US3780180A - N-substituted amino-n-nitroso-aminoace-tonitriles in the treatment of hypertension - Google Patents

N-substituted amino-n-nitroso-aminoace-tonitriles in the treatment of hypertension Download PDF

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US3780180A
US3780180A US00326405A US3780180DA US3780180A US 3780180 A US3780180 A US 3780180A US 00326405 A US00326405 A US 00326405A US 3780180D A US3780180D A US 3780180DA US 3780180 A US3780180 A US 3780180A
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nitroso
aminoacetonitrile
methyl
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tablets
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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
    • A61K31/275—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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines

Definitions

  • R represents hydrogen, alkyl or where m is 0, 1' or 2;
  • R and R each, independently, represent lower alkyl, i.e., alkyl having 1 to 4 carbon atoms, e.g., methyl, ethyl, n-propyl and the like; lower alkenyl, i.e., alkenyl having 3 to 5 carbon atoms, e.g., allyl, and the like; lower alkynyl, i.e., alkynyl having 3 to 5 carbon atoms; e.g., propargyl and the like; w-hydroxyloweralkyl, i.e., whydroxyloweralkyl having 2 to 4 carbon atoms, e.g., ,6- hydroxyethyl and the like; cycloalkyl having 3 to 8 carbon atoms, e.g., cyclohexyl and the like;
  • R and R each, independently, represent hydrogen
  • droxy halo having an atomic weight of about 19 to 36; cyano trifluoromethyl; lower alkyl as defined above; lower alkoxy i.e., alkoxy having 1 to 4 carbon atoms, e.g., methoxy, ethoxy, and the like; alkanoyloxy having 2 to 4 carbon atoms, e.g., acetoxy and the like; alkanoyl having 2 to 4 carbon atoms, e.g., acetyl and the like; w-hydroxy-lower alkyl, i.e., w-hydIOXY-IOWeI alkyl having 2 to 4 carbon atoms, e.g., fi-hydroxyethyl and the like; di-lower alkyl amino, i.e., di-lower alkyl amino wherein the lower alkyl is as defined above, e.g., dimethylamino, diethylamino and the like; or
  • R and R together on adjacent atoms may be CH OCH or -OCH 0-; or R and R together with N represent (2 (B6) (Rm (R 2)n X N- Q where n is 4, 5 or 6; p is 0, 1 or 2; X represents -O-- or 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 where 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, a,p-dich1oroethyl 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 hypotensive/anti-hypertensive agents.
  • the preferred compound for this use is N-morpholino-N-nitroso-arninoacetonitrile.
  • N disubstituted amino-N-nitroso-aminoacetonitriles which can be used in the pharmaceutical compositions of this invention include N-diallylamino-N-nitroso-arninoacetonitrile N-dimethylamino-N-nitroso-arninoacetonitrile N-diallylamino-N-nitroso-u-phenethyl-aminoacetonitrile N-diallylamino-N-nitroso-a-methyl-aminoacetonitrile N-methylpropargylamino-N-nitroso-aminoacetonitrile N- N-allyl-p-hydroxyethylamino -N-nitroso-aminoacetonitrile N-methylcyclohexylamino-N-nitroso-aminoacetonitrile N-methylphenylamino-N-nitroso-aminoacetonitrile N-methylphenylethylamino
  • N-heterocyclic substittued-N-nitroso-aminoacetonitriles contemplated as active agents in the compositions of this invention include N-piperidino-N-nitroso-aminoacetonitrile N-piperidino-N-nitrosoa-methyl-amin oacetonitrile N-hexamethyleneimino-N-nitroso-aminoacetonitrile N- (4-hydroxypiperidino -Nnitrosoaminoacetonitrile N- (2, 4-dichloropiperidino -N-nitroso-amino acetonitrile N- (4-methylpiperidino -N-nitroso-aminoacetonitrile N- 4-methoxypip eridino -N-nitro so-aminoacetonitrile N- 4-acetylpip eridino )-N-nitroso-aminoacetonitrile N-
  • the compounds of Formula I are useful because they possess pharmacological activity in animals.
