US3192110A - Therapeutic aryl and thienyl hydroxylamines - Google Patents

Therapeutic aryl and thienyl hydroxylamines Download PDF

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US3192110A
US3192110A US189722A US18972262A US3192110A US 3192110 A US3192110 A US 3192110A US 189722 A US189722 A US 189722A US 18972262 A US18972262 A US 18972262A US 3192110 A US3192110 A US 3192110A
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compounds
thienyl
acid
hydroxylamines
hydroxylamine
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US189722A
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John H Biel
Jerry E Robertson
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Colgate Palmolive Co
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Colgate Palmolive Co
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    • 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
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms

Definitions

  • R is hydrogen or at least one substituent of the group consisting of hydroxy, halogens such as bromine and chlorine, trifiuoromethyl, lower alkoxy groups such as methoxy, ethoxy and propoxy, lower alkylenedioxy such as 3,4-methylenedioxy, nitro and acyloxy groups from carboxylic acids as where R represents where R is a lower alkyl such as methyl and ethyl, phenyl and and' a phenyl-lower alkyl such as benzyl and phenethyl,
  • DOPA is, of course, beta-(3,4-dihydroxyphenyl) -L- alanine.
  • GABA gamma aminobutyric acid
  • the invention is particularly concerned with the compounds of the formulas ULOHFWNH.
  • the compounds in which Y is of three or more carbons are indicated to be local vasoconstrictors, central stimulants, cardiac stimulants and analeptic agents.
  • the mood lifting properties of the compounds indicates their use in the treatment of mental depression. Relief of anxiety (tranquilization) produces a calming efiect.
  • R has the significance assigned above.
  • aralkanols that can be used in the process are benzyl alcohol, p-nitrobenzyl alcohol, 2,6-dimethoxybenzyl alcohol, 3,4-methylenedioxybenzyl alcohol, p-hydroxybenzyl alcohol, Z-thienylmethyl alcohol and 3- thienylmethyl alcohol.
  • Representative of the compounds of this invention which are produced as described are O-benzylhydroxylamine, O-(2,6-dimethoxybenzyl)-hydroxylamine, O-(3,4- methylenedioxybenzyl -hydroxylamine, 0- (p-hydroxylbenzyl) -hydroxylamine, O- (Z-thienylmethyl -hydroxylamine and O-(3-thienylmethyl)-hydroxylamine.
  • a general method of producing the O-phenylalkylhydroxylamines comprises reacting a phenylalkyl halide with hydroxyurethane to form a O-phenylalkylhydroxylurethane which, upon hydrolysis, yields a O-phenylalkylhydroxylamine.
  • This process can be represented as follows:
  • Some of the compounds which are readily produced by these-methods are .O-phenylisopropylhydroxylamine, O [2 (1 phenylpropyD] hydroxylamine, O [2 (3- thienyl)-ethyl]-hydroxylamine and O-l[2 (2 thienyl)- pro pyl] -hydroxylamine.
  • O-aralkylhydroxylamines with which this invention is concerned form acid addition salts with organic and inorganic acids such as hydrochloric acid, sulfuric acid,phosphoric acid, citric acid, maleic acid, tartaric acid, fumaric acid and glutamic acid.
  • organic and inorganic acids such as hydrochloric acid, sulfuric acid,phosphoric acid, citric acid, maleic acid, tartaric acid, fumaric acid and glutamic acid.
  • the O-aralkylhydroxylamines can be administered as the base, or in the form of a nontoxic acid addition salt, as a unit dosage in pure undiluted form to obtain the desired therapeutic. effect.
  • Pharmaceutical unit dosage forms can be readily produced by intimately mixing one or more of the compounds with a suitable pharmaceutical carrier.
  • the carrier can be either a liquid or a solid. When a liquid is used either a solution or a suspension can be produced. Flavoring substances may be included as desired. Sterile water is the preferred liquid carrier; it readily dissolves the salts to form solutions.
  • Solid pharmaceutical carriers such as starch, sugar and talc can be used to form powders; Such powders can be tableted by the use of suitable lubricants such as magnesium stearate, binders such as gelatin and disintegrating agents like sodium bicarbonate in combination with citric or tartaric acid.
  • suitable lubricants such as magnesium stearate, binders such as gelatin and disintegrating agents like sodium bicarbonate in combination with citric or tartaric acid.
  • a typical hard gelatin capsule can have the composition:
  • the preferred route of' administering the O-aralkylhydroxylamines is oral and for this method tablets and capsules are ordinarily recommended.
  • the unit-dosage compositions can contain from about mgm. to 1000,
  • EXAMPLE 1 O-benzylhydroxylamine hydrochloride An ethereal solution of monochloroamine was prepared by mixing at 0-5 C., 414 ml. of 4.15 N sodium hypochlorite and 902 ml. of 1.79 N ammonium hydroxide and extracting with three 300 ml. portions of ether. The combined ethereal extracts were dried over calcium chloride and utilized as described below. Sodium (11.5 g., 0.50 mole) was dissolved with warming in a mixture of 260 ml. dry benzyl alcohol and 200 ml. of dry dioxane held in a 1 liter round bottom flask equipped with a stirrer, condenser, and ice jacketed dropping funnel.
  • EXAMPLE 2 O-p-methoxybenzylhydroxylamine hydrochloride To a solution of 70 g. (0.5 mole) of p-methoxybenzylalcohol in 100 ml. of dioxane was added 2.3 g; (0.1 mole) of sodium. After all of the sodium had reacted,'the mixture was heated to C. and about 325 ml. of ether solution containing about 0.1 mole of monochloram-ine (pre-dried with calcium chloride) was added at such a rate that the ether could be conveniently. distilled 011 through an 18" glass-packed column. The addition time was about 30 minutes. The mixture was cooled, filtered and the solvent removed under reduced pressure on a water bath.
  • a pharmaceutical composition in unit dosage form comprising from 25 to 1000 mgm. of a member of the group consisting of compounds of the formula and 5 wherein R is a member of the group consisting of lower :alkyl, phenyl and phenyl-lower .alkyl, and Y is lower alkylene having at least two carbons, and a pharmaceutical diluent.
  • a pharmaceutical composition in unit dosage fiorm comprising from 25 to 1000 mgm. of O-phenyl-lower alkyl hydroxylarnine wherein said lower alkyl has at least two carbons, and a pharmaceutical diluent.
  • a pharmaceutical composition in unit dosage form comprising from 25 to 1000 mg-m. of O-thienyl-lower alkyl hydroxylamine wherein said lower alkyl has at least two carbons, and a pharmaceutical diluent.
  • a hypotensive eflect which comprises orally administering to an animal sufiiering with hypertension a nontoxic chemotherapeutically eifective amount of .a member of the group consisting of compounds of the formulas and wherein R is at least one member of the group consisting of hydrogen, hydroxy, halogen, trifiuoromethyl, lower alkoxy, lower alkylenedioxy, nitro and O Rr-ii-O wherein R is a member of the group consisting of lower .alkyl, phenyl and phenyl-lower alkyl, and Y is lower a lkylene.

