US2676971A - Quaternary ammonium derivatives of aminoalkylxanthenes and aminoalkylthiaxanthenes - Google Patents

Quaternary ammonium derivatives of aminoalkylxanthenes and aminoalkylthiaxanthenes Download PDF

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US2676971A
US2676971A US222294A US22229451A US2676971A US 2676971 A US2676971 A US 2676971A US 222294 A US222294 A US 222294A US 22229451 A US22229451 A US 22229451A US 2676971 A US2676971 A US 2676971A
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John W Cusic
Richard A Robinson
Clinton A Dornfeld
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GD Searle LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/90—Xanthenes with hydrocarbon radicals, substituted by amino radicals, directly attached in position 9

Definitions

  • the present invention relates to a new type of quaternary ammonium salts, and more particularly to those of aminoalkyl derivatives of xanthene and thiaxanthene, wherein the aminoalkyl radical is attached to the methylene radical in the 9-position of the central ring.
  • the compounds which constitute our invention are represented by the structural formula and include such radicals as ethylene, propylene,
  • radicals which R, R, and R" represent are such lower alkyl groups as methyl, ethyl, propyl, butyl, amyl and hexyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyamyl, hydroxythexyl, wherein the propyl, butyl, amyl, and hexyl groups may be either of the straight-chain or branchedchain type.
  • radicals may be of unsaturated type as in the case of allyl, crotyl, methallyl, other butenyls, pentenyls and the likev
  • the radical NRR' may also be a nitrogen-containing hetermonocyclic radical such as piperidine, lupetidine, pyrrolidine, morpholine, thiamorpholine, piperazine, N-alkylpiperazine and the like.
  • the radical Z represents one equivalent of an anion such as fluoride, bromide, chloride, iodide, sulfate, phosphate, citrate, oxalate, benzenesulfonate, ascorbate and sulfamate.
  • the tertiary bases are converted to compounds of a different and highly valuable therapeutic activity.
  • the quaternary salts which constitute this invention are active cardiovascular agents capable of producing a pronounced degree of vasodilatation and of decreasing pathologic levels of blood pressure. They are active in preventing the transmission of sympathetic and parasympathetic autonomic nerve impulses through the ganglia.
  • EXAMPLE 1 p- (9-ranthyl) ethyltrimethylammonium chloride To an ether solution of n-butyl lithium, prepared from 832 parts of n-butyl chloride and 126 parts of lithium, 546 parts of xanthene are added 'portionwise, and the mixture is heated at isflux temperature for one hour. Then 432 parts of the hydrochloride of (p-chloroethyl) dimethylamine are added gradually. When the vigorous reaction subsides, the mixture is heated at reflux temperature for 12 hours. After cooling, it is treated with dilute hydrochloric acid. The aqueous layer is separated, rendered alkaline by addition of sodium hydroxide and extracted with ether.
  • the ether extract is dried over anhydrous potassium carbonate, filtered, and evaporated.
  • the Q-(B-dimethylaminoethyl) xanthene is distilled at about -180" C. at 2-3 mm. pressure. Its hydrochloride melts at about 183-185 C.
  • the hydrochloride oi 9(cdimethylaminopropyl)xanthene precipitates from the aqueous solution. It is collected on a filter and dried in vacuum at 65 C. for several hours. The crystals melt at about 255-256 C.
  • An aqueous solution or" the hydrochloride is rendered alkaline by the addition of sodium hydroxide and extracted with ether. The ether extract is dried over anhydrous potassium carbonate, filtered, and evaporated.
  • the aqueous layer is separated, rendered alkaline with sodium hydroxide and extracted with ether.
  • the extract is dried over anhydrous potassium carbonate, filtered, and evaporated.
  • the 9-(fi-diisopropylaminoethyhxanthene is distilled at about l6l-l63 C. and 1.5 mm. pressure.
  • 160 parts of the distillate are heated in a sealed pressure reactor with 228 parts of methyl iodide in 600 parts of butanone at C. for one hour. After storage at room temperature for several hours, precipitation occurs. The precipitate is collected on a filter.