  • they are useful as hypotensive/ anti-hypertensive agents as indicated by their activity in renal hypertensive rat given 30 mg./kg. of active compound using the technique of A. Grollman (Proc. Soc. Exptl. Biol. and Med. 57:102, 1944) and indirectly measuring the blood pressure from the caudal artery in the tail using a pneumatic pulse transducer.
  • Compound I may be administered orally or parenterally as such or admixed with conventional pharmaceutical carriers.
  • 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 talc.
  • 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 talc.
  • the tablets may be uncoated or coated
  • 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 stearate and 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 kaloin.
  • 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-hypertensive eifective dosage of active ingredient employed for the treatment of hypertension 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 of from about 0.1 milligram to about 50 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, the total daily dosage is from about 7 to about 200 milligrams.
  • Dosage forms suitable for internal use comprise from about 1.75 to about milligrams of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.
  • compositions from the standpoint of preparation and ease of administration are solid compositions, particularly hard-filled capsules and tablets containing about 25 to 100 milligrams of active ingredient.
  • EXAMPLE 1 Tablets Tablets suitable for oral administration which contain the following ingredients may be prepared by conventional 6 Similarly, tablets and capsules are prepared using: N-(2-hydroxymorpholino)-N-nitroso-aminoacetonitrile; N-(Z-methylmorpholino)-N-nitroso-aminoacetonitrile; N-(Z-methoxymorpholino)-N-nitroso-aminoacetonitrile;
  • N(z'acetoxymorphohno)'N'mtroso'ammoacetommle Ingredient Weight (mg in place of the N-(Z-chloromorpholino)-N-nitroso-amino- N morpholino N nitroso aminoacetonitrile 50 acetomtrlle above and are used as above in treating hyper- Tragacanth l0 l0 tenslon' Lactose 197.; EXAMPLES 7 AND 8 $212; lsltarch Sterile suspension for injection and oral liquid suspension Magnesium stearate 2.5 T l 0Wing pharmaceutical compositions are formu- EXAMPLE 2 lated with the indicated amount of active agent using conventional techniques.
  • the injectable suspension and the Dry filled capsules oral hquid suspension represent formulations usual as Capsules suitable for oral administration which condose? and admmlstereq m.the.treatment of tain the following ingredients are prepared in a convenhypiarton' The mlectible Suspenslon s'mable 0.1- tional manner.
  • Such capsules are useful in treating hypermlmstrqtwn. or twlce whereas h oral hquld tension at a dose of one Capsule 2 to 4 times a day suspension is suitably administered 2 to 4 times per day for thls purpose.
  • EXAMPLE 4 The following formulations for syrups or elixirs con- Injectable suspension and oral liquid suspensions-are ta-ining an eifective amount of active compound may be lmllarly prepared using: formulated conventlonal methods- N-(2-chloromorpholino)-N-nitroso-aminoacetonitrile;
  • paraben 8 2 1n place of the N-(Z-hydroxymorpholino)-N-nitrosoamigggg ifim 0 j noacetonitrile above and are used as above in treating l hypertension.
  • l Quantlty sufilclent to ad ust pH.
  • EXAMPLES 9 AND 10 EXAMPLES 5 AND 6 I Tablets and capsules suitable for 0 m1 administration Tablets and capsules suitable for oral administration Tablets and capsules containing the ingredients indi- Tablets and capsules containing the f 'g cated below may be prepared by conventional techniques Gated bfilow y be P FP y CI ⁇ Vel1i1l1al techl'llqlles and are useful in treating hypertension at a dose of one and are useful treatlPg hypertellslofl at a dose of O e tablet 0r capsule 2 to 4 times a day.
  • Tablet Capsu e Ingredient Tablet Capsule N-g-chloromorDhohm)-N-n1troso-aminoacetoni- 50 50 7o gdiany]aglino N nitmso aminoacetonimle u IHE'QPQTI iiifii q 197.5 250 Lactose Com star 25 Corn star -h Tnlonm 15 Talcum Magnesium stearate 2. 5 Magneslum stearate To 300 300 Total Tablets and capsules are similarly prepared using:
  • 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 hypertension at a dose of one tablet or capsule 2 to 4 times a day.
  • N-(N-methyl-3,4-methylenedioxybenzylamino)-N- nitroso-aminoacetonitrile in place of the N-(N-methyl-o-toluidino)-N-nitroso-aminoacetonitrile above and are used as above in treating hypertension.