Description

United States Patent 3,192,110 THERAPEUTIC ARYL AND TEHENYL HYDROXYLAMINES John H. Biel and Jerry E. Robertson, both of Milwaukee,
Wis., assignors to Colgate-Palmolive Company, a cor= poration of Delaware No Drawing. Filed Apr. 24, 1962, Ser. No. 189,722
' 8 Claims. (Cl. 16765) |L l HNH,
wherein R is hydrogen or at least one substituent of the group consisting of hydroxy, halogens such as bromine and chlorine, trifiuoromethyl, lower alkoxy groups such as methoxy, ethoxy and propoxy, lower alkylenedioxy such as 3,4-methylenedioxy, nitro and acyloxy groups from carboxylic acids as where R represents where R is a lower alkyl such as methyl and ethyl, phenyl and and' a phenyl-lower alkyl such as benzyl and phenethyl,
and Y is a straight or branched lower alkylene, advisably of not more than five carbons, such as methylene, ethylene, propylene and isopropylene, have DOPA decarboxylase inhibitory activity. DOPA is, of course, beta-(3,4-dihydroxyphenyl) -L- alanine.
Because of the DOPA decarboxylase inhibitory activity of these compounds, they are useful hypotensive and tranquilizing agents when administered in nontoxic chemotherapeutic amounts. The levels of gamma aminobutyric acid (GABA) in the brain could also be raised by the administration of these compounds and, thus, they can be useful anticonvulsants. I
The invention is particularly concerned with the compounds of the formulas ULOHFWNH.
and
'ice
the over-all effect of this dual enzyme inhibition is a depletion of serotonin, norepinephrine and epinephrine stores in the body, these compounds would be expected to produce significant therapeutic effects in hypertension and in the treatment of anxiety and mental depression. Since certain oxidation products of epinephrine such as adrenochrome and adrenolutin are thought to be implicated in the etiology of schizophrenia, such drugs might also be of value in the treatment of psychotic states.
The compounds in which Y is of three or more carbons are indicated to be local vasoconstrictors, central stimulants, cardiac stimulants and analeptic agents. The mood lifting properties of the compounds indicates their use in the treatment of mental depression. Relief of anxiety (tranquilization) produces a calming efiect.
O-benzylhydroxylamine and a process for its production is shown by Theilacker et al. in Angewandte Chemie, 68, 303 (1956) and Chem. Abstr. 52, 15454 (1958). This reaction can be represented as follows, as well as its application to the preparation of O-thienylmethylhydroxylamines:
wherein R has the significance assigned above.
Some of the aralkanols that can be used in the process are benzyl alcohol, p-nitrobenzyl alcohol, 2,6-dimethoxybenzyl alcohol, 3,4-methylenedioxybenzyl alcohol, p-hydroxybenzyl alcohol, Z-thienylmethyl alcohol and 3- thienylmethyl alcohol.
Representative of the compounds of this invention which are produced as described are O-benzylhydroxylamine, O-(2,6-dimethoxybenzyl)-hydroxylamine, O-(3,4- methylenedioxybenzyl -hydroxylamine, 0- (p-hydroxylbenzyl) -hydroxylamine, O- (Z-thienylmethyl -hydroxylamine and O-(3-thienylmethyl)-hydroxylamine.
A general method of producing the O-phenylalkylhydroxylamines, and a process which is equally applicable to production of the O-thienylalkylhydroxylamines, comprises reacting a phenylalkyl halide with hydroxyurethane to form a O-phenylalkylhydroxylurethane which, upon hydrolysis, yields a O-phenylalkylhydroxylamine. This process can be represented as follows:
acid or wherein X is a reactive halogen and R and Y have the assigned meaning. This process is described by A. T, Fuller et al. in J. Chem. Soc. 963 (1947) and it was used by Major et al. in J. Med. Pharm. Chem. 4, 51 (1961) to make O-(beta phenethyl) hydroxylarnine. The compounds in which Y is a lower alkylene having at least two carbons appear to be novel.
