pharmaceutica N.V. Tricyclic δ- opioid modulators
US20100093709A1 (en) * 2004-12-22 2010-04-15 Coats Steven J Tricyclic delta opioid modulators
US7589104B2 (en) 2004-12-22 2009-09-15 Janssen Pharmaceutica Nv Tricyclic-bridged piperidinyline derivatives as §-opioid modulators
US20060135522A1 (en) * 2004-12-22 2006-06-22 Carson John R Tricyclic delta-opioid modulators
US20060135763A1 (en) * 2004-12-22 2006-06-22 Coats Steve J Tricyclic delta-opioid modulators
US7652005B2 (en) 2004-12-22 2010-01-26 Janssen Pharmaceutica N.V. Tricyclic δ-opioid modulators
US7432257B2 (en) * 2005-01-06 2008-10-07 Janssen Pharmaceutica N.V. Piperdinyl-phenoxazine and phenothiazine derivatives as δ-opioid modulators
US20080318937A1 (en) * 2005-01-06 2008-12-25 Coats Steven J Tricyclic delta-opioid modulators
US20060148823A1 (en) * 2005-01-06 2006-07-06 Coats Steven J Tricyclic delta-opioid modulators
US20090275610A1 (en) * 2005-06-16 2009-11-05 Decorte Bart Tricyclic opioid modulators
US7582650B2 (en) 2005-06-16 2009-09-01 Janssen Pharmaceutica N.V. Tricyclic opioid modulators
US20060287297A1 (en) * 2005-06-16 2006-12-21 Decorte Bart Tricyclic opioid modulators

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