  • the ,6-(9xanthyl)ethyldiisopropylmethylarnmonium iodide melts at about 193-124: C. with decomposition.
  • the extract is dried over anhydrous potassium carbonate, filtered, and evaporated.
  • the 9-(fi-dimethylaminoethyl)thiaxanthene is then distilled at l80-18 C. and 2 mm. pressure.
  • the hydrochloride of this base melts at about 203-204 C. it is advantageous to carry out this reaction under nitrogen.
  • the combined toluene solutions are extracted with dilute hydrochloric acid.
  • the aqueous layer is separated, rendered alkaline by the addition of sodium hydroxide, and extracted with ether.
  • the ether extract is dried over anhydrous potassium carbonate, filtered, and evaporated.
  • the 9-(ethylmethylaminoethyl)thiaxanthene is distilled at about l70 C. and 0.4 mm. pressure.

Description

Patented Apr. 27, 1954 UNITED STATES ATENT OFFICE QUATERNARY AMMONIUM DERIVATIVES F AMINOALKYLXANTHENES AND AMINO- ALKYLTHIAXANTHENES No Drawing. Application April 21, 1951, Serial No. 222,294
12 Claims.
The present invention relates to a new type of quaternary ammonium salts, and more particularly to those of aminoalkyl derivatives of xanthene and thiaxanthene, wherein the aminoalkyl radical is attached to the methylene radical in the 9-position of the central ring. The compounds which constitute our invention are represented by the structural formula and include such radicals as ethylene, propylene,
butylene, amylene, hexylene, and polymethylenes from trimethylene to octamethylene. Among the radicals which R, R, and R" represent are such lower alkyl groups as methyl, ethyl, propyl, butyl, amyl and hexyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyamyl, hydroxythexyl, wherein the propyl, butyl, amyl, and hexyl groups may be either of the straight-chain or branchedchain type. Further, these radicals may be of unsaturated type as in the case of allyl, crotyl, methallyl, other butenyls, pentenyls and the likev The radical NRR' may also be a nitrogen-containing hetermonocyclic radical such as piperidine, lupetidine, pyrrolidine, morpholine, thiamorpholine, piperazine, N-alkylpiperazine and the like. The radical Z represents one equivalent of an anion such as fluoride, bromide, chloride, iodide, sulfate, phosphate, citrate, oxalate, benzenesulfonate, ascorbate and sulfamate.
Certain of the starting materials for the compounds which constitute this invention are the subject of U. S. Patent No. 2,368,006 of John W. I
Cusic issued January 23, 1945. The tertiary bases of the type described in this patent are quaternized by treatment with organic esters of sul-= furic, hydrohalic, aromatic sulfonic and related acids. Among such esters are the methyl halides, ethyl halides, propyl halides, isopropyl halides, and other alkyl halides, benzyl halides, phenethyl halides, naphthylmethyl halides, dimethyl 2 sulfate, diethyl sulfate, methyl benzenesulfonate, ethyl toluenesulfonate, ethylene chlorohydrin, propylene chlorohydrins, and related alkylene halohydrins, allyl halides, methallyl halides and crotyl halides.
By this quaternization process, the tertiary bases are converted to compounds of a different and highly valuable therapeutic activity. Thus the quaternary salts which constitute this invention are active cardiovascular agents capable of producing a pronounced degree of vasodilatation and of decreasing pathologic levels of blood pressure. They are active in preventing the transmission of sympathetic and parasympathetic autonomic nerve impulses through the ganglia.
My invention will be described more fully in conjunction with the following examples. It will be understood, however, that these examples are given by way of illustration only, and that the invention is not to be construed as limited in spirit or in scope by the details set forth. It will be apparent to chemists skilled in the art of organic synthesis that many modifications in materials, conditions and methods may be made without departing from the invention. In each of these examples, temperatures are given in degrees centigrade (C.), amounts of materials in parts by weight, and pressures during vacuum distillation in millimeters (mm) of mercury.