Another convenient route to the O-substituted hy droxylamines is through benzohydroxamic acid accord- I ing to the scheme whereinR, X .and Y have the significance previously assigned and g is phenyl. Fuller et a1 supra also illustrate this route.
A convenient reference to the various preparations of O-substituted hydroxylarnines is C. D. Hurd in Gilm-an, Organic Chemistry, 1st ed., vol. 1, John Wiley & Sons, Inc, N.Y., 1938, pp. 677679.
Some of the compounds which are readily produced by these-methods are .O-phenylisopropylhydroxylamine, O [2 (1 phenylpropyD] hydroxylamine, O [2 (3- thienyl)-ethyl]-hydroxylamine and O-l[2 (2 thienyl)- pro pyl] -hydroxylamine.
The O-aralkylhydroxylamines with which this invention is concerned form acid addition salts with organic and inorganic acids such as hydrochloric acid, sulfuric acid,phosphoric acid, citric acid, maleic acid, tartaric acid, fumaric acid and glutamic acid.
The O-aralkylhydroxylamines can be administered as the base, or in the form of a nontoxic acid addition salt, as a unit dosage in pure undiluted form to obtain the desired therapeutic. effect. However, it is desirable in most instances to administer the compounds combined with a suitable pharmaceutical carrier or diluent to achieve a more convenient size to dosage relationship.
Pharmaceutical unit dosage forms can be readily produced by intimately mixing one or more of the compounds with a suitable pharmaceutical carrier. The carrier can be either a liquid or a solid. When a liquid is used either a solution or a suspension can be produced. Flavoring substances may be included as desired. Sterile water is the preferred liquid carrier; it readily dissolves the salts to form solutions.
Solid pharmaceutical carriers such as starch, sugar and talc can be used to form powders; Such powders can be tableted by the use of suitable lubricants such as magnesium stearate, binders such as gelatin and disintegrating agents like sodium bicarbonate in combination with citric or tartaric acid.
A typical hard gelatin capsule can have the composition:
Mg. O-benzylhydroxylamine HCl 50 Lactose 200 Starch 16 Talc 8 The preferred route of' administering the O-aralkylhydroxylamines is oral and for this method tablets and capsules are ordinarily recommended. The unit-dosage compositions can contain from about mgm. to 1000,
and advisably 50 to 200 mgm. of the active compound with the dosage determined in view of the activity of the particular O-aralkylhydroxylamine used as well as the contemplated administration per day. In general, daily administration of 100 mgm. to 4000 mgm. achieves the therapeutic effects given above.
The following examples are presented to illustrate the preparation of the compounds concerned in this invention.
EXAMPLE 1 O-benzylhydroxylamine hydrochloride An ethereal solution of monochloroamine was prepared by mixing at 0-5 C., 414 ml. of 4.15 N sodium hypochlorite and 902 ml. of 1.79 N ammonium hydroxide and extracting with three 300 ml. portions of ether. The combined ethereal extracts were dried over calcium chloride and utilized as described below. Sodium (11.5 g., 0.50 mole) was dissolved with warming in a mixture of 260 ml. dry benzyl alcohol and 200 ml. of dry dioxane held in a 1 liter round bottom flask equipped with a stirrer, condenser, and ice jacketed dropping funnel. At a solution temperature of 75-85 C. all of the ethereal monochloramine (ca. 0.5 mole) solution, prepared as describm above, was added at such a rate that the ether could be conveniently stripped through a 50 cm. packed column. Care was taken during the addition to avoid allowing the chloramine solutionto touch the hot sides of the reaction vessel. The addition required about 1 hour and the temperature was maintained for an additional 0.5 hour. The apparatus was adjusted for direct distillation and the solvents were removed under water raspirator vacuum. The-residue was filtered to remove sodium chloride and then distilled at less than 1 mm. (ca. 65-75 C./ 0.2 mm.) until only a gum remained as a residue. The distillate was treated with ethereal hydrogen chloride until precipitation was completed and the crude product collected. Recrystallization from methanol-m hexane vafiorded 38 g. (50%) of product, M.P. 230-255 C. (sublimes) reported M.P. ZOO-250 C. and 230- 260 C.
