US3826832A - N-substituted amino-n-nitro-amino-acetonitriles as anti-anginal agents - Google Patents

N-substituted amino-n-nitro-amino-acetonitriles as anti-anginal agents Download PDF

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US3826832A
US3826832A US00258610A US25861072A US3826832A US 3826832 A US3826832 A US 3826832A US 00258610 A US00258610 A US 00258610A US 25861072 A US25861072 A US 25861072A US 3826832 A US3826832 A US 3826832A
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nitroso
aminoacetonitrile
suspension
methyl
carbon atoms
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P Anderson
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Sandoz AG
Sandoz Wander Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins

Definitions

  • the active agents with which this invention is concerned may be represented by the following structural formula r, B2 BN R1 N r'1 H CN f (I) where l hydrogen, alkyl or R represents mis0,1or2;and R and R each, independently, represent lower alkyl, i.e., alkyl having 1 to 4 carbon atoms, e.g., methyl, ethyl, 11-p1'opyl and the l ike; lower alkenyl, i.e., alkenyl hav- '-.ingl3-:t
  • .hydroxylower alkyl having 2 to 4 carbon atoms, e.g., B.-l1ydrox yethyl v and the like; cycloalkyl having 3 to 8 carbon atoms, e.g., cyclohexyl and the like;
  • -R and" R each, independently,- represent hydrogen; hy- L droxy;-halo"having-- anatomieweight of about 19 to fipcyariottrifluoromethyl; lower alkyl as defined above; lowfl alkoxy i.e.,- alkoxyhaving- 1 to 4 carbon atoms,
  • R5 together on adjacent atoms may be where- CH OCH or OCH O; or R and R together with N represent where n is 4, 5 or 6; p is 0, 1 or 2; X represents O or RYN where R is hydrogen; lower alkyl as defined above; alkanoyl having 2 to 4 carbon atoms; w-hydroxy lower alkyl as defined above; alkoxyalkyl having 2 to 4 carbon atoms, e.g., methoxyethyl and the like; lower alkyl having 1 to 4 carbon atoms substituted with 1 to 4 halogen atoms having an atomic weight between 19 to 36, e.g., trifluoromethyl and the like or m is as defined above; and
  • R represents hydroxy; halo as defined above; lower alkyl,
  • lower alkoxy as defined above, alkanoyl having 2 to 4 carbon atoms; alkanoyloxy having 2 to 4 carbon atoms; w-hydroxy lower alkyl, as defined above, alkoxyalkyl having 2 to 4 carbon atoms, e.g., methoxyethyl and the like; lower alkyl having 1 to 4 carbon atoms substituted with 1 to 4 halogens having an atomic weight between about 19 to 36, e.g., trifluoromethyl, ap-dichloroethyl and the like; or
  • R and R are both trifluoromethyl or when more than one of R is trifluoromethyl on a phenyl ring, they are on other than adjacent carbon atoms.
  • the compounds of formula (I) are known and may be prepared according to methods disclosed in the literature from known materials.
  • the present invention contemplates only the novel use of such compounds, particularly as anti-anginal agents.
  • the preferred compound for this use is N-morpholino-N-nitroso-aminoacetonitrile.
  • N-disubstituted amino-N-nitroso-aminoacetonitriles which can be used in the treatment of angina pectoris include where N- (N-ethyl-o-trifiuoromethylphenylamino -N-nitrosoaminoacetonitrile N- (N-methyl-o-methoxyphenylamino) -N-nitroso-aminoacetonitrile N- N-rnethyl-o-toluidino -N-nitroso-aminoacetonitrile N- N-methyl-p-acetoxyphenylamino -N-nitroso-arninoacetonitrile N- N-methyl-p-acetylphenylamino) -N-nitroso-amino acetonitrile N- N-methyl-o- S-hydroxyethyl] phenylamino -N- nitroso-aminoacetonitrile N-
  • N-heterocyclic substituted-N-nitroso-aminoacetonitriles contemplated as active agents in the compositions of this invention include N-piperidino-N-nitroso-aminoacetonitrile N-piperidino-N-nitroso-a-methyl-aminoacetonitrile N-hexamethyleneimino-N-nitroso-aminoacetonitrile N- 4-hydroxypiperidino -N-nitroso-amino acetonitrile N- 2,4-dichloropiperidino -N-nitroso-aminoacetonitrile N- (4-methylpiperidino -N-nitroso-aminoacetonitrile N- (4-methoxypiperidino -N-nitroso-aminoacetonitrile N- (4-acetylpiperidino) -N-nitroso-aminoacetonitrile N- (4-acetoxypiperidino
  • the compounds are useful as anti-anginal agents as indicated by an increase in coronary blood flow and by a reduction of myocardial oxygen consumption in an anesthetized dog given 20 milligrams per kilogram of body weight of a compound of formula (I) intravenously.
  • compound (I) may be administered orally or parenterally as such or admixed with conven tional pharmaceutical carriers. They may be administered orally in such forms as tablets, dispersible powders,.gran.- ules, capsules, syrups and elixirs, and parenterally as solutions, suspensions, dispersions, emulsions, and the like, e.g., a sterile injectable aqueous suspension.
  • the compositions for oral use may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation.
  • Tablets may contain the active ingredient in admixture with conventional pharmaceutically acceptable excipients, e.g., inert diluents, such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch, gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and tale.
  • excipients e.g., inert diluents, such as calcium carbonate, sodium carbonate, lactose and talc
  • granulating and disintegrating agents e.g., starch and alginic acid
  • binding agents e.g., starch, gelatin and acacia
  • lubricating agents e.g., magnesium stearate, stearic acid and tale.
  • the tablets may be uncoated or coated by known techniques to
  • suspensions, syrups and elixirs may contain the active ingredient-in admixture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents (methylcellulose, tragacanth and sodium alginate), wetting agents (lecithin, polyoxyethylene stearateand polyoxyethylene sorbitan monooleate) and preservatives (ethyl-p-hydroxybenzoate).
  • Capsules may contain the active ingredient alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate and kaolin.
  • the injectable compositions are formulated as known in the art and may contain appropriate dispersing or wetting agents and suspending agents identical or similar to those mentioned above. These pharmaceutical preparations may contain up to about of the active ingredient in combination with the carrier or adjuvant.
