US2775595A - Chzohz - Google Patents
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- US2775595A US2775595A US2775595DA US2775595A US 2775595 A US2775595 A US 2775595A US 2775595D A US2775595D A US 2775595DA US 2775595 A US2775595 A US 2775595A
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- United States
- Prior art keywords
- diaza
- anthracene
- gms
- methoxy
- hydroxy
- Prior art date
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- -1 9-SUBSTITUTED 1.10-DIAZA-ANTHRACENE Chemical class 0.000 claims description 26
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 34
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 28
- 125000004432 carbon atoms Chemical group C* 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 150000001875 compounds Chemical class 0.000 description 20
- 239000000203 mixture Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 14
- 150000003839 salts Chemical class 0.000 description 14
- 239000011780 sodium chloride Substances 0.000 description 14
- 125000003545 alkoxy group Chemical group 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 12
- 125000005843 halogen group Chemical group 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 10
- 125000001309 chloro group Chemical group Cl* 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 238000009835 boiling Methods 0.000 description 8
- QUSNBJAOOMFDIB-UHFFFAOYSA-N ethyl amine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- QWBBPBRQALCEIZ-UHFFFAOYSA-N 2,3-Dimethylphenol Chemical compound CC1=CC=CC(O)=C1C QWBBPBRQALCEIZ-UHFFFAOYSA-N 0.000 description 6
- WGYKZJWCGVVSQN-UHFFFAOYSA-N Propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000003610 charcoal Substances 0.000 description 6
- 150000001896 cresols Chemical class 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 6
- 239000012442 inert solvent Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- MQKHDOIYZNMNCO-UHFFFAOYSA-N 10-chloro-2-methoxybenzo[b][1,5]naphthyridine Chemical compound C1=CC=CC2=C(Cl)C3=NC(OC)=CC=C3N=C21 MQKHDOIYZNMNCO-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- KHPZCNJKNIHKPI-UHFFFAOYSA-N 7,10-dichloro-2-methoxybenzo[b][1,5]naphthyridine Chemical compound C1=C(Cl)C=CC2=C(Cl)C3=NC(OC)=CC=C3N=C21 KHPZCNJKNIHKPI-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 4
- 125000004429 atoms Chemical group 0.000 description 4
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 230000000875 corresponding Effects 0.000 description 4
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 125000006308 propyl amino group Chemical group 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N 1,2-ethanediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- WWVCYITZVMBKKZ-UHFFFAOYSA-N 2-butoxy-7,10-dichlorobenzo[b][1,5]naphthyridine Chemical compound C1=C(Cl)C=CC2=C(Cl)C3=NC(OCCCC)=CC=C3N=C21 WWVCYITZVMBKKZ-UHFFFAOYSA-N 0.000 description 2
- IGZHANSFKZYWKS-UHFFFAOYSA-N 7-chloro-2-methoxy-10-phenoxybenzo[b][1,5]naphthyridine Chemical compound C12=NC(OC)=CC=C2N=C2C=C(Cl)C=CC2=C1OC1=CC=CC=C1 IGZHANSFKZYWKS-UHFFFAOYSA-N 0.000 description 2
- LHIJANUOQQMGNT-UHFFFAOYSA-N Aminoethylethanolamine Chemical compound NCCNCCO LHIJANUOQQMGNT-UHFFFAOYSA-N 0.000 description 2
- GYHSTFALDNABOJ-UHFFFAOYSA-N COC1=NC2=C(OC3=CC=CC=C3)C3=CC=CC=C3N=C2C=C1 Chemical compound COC1=NC2=C(OC3=CC=CC=C3)C3=CC=CC=C3N=C2C=C1 GYHSTFALDNABOJ-UHFFFAOYSA-N 0.000 description 2
- UYSXBJCNACEATD-UHFFFAOYSA-N Cl.Cl.N1=NC=CC2=CC3=CC=CC=C3C=C12 Chemical compound Cl.Cl.N1=NC=CC2=CC3=CC=CC=C3C=C12 UYSXBJCNACEATD-UHFFFAOYSA-N 0.000 description 2
- HKYWGNXRHCQJNK-UHFFFAOYSA-N ClC1=NC2=C(C3=CC=CC=C3N=C2C=C1)OC1=CC=CC=C1 Chemical compound ClC1=NC2=C(C3=CC=CC=C3N=C2C=C1)OC1=CC=CC=C1 HKYWGNXRHCQJNK-UHFFFAOYSA-N 0.000 description 2