EXAMPLE 1 p- (9-ranthyl) ethyltrimethylammonium chloride To an ether solution of n-butyl lithium, prepared from 832 parts of n-butyl chloride and 126 parts of lithium, 546 parts of xanthene are added 'portionwise, and the mixture is heated at isflux temperature for one hour. Then 432 parts of the hydrochloride of (p-chloroethyl) dimethylamine are added gradually. When the vigorous reaction subsides, the mixture is heated at reflux temperature for 12 hours. After cooling, it is treated with dilute hydrochloric acid. The aqueous layer is separated, rendered alkaline by addition of sodium hydroxide and extracted with ether. The ether extract is dried over anhydrous potassium carbonate, filtered, and evaporated. The Q-(B-dimethylaminoethyl) xanthene is distilled at about -180" C. at 2-3 mm. pressure. Its hydrochloride melts at about 183-185 C.
370 parts of the base are reacted at room temperature with 129 parts of methyl chloride in 710 parts of acetone in a shielded pressure reactor. An oil separates which on treatment with anhydrous ether crystallizes within a few minutes. It is filtered, washed with ether and dried in vacuo over sodium hydroxide. The e-(Q-xanthyl) -ethyltrimethylamrnonium chloride melts at about l80-l9i C. It has the structural formula:
[3- (Q-mzmthyl) propyldimethylhydroxyethylammom'um bromide To a mixture of 300 parts of xanthene, 130 parts of sodarnide and 1700 parts of anhydrous toluene, 260 parts of the hydrochloride of (echloropropyl)diinethylamine are added in the course of one hour while the temperature is maintained at 160 C. There is a slow evolution of ammonia. The mixture is stirred at reflux temperature for 12 hours and then filtered while hot with the aid of a filter aid. The residue is collected on the filter and washed with additional toluene. The combined toluene solutions are cooled and extracted with cold dilute hydrochloric acid. The hydrochloride oi 9(cdimethylaminopropyl)xanthene precipitates from the aqueous solution. It is collected on a filter and dried in vacuum at 65 C. for several hours. The crystals melt at about 255-256 C. An aqueous solution or" the hydrochloride is rendered alkaline by the addition of sodium hydroxide and extracted with ether. The ether extract is dried over anhydrous potassium carbonate, filtered, and evaporated.
175 parts of the base thus obtained are heated with 9() parts of ethylene bromohydrin in 400 parts of butanone at reflux temperature for 3 hours and then. chilled at 0 C. After decantation of the supernatant liquid, the oil is stirred repeatedly with anhydrous ether, and the ether decanted. After drying, the ,B-(Q-xanthyDpropyldimethylhydroxyethyl bromide is obtained as a colorless material with no sharp melting point. It has the structural formula:
( H CHz-OH h-GHr-CHrOEBr CH3 CH:
EXAMPLE 3 [-3- (Qmanthyl) ethyldiethylmethylammonium methosulfate A mixture of 910 parts of xanthene, 150 parts of lithium and 2600 parts of anhydrous xylene is stirred and heated to about 110 C. A xylene solution of 813 parts of (fi-chloroethyl) diethylainine is added dropwise and the ten perature maintained at 110 C. for 12 hours. The reaction mixture is then filtered, and the filtrate extracted with dilute hydrochloric acid. The aqueous layer is separated, rendered alkaline by addition of sodium hydroxide and extracted with ether. The ether extract is dried over anhydrous potassium carbonate, filtered, and evaporated. The product boils at about i ls-152 C. and 1 mm. pressure. An alternate procedure is given in U. S. Patent No. 2,368,005 of John W. Cusic, which was issued January 23, 1945,
100 parts or" the base thus obtained are mixed with 133 parts of dimethyl sulfate in 400 parts of butanone and then stored at 0 C. for 4 hours. Upon addition of ether and further chilling a White precipitate forms which is collected on a filter and washed well with ether. The [3-(9- xanthyl)ethyldiethylmethylammonium methosulfate melts at about 120-121 C. It has the structural formula:
EXAMPLE 4 [3- (Q-xanthyl) ethyZdiisopropylmethylammonium iodide A solution of hutyl lithium in 7000 parts of ether is prepared from 84 parts of lithium wire and 555 parts of n-hutyl chloride. Addition of 384 parts of xanthene in portions results in the formation of an orange color. After refluxing for one hour, 400 parts 01' the hydrochloride of (,B-chloroethyl) diisoprop-ylamine are added gradually at such a rate as the vigorous reaction permits. After heating at reflux temperature for 10 hours, the cooled mixture is treated with dilute hydrochloric acid. The aqueous layer is separated, rendered alkaline with sodium hydroxide and extracted with ether. The extract is dried over anhydrous potassium carbonate, filtered, and evaporated. The 9-(fi-diisopropylaminoethyhxanthene is distilled at about l6l-l63 C. and 1.5 mm. pressure.