  • the anti-anginal etfective dosage of active ingredient employed for the treatment ,of angina pectoris may vary depending on the particular compound employed and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds (I) are administered at a daily dosage oflfrom about 0.01 milligram to about 25 milligrams per kilogram of animal body weight, preferably given :in divided doses two to four times a day, or in sustained release form For most large mammals in need of said treatment, thetotal daily dosage is from about 0.7 to about 50 milligrams, preferably administered sublingually.
  • Dosage forms suitable for internal use comprise from about 0.175 to about 25 milligrams of the active compound in intimate admix- EXAMPLE 1 Tablets Tablets suitable for oral administration which contain the following ingredients may be prepared by conventional tabletting techniques. Such tablets are useful in treating agina pectoris at a dose of one tablet 2 to 4 times a day.
  • EXAMPLE 2 Dry Filled Capsules
  • Capsules suitable for oral administartion which contain the following ingredients are prepared in a conventional manner. Such capsules are useful in treating angina pectoris at a dose of one capsule 2 to 4 times a day.
  • Sterile injectable Oral liquid Ingredients suspension suspension N-morpholino-N-nitrosoamino- 10 10 acetonitrile.
  • Sodium carboxy methylcellulose U.S.P 1 25 12.5.
  • Methyl cellulose 0.4
  • Polyvinylpyrrnlidnnn i Lecithin 3 Benzyl alcohol ()1 Magnesium aluminum silicate 47.5. Flav r Q3.
  • Polysorhate 80 eg. Tween 80
  • U.S.P Sorbital solution 70% U.S.P 2,500. Bufigifiasgent to adjust pH for desired Q.s Q.s.
  • Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in treating angina pectoris at a dose of one table or capsule 2 to 4 times a day.
  • tablets and capsules are prepared using N- 2-hydroxymorpholino) -N-nitroso-aminoacetonitrile; N-(Z-methylmorpholino)-N-nitroso-aminoactonitrile; N- (Z-methoxymorpholino -N-nitroso-aminoacetonitrile; N- Z-acetylrnorpholino -N-nitroso-aminoacetonitrile or N- (2-acetoxymorpholino -N-nitro so-aminoacetonitrile in place of the N-(Z-chloromorpholino)-N-nitrosoaminoacetonitrile above and are used as above in treating angina pectoris.
  • EXAMPLES 7 and 8 Sterile Suspension for Injection and Oral Liquid Suspension
  • the following pharmaceutical compositions are formulated with the indicated amount of active agent using conventional techniques.
  • the injectable suspension and the oral liquid suspension represent formulations useful as unit doses and may be administered in the treatment of angina pectoris.
  • the injectable suspension is suitable for administration once or twice a day whereas the oral liquid suspension is suitably administered 2 to 4 times per day for this purpose.
  • Sterile injectable sus- Oral liquid Ingredients pension suspension N -(2-hydroxymorpholino)-N-nitroso- 10 10.
  • Injectable suspension and oral liquid suspensions are similarly prepared using N-(2-chloromorpholino)-N-nitroso-aminoacetonitrile; N-(Z-methylmorpholino)-N-nitroso-aminoacetonitrile; N-(3-B-hydroxymethylmorpholino)-N-nitroso-aminoacetonitrile; N-(3-methoxymethylmorpholino)-N-nitroso-aminoacetonitrile; N-(3-trifluorornethylmorpholino)-N-nitroso-aminoacetonitrile or N-(3-benzylmorpholino)-N-nitroso-aminoacetonitrile in place of the N-(2 hydroxymorpholino)-N-nitrosoaminoacetonitrile above and are used as above in treating angina pectoris.
  • Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in treating angina pectoris at a dose of one tablet or capsule 2 to 4 times a day.
  • Tablets and capsules are similarly prepared using N -dimethylamino-N-nitroso-aminoacetonitrile; N-diallylamino-N-nitroso-a-phenethyl-aminoacetonitrile; N-diallylamino-N-nitroso-a-methyl-aminoacetonitrile; N-methylpropylamino-N-nitroso-aminoacetonitrile; N- (N-allyl-p-hydroxymethylamino) -N-nitrosoaminoacetonitrile; or N-methylcyclohexylamino-N-nitroso-aminoacetonitrile in place of the N-N-diallylamino-N-nitroso-aminoacetonitrile above and are used as above in treating angina pectoris.
  • EXAMPLES 11 and 12 Tablets and Capsules Suitable For Oral Administration Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in treating angina pectoris at a dose of one tablet or capsule 2 to 4 times a day.
  • the following pharmaceutical compositions are formulated with the indicated amount of active agent using conventional techniques.
  • the injectable suspension and the oral liquid :suspension represent formulations useful as unit doses and may be administered in the treatment of angina pectoris.
  • the injectable suspension is suitable for administration once a day whereas the oral liquid suspension is suitably administered 2 to 4 times per day for this purpose.
  • Sterile Suspension Weight (mgt) Sterile i injeetable Oral liquid Ingredients suspension suspension N-(N-methyl-o-toluidino)-N-nitroso- 10-. 1o.
  • Sorbitol solution 70% U.S.P 2,500.
  • Buffer agent to adjust pH for desired Q.s Q.s.
  • N-(N-methyl3,4-methylenedioxybenzylamino)-N- nitroso-aminoacetonitrile in place of the N-(N-methyl-o-toluidino)-N-nitroso aminoacetonitrile above and are used as above in treating angina pectoris.
  • EXAMPLES l5 and 16 Tablets and Capsules Suitable For Oral Administration Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in treating angina pectoris at a dose of one tablet or capsule 2 to 3 times a day. 4
  • tablets and capsules are prepared using N-piperidino-N-nitroso-a-methyl-aminoacetonitrile; N-hexyleneimino-N-nitroso-aminoaceto nitrile;
  • EXAMPLES l7 and 18 Sterile Suspension for Injection and Oral Liquid Suspension
  • the following pharmaceutical compositions are formulated with the indicated amount of active agent using conventional techniques.
  • the injectable suspension and the oral liquid suspension represent formulations useful as unit doses and may be administered in the treatment of angina pectoris.
  • the injectable suspension is suitable for administration once a day whereas the oral liquid suspension is suitably administered 2 to 4 times per day for this purpose.
  • Sterile injectable suspen- Oral liquid Ingredients sion suspension N-(QB-hydroxyethyflpiperazino)N- 10 l0.