- 241000333074 Eucalyptus occidentalis Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- SOIJWBIPWKSGET-UHFFFAOYSA-N anthracene;dihydrochloride Chemical compound Cl.Cl.C1=CC=CC2=CC3=CC=CC=C3C=C21 SOIJWBIPWKSGET-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000006309 butyl amino group Chemical group 0.000 description 2
- 239000003518 caustics Substances 0.000 description 2
- 230000005591 charge neutralization Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000005712 crystallization Effects 0.000 description 2
- 125000004990 dihydroxyalkyl group Chemical group 0.000 description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 239000012433 hydrogen halide Substances 0.000 description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 2
- 125000004888 n-propyl amino group Chemical group [H]N(*)C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000001264 neutralization Effects 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 201000001181 parasitic helminthiasis infectious disease Diseases 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- 201000004409 schistosomiasis Diseases 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- R is an alkoxy group having one to six carbon atoms and preferably containing not more than four carbon atoms
- Y is a hydrogen or halogen atom
- R is a monoor di-hydroxy alkyl group having at least two but not more than six carbon atoms, and preferably containing not more than four carbon atoms
- n is an integer having a minimum value of two and a maximum value of six, and is preferably two, three or four.
- the invention also includes the acid salts of the said 9-substituted- 1 .10-diaza-anthracenes.
- the said 9-substituted-1.l0-diaza-anthracenes are produced by heating a 9-substituted-1.IO-diaza-anthracene having, in one tautomeric form, the general formula NH2.(CH2)n.NHR'
- the 1.10-diaza-anthracenes which form the starting material for the present process and contain a halogen 2,775,595 a ented ec. 2.5,
- the 9-phenoxy compounds may be produced from the 9-halogeno compounds by heating the latter with phenol, a cresol, a xylenol or other polyalkylphenol or a mixture of two or more of such compounds.
- the resulting 9-phenoxy compound or mixture of 9-phenoxy compounds may be used as produced in situ or may be first isolated if desired.
- the reaction may be carried out in the presence of an inert solvent: in the case of the 9-phenoxy compounds an excess of the phenol or phenols used to produce the compound or compounds may constitute the inert solvent.
- hydroxy amines having the general forrnula NHz(CH2)n.NHR which may be employed include 2 (2' hydroxyethylamino) ethylamine, 3 (2 hydroxyethylamino) n propylamine, 2 (2 hydroxyn propylamino) ethylamine, 3 (2 hydroxy n propylamino) propylamine, 3 (3" hydroxy n butylamino) n propylamine, 2 (2 hydroxy iso butylamino) ethylamine, 2 (2.3' dihydroxy n propylamino) ethylamine and 3 (2.3' dihydroxy 11 propylamino) n propylarnine.
- the 9-halogeno-Ll0-diazaanthracene may be heated with the hydroxy amine having the general formula NH2(CH2)n,NHR' in the presence or absence of an inert solvent.
- the phenoxy compound may be first prepared by heating the 9-haloge'no-L10- diaza-anthracene with phenol, a cresol, a xylenol or other polyalkylphenol or a mixture of two or more such compounds and the hydroxyamine then added or alternatively the phenol and the hydroxyamine may be heated together with the 9-halogeno-1.10-diaza-anthracene.
- the phenoxy compound may be prepared as outlined above and isolated before heating with the hydroxyamine.
- the new compounds in the form of the free bases may be isolated by pouring the cooled reaction mixture into an excess of aqueous caustic alkali, separating the product and crystallizing from a suitable solvent.
- the free bases may also be produced by neutralization of their hydrohalide salts. They can be crystallized from basic solvents such as pyridine and the alkyl pyridines.