Analysis.Calcd. for C H NOCI: Chloride, 22.22. Found: Chloride, 22.22.
EXAMPLE 2 O-p-methoxybenzylhydroxylamine hydrochloride To a solution of 70 g. (0.5 mole) of p-methoxybenzylalcohol in 100 ml. of dioxane was added 2.3 g; (0.1 mole) of sodium. After all of the sodium had reacted,'the mixture was heated to C. and about 325 ml. of ether solution containing about 0.1 mole of monochloram-ine (pre-dried with calcium chloride) was added at such a rate that the ether could be conveniently. distilled 011 through an 18" glass-packed column. The addition time was about 30 minutes. The mixture was cooled, filtered and the solvent removed under reduced pressure on a water bath. The residue was distilled rapidly at less than 1 mm. with a major fraction distilling at 65-70" C./0.3 mm. Dilution of the total distillate with about half its volume of ether followed by addition of excess ethereal HCl and cooling gave a solid which was collected, washed with ether and dried to afiord 8.5 gm. (45%) of the product, M.P. 208210 C.
Analysis.0alcd. for C H NO C1: Cl, 18.73; N, 7.39. Found: Cl, 18.89; N, 7.14.
Various changes and modifications of the invention can be made and, to the extent that such variations incorporate the spirit of .this invention, they are intended to be included Within the scope of the appended claims.
What is claimed is:
:1. A pharmaceutical composition in unit dosage form comprising from 25 to 1000 mgm. of a member of the group consisting of compounds of the formula and 5 wherein R is a member of the group consisting of lower :alkyl, phenyl and phenyl-lower .alkyl, and Y is lower alkylene having at least two carbons, and a pharmaceutical diluent.
2. A pharmaceutical composition in unit dosage fiorm comprising from 25 to 1000 mgm. of O-phenyl-lower alkyl hydroxylarnine wherein said lower alkyl has at least two carbons, and a pharmaceutical diluent.
3. A pharmaceutical composition in unit dosage form comprising from 25 to 1000 mg-m. of O-thienyl-lower alkyl hydroxylamine wherein said lower alkyl has at least two carbons, and a pharmaceutical diluent.
4. The method of inducing a hypotensive eflect which comprises orally administering to an animal sufiiering with hypertension a nontoxic chemotherapeutically eifective amount of .a member of the group consisting of compounds of the formulas and wherein R is at least one member of the group consisting of hydrogen, hydroxy, halogen, trifiuoromethyl, lower alkoxy, lower alkylenedioxy, nitro and O Rr-ii-O wherein R is a member of the group consisting of lower .alkyl, phenyl and phenyl-lower alkyl, and Y is lower a lkylene.
5. The method of claim 4 in which about 100 to 4000 mgm of the compound as defined therein is administered 4 chemotherapeutic amount of a member of the group consisting of compounds of the formulas Q wmsm and wherein R is at least one member of the group consisting of hydrogen, hydroxy, halogen, tr-ifluoromethyl, lower alkoxy, lower alkylenedioxy, nitro and References Cited by the Examiner UNITED STATES PATENTS 2,853,493 9/ 5 8 Weston 260332.3 2,890,984 6/59 Sahyun 16765 2,987,442 6/ 61 McLea-n 16765 3,013,019 12/6 1 Springdale 260332.3 3,051,722 8/62 Biel 16765 OTHER REFERENCES Burger: Medicinal Chemistry, 1960, Interscience,p. 394. Richter: Organic Chemistry, vol. IV, 1947, pp. 24-25, Elsevier Co.
Truitt: Chem. Abst., Vol.48, 1954, p. 5816((1).
JULIAN S. LEVITT, Primary Examiner.
M. O. WOLK, LEWIS GOTTS, Examiners.