  • Sterile in ectable suspensions and oral liquid suspensions similarly are prepared using N-(4-[fi-hydroxyethyl]piperidino)-N-nitroso-oz-methyl aminoacetonitrile; N-(4-methoxyethylpiperidino)-N-mtroso-ammoacetonitrile; N-(4-trifluoromethylpiperidino)-N-mtroso-ammoacetonitrile; N-(Z-benzylpiperidino)-N-nitroso-am1noacetomtr1le or N-(Z-phenylpiperidino)-N-nitroso-aminoacetomtnle in place of the N (4 [B-hydroxyethyflpiperazino)-N- nitroso-aminoacetom'trile above and are used as above in treating angina pectoris. 40
  • EXAMPLES 19 and 20 Sterile Suspension for Injection and Oral Liquid Suspension
  • the following pharmaceuticalcompositions are forrnulated with the indicated amount of active agent using conventional techniques.
  • the injectable suspension and the oral liquid suspension represent formulations useful as unit doses and may be administered in the treatment of angina pectoris.
  • the injectable suspension is suitable 5 for administration. once a day whereas the oral liquid suspension is suitably administered 2 to 4 times per day for this purpose.
  • Sterile injectable Oral liquid Ingredients suspension suspension N-isoquinolino-N-nitroso-amino- 10.... 10
  • Sorbitol solution ; U.S.P 2,500 Buffer agent to adjust pH for desired Q. Q5.
  • N- l-acetylisoquinolino) -N-nitroso-aminoacetonitrile in place of N isoquinolino-N-nitroso-aminoacetonitrile above and are used as above in treating angina pectoris.
  • EXAMPLES 21 and 22 Tablets and Capsules Suitable For Oral Administration Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in treating angina pectoris at a dose of one tablet or capsule 2 to 4 times a day.
  • Sterile injectable Oral liquid Ingredients suspension suspension Npipglrazino-N-nitroso-aminoaeeto- 10 10.
  • H1 T1 8. Sodium carboxy methyl cellulose U.S.P. 1.25 12.5. Methyl cellulose 0.4 Polyvinylpyr rolidone Lecithin Benzyl almhnl 0.01.. Magnesium aluminum silicate 47.5 Flavor Q,.s. Color Qs. Methyl paraben, U.S.P 4.5. Propyl paraben U.S.P 1.0. Polysorbate eg. Tween 80), U.S.P. 5. Sorbitol solution, 70%, U.S.P. 2,500 Buffer agent to adjust pH for desired Q.s Q.s.
  • tablets and capsules are prepared using in place of the N (4 fi-hydroxyethylpiperazino)-N- nitroso-aminoacetonitrile above and are used as above in treating angina pectoris.
  • a method for treating angina pectoris which comprises orally or parenterally administering to a mammal in need of said treatment an anti-anginal elfective amount of a compound of the formula:
  • R represents hydrogen, lower alkyl or orms-Q m is O, 1 or 2;
  • R represents hydroxy; halo having an atomic weight of about 19 to 36; lower alkyl; lower alkoxy, alkanoyl having 2 to 4 carbon atoms; alkanoyloxy having where 2 to 4 carbon atoms; w-hydroxy lower alkyl; alkoxyalkyl having 2 to 4 carbon atoms; lower alkyl having 1 to 4 carbon atoms substituted with l to 4 halogen atoms having an atomic weight between about 19 to 36; or
  • R is hydrogen; lower alkyl; alkanoyl having 2 to 4 carbon atoms; w-hydroxy lower alkyl; alkoxyalkyl having 2 to 4 carbon atoms; lower alkyl having 1 to 4 carbon atoms substituted with 1 to 4 halogen atoms having an atomic weight between 19 to 36; or
  • a method according to claim 1 wherein the compound is administered to a mammal in need of said treatment at a daily dosage of from about 0.7 milligrams to about 50 milligrams.
  • a tablet suitable for sublingual administration useful for treating angina pectoris according to Claim 1 comprising as an active ingredient thereof 0.175 to 25 mg. of a compound of the formula:
  • R represents hydrogen, lower alkyl or where m is 0, l, or 2;
  • R represents hydroxy; halo having an atomic weight of about 19 to 36; lower alkyl; lower alkoxy, alkanoyl having 2 to 4 carbon atoms; alkanoyloxy having 2 to 4 carbon atoms; w-hydroxy lower alkyl; alkoxyalkyl having 2 to 4 carbon atoms; lower alkyl 13 14 having 1 to 4 carbon atoms substituted with 1 to 4 where halogen atoms having an atomic weight between m is 0, 1, or 2 about 19 to 36; or in combination with pharmaceutically acceptable excipients.
  • (GH2)m 5 6.
  • a tablet according to claim 5 in which the active ingredient is N-(4-j3-hydroxyethyl-piperazino)-N-nitrosowhere u-methyl-aminoacetonitri1e.
  • m is O, 1, or 2, and where References Cited p is 0,1, or 2, and is hydrogen; lower alkyl; alkanoyl having 2 to 4 10 Derwent Farmdoc, 30,749, Neth. Patent No. 6710945,

Abstract

CERTAIN KNOWN N-SUBSTTITUTED AMINO-N-NITROSO-AMINOACETONITRILES, E.G., N-(4-,B-HYDROXYETHYL-PIPERAZINO)-N-NITROSO-A-METHYL-AMINOACETONITRILE, HAVE BEEN FOUND TO BE USEFUL AS ANTI-ANGINAL AGENTS.

Description

United States Patent Office Patented July 30, 1974 "3,826,832 N-SUBSTlTUTED-AMINO N NITRO-AMINO- ACETONITRILES AS ANTI-ANGINAL AGENTS PaulLaAnderson, Dover, N.J., assignor to Sand -Wander, Inc., Hanover, NJ.
No Drawing. Continuatio n-in-part of application Ser. No. 44,654, June 8, 1970, and a division of application Ser. No. 113,622,-Feb. 8, 1971.-This application June 1, 1972, Ser. No. 258,610 r v- .Int. (:1. A61k27/00 *ABSTRACT OF THE DISCLOSURE Teen-tin known I N-s ubstituted amino-N-nitroso-aminoacetorii 'l es, e "g., N (4-,,3-hydroxyethyl-piperazino)-N-nitroso aunethyl-aminoacetonitrile, have been found to be useful as an'ti-anginal agents.