- the new compounds in the form of their hydrohalide salts may be readily isolated from reaction mixtures in which the 9-halogeno1.l0sdiazo-anthracene has been heated with the hydroxyamine in the presence or absence of a phenol, cresol, xylenol or mixture of two or more such compounds by pouring the cooled reaction mixture into a large volume of anhydrous ether, acetone or methyl ethyl ketone and collecting the precipitate of the monohydrohalide of the base.
- the monohydrohalide may be readily recrystallized from the corresponding dilute aqueous hydrogen halide to yield the dihydrohalide of the base and may also containone or more molecules of water of crystallization. Since it is preferred to employ the 9-chloro-LIOTdiaZa-anthracene in the process this method readily lends itself to the production of the monoand di-hydrochlorides of the new bases.
- the new compounds and their salts have been found to possess valuable pharmacological properties. They are useful in the treatment of a variety of helminth infections both in human beings and in animals and are of low toxicity.
- Example 1 28. gms. of 2-methoxy-.6.9-dichloro-1.IO-diaza-anthracene is heated with 100 gms. of dry phenol for 1 hour. To the resulting reaction mixture is added 16 gms. of 2- (2'.3-dihydroxy-n4propylamino)-ethylamine (obtained by the interaction of ethylene diamine with glycerol ocmonochlorohydrin) and the mixture heated at 110-115 C. for a further 1 /2 hours. The reaction mixture is then allowed to cool, poured into 300 cc. of acetone containing 12.5 cc. of 10.N. hydrochloric acid and the mixture allowed to stand overnight.
- 2- (2'.3-dihydroxy-n4propylamino)-ethylamine obtained by the interaction of ethylene diamine with glycerol ocmonochlorohydrin
- the LD 50 value of this compound when administered orally to mice is 800 mg./kg. It is very active against human schistosomiasis when administered in a dosage of the order of 12 mg./kg. per day for five consecutive days or in a lesser dosage for a longer period.
- Example 2 A solution of 28 gms. of 2-methoxy6.9-dichloro-1.10- diaza-anthracene in 200 gms. of phenol is heated to 110- 115 C. for 1 hour. 2 gms. of 2-(2-hydroxypropylamino-ethylamine is added and the resulting solution heated at the same temperature for 2 hours, cooled, and poured into 700 cc. of acetone containing 12 cc. of 10 N hydrochloric acid. After keeping overnight in the re frigerator the yellow precipitate is filtered oif, washed with dry acetone, and dissolved in 400 ccs. of boiling water.
- the solution is filtered with charcoal, reheated to about 80 C., and 100 cos. of saturated aqueous ammonium chloride added: after keeping overnight, the yellow micro-crystalline precipitate of 2-rnethoxy6- ch1oro-9-[2-(2"-hydroxy propylamino) ethylamino] 1.10-diaza-anthracene dihydrochloride (32 g.; M. P. 264 C.) is filtered off and dried at 60 C.
- Example 3 By using 32 gms. of 2-n-butoxy-6.9-dichloro-l.IO-diazaanthracene in place of the 28 gms. of the corresponding Z-methoxy-derivative in Example 2, there is obtained in like manner 36 gms. of 2-n-butoxy-6-chloro-9-[2'- (2"-hydroxypropylamine) ethylamino] 1.10 diazaanthracene dihydrochloride in the form of a bright yellow microcrystalline powder.
- Example 4 A solution of 28 gms. of 2-methoxy-6.9-dichloro-1.10- diaza-anthracene in 200 gms. of phenol is heated at 110 C. for 1 hour. 11 gms. of 2-(2-hydroxyethylamino)- ethylamine is added and the mixture heated for 2 hours at 115 C., cooled and poured into 700 ccs. of acetone containing 12 ccs. of 10 N hydrochloric acid. After keeping overnight, the yellow precipitate is collected, washed with acetone and dissolved in 400 ccs. of boiling water. The solution is filtered with charcoal, reheated to about C. and diluted with ccs.