  • Ingredient Tablet Capsule Tablets and capsules containing themgredrentsundrcated below may be prepared by conventional techniques and 'i i iip fi i3 are useful in treating hypertension at a dose of one Lactose 197. 5 250 tablet or capsule 2 to 4 times a day. (ll orn star h R 011m Magnesium steamfe 2. 5 Weight (mg') TOM 300 300
  • tablets and capsules are prepared using: Tragar'anth 10 l Lactose 197.
  • EXAMPLES 13 AND 14 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 hypertension.
  • 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 Oral injectable liquid Ingredients suspension suspension N-(HB-hydroxyethyllpiperazino)-N-nitrosom-ninnnnntnnifrile Sodium carboxy methyl cellulose, U.S.P.... Methyl cellulose Polyvinylpurrolidone Tmr-ii'hin Benzyl alcohol Magnesium aluminum silicate Flav r Color Y Methyl paraben, U.S.P Propyl paraben U.S.P Polysorbate (e.g. Tween 80), U.S.P Sorbitol solution, 70%, U.S.P Blflltil agent to adjust pH for desired st Water 1 For injection q.s. to 1 m1. 1 q.s. to 5 ml.
  • EXAMPLES 19 and 20 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 hypertension.
  • 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 Oral injectable liquid Ingredients suspension suspension N-isoquinolino-N-nitroso-aminoacetonitrile. Sodium carboxy methyl cellulose, U.S.P Methyl cellulose Polyvinylpyrrolidone Lecithin Benzyl alcohol. Magnesium aluminum silicate Flavor. Color Methyl paraben, U.S.P Propyl paraben U.S.P Polysorbate 80 ⁇ c.g. Tween 80), Sorbitol solution, 70%, U.S.P Bufier agent to adjust pH for d 1 For injection q.s. to 1 ml. 1 Q.s. to m1.
  • Sterile injectable suspensions and oral liquid suspensions similarly are prepared using: N- l-hydroxyisoquinolino -N-nitroso-aminoacetonitrile; N- l-chloroisoquinolino) -N-nitroso-aminoacetonitrile; N-( l-methylisoquinolino) -N-nitroso-aminoacetonitrile; N-(I-methoxyisoquinolino)-N-nitroso-aminoacetonitrile, or N l-acetylisoquinolino -N-nitroso-aminoacetonitrile in place of N-isoquinolino-N-nitroso-aminoacetonitrile above and are used as above in treating hypertension.
  • 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 hypertension at a dose of one tablet or capsule 2 to 4 times a day.
  • N- l-benzylsquinolino) -N-nitroso-aminoacetonitrile as the active ingredient in place of the N-(l-B-hydroxyethylisoquinolino)-N-nitroso-aminoacetonitrile above and are used as above in treating hypertension.
  • 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 hypertension.
  • the injectable suspension is suitable for administration once a day whereas the oral liquid sus pension is suitable administered 2 to 4 times per day for this purpose.
  • Sterile Oral injectable liquid Ingredients suspension suspension N-piperazino-N-nitroso-aminoacetonitrile Sodium carboxy methyl cellulose, U.S.P Methyl cellulose Polyvinylpyrrolidone Lecithin Benzyl alcohol Magnesium aluminum Flavor Color Methyl paraben, U.S.P Propyl paraben, U.S.P Polysorbate (e.g. Tween 80), U.S.P. Sorbitol solution, 70%, U.S.P Bufier agent to adjust pH for desir 1 For injection, (1.5. to 1 ml. 1 Q.s. to 5 ml.
  • 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 hypertension at a dose of one tablet or capsule 2 to 4 times a day.
  • tablets and capsules are prepared using:
  • N- (4-B-hydroxyethylpip erazino -N-nitrosox-phenylaminoacetonitrile in place of the N-(4-;3-hydroxyethylpiperazino)-N-nitroso-aminoacetonitrile above and are used as above in treating hypertension.
  • a method for treating hypertension which comprises orally or parenterally administering to a mammal in need of said treatment an anti-hypertensive effective amount of a compound of the formula 12 where R represents hydrogen, alkyl or 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 having 1 to 4 carbon atoms substituted with 1 to 4 halogen atoms having an atomic weight between about 19 to 36; or
  • n and p each independently is 0, 1 or 2.