7 This is adivisi'on of application Ser. No. 113,622, filed Feb. 8, 'l 97'l.- a is'a"continuation-in-partof copending application Set-(No. 44,654, filed J une 8, 1970. '-"This"'inven'tior'r relates to N-nitroso-aminoacetonitrile derivativesl'More particularly, this invention concerns the use of=N-substituted aminwN-nitroso-aminoacetonitriles V ginal'agents and'to pharmaceutical compositions coiita ing'" the-above compounds as an active ingredient thereofk The active agents with which this invention is concerned may be represented by the following structural formula r, B2 BN R1 N r'1 H CN f (I) where l hydrogen, alkyl or R represents mis0,1or2;and R and R each, independently, represent lower alkyl, i.e., alkyl having 1 to 4 carbon atoms, e.g., methyl, ethyl, 11-p1'opyl and the l ike; lower alkenyl, i.e., alkenyl hav- '-.ingl3-:t o 5 carbon-atoms, e.g., allyl, and the like; lower alkynyl,.i.e., alkynyl having 3 to 5 carbon atoms; e.g., :5, propargyl and the like; w-hydroxyloweralkyl, i.e., w-
.hydroxylower alkyl,having 2 to 4 carbon atoms, e.g., B.-l1ydrox yethyl v and the like; cycloalkyl having 3 to 8 carbon atoms, e.g., cyclohexyl and the like;
-R and" R each, independently,- represent hydrogen; hy- L droxy;-halo"having-- anatomieweight of about 19 to fipcyariottrifluoromethyl; lower alkyl as defined above; lowfl alkoxy i.e.,- alkoxyhaving- 1 to 4 carbon atoms,
;g.,zmethoxy; ethoxy tand the like; alkanoyloxyvhavmg 210 11 "carbon atoms,e.g.,.acetoxy and the like; 7 alkanoyfhavingfl 'to 4icarbon atoms, e.g.,"acetyl and thei'like;'2q hydr6iry1loweralkyl, .-i.e., wehydroxy-lower lkyihhving'ii tdfi ca'rbomatoms; e.g;, fi-hydroxyethyl ridrtherlike;dialowenalkylsamino, i.e., di-lower alkyl amindwhereiirithe 1owerialky1;is- :as defined above, e.g.,
dimethylamino,:diethylamino'and the like; or
-'R*. iand R5 together on adjacent atoms may be where- CH OCH or OCH O; or R and R together with N represent where n is 4, 5 or 6; p is 0, 1 or 2; X represents O or RYN where R is hydrogen; lower alkyl as defined above; alkanoyl having 2 to 4 carbon atoms; w-hydroxy lower alkyl as defined above; alkoxyalkyl having 2 to 4 carbon atoms, e.g., methoxyethyl and the like; lower alkyl having 1 to 4 carbon atoms substituted with 1 to 4 halogen atoms having an atomic weight between 19 to 36, e.g., trifluoromethyl and the like or m is as defined above; and
R represents hydroxy; halo as defined above; lower alkyl,
as defined above; lower alkoxy, as defined above, alkanoyl having 2 to 4 carbon atoms; alkanoyloxy having 2 to 4 carbon atoms; w-hydroxy lower alkyl, as defined above, alkoxyalkyl having 2 to 4 carbon atoms, e.g., methoxyethyl and the like; lower alkyl having 1 to 4 carbon atoms substituted with 1 to 4 halogens having an atomic weight between about 19 to 36, e.g., trifluoromethyl, ap-dichloroethyl and the like; or
where m is as defined above, provided that when R and R are both trifluoromethyl or when more than one of R is trifluoromethyl on a phenyl ring, they are on other than adjacent carbon atoms.
The compounds of formula (I) are known and may be prepared according to methods disclosed in the literature from known materials. The present invention contemplates only the novel use of such compounds, particularly as anti-anginal agents. The preferred compound for this use is N-morpholino-N-nitroso-aminoacetonitrile.
Other N-disubstituted amino-N-nitroso-aminoacetonitriles which can be used in the treatment of angina pectoris include where N- (N-ethyl-o-trifiuoromethylphenylamino -N-nitrosoaminoacetonitrile N- (N-methyl-o-methoxyphenylamino) -N-nitroso-aminoacetonitrile N- N-rnethyl-o-toluidino -N-nitroso-aminoacetonitrile N- N-methyl-p-acetoxyphenylamino -N-nitroso-arninoacetonitrile N- N-methyl-p-acetylphenylamino) -N-nitroso-amino acetonitrile N- N-methyl-o- S-hydroxyethyl] phenylamino -N- nitroso-aminoacetonitrile N-( N-methyl-p-dimethylaminophenylamino -N-nitrosoaminoacetonitrile N-(N-methyl-3,4-dimethyleneoxyphenylamino) -N- nitroso-aminoacetonitrile or N- (N-methyl-3,4-methylenedioxybenzylamino -N-nitrosoaminoacetonitrile.