- Example 5 By using 15 gms. of 3-(2'.3-dihydroxypropylamino)- propylamine in place of the 2-(2'-hydroxyethylamino)- ethylamine in Example 4, there is obtained in like manner 27 gms. of 2-methoxy-6-chloro-9-[3-(2.3"-dihydroxypropylamino) propylamino1-1.lO-diaza-anthracene dihydrochloride as a yellow micro-crystalline powder, M. P. 220 C.
- Example 6 By using 24.4 gms. of 2-methoxy-9-chloro-1.10-diazaanthracene in place of the 28 gms. 2-methoxy-6.9-dichloro-l.IO-diaza-anthracene in Example 4 there is obtained in like manner 27 gms. of 2-methoxy-9-[2'-(2"- hydroxyethylamino)-ethylamino] -l .IO-diaza anthracene dihydrochloride as a bright yellow micro-crystalline powder.
- a 9-substituted LIO-diaZa-anthracene having, in one tautomeric form, the general formula in which R is an alkoxy group having one to six carbon atoms, Y is selected from the group consisting of hydrogen and halogen atoms, R is an hydroxy-alkyl group having at least two but less than seven carbon atoms and at least one but less than three hydroxyl groups and n is an integer having a minimum value of two and a maximum value of six, and acid salts thereof.
- a 9-substituted 1.10-diaza-anthracene having, in one tautomeric form, the general formula in which R is an alkoxy group having one to six carbon atoms.
- a 9-substituted 1.10-diaza-anthracene having, in one tautomeric form, the general formula NH.CHn.CH2CH2.NH.CHn-CHOH.CH2OH in which R is an alkoxy group having one to six carbon atoms.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
United States Patent SUBSTITUTED LItD-DIAZA-ANTHRACENES Alan August Goldberg, Shepton Mallet, England, assignor t Ward Blenkinsop & Company Limited, London,'England, a British company No Drawing. Application July 1955, Serial No. 520,097
Claims priority, application Great Britain July 8, 1954 12 Claims. (Cl. 260-288) in which R is an alkoxy group having one to six carbon atoms and preferably containing not more than four carbon atoms, Y is a hydrogen or halogen atom, R is a monoor di-hydroxy alkyl group having at least two but not more than six carbon atoms, and preferably containing not more than four carbon atoms, and n is an integer having a minimum value of two and a maximum value of six, and is preferably two, three or four. The invention also includes the acid salts of the said 9-substituted- 1 .10-diaza-anthracenes.
The group R may be an omega=hydroxy straight chain alkyl group having two to six carbon atoms such as p-hydroxyethyl; it may also be a straight chain alkyl group carrying the hydroxyl group on a carbon atom other than the terminal carbon atom, such as fl-hydroxyn-propyl or 'y-hydroxy-n-butyl: itmay also be a branched chain alkyl group carrying an hydroxyl group such as fl-hydroxy-iso-butyl: or it may be a dihydroxy alkyl group such as B,v-dihydroxy-n-propyl.
In accordance with a feature of the invention the said 9-substituted-1.l0-diaza-anthracenes are produced by heating a 9-substituted-1.IO-diaza-anthracene having, in one tautomeric form, the general formula NH2.(CH2)n.NHR'
in which R and n are as above defined.
The 1.10-diaza-anthracenes which form the starting material for the present process and contain a halogen 2,775,595 a ented ec. 2.5,
atom in the 9-position may be produced as disclosed in British patent specification No. 704,238. The 9-phenoxy compounds may be produced from the 9-halogeno compounds by heating the latter with phenol, a cresol, a xylenol or other polyalkylphenol or a mixture of two or more of such compounds. The resulting 9-phenoxy compound or mixture of 9-phenoxy compounds may be used as produced in situ or may be first isolated if desired. The reaction may be carried out in the presence of an inert solvent: in the case of the 9-phenoxy compounds an excess of the phenol or phenols used to produce the compound or compounds may constitute the inert solvent. Specific examples of compounds which may be employed are 2 methoxy 9 chloro 1.10 diaza anthracene, 2 methoxy 9 phenoxy 1.10 diaza anthracene, 2 methoxy 6.9 dichloro 1.10 diaza anthracene, 2 methoxy 6 chloro 9 phenoxy 1.10 diaza anthracene, 2 n butoxy 6.9 dichloro 1.10 diaza anthracene and 2 n butoxy 6 7 chloro 9 phenoxy 1.10- diaza anthracene.