  • a method according to claim 1 wherein the compound is administered to a mammal in need of said treatment at a daily dose of from about 7 milligrams to about 200 milligrams.

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Abstract

CERTAIN KNOWN N-SUBSTITUTED AMINO-N-NITROSO-AMINOACETONITRILE, E.G., N-MORPHOLINO-N-NITROSO-AMINOACETONITRILE, HAVE BEEN FOUND TO BE USEFUL AS HYPOTENSIVE/ANTIHYPERTENSIVE AGENTS.

Description

United States Patent N-SUBSTITUTED AMINO-N-NITROSO-AMINOACE- TONITRILES IN THE TREATMENT OF HYPER- TENSION Paul L. Anderson, Dover, N.J., assignor to Sandoz- Wander, Inc., Hanover, NJ.
No Drawing. Continuation-impart of abandoned application Ser. No. 41,056, May 27, 1970. This application Feb. 4,1971, Ser. No. 326,405
Int. Cl. A61k 27/00 U.S. Cl. 424248 4 Claims ABSTRACT OF THE DISCLOSURE Certain known N-substituted amino-N-nitroso-aminoacetonitrile, e.g., N morpholino-N-nitroso-aminoacetonitrile, have been found to be useful as hypotensive/antihypertensive agents.
where R represents hydrogen, alkyl or where m is 0, 1' or 2; and
R and R each, independently, represent lower alkyl, i.e., alkyl having 1 to 4 carbon atoms, e.g., methyl, ethyl, n-propyl and the like; lower alkenyl, i.e., alkenyl having 3 to 5 carbon atoms, e.g., allyl, and the like; lower alkynyl, i.e., alkynyl having 3 to 5 carbon atoms; e.g., propargyl and the like; w-hydroxyloweralkyl, i.e., whydroxyloweralkyl having 2 to 4 carbon atoms, e.g., ,6- hydroxyethyl and the like; cycloalkyl having 3 to 8 carbon atoms, e.g., cyclohexyl and the like;
where m is as defined above; and
R and R each, independently, represent hydrogen; hy-
droxy; halo having an atomic weight of about 19 to 36; cyano trifluoromethyl; lower alkyl as defined above; lower alkoxy i.e., alkoxy having 1 to 4 carbon atoms, e.g., methoxy, ethoxy, and the like; alkanoyloxy having 2 to 4 carbon atoms, e.g., acetoxy and the like; alkanoyl having 2 to 4 carbon atoms, e.g., acetyl and the like; w-hydroxy-lower alkyl, i.e., w-hydIOXY-IOWeI alkyl having 2 to 4 carbon atoms, e.g., fi-hydroxyethyl and the like; di-lower alkyl amino, i.e., di-lower alkyl amino wherein the lower alkyl is as defined above, e.g., dimethylamino, diethylamino and the like; or
R and R together on adjacent atoms may be CH OCH or -OCH 0-; or R and R together with N represent (2 (B6) (Rm (R 2)n X N- Q where n is 4, 5 or 6; p is 0, 1 or 2; X represents -O-- or 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 where 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, a,p-dich1oroethyl 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 hypotensive/anti-hypertensive agents. The preferred compound for this use is N-morpholino-N-nitroso-arninoacetonitrile.