The N-heterocyclic substituted-N-nitroso-aminoacetonitriles contemplated as active agents in the compositions of this invention include N-piperidino-N-nitroso-aminoacetonitrile N-piperidino-N-nitroso-a-methyl-aminoacetonitrile N-hexamethyleneimino-N-nitroso-aminoacetonitrile N- 4-hydroxypiperidino -N-nitroso-amino acetonitrile N- 2,4-dichloropiperidino -N-nitroso-aminoacetonitrile N- (4-methylpiperidino -N-nitroso-aminoacetonitrile N- (4-methoxypiperidino -N-nitroso-aminoacetonitrile N- (4-acetylpiperidino) -N-nitroso-aminoacetonitrile N- (4-acetoxypiperidino -N-nitrosoaminoacetonitrile N- (4- [,B-hydroxyethyl] -piperidino -N-nitroso-aminoacetonitrile N- 4-methoxyethylpiperidino) -N-nitroso-aminoacetonitrile N- (4-trifluoromethylpiperidino) -N-nitroso-aminoacetonitrile N- (Z-benzylpiperidino) -N-nitroso-aminoacetonitrile N- 2-phenylpiperidino -N-nitroso-aminoacetonitrile N-isoquinolino-N-nitroso-aminoacetonitrile N- 1-hydroxyisoquinolino1 -N-nitroso-aminoacetonitrile N- l-chloroisoquinolino] -N-nitroso-aminoacetonitrile N-[ l-methylisoquinolino] -N-nitroso-aminoacetonitrile N-[ l-methoxyisoquinolino] -N-nitroso-aminoacetonitrile N- l-acetylisoquinolino] -N-nitroso-arninoacetonitrile N-[ l-acetoxyisoquinolino] -N-nitroso-aminoacetonitrile N- 1-fi-hydroxyethylisoquinolino -N-nitroso-aminoacetonitrile N- l-methoxyethylisoquinolino] -N-nitroso-aminoacetonitrile N- [4-trifluoromethylisoquinolino] -N-nitroso-aminoacetonitrile N-[ l-benzylisoquinolino] -N-nitroso-aminoacetonitrile N- Z-hydroxymorpholino -N-nitroso-amino acetonitrile N- 2-chloromorpholino -N-nitroso-aminoacetonitrile N- 2-methylmorpholino) -N-nitroso-aminoacetonitrile N- (2-methoxymorpholino) -N-nitroso-aminoacetonitrile N- (2-acetylmorpholino -N-nitro so-aminoacetonitrile N- (Z-acetoxymorpholino )-N-nitroso-aminoacetonitrile N-( 3-fl-hydroxyethylmorpholino) -N-nitroso-aminoacetonitrile N- 3-methoxyethylmorpholino) -N-nitroso-aminoacetonitrile N'( 3 -trifluoromethylmorpholino) -N-nitroso-aminoacetonitrile N- (3 -benzylmorpholino) -N-nitroso-aminoacetonitrile N-piperazino-N-nitro so-aminoacetonitrile N- 2-hydroxypiperazino] -N-nitroso-aminoacetonitrile N- [2-chloro-4-methylpiperazino] -N-nitroso-aminoacetonitrile N- [Z-methyl-4-acetylpiperazino] -N-nitroso-aminoacetonitrile N- [2-methoxypiperazino] -N-nitroso-aminoacetonitrile N- [2acetylpiperazino] -N-nitroso-aminoacetonitrile N- [2-acetoxypiperazino] -N-nitroso-aminoacetonitrile As indicated previously, the compounds of formula (I) are useful because they possess pharmacological activity in animals. In particular, the compounds are useful as anti-anginal agents as indicated by an increase in coronary blood flow and by a reduction of myocardial oxygen consumption in an anesthetized dog given 20 milligrams per kilogram of body weight of a compound of formula (I) intravenously.
For such usage, compound (I) may be administered orally or parenterally as such or admixed with conven tional pharmaceutical carriers. They may be administered orally in such forms as tablets, dispersible powders,.gran.- ules, capsules, syrups and elixirs, and parenterally as solutions, suspensions, dispersions, emulsions, and the like, e.g., a sterile injectable aqueous suspension. The compositions for oral use may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutically acceptable excipients, e.g., inert diluents, such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch, gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and tale. The tablets may be uncoated or coated by known techniques to delay distintegration and absorption in the gastro-intestinal tract and thereby provide a 'sustained action over a longer period. Similarly, suspensions, syrups and elixirs may contain the active ingredient-in admixture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents (methylcellulose, tragacanth and sodium alginate), wetting agents (lecithin, polyoxyethylene stearateand polyoxyethylene sorbitan monooleate) and preservatives (ethyl-p-hydroxybenzoate). Capsules may contain the active ingredient alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate and kaolin. The injectable compositions are formulated as known in the art and may contain appropriate dispersing or wetting agents and suspending agents identical or similar to those mentioned above. These pharmaceutical preparations may contain up to about of the active ingredient in combination with the carrier or adjuvant.
The anti-anginal etfective dosage of active ingredient employed for the treatment ,of angina pectoris may vary depending on the particular compound employed and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds (I) are administered at a daily dosage oflfrom about 0.01 milligram to about 25 milligrams per kilogram of animal body weight, preferably given :in divided doses two to four times a day, or in sustained release form For most large mammals in need of said treatment, thetotal daily dosage is from about 0.7 to about 50 milligrams, preferably administered sublingually. Dosage forms suitable for internal use comprise from about 0.175 to about 25 milligrams of the active compound in intimate admix- EXAMPLE 1 Tablets Tablets suitable for oral administration which contain the following ingredients may be prepared by conventional tabletting techniques. Such tablets are useful in treating agina pectoris at a dose of one tablet 2 to 4 times a day.
Ingredient: Weight (mg) N-morpholino-N-nitroso-aminoacetonitrile 10 Tragacanth 10 Lactose 237.5 Corn Starch 25 Talcum 15 Magnesium Stearate 2.5
EXAMPLE 2 Dry Filled Capsules Capsules suitable for oral administartion which contain the following ingredients are prepared in a conventional manner. Such capsules are useful in treating angina pectoris at a dose of one capsule 2 to 4 times a day.
Ingredient: Weight (mg.) N-morpholino-N-nitroso-aminoacetonitrile 10 Inert solid diluent (starch, lactose, kaolin) 290 EXAMPLES 3 and 4 Sterile Suspension for Injection and Oral Liquid Suspension The following pharmaceutical compositions are formulated with the indicated amount of active agent using conventional techniques. The injectable suspension and the oral liquid suspension represent formulations useful as unit doses and may be administered in the treatment of angina pectoris. The injectable suspension is suitable for administration once a day whereas the oral liquid suspension is suitably administered 2 to 4 times per day for this purpose.
Weight (mg.)
Sterile injectable Oral liquid Ingredients suspension suspension N-morpholino-N-nitrosoamino- 10 10 acetonitrile. Sodium carboxy methylcellulose U.S.P 1 25 12.5. Methyl cellulose 0.4 Polyvinylpyrrnlidnnn i Lecithin 3 Benzyl alcohol ()1 Magnesium aluminum silicate 47.5. Flav r Q3. Cnlnr Q5, Methyl paraben, U.S.P 4.5. Propyl paraben U.S.P 1.0. Polysorhate 80 (eg. Tween 80) U.S.P Sorbital solution, 70% U.S.P 2,500. Bufigifiasgent to adjust pH for desired Q.s Q.s.
sta y.
r For imection, Q.s. to 5 m1. wate q.s.' to 1 ml.
EXAMPLES 5 and 6 Tablets and Capsules Suitable for Oral Administration Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in treating angina pectoris at a dose of one table or capsule 2 to 4 times a day.
Weight (mg) Ingredient Tablet Capsule N-(Z-chloromorpholino) -N-nitrosoaminoacetonitrile 10 10 Tragacanth 10 Lactose 237. 5 290 Corn starch 25 Talmim Magnesium steamte 2. 5
Total 300. 0 300 Similarly, tablets and capsules are prepared using N- 2-hydroxymorpholino) -N-nitroso-aminoacetonitrile; N-(Z-methylmorpholino)-N-nitroso-aminoactonitrile; N- (Z-methoxymorpholino -N-nitroso-aminoacetonitrile; N- Z-acetylrnorpholino -N-nitroso-aminoacetonitrile or N- (2-acetoxymorpholino -N-nitro so-aminoacetonitrile in place of the N-(Z-chloromorpholino)-N-nitrosoaminoacetonitrile above and are used as above in treating angina pectoris.