Examples of hydroxy amines having the general forrnula NHz(CH2)n.NHR which may be employed include 2 (2' hydroxyethylamino) ethylamine, 3 (2 hydroxyethylamino) n propylamine, 2 (2 hydroxyn propylamino) ethylamine, 3 (2 hydroxy n propylamino) propylamine, 3 (3" hydroxy n butylamino) n propylamine, 2 (2 hydroxy iso butylamino) ethylamine, 2 (2.3' dihydroxy n propylamino) ethylamine and 3 (2.3' dihydroxy 11 propylamino) n propylarnine.
When Z is a halogen atom the 9-halogeno-Ll0-diazaanthracene may be heated with the hydroxy amine having the general formula NH2(CH2)n,NHR' in the presence or absence of an inert solvent.
When Z is a phenoxy group the phenoxy compound may be first prepared by heating the 9-haloge'no-L10- diaza-anthracene with phenol, a cresol, a xylenol or other polyalkylphenol or a mixture of two or more such compounds and the hydroxyamine then added or alternatively the phenol and the hydroxyamine may be heated together with the 9-halogeno-1.10-diaza-anthracene. Alternatively the phenoxy compound may be prepared as outlined above and isolated before heating with the hydroxyamine.
The new compounds in the form of the free bases may be isolated by pouring the cooled reaction mixture into an excess of aqueous caustic alkali, separating the product and crystallizing from a suitable solvent. The free bases may also be produced by neutralization of their hydrohalide salts. They can be crystallized from basic solvents such as pyridine and the alkyl pyridines.
The new compounds in the form of their hydrohalide salts may be readily isolated from reaction mixtures in which the 9-halogeno1.l0sdiazo-anthracene has been heated with the hydroxyamine in the presence or absence of a phenol, cresol, xylenol or mixture of two or more such compounds by pouring the cooled reaction mixture into a large volume of anhydrous ether, acetone or methyl ethyl ketone and collecting the precipitate of the monohydrohalide of the base. The monohydrohalide may be readily recrystallized from the corresponding dilute aqueous hydrogen halide to yield the dihydrohalide of the base and may also containone or more molecules of water of crystallization. Since it is preferred to employ the 9-chloro-LIOTdiaZa-anthracene in the process this method readily lends itself to the production of the monoand di-hydrochlorides of the new bases.
The new compounds and their salts have been found to possess valuable pharmacological properties. They are useful in the treatment of a variety of helminth infections both in human beings and in animals and are of low toxicity.
The following examples illustrate the nature of the invention and the manner in which it may be performed:
Example 1 28. gms. of 2-methoxy-.6.9-dichloro-1.IO-diaza-anthracene is heated with 100 gms. of dry phenol for 1 hour. To the resulting reaction mixture is added 16 gms. of 2- (2'.3-dihydroxy-n4propylamino)-ethylamine (obtained by the interaction of ethylene diamine with glycerol ocmonochlorohydrin) and the mixture heated at 110-115 C. for a further 1 /2 hours. The reaction mixture is then allowed to cool, poured into 300 cc. of acetone containing 12.5 cc. of 10.N. hydrochloric acid and the mixture allowed to stand overnight. The resulting yellow precipitate is collected, washed first with ether and then with acetone, then dissolved in 400 cc. of boiling water and the solution filtered with charcoal. The filtered solution is reheated to about 80 C. and 200 cc. of N hydrochloric acid added thereto: bright yellow microcrystalline needles commence to separate. The mixture is quickly chilled and after several hours the needles, which are 2-methoxy-6-chloro-9-[2 (2".3-dihydroxy-npropylamino)-ethylamino] 1.10-diaZa-anthracene dihydrochloride, are collected (yield 27 gms.) and are found to have a melting point of 264-268 C. Found: N, 12.6%; CI, 24.0%: CmHzsOsNrCl; requires N, 12.5%; CI, 23.8%.