160 parts of the distillate are heated in a sealed pressure reactor with 228 parts of methyl iodide in 600 parts of butanone at C. for one hour. After storage at room temperature for several hours, precipitation occurs. The precipitate is collected on a filter. The ,6-(9xanthyl)ethyldiisopropylmethylarnmonium iodide melts at about 193-124: C. with decomposition.
C Jjoruonm EXANIPLE 5 e- (Q-thz'aranthyl) ethyltrimethylammonium chloride An ether solution of butyl lithium is prepared 1 from parts of 11-butyl chloride and 18.2 parts of lithium, heated for one hour at reflux temperature and then treated With 99 parts of thiaxanthene. After refluxing for one hour, '72 parts of the hydrochloride of (fi-chloroethyl)dimethylamine are added gradually at such a rate as the vigorous reaction permits. After refluxing for 10 hours, the mixture is cooled and treated with dilute hydrochloric acid. The aqueous layer is separated, rendered alkaline ith sodium hydroxide, and extracted With ether. The extract is dried over anhydrous potassium carbonate, filtered, and evaporated. The 9-(fi-dimethylaminoethyl)thiaxanthene is then distilled at l80-18 C. and 2 mm. pressure. The hydrochloride of this base melts at about 203-204 C. it is advantageous to carry out this reaction under nitrogen.
parts of the base are sealed with 120 parts of methyl chloride in 800 parts of acetone in a P11355111? eactor and stored for 12 hours at room temperature. The reaction mixture is poured on an equivalent amount of anhydrous ether, Crystallization occurs within a short time. The crystals are collected on a filter, washed with anhydrous ether and dried in vacuo over sodium hydroxide. The 18 9 thiaxanthyDethyltrimethylammonium chloride melts at approximately 210 .C'. It has the structural formula EXAMPLE 6 5-(9 thiaxmithyl)ethyldimethyl (fi-hydroryethylmmmom'um bromide EXAMPLE 7 ,6- Q-thiaxanthyl) propyldimethylallylammonium iodide A solution of sodamide (prepared from 69 parts of sodium), 600 parts of thiaxanthene, and 2200 parts of anhydrous toluene is treated with 473 parts of the hydrochloride of (fi-chloropropyl) dimethylamine, and the mixture is heated at reflux temperature for 12 hours. The mixture is filtered while still hot, and the filtrate cooled in an ice bath. Any precipitate of thiaxanthene is removed by filtration, and the filtrate is extracted with dilute hydrochloric acid. The ex tract is made alkaline and extracted with ether. The ether solution is dried over anhydrous potassium carbonate, filtered, and evaporated. The 9-(dimethylaminopropyl)thiaxanthene is distilled at about 147-153" C. and 0.4 mm. pressure.