EXAMPLES 7 and 8 Sterile Suspension for Injection and Oral Liquid Suspension The following pharmaceutical compositions are formulated with the indicated amount of active agent using conventional techniques. The injectable suspension and the oral liquid suspension represent formulations useful as unit doses and may be administered in the treatment of angina pectoris. The injectable suspension is suitable for administration once or twice a day whereas the oral liquid suspension is suitably administered 2 to 4 times per day for this purpose.
Weight (mg.)
Sterile injectable sus- Oral liquid Ingredients pension suspension N -(2-hydroxymorpholino)-N-nitroso- 10 10.
aminoacetonitrile. Sodium carboxy methyl cellulose U.S.P 1. 25.-.- 12. 5 Methyl cellulose 0. 4 Polyvinylpnynli d rm 9 5 "Lecithin 3 Benzyl alnnhnl 0. ()1 Magnesium aluminum silicate 47. 5.- Flav Q,.s. Cnlnr Q3, Methyl paraben, U.S.P 4. 5. Propyl paraben, U.S.P 1. 0. Polysorbate (e.g. Tween 80), U.S.P 5. Sorbitol solution, 70%, U.S.P 5. Buffer agent to adjust pH for desired-.. Q.s. Q.s. Water For injection, Q.s. to 5 ml.
(1.9. to 1 ml.
Injectable suspension and oral liquid suspensions are similarly prepared using N-(2-chloromorpholino)-N-nitroso-aminoacetonitrile; N-(Z-methylmorpholino)-N-nitroso-aminoacetonitrile; N-(3-B-hydroxymethylmorpholino)-N-nitroso-aminoacetonitrile; N-(3-methoxymethylmorpholino)-N-nitroso-aminoacetonitrile; N-(3-trifluorornethylmorpholino)-N-nitroso-aminoacetonitrile or N-(3-benzylmorpholino)-N-nitroso-aminoacetonitrile in place of the N-(2 hydroxymorpholino)-N-nitrosoaminoacetonitrile above and are used as above in treating angina pectoris.
EXAMPLES 9 and 10 Tablets and Capsules Suitable For Oral Administration Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in treating angina pectoris at a dose of one tablet or capsule 2 to 4 times a day.
Weight (mg.)
Tablet Capsule Ingredient N-diallylamino-N-nitmso-aminoaeetonitrile Magnesiuni stearate "I.
Total; 300.0
Tablets and capsules are similarly prepared using N -dimethylamino-N-nitroso-aminoacetonitrile; N-diallylamino-N-nitroso-a-phenethyl-aminoacetonitrile; N-diallylamino-N-nitroso-a-methyl-aminoacetonitrile; N-methylpropylamino-N-nitroso-aminoacetonitrile; N- (N-allyl-p-hydroxymethylamino) -N-nitrosoaminoacetonitrile; or N-methylcyclohexylamino-N-nitroso-aminoacetonitrile in place of the N-N-diallylamino-N-nitroso-aminoacetonitrile above and are used as above in treating angina pectoris.
EXAMPLES 11 and 12 Tablets and Capsules Suitable For Oral Administration Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in treating angina pectoris at a dose of one tablet or capsule 2 to 4 times a day.
Weight (mg) Tablet Capsule Ingredient N-methylphenylamlno-N-nitroso-aminoacetonitrile. Tinfim' nnth Lactose Corn Starch Talcum. Magnesium stearate Total Similarly tablets and capsules are prepared using EXAMPLES '13 and 14 for Injection and Oral Liquid Suspension The following pharmaceutical compositions are formulated with the indicated amount of active agent using conventional techniques. The injectable suspension and the oral liquid :suspension represent formulations useful as unit doses and may be administered in the treatment of angina pectoris. The injectable suspension is suitable for administration once a day whereas the oral liquid suspension is suitably administered 2 to 4 times per day for this purpose.
Sterile Suspension Weight (mgt) Sterile i injeetable Oral liquid Ingredients suspension suspension N-(N-methyl-o-toluidino)-N-nitroso- 10-. 1o.
aminoaeetronitrile. Sodium carboxy methyl cellulose U.S.P $.25. .4-
Benzyl alcohol t.
Magnesium aluminum silicate. 47 5 Flavor Q,.s Color Q.s
Methyl paraben, U.S. Propyl paraben 'U.S.P Polysorbate S0 e.g. Tween U.S.P.
Sorbitol solution, 70% U.S.P 2,500.
Buffer agent to adjust pH for desired Q.s Q.s.
stability.
Water Forinjeetilgrli,v Q.s.to5ml.
q.s. to l Sterile injectable suspensions and oral liquid suspensions are similarly prepared using N N-methyl-l -acetoxyphenylarnino -N-nitrosoaminoacetonitrile;
N- N-methyl-p-acetylphenylamino -N-nitroso aminoacetonitrile;
N- n-methyl-ofl-hydroxyethyl] phenylamino -N- nitroso-aminoacetonitrile;
N-(N-methyl-p-dimethylaminophenylamino )'-N- nitroso-aminoacetonitrile; I
N-(N-methyl-3,4-dimethyleneoxyphenylamino)-N- nitroso-aminoacetonitrile; or
N-(N-methyl3,4-methylenedioxybenzylamino)-N- nitroso-aminoacetonitrile in place of the N-(N-methyl-o-toluidino)-N-nitroso aminoacetonitrile above and are used as above in treating angina pectoris.
EXAMPLES l5 and 16 Tablets and Capsules Suitable For Oral Administration Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in treating angina pectoris at a dose of one tablet or capsule 2 to 3 times a day. 4
Weight (mg) Ingredient Tablet Capsule Npiperidino-N-nitroso-aminoaeetonitrile Magnesium stearate .II.
Total Similarly, tablets and capsules are prepared using N-piperidino-N-nitroso-a-methyl-aminoacetonitrile; N-hexyleneimino-N-nitroso-aminoaceto nitrile;
N- (4-hydroxypiperidino) -N-nitroso-aminoacetonitrile; N- 2,4-dichloropiperidino -N-nitroso-aminoacetonitrile; N- (4-methylpiperidino -N-nitroso-aminoacetonitrile; N- (4-methoxypiperidino -N-nitroso-aminoacetonitrile; N- (4-acetylpiperidino -N-nitroso-aminoacetonitrile; or N- (4-acetoxypiperidino )-N-nitroso-aminoacetonitrile,
in place of the N-piperazino-N-nitroso-aminoacetonitrile above and are used as above in treating angina pectoris.