Other N disubstituted amino-N-nitroso-aminoacetonitriles which can be used in the pharmaceutical compositions of this invention include N-diallylamino-N-nitroso-arninoacetonitrile N-dimethylamino-N-nitroso-arninoacetonitrile N-diallylamino-N-nitroso-u-phenethyl-aminoacetonitrile N-diallylamino-N-nitroso-a-methyl-aminoacetonitrile N-methylpropargylamino-N-nitroso-aminoacetonitrile N- N-allyl-p-hydroxyethylamino -N-nitroso-aminoacetonitrile N-methylcyclohexylamino-N-nitroso-aminoacetonitrile N-methylphenylamino-N-nitroso-aminoacetonitrile N-methylphenylethylamino-N-nitroso-aminoacetonitrile N-dibezylamino-N-nitroso-aminoacetonitrile N-(N-methyl-p-hydroxyphenylamino)-N-nitrosoarninoacetonitrile N-(N-propyl-p-chlorophenylamino)-N-nitroso-aminoacetonitrile N- N-methyl-p-cyanophenylamino) -N-nitrosouphenyl-aminoacetonitrile N- (N-ethyl-o-trifiuoromethylphenylamino) -N-nitrosoaminoacetonitrile N-(N-methyl-o-methoxyphenylamino)-N-nitrosoaminoacetonitrile N- (N-methyl-o-toluidino) -N-nitroso-aminoacetonitrile N-(N-methyl-p-acetoxyphenylamino) -N-nitrosoaminoacetonitrile N-(N-methyl-p-acetylphenylamino)-N-nitrosoaminoacetonitrile N-(N-methyl-o- [p-hydroxyethyl]phenylamino)-N- nitroso-aminoacetonitrile N- (N-methyl-p-dimethylaminophenylamino)-N- nitroso-aminoacetonitrile N-(N-methy1-3,4-dimethyleneoxyphenylamino)-N- nitroso-aminoacetonitrile or N- (N-methyl-3 ,4-methylenedioxybenzylamino) -N- nitroso-aminoacetonitrile.
The N-heterocyclic substittued-N-nitroso-aminoacetonitriles contemplated as active agents in the compositions of this invention include N-piperidino-N-nitroso-aminoacetonitrile N-piperidino-N-nitrosoa-methyl-amin oacetonitrile N-hexamethyleneimino-N-nitroso-aminoacetonitrile N- (4-hydroxypiperidino -Nnitrosoaminoacetonitrile N- (2, 4-dichloropiperidino -N-nitroso-amino acetonitrile N- (4-methylpiperidino -N-nitroso-aminoacetonitrile N- 4-methoxypip eridino -N-nitro so-aminoacetonitrile N- 4-acetylpip eridino )-N-nitroso-aminoacetonitrile N- (4- acetoxypiperidino -N-nitroso -amino acetonitrile N-( 4- fi-hydroxyethyl] -piperidino -Nnitroso-aminoacetonitrile N- 4-methoxyethylpip eridino -N-nitrosoaminoacetonitrile N- 4-trifiuoromethylpip eridino -N-nitroso-aminoacetonitrile N- 2-b enzylpiperidino -N-nitroso-aminoacetonitrile N- 2-phenylpip eridino) -N-nitroso-aminoacetonitrile N-isoquinolino-N-nitroso-aminoacetonitrile N- l-hydroxyisoquinolino] -N-nitroso-aminoacetonitrile N- l-chloroisoquinolino] -N-nitroso-aminoacetonitrile N-'[ l-methylisoquinolino] -N-nitroso-amino acetonitrile N- l-methoxyisoquinolino -N-nitroso-aminoacetonitrile N-[ l-acetylisoquinolino] -N-nitroso-aminoacetonitrile v N- l-acetoxyisoquinolino] -N-nitroso-aminoacetonitrile N- 113-hydroxyethylisoquinolino1 -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-aminoacetonitrile N- (2-chloromorpholino -N-nitroso-aminoacetonitrile N- (Z-methylmorpholino -N-nitroso-aminoacetonitrile N- (2-methoxymorpholino) -N-nitroso-aminoacetonitrile N-( 2-acetylmorpholino -N-nitroso-aminoacetonitrile N- (2-acetoxymorpholino )-N-nitroso-aminoacetonitrile N-( 3-fl-hydroxyethylmorpholino) -N-nitroso-aminoacetonitrile N- 3-methoxyethylmorpholino) -N-nitroso-aminoacetonitrile N- (3 -trifluoromethy1morpholino -N-nitroso-aminoacetonitrile N- 3-benzylmorpholino -N-nitroso-aminoacetonitrile N-pip erazino-N-nitroso-amino acetonitrile N- [2-hydroxypiperazino] -N-nitroso-amino acetonitrile N- [2-chloro-4-methylpiperazino] -N-nitroso-aminoacetonitrile N- [2-methyl-4-acetylpip erazino] -N-nitroso-aminoacetonitrile N- [Z-methoxypiperazino -N-nitroso-aminoacetonitrile N- [Z-acetylpiperazino] -N-nitroso-aminoacetonitrile N- [2-acetoxypiperazino] -N-nitroso-aminoacetonitrile N- [Z-fi-hydroxyethylpiperazino] -N-nitroso-aminoacetonitrile N- [Z-methoxyethylpiperazino] -N-nitroso-aminoacetonitrile N- 3-trifluoromethylpiperazino -N-nitroso-aminoacetonitrile N- [3-benzylpiperazino] -N-nitroso-aminoacetonitrile N- [4- fl-hydroxyethylpip erazino] -N-nitroso-aminoacetonitrile N- [4-methoxyethylpiperazino] -N-nitroso-aminoacetonitrile N- [4-trifluoromethylpiperazino] -N-nitroso-aminoacetonitrile N- [4-benzylpiperazino] -N-nitroso-aminoacetonitrile or N- [4-fl-hydroxyethylpiperazino] -N-nitroso-a-methylaminoacetonitrile.