The LD 50 value of this compound when administered orally to mice is 800 mg./kg. It is very active against human schistosomiasis when administered in a dosage of the order of 12 mg./kg. per day for five consecutive days or in a lesser dosage for a longer period.
Example 2 A solution of 28 gms. of 2-methoxy6.9-dichloro-1.10- diaza-anthracene in 200 gms. of phenol is heated to 110- 115 C. for 1 hour. 2 gms. of 2-(2-hydroxypropylamino-ethylamine is added and the resulting solution heated at the same temperature for 2 hours, cooled, and poured into 700 cc. of acetone containing 12 cc. of 10 N hydrochloric acid. After keeping overnight in the re frigerator the yellow precipitate is filtered oif, washed with dry acetone, and dissolved in 400 ccs. of boiling water. The solution is filtered with charcoal, reheated to about 80 C., and 100 cos. of saturated aqueous ammonium chloride added: after keeping overnight, the yellow micro-crystalline precipitate of 2-rnethoxy6- ch1oro-9-[2-(2"-hydroxy propylamino) ethylamino] 1.10-diaza-anthracene dihydrochloride (32 g.; M. P. 264 C.) is filtered off and dried at 60 C.
It can be recrystallized by dissolving 20 gms. of the salt in 200 ccs. of boiling water and then adding 20 ccs. of 10 N hydrochloric acid; the dihydrochloride slowly separates in clusters of small yellow aggregates, M. P. 266268 C. (Found: N, 12.6; CI, 24.3. C1sH21ON4Cl. 2HC1.1H2O requires: N. 12.8; C1, 24.4%.)
Example 3 By using 32 gms. of 2-n-butoxy-6.9-dichloro-l.IO-diazaanthracene in place of the 28 gms. of the corresponding Z-methoxy-derivative in Example 2, there is obtained in like manner 36 gms. of 2-n-butoxy-6-chloro-9-[2'- (2"-hydroxypropylamine) ethylamino] 1.10 diazaanthracene dihydrochloride in the form of a bright yellow microcrystalline powder.
Example 4 A solution of 28 gms. of 2-methoxy-6.9-dichloro-1.10- diaza-anthracene in 200 gms. of phenol is heated at 110 C. for 1 hour. 11 gms. of 2-(2-hydroxyethylamino)- ethylamine is added and the mixture heated for 2 hours at 115 C., cooled and poured into 700 ccs. of acetone containing 12 ccs. of 10 N hydrochloric acid. After keeping overnight, the yellow precipitate is collected, washed with acetone and dissolved in 400 ccs. of boiling water. The solution is filtered with charcoal, reheated to about C. and diluted with ccs. of saturated ammonium chloride solution; 2-methoxy-6- -chloro-9- [2-(2"1hydroxyethylamino -ethylamino] -1. l0- diaza-anthracene dihydrochloride (30 gms.) slowly separates as a yellow microcrystalline powder, M. P. 280 C. (Found: N, 12.8; Cl, 24.1. C17H19ON4CL2HCL2H2O requires: N, 12.8: C1, 24.4%.)
On order to obtain the free base a warm aqueous solution of the dihydrochloride is poured into an excess of stirred cold N sodium hydroxide, the yellow precipitate collected and washed with water. The free base crystallizes from dilute pyridine in bright yellow needles, M. P. 172 C.
Example 5 By using 15 gms. of 3-(2'.3-dihydroxypropylamino)- propylamine in place of the 2-(2'-hydroxyethylamino)- ethylamine in Example 4, there is obtained in like manner 27 gms. of 2-methoxy-6-chloro-9-[3-(2.3"-dihydroxypropylamino) propylamino1-1.lO-diaza-anthracene dihydrochloride as a yellow micro-crystalline powder, M. P. 220 C.
Example 6 By using 24.4 gms. of 2-methoxy-9-chloro-1.10-diazaanthracene in place of the 28 gms. 2-methoxy-6.9-dichloro-l.IO-diaza-anthracene in Example 4 there is obtained in like manner 27 gms. of 2-methoxy-9-[2'-(2"- hydroxyethylamino)-ethylamino] -l .IO-diaza anthracene dihydrochloride as a bright yellow micro-crystalline powder.