EXAMPLES l7 and 18 Sterile Suspension for Injection and Oral Liquid Suspension The following pharmaceutical compositions are formulated with the indicated amount of active agent using conventional techniques. The injectable suspension and the oral liquid suspension represent formulations useful as unit doses and may be administered in the treatment of angina pectoris. The injectable suspension is suitable for administration once a day whereas the oral liquid suspension is suitably administered 2 to 4 times per day for this purpose.
Weight (mg.)
Sterile injectable suspen- Oral liquid Ingredients sion suspension N-(QB-hydroxyethyflpiperazino)N- 10 l0.
nitroso aminoacetonitrile. Sodium carboxy methyl cellulose 1.25 12.5.
U.S.P. Methyl cellulose 0.4 Polyvinylpyrrolidone Lecithin Benzyl alcohol Magnesium aluminum silicate Flavor Cnlnr .8. Methyl paraben, U.S.P 4.5. Propyl paraben, U.S.P 1.0. Polysorbate 80 (e.g. Tween 80) 5. Sorbitol solution, 70%, 11.82.... 2,500. Butler agent to adjust pH for d Q,.s.
t 'u S ab! ty For injection, Q.s. to 5 ml.
q.s. to 1 ml.
Sterile in ectable suspensions and oral liquid suspensions similarly are prepared using N-(4-[fi-hydroxyethyl]piperidino)-N-nitroso-oz-methyl aminoacetonitrile; N-(4-methoxyethylpiperidino)-N-mtroso-ammoacetonitrile; N-(4-trifluoromethylpiperidino)-N-mtroso-ammoacetonitrile; N-(Z-benzylpiperidino)-N-nitroso-am1noacetomtr1le or N-(Z-phenylpiperidino)-N-nitroso-aminoacetomtnle in place of the N (4 [B-hydroxyethyflpiperazino)-N- nitroso-aminoacetom'trile above and are used as above in treating angina pectoris. 40
EXAMPLES 19 and 20 Sterile Suspension for Injection and Oral Liquid Suspension The following pharmaceuticalcompositions are forrnulated with the indicated amount of active agent using conventional techniques. The injectable suspension and the oral liquid suspension represent formulations useful as unit doses and may be administered in the treatment of angina pectoris. The injectable suspension is suitable 5 for administration. once a day whereas the oral liquid suspension is suitably administered 2 to 4 times per day for this purpose.
Weight (mg.)
Sterile injectable Oral liquid Ingredients suspension suspension N-isoquinolino-N-nitroso-amino- 10.... 10
aeetonitn'le. f Sodiumcarboxymethyl ce11uJ0se-U.S.P 1.25 125 Methyl'eellulose 0.4 Polyvinylpyrrolidone. 5 Lecithin i Benzyl alcohol 0.01 Magnesium aluminum silicate Flavor- I Color I q Methyl paraben,U.S.P...* Propyl paraben U.SAP Polysorbate 80 e.g. Tween 80), U.S. 5.
Sorbitol solution; U.S.P 2,500 Buffer agent to adjust pH for desired Q. Q5.
stability. 70 Water For injection, 01.5. to 5m].
q.s. to 1 ml.
' Sterile injectable suspensions and oral liquid suspensionssimilarly areprepared using,v
N-( l-hydroxyiso quinolino -N-nitroso-aminoacet0nitrile N- l-chloroisoquinolino -N-nitros0-amino acetonitrile N- l-methylisoquinolino -N-nitroso-aminoacetonitrile;
N- l-methoxyisoquinolino )-N-nitroso-aminoacetonitrile N- l-acetylisoquinolino) -N-nitroso-aminoacetonitrile in place of N isoquinolino-N-nitroso-aminoacetonitrile above and are used as above in treating angina pectoris.
EXAMPLES 21 and 22 Tablets and Capsules Suitable For Oral Administration Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in treating angina pectoris at a dose of one tablet or capsule 2 to 4 times a day.
Weight (mg.)
Ingredient Tablet Capsule N-(1-B-hydroxyethylisoquinolino)-N- nitrosoaminoacetonitrile 10 10 Tragacanth 10 Lactose 2 Total Similarly tablets and capsules are prepared using EXAMPLES 23 and 24 Sterile Suspension for Injection and Oral Liquid Suspension The following pharmaceutical compositions are formulated with the indicated amount of active agent using conventional techniques. The injectable suspension and the oral liquid suspension represent formulations useful as unit doses and may be administered in the treatment of angina pectoris. The injectable suspension is suitable for administration once a day whereas the oral liquid suspension is suitably administered 2 to 4 times per day for this purpose.
Weight (mg.)
Sterile injectable Oral liquid Ingredients suspension suspension Npipglrazino-N-nitroso-aminoaeeto- 10 10.
H1 T1 8. Sodium carboxy methyl cellulose U.S.P. 1.25 12.5. Methyl cellulose 0.4 Polyvinylpyr rolidone Lecithin Benzyl almhnl 0.01.. Magnesium aluminum silicate 47.5 Flavor Q,.s. Color Qs. Methyl paraben, U.S.P 4.5. Propyl paraben U.S.P 1.0. Polysorbate eg. Tween 80), U.S.P. 5. Sorbitol solution, 70%, U.S.P. 2,500 Buffer agent to adjust pH for desired Q.s Q.s.
stability. Water.... For injection, q.s. to 5 m1.
q.s. to 1 ml.
Sterile injectable suspensions and oral liquid suspensions are similarly prepared using N-(Z-hydroxypiperazino)-N-nitroso-aminoacetonitrile;
N-(2-chloro-4emethylpiperazino)-N-nitros0-aminoacetonitrile;
EXAMPLES 25 and 26 Tables and Capsules Suitable for Oral Administration Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in treating angina pectoris at a dose of one tablet or capsule 2 to 4 times a day.
Weight (mg) Tablet Capsule Ingredient N-(4-B-hydroxyethylpiperazino) -N- nitrosoaminoacetonitrile 1O Tragacanth 10 Lactose 237. 5 290 Corn starch..... 25 Taleum Magnesium stearate 2. 5
Total 300. 0 300 Similarly, tablets and capsules are prepared using in place of the N (4 fi-hydroxyethylpiperazino)-N- nitroso-aminoacetonitrile above and are used as above in treating angina pectoris.