As previously indicated, the compounds of Formula I are useful because they possess pharmacological activity in animals. In particular, they are useful as hypotensive/ anti-hypertensive agents as indicated by their activity in renal hypertensive rat given 30 mg./kg. of active compound using the technique of A. Grollman (Proc. Soc. Exptl. Biol. and Med. 57:102, 1944) and indirectly measuring the blood pressure from the caudal artery in the tail using a pneumatic pulse transducer. For such usage, Compound I may be administered orally or parenterally as such or admixed with conventional pharmaceutical carriers. They may be administered orally in such forms as tablets, dispersible powders, granules, 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 talc. The tablets may be uncoated or coated by known techniques to delay disintegration 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 stearate and 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 kaloin. 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-hypertensive eifective dosage of active ingredient employed for the treatment of hypertension 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 of from about 0.1 milligram to about 50 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, the total daily dosage is from about 7 to about 200 milligrams. Dosage forms suitable for internal use comprise from about 1.75 to about milligrams of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.
The preferred pharmaceutical compositions from the standpoint of preparation and ease of administration are solid compositions, particularly hard-filled capsules and tablets containing about 25 to 100 milligrams of active ingredient.
EXAMPLE 1 Tablets Tablets suitable for oral administration which contain the following ingredients may be prepared by conventional 6 Similarly, tablets and capsules are prepared using: N-(2-hydroxymorpholino)-N-nitroso-aminoacetonitrile; N-(Z-methylmorpholino)-N-nitroso-aminoacetonitrile; N-(Z-methoxymorpholino)-N-nitroso-aminoacetonitrile;
tabletting techniques. Such tablets are useful in treating 5 N'(2'acety1mrph1inf) p i or hypertension at a dose of one tablet 2 to 4 times a day. N(z'acetoxymorphohno)'N'mtroso'ammoacetommle Ingredient: Weight (mg in place of the N-(Z-chloromorpholino)-N-nitroso-amino- N morpholino N nitroso aminoacetonitrile 50 acetomtrlle above and are used as above in treating hyper- Tragacanth l0 l0 tenslon' Lactose 197.; EXAMPLES 7 AND 8 $212; lsltarch Sterile suspension for injection and oral liquid suspension Magnesium stearate 2.5 T l 0Wing pharmaceutical compositions are formu- EXAMPLE 2 lated with the indicated amount of active agent using conventional techniques. The injectable suspension and the Dry filled capsules oral hquid suspension represent formulations usual as Capsules suitable for oral administration which condose? and admmlstereq m.the.treatment of tain the following ingredients are prepared in a convenhypiartenilon' The mlectible Suspenslon s'mable 0.1- tional manner. Such capsules are useful in treating hypermlmstrqtwn. or twlce whereas h oral hquld tension at a dose of one Capsule 2 to 4 times a day suspension is suitably administered 2 to 4 times per day for thls purpose. Ingredient: Weight (mg.) N-morpholino-N-nitroso-aminoacetonitrile 50 Inert solid diluent (starch, lactose, kaolin) 250 weightfing) St 111 0 EXAMPLE 3 lmeetiibl uqtifii Sterile solution for injection Ingredients suspension suspensim N-(Z-hydroxymo h li -N-nit The following ingredients are dlssolved m water for m- S mpiflflm'etnflitrriiii o no) mojection. The resulting solution is filtered through an apff propriate medium to render a clear solution. The solution yg pylpyrrolidone is then autoclaved to render it steril 2gzyilcoh(l)l Q 0. 0i Ingredient: Weight 3 523 malmmumsmm" 3 :3