283 parts of the distillate are heated with 185 parts of allyl iodide in butanone solution for one hour at 90 C. The mixture is then chilled, whereupon an oil separates which solidifies upon treatment with anhydrous ether. It has the structural formula:
HCHz-(JHN-CH2-CH=CH:.I O on! om EXAMPLE 8 p (9 thiaazanthyl)ethylbenzylethylmethylammom'um bromide A mixture of sodamide (prepared from 138 parts of sodium), 600 parts of thiaxanthene and 2200 parts of anhydrous toluene is treated portionwise with 4'73 parts of the hydrochloride of (fi-chloroethyl) ethylmethylamine. The addition is carried out at a temperature of about C. The mixture is then heated at reflux temperature for 4 hours and then at 90 C. for 12 hours. It is filtered and the residue washed with toluene. The combined toluene solutions are extracted with dilute hydrochloric acid. The aqueous layer is separated, rendered alkaline by the addition of sodium hydroxide, and extracted with ether. The ether extract is dried over anhydrous potassium carbonate, filtered, and evaporated. The 9-(ethylmethylaminoethyl)thiaxanthene is distilled at about l70 C. and 0.4 mm. pressure.
85 parts of the distillate are heated with 56 parts of benzyl bromide in 400 parts of butanone at reflux temperature for 2 hours and then chilled. The separating oil is isolated and treated with anhydrous ether, whereupon a white solid is obtained. The B(9-thiaxanthyl)ethylbenzylethylmethylammonium bromide has the structural formula:
We claim: 1. The quaternary salts of the structural formula I Q Z wherein X is an element of periodic group VI of a molecular weight below 40, alk is a lower alkylene radical containing at least two carbon atoms and Z is one equivalent of an anion.
3. The (9 xanthyl) alkyltrialkylammonium salts of the structural formula lower alkyl low er alkyl 6 a1kN C 1 lower alkyl wherein alk is a lower alkylene radical containing at least two carbon atoms and Z is one equivalent of an anion.
lower alkyl lower alkyl lower alkyl b CHalk-N lower alkyl wherein all: is a lower alkylene radical containing at least two carbon atoms and Z is one equivalent of an anion.
9. The ,8 9-thiaxanthyl) ethyltri-lower-alkylammonium salts.
10. The 549 thiaxanthyl)ethyltrimethylammonium salts.
11. The quaternary ammonium salts of the structural formula lower alkyl 1 lower alkyl H-alk- N Z I 5- (9-xanthyl) ethyltri-lower-alkylam- 8 wherein X is an element of periodic group VI of a molecular weight below 40, alk is a lower alkylene radical containing at least two carbon atoms, R is a hydroxylated lower alkyl radical and Z is one equivalent of an anion.
12. The (9-xanthyl) ethylhydroxyethyldi-lower-alkylammonium salts.
References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,368,006 Cusic Jan. 23, 1945 2,512,307 Clinton et al June 20, 1950 FOREIGN PATENTS Number Country Date 618,034 Great Britain Feb. 15, 1949 OTHER REFERENCES Wheatley et al., JACS vol. 72, Dec. 1950 (5575-5577).
Jensen et al., Acta Chemica Scandinavica 2 (1948), 381-384.
Hackhs Chem. Diet, 3rd ed. Blakiston Co.
Chemical Abstracts, vol. 34, p. 5363 1940.