EXAMPLE 27 A tablet suitable for the preferred sublingual mode of administration may contain the following ingredients and may be prepared by conventional tabletting techniques. Such tablets are useful in treating angina pectoris and are taken sublingually as the need arises.
Ingredient: Weight (mg.) N-morpholino-N-nitroso-aminoacetonitrile 10 Mannitol 43.5 Lactose 43.5 Polyvinyl pyrrolidine 2.0 Magnesium stearate 1.0
Similarly, tablets useful in the treatment of angina pectoris which may be administered sublingually are prepared using N-diallylamino-N-nitroso-aminoacetonitrile;
N-methylphenylamino-N-nitroso-aminoacetonitrile,
N-piperidino-N-nitroso-aminoacetonitrile,
N-isoquinolino-N-nitroso-aminoacetonitrile,
N- (4-B-hydroxyethylpiperazino -N-nitroso-aminoacetonitrile or N- (4-fi-hydroxyethylpiperazino -N-nitroso-a-methylaminoacetonitrile in place of the N-morpholino-N-nitroso-aminoacetonitrile above.
What is claimed is:
1. A method for treating angina pectoris which comprises orally or parenterally administering to a mammal in need of said treatment an anti-anginal elfective amount of a compound of the formula:
where R represents hydrogen, lower alkyl or orms-Q m is O, 1 or 2; and
R represents hydroxy; halo having an atomic weight of about 19 to 36; lower alkyl; lower alkoxy, alkanoyl having 2 to 4 carbon atoms; alkanoyloxy having where 2 to 4 carbon atoms; w-hydroxy lower alkyl; alkoxyalkyl having 2 to 4 carbon atoms; lower alkyl having 1 to 4 carbon atoms substituted with l to 4 halogen atoms having an atomic weight between about 19 to 36; or
where m is 0, 1 or 2, and
where pis O,lor 2, and
R is hydrogen; lower alkyl; alkanoyl having 2 to 4 carbon atoms; w-hydroxy lower alkyl; alkoxyalkyl having 2 to 4 carbon atoms; lower alkyl having 1 to 4 carbon atoms substituted with 1 to 4 halogen atoms having an atomic weight between 19 to 36; or
where m is 0, 1 or 2.
2. A method according to claim 1 wherein the compound is administered to a mammal in need of said treatment at a daily dosage of from about 0.7 milligrams to about 50 milligrams.
3. A method according to claim 1 wherein the compound is administered to a mammal in need of said treatment in a unit dosage form comprising said compound to the extent of from about 0.175 milligrams to about 25 milligrams per unit dosage.
4. A method according to claim 1 in which the compound is N-(4-5-hydroxyethyl-piperazino)'N-nitroso-amethyl-aminoacetonitrile.
5. A tablet suitable for sublingual administration useful for treating angina pectoris according to Claim 1 comprising as an active ingredient thereof 0.175 to 25 mg. of a compound of the formula:
NO R1 Where R represents hydrogen, lower alkyl or where m is 0, l, or 2; and
R represents hydroxy; halo having an atomic weight of about 19 to 36; lower alkyl; lower alkoxy, alkanoyl having 2 to 4 carbon atoms; alkanoyloxy having 2 to 4 carbon atoms; w-hydroxy lower alkyl; alkoxyalkyl having 2 to 4 carbon atoms; lower alkyl 13 14 having 1 to 4 carbon atoms substituted with 1 to 4 where halogen atoms having an atomic weight between m is 0, 1, or 2 about 19 to 36; or in combination with pharmaceutically acceptable excipients. (GH2)m 5 6. A tablet according to claim 5 in which the active ingredient is N-(4-j3-hydroxyethyl-piperazino)-N-nitrosowhere u-methyl-aminoacetonitri1e.
m is O, 1, or 2, and where References Cited p is 0,1, or 2, and is hydrogen; lower alkyl; alkanoyl having 2 to 4 10 Derwent Farmdoc, 30,749, Neth. Patent No. 6710945,
carbon atoms; w-hydroxy lower alkyl; alkoxyalkyl Pages Publishfid 1953- having 2 to 4 carbon atoms; lower alkyl having 1 to 4 carbon atoms substituted with 1 to 4 halogen atoms JEROME GOL'DBERG Pnmary Exammer
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5691423A (en) * 1992-08-24 1997-11-25 The United States Of America As Represented By The Department Of Health And Human Services Polysaccharide-bound nitric oxide-nucleophile adducts
US5714511A (en) * 1995-07-31 1998-02-03 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Selective prevention of organ injury in sepsis and shock using selection release of nitric oxide in vulnerable organs
US5721365A (en) * 1989-09-15 1998-02-24 Us Health N-substituted piperazine NONOates
US5731305A (en) * 1989-09-15 1998-03-24 The United States Of America As Represented By The Department Of Health And Human Services Anti-hypertension compositions of secondary amine-nitric oxide adducts and use thereof
US5910316A (en) * 1992-08-24 1999-06-08 The United States Of America, As Represented By The Department Of Health And Human Services Use of nitric oxide-releasing agents to treat impotency
US6451337B1 (en) 1998-11-25 2002-09-17 The University Of Akron Chitosan-based nitric oxide donor compositions

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5721365A (en) * 1989-09-15 1998-02-24 Us Health N-substituted piperazine NONOates
US5731305A (en) * 1989-09-15 1998-03-24 The United States Of America As Represented By The Department Of Health And Human Services Anti-hypertension compositions of secondary amine-nitric oxide adducts and use thereof
US5691423A (en) * 1992-08-24 1997-11-25 The United States Of America As Represented By The Department Of Health And Human Services Polysaccharide-bound nitric oxide-nucleophile adducts
US5910316A (en) * 1992-08-24 1999-06-08 The United States Of America, As Represented By The Department Of Health And Human Services Use of nitric oxide-releasing agents to treat impotency
US6290981B1 (en) 1992-08-24 2001-09-18 The United States Of America As Represented By The Department Of Health And Human Services Use of nitric oxide-releasing agents to treat impotency
US5714511A (en) * 1995-07-31 1998-02-03 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Selective prevention of organ injury in sepsis and shock using selection release of nitric oxide in vulnerable organs
US6451337B1 (en) 1998-11-25 2002-09-17 The University Of Akron Chitosan-based nitric oxide donor compositions

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