O 01' N i N mtroso ammo 1 Methyl paraben, U.S.P i l riiiilag'ifiaaare U s P "2 golcilflgrms gt gi 'd d Sorbitolsolutl0n, 7i) %,U.S.P 5
ys em S 6511'6 Bufier agent to ad ust pH for desired sta- Lecithin 0.5. 212 Q-f- Q-f- Sodium chloride 'As desired. 40 O O Fori ection, .s.t01ml. Water for IDJCCHOII To desired volume. Q'a {3 m1. q
EXAMPLE 4 The following formulations for syrups or elixirs con- Injectable suspension and oral liquid suspensions-are ta-ining an eifective amount of active compound may be lmllarly prepared using: formulated conventlonal methods- N-(2-chloromorpholino)-N-nitroso-aminoacetonitrile;
Percent by weight N-(Z-methylmorpholino)-N-nitroso-aminoacetonitrile; S m 'fly ymethylmorpholino)-N-nitrosoi y p tonitrile; gr-i ho n ignitmso-aminoaeetonitule N-(3-rnethoxymethylmorpholino)-N-nitroso-aminoace- Sli dium l aerizoate: 1-. 5 1. 5 p g s gfl g t- 5 g- N- 3-tr1iluoromethylmorpholino -N-nitroso-aminoace- Sim esyrup, U.s.P. III 30-70 0 tomtrlle,
s u igion (70% :3 :3 N-(3-benzylmorph0l1no)-N-nitroso-aminoacetonitrile M h 1 0 2.5-20
paraben 8 2 1n place of the N-(Z-hydroxymorpholino)-N-nitrosoamigggg ifim 0 j noacetonitrile above and are used as above in treating l hypertension. l Quantlty sufilclent to ad ust pH. EXAMPLES 9 AND 10 EXAMPLES 5 AND 6 I Tablets and capsules suitable for 0 m1 administration Tablets and capsules suitable for oral administration Tablets and capsules containing the ingredients indi- Tablets and capsules containing the f 'g cated below may be prepared by conventional techniques Gated bfilow y be P FP y CI}Vel1i1l1al techl'llqlles and are useful in treating hypertension at a dose of one and are useful treatlPg hypertellslofl at a dose of O e tablet 0r capsule 2 to 4 times a day. tablet capsule 2 to 4t1mes a w ht $2.9 1 Weight (mg) T 1 t Ingredient ab 6 Capsu e Ingredient Tablet Capsule N-g-chloromorDhohm)-N-n1troso-aminoacetoni- 50 50 7o gdiany]aglino N nitmso aminoacetonimle u IHE'QPQTI iiifii q 197.5 250 Lactose Com star 25 Corn star -h Tnlonm 15 Talcum Magnesium stearate 2. 5 Magneslum stearate To 300 300 Total 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-nitroso-aminoacetonitrile, or N-methylcyclohexylamino-N-nitroso-aminoacetonitrile in place of the N-N-diallylamino-N-nitroso-aminoacetonitrile above and are used as above in treating hypertension.
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 hypertension at a dose of one tablet or capsule 2 to 4 times a day.
sions are similarly prepared using:
N-(N-methyl-l-acetoxyphenylamino)-N-nitroso-aminoacetonitrile;
N- N-methyl-p-acetylphenylamino) -N-nitro so-aminoacetonitrile;
N-(n-methyl-o-[B-hydroxyethyl]phenylamino-N-nitrosoaminoacetonitrile;
N- N-rnethyl-p-dimethylaminophenyl amino) -N-nitrosoaminoacetonitrile;
N- (N-methyl-3 ,4-dimethyleneoxyphenylamino -N- nitroso-aminoacetonitrile; or
N-(N-methyl-3,4-methylenedioxybenzylamino)-N- nitroso-aminoacetonitrile in place of the N-(N-methyl-o-toluidino)-N-nitroso-aminoacetonitrile above and are used as above in treating hypertension.