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1. THE QUATERNARY SALTS OF THE STRUCTURAL FORMULA FORMULA
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Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1044103B (en) * 1956-06-12 1958-11-20 Hoffmann La Roche Process for the production of xanthene or thioxanthene derivatives
US2902484A (en) * 1954-04-27 1959-09-01 Rhone Poulenc Sa Phenthiazine derivatives and processes for their preparation
US2940969A (en) * 1957-07-18 1960-06-14 American Cyanamid Co 1-substituted-4-[3-(9-xanthylidene)-propyl] piperazines and 1-substituted-4-[3-(10-thiaxanthylidene) propyl]-piperazines
US2947747A (en) * 1959-06-08 1960-08-02 Smith Kline French Lab Trifluoromethyl substituted phenoxazines
US2947745A (en) * 1958-08-11 1960-08-02 Smith Kline French Lab Substituted phenoxazine sedative agents
US2951082A (en) * 1956-07-09 1960-08-30 Merck & Co Inc Substituted thiaxanthenes
US2956060A (en) * 1953-01-07 1960-10-11 Wander Ag Dr A Xanthene derivatives and process of making same
US2956996A (en) * 1960-10-18 Alkylated phenotfflazenecarboxamede
US2969358A (en) * 1958-12-08 1961-01-24 Searle & Co 2-chloro-10-phenothiazinecarbonylpiperazines
US3000885A (en) * 1958-08-07 1961-09-19 Searle & Co 2-acyl-10-oxyalkylpiperidinoalkylphenothiazines and process
US3025291A (en) * 1958-10-02 1962-03-13 Searle & Co Nu-hydroxyalkylpiperidinoalkyl-2-chloro-10-phenothiazinecarboxamides and process
US3075976A (en) * 1957-10-21 1963-01-29 Rhone Poulenc Sa Phenthiazine derivatives
US3079390A (en) * 1958-12-12 1963-02-26 Searle & Co N-substituted 3-amino-1, 2, 4-benzotriazine-1-oxides
US3082208A (en) * 1958-07-07 1963-03-19 Sterling Drug Inc 10-[(1-piperidyl)lower-alkyl]-loweralkanoylphenothiazines
US3094526A (en) * 1957-08-23 1963-06-18 Sterling Drug Inc 10-[(3-and 4-hydroxy-1-piperidyl) loweralkyl phenothiazines
US3100207A (en) * 1959-07-08 1963-08-06 Smith Kline French Lab 10-aminoalkylbenzo[b,f]thiepin and -dibenz[b,f]oxepin derivatives
US3133068A (en) * 1957-05-09 1964-05-12 Geigy Chem Corp 5-substituted dibenz[b, f] azepine compounds
US3162637A (en) * 1960-03-14 1964-12-22 Colgate Palmolive Co Piperazinoalkyl esters of 9-hydroxyfluorene-9-carboxylic acid
US3179564A (en) * 1961-02-23 1965-04-20 Wander Ag Dr A Antirigor thioxanthenes
US3193549A (en) * 1958-07-07 1965-07-06 Sterling Drug Inc 10-[(1-piperidyl)lower-alkyl]-trifluoromethylphenothiazines
US3236854A (en) * 1961-09-08 1966-02-22 Rhone Poulenc Sa Azathioxanthene derivatives
US3258488A (en) * 1963-08-12 1966-06-28 Colgate Palmolive Co Dibenzo[a, d]cycloheptene derivatives
US3285919A (en) * 1961-05-10 1966-11-15 Sahyun Melville Piperazinyl alkyl thiaxanthene derivatives
US3359263A (en) * 1962-10-19 1967-12-19 Koninklijke Pharma Fab Nv Nu-substituted-1-phenyl-2-aminopropanes
US3409614A (en) * 1965-07-23 1968-11-05 Smith Kline French Lab Phenoxazinyl aminocyclopropanes
US3409640A (en) * 1959-07-22 1968-11-05 Schering Corp 5-(3'-dimethylamino-2'-methyl-propyl)dibenzocycloheptenes
US3436391A (en) * 1962-01-26 1969-04-01 Kefalas As Dihydroanthracene compounds
US3475427A (en) * 1966-02-03 1969-10-28 Smithkline Corp Phenoxazines
US3609167A (en) * 1962-04-02 1971-09-28 Smith Kline French Lab IBENZO{8 b,e{9 {0 THIEPINES