I claim:
1. A 9-substituted LIO-diaZa-anthracene having, in one tautomeric form, the general formula in which R is an alkoxy group having one to six carbon atoms, Y is selected from the group consisting of hydrogen and halogen atoms, R is an hydroxy-alkyl group having at least two but less than seven carbon atoms and at least one but less than three hydroxyl groups and n is an integer having a minimum value of two and a maximum value of six, and acid salts thereof.
2. A 9-substituted 1.10-diaza-anthracene having, in one tautomeric form, the general formula 3. A 9-substituted 1.10-diaza-anthracenc having, in one tautomeric form, the general formula in which R is an alkoxy group having one to six carbon atoms, R is an hydroxy-alkyl group having at least two but less than sevencarbon atoms and at least one but less than three hydroxyl (gro ps and ,n i an. integer having a minimum value of two and a maximum value of six, and acid salts thereof.
4. A 9-substituted 1.10-diaza-anthracene having, in one tautomeric form, the general formula in which R is an alkoxy group having one to six carbon atoms.
5. A 9-substituted 1.10-diaza-anthracene having, in one tautomeric form, the general formula NH.CHn.CH2CH2.NH.CHn-CHOH.CH2OH in which R is an alkoxy group having one to six carbon atoms.
6. 2 methoxy 6 chloro 9 [2' (2".3" dihydroxyn-propylamino) -ethylamino]-1.10-diaza-anthracene.
7. 2 methoxy 6 chloro 9 [2' (2" hydroxy npropylamino) -ethylamino]-1.l-diaza-anthracene.
8. 2 n butoxy 6 chloro 9 [2' (2" hydroxy npropylamino) -ethylamino]-1.IO-diaza-anthracene.
9. 2 methoxy 6 chloro 9 [2 (2 hydroxyethylamino -ethylamino] -l l O-diaza-anthracene.
10. 2 methoxy 6 chloro 9 [3 (2".3" dihydroxypropylamino -propylamino] -l.10-diaza-anthracene.
11. A process for preparing a 9-substituted 1.10-diazaanthracene having, in one tautomeric form, the general formula IITHXOHa) n-NHR' in which R is an alkoxy group having one to six carbon atoms, Y is selected from the group consisting of hydrogen and halogen atoms, R is an hydroxy alkyl group having at least two but less than seven carbon atoms and at least one but less than three hydroxyl groups and n is an integer having a minimum value of two and a maximum value of six which comprises heating a 9-substituted LIO-diaZa-anthracene having, in one tautomeric form, the general formula in which R and Y are as above defined and Z is selected from the group consisting of halogen atoms and phenoxy, alkylphenoxy and polyalkylphenoxy groups, with a hydroxyamine having the general formula in which R and n are as above defined, and isolating the product.
12. A process for preparing a 9-substituted 1.10-diazaanthracene having, in one tautomeric form, the general formula in which R and Y are as above defined and Z is selected from the group consisting of halogen atoms and phenoxy, alkylphenoxy and polyalkylphenoxy groups, with a hydroxyamine having the general formula NHz. CH2) 11,.NHR'
in which R and n are as above defined, and isolating the product.
No references cited.
Claims (1)
1. A 9-SUBSTITUTED 1.10-DIAZA-ANTHRACENE HAVING, IN ONE TAUTOMERIC FORM, THE GENERAL FORMULA
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| Publication Number | Publication Date |
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| US2775595A true US2775595A (en) | 1956-12-25 |
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| US2775595D Expired - Lifetime US2775595A (en) | Chzohz |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2877227A (en) * | 1959-03-10 | Chichi | ||
| US3000894A (en) * | 1957-10-31 | 1961-09-19 | Diamond Alkali Co | Chloral derivatives of amino quinoline |
-
0
- US US2775595D patent/US2775595A/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2877227A (en) * | 1959-03-10 | Chichi | ||
| US3000894A (en) * | 1957-10-31 | 1961-09-19 | Diamond Alkali Co | Chloral derivatives of amino quinoline |
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