Claims (1)

1. A PHARMACEUTICAL COMPOSITION IN UNIT DOSAGE FORM COMPRISING FROM 25 TO 1000 MGM. OF A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5516806A (en) * 1993-04-13 1996-05-14 Ciba-Geigy Corporation Ornithine decarboxylase inhibiting cyclic aminooxy compounds
US20110053941A1 (en) * 2007-11-30 2011-03-03 Newlink Genetics IDO Inhibitors

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2853493A (en) * 1952-07-28 1958-09-23 Abbott Lab Preparation of thiophenecarboxaldehydes
US2890984A (en) * 1955-08-04 1959-06-16 Pfizer & Co C Pharmaceutical composition containing 2-(1, 2, 3, 4-tetrahydro-1-naphthyl)imidazo-line
US2987442A (en) * 1959-02-17 1961-06-06 Smith Kline French Lab Method of treating hypertension with [2-(2, 6-dimethylphenoxy)-propyl]-trimethyl ammonium salts
US3013019A (en) * 1959-07-29 1961-12-12 Nat Distillers Chem Corp Bis(p-benzoylephenyl) thiophenes
US3051722A (en) * 1960-10-21 1962-08-28 Lakeside Lab Inc 5-pyrrolidone-2-carboxamides

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2853493A (en) * 1952-07-28 1958-09-23 Abbott Lab Preparation of thiophenecarboxaldehydes
US2890984A (en) * 1955-08-04 1959-06-16 Pfizer & Co C Pharmaceutical composition containing 2-(1, 2, 3, 4-tetrahydro-1-naphthyl)imidazo-line
US2987442A (en) * 1959-02-17 1961-06-06 Smith Kline French Lab Method of treating hypertension with [2-(2, 6-dimethylphenoxy)-propyl]-trimethyl ammonium salts
US3013019A (en) * 1959-07-29 1961-12-12 Nat Distillers Chem Corp Bis(p-benzoylephenyl) thiophenes
US3051722A (en) * 1960-10-21 1962-08-28 Lakeside Lab Inc 5-pyrrolidone-2-carboxamides

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5516806A (en) * 1993-04-13 1996-05-14 Ciba-Geigy Corporation Ornithine decarboxylase inhibiting cyclic aminooxy compounds
US20110053941A1 (en) * 2007-11-30 2011-03-03 Newlink Genetics IDO Inhibitors
US10047066B2 (en) 2007-11-30 2018-08-14 Newlink Genetics Corporation IDO inhibitors

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