WO1997046549A1 (en) * 1996-06-05 1997-12-11 Novartis Ag Anti-neurodegeneratively effective xanthene derivatives
JP2014533264A (en) * 2011-11-15 2014-12-11 イッサム リサーチ デベロップメント カンパニー オブ ザ ヘブリュー ユニバーシティー オブ エルサレム リミテッド Tricyclic compounds, compositions containing them and their use

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Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2956996A (en) * 1960-10-18 Alkylated phenotfflazenecarboxamede
US2956060A (en) * 1953-01-07 1960-10-11 Wander Ag Dr A Xanthene derivatives and process of making same
US2902484A (en) * 1954-04-27 1959-09-01 Rhone Poulenc Sa Phenthiazine derivatives and processes for their preparation
DE1044103B (en) * 1956-06-12 1958-11-20 Hoffmann La Roche Process for the production of xanthene or thioxanthene derivatives
US2951082A (en) * 1956-07-09 1960-08-30 Merck & Co Inc Substituted thiaxanthenes
US3133068A (en) * 1957-05-09 1964-05-12 Geigy Chem Corp 5-substituted dibenz[b, f] azepine compounds
US2940969A (en) * 1957-07-18 1960-06-14 American Cyanamid Co 1-substituted-4-[3-(9-xanthylidene)-propyl] piperazines and 1-substituted-4-[3-(10-thiaxanthylidene) propyl]-piperazines
US3094526A (en) * 1957-08-23 1963-06-18 Sterling Drug Inc 10-[(3-and 4-hydroxy-1-piperidyl) loweralkyl phenothiazines
US3075976A (en) * 1957-10-21 1963-01-29 Rhone Poulenc Sa Phenthiazine derivatives
US3082208A (en) * 1958-07-07 1963-03-19 Sterling Drug Inc 10-[(1-piperidyl)lower-alkyl]-loweralkanoylphenothiazines
US3193549A (en) * 1958-07-07 1965-07-06 Sterling Drug Inc 10-[(1-piperidyl)lower-alkyl]-trifluoromethylphenothiazines
US3000885A (en) * 1958-08-07 1961-09-19 Searle & Co 2-acyl-10-oxyalkylpiperidinoalkylphenothiazines and process
US2947745A (en) * 1958-08-11 1960-08-02 Smith Kline French Lab Substituted phenoxazine sedative agents
US3025291A (en) * 1958-10-02 1962-03-13 Searle & Co Nu-hydroxyalkylpiperidinoalkyl-2-chloro-10-phenothiazinecarboxamides and process
US2969358A (en) * 1958-12-08 1961-01-24 Searle & Co 2-chloro-10-phenothiazinecarbonylpiperazines
US3079390A (en) * 1958-12-12 1963-02-26 Searle & Co N-substituted 3-amino-1, 2, 4-benzotriazine-1-oxides
US2947747A (en) * 1959-06-08 1960-08-02 Smith Kline French Lab Trifluoromethyl substituted phenoxazines
US3100207A (en) * 1959-07-08 1963-08-06 Smith Kline French Lab 10-aminoalkylbenzo[b,f]thiepin and -dibenz[b,f]oxepin derivatives
US3409640A (en) * 1959-07-22 1968-11-05 Schering Corp 5-(3'-dimethylamino-2'-methyl-propyl)dibenzocycloheptenes
US3162637A (en) * 1960-03-14 1964-12-22 Colgate Palmolive Co Piperazinoalkyl esters of 9-hydroxyfluorene-9-carboxylic acid
US3179564A (en) * 1961-02-23 1965-04-20 Wander Ag Dr A Antirigor thioxanthenes
US3285919A (en) * 1961-05-10 1966-11-15 Sahyun Melville Piperazinyl alkyl thiaxanthene derivatives
US3236854A (en) * 1961-09-08 1966-02-22 Rhone Poulenc Sa Azathioxanthene derivatives
US3436391A (en) * 1962-01-26 1969-04-01 Kefalas As Dihydroanthracene compounds
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WO1997046549A1 (en) * 1996-06-05 1997-12-11 Novartis Ag Anti-neurodegeneratively effective xanthene derivatives
JP2014533264A (en) * 2011-11-15 2014-12-11 イッサム リサーチ デベロップメント カンパニー オブ ザ ヘブリュー ユニバーシティー オブ エルサレム リミテッド Tricyclic compounds, compositions containing them and their use

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