EXAMPLES 15 AND 16 Tablets and capsules suitable for oral administration Weight (mg.) 20 Ingredient Tablet Capsule Tablets and capsules containing themgredrentsundrcated below may be prepared by conventional techniques and 'i i iip fi i3 are useful in treating hypertension at a dose of one Lactose 197. 5 250 tablet or capsule 2 to 4 times a day. (ll orn star h R 011m Magnesium steamfe 2. 5 Weight (mg') TOM 300 300 Ingredient Tablet Capsule N-piperidino-N-nitroso-aminoacetonitrile 50 50 Similarly tablets and capsules are prepared using: Tragar'anth 10 l Lactose 197. 5 250 N-methylphenethylammo-N-mtroso-ammoacetomtnle; Cornstarch- 25 Talcum" 15 N-dibenzylam1no-N-mtroso-aminoacetomtrile, Magnesium Stem/LL 5 N-(N-methyl-p-hydroxyphenylamino)-N-nitroso-ammo- Tm 300 300 acetonitrile; N-(N-propyl-p-chlorophenylamino)-N-nitroso-aminoacetonitrile; S1m1larly, tablets and capsules are prepared using.
N-(N-methyl-p-cyanophenylamino)-N-nitroso-aminoacetonitrile; N-(N-ethyl-o-trifiuoromethylphenylamino)-N-nitrosoaminoacetonitrile; N-(N-methyl-o-methoxyphenylamino)-N-nitroso-aminoacetonitrile, or N-(N-methyl-o-toluidino)-N-nitroso-aminoacetonitrile in place of the N-methylphenylamino-N-nitroso-aminoacetonitrile above and are used as above in treating hypertension.
EXAMPLES 13 AND 14 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 hypertension. 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 suspension Oral liquid suspension wntnr n I For injection, q.s. to 1 ml. I q.s. to 5 ml.
Sterile injectable suspensions and oral liquid suspen- N-piperidino-N-nitroso-m-methyl-aminoacetonitrile; N-hexyleneimino-N-nitroso-aminoacetonitrile; N-(4-hydroxypiperidino)-N-nitroso-aminoacetonitrile; N-(2,4-dichloropiperidino)-N-nitroso-aminoacetonitrile; N- (4-methylpiperidino -N-nitroso-aminoacetonitrile;
N- 4-methoxypiperidino -N-nitroso-amino acetonitrile; 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 hypertension.
EXAMPLES 17 AND 18 Sterile suspension for injection and oral liquid suspension Weight (mg.)
Sterile Oral injectable liquid Ingredients suspension suspension N-(HB-hydroxyethyllpiperazino)-N-nitrosom-ninnnnntnnifrile Sodium carboxy methyl cellulose, U.S.P.... Methyl cellulose Polyvinylpurrolidone Tmr-ii'hin Benzyl alcohol Magnesium aluminum silicate Flav r Color Y Methyl paraben, U.S.P Propyl paraben U.S.P Polysorbate (e.g. Tween 80), U.S.P Sorbitol solution, 70%, U.S.P Blflltil agent to adjust pH for desired st Water 1 For injection q.s. to 1 m1. 1 q.s. to 5 ml.
Sterile injectable suspensions and oral liquid suspensions similarly are prepared using:
N- (4' fi-hydroxyethyl] piperidino) -N-nitroso-u-methylaminoacetonitrile;
N- (4-methoxyethylpiperidino -N-nitroso-aminoacetonitrile;
N- (4-trifluoromethylpiperidino -N-nitroso-amino acetonitrile;
N-(Z-benzylpiperidino)-N-nitroso-aminoacetonitrile, or
N- (Z-phenylpiperidino) -N-nitro so-aminoacetonitrile in place of the N-(4- [B-hydroxyethyl]piperazino)-N- nitrosoaminoacetonitnle above and are used as above in treating hypertension.
EXAMPLES 19 and 20 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 hypertension. 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 Oral injectable liquid Ingredients suspension suspension N-isoquinolino-N-nitroso-aminoacetonitrile. Sodium carboxy methyl cellulose, U.S.P Methyl cellulose Polyvinylpyrrolidone Lecithin Benzyl alcohol. Magnesium aluminum silicate Flavor. Color Methyl paraben, U.S.P Propyl paraben U.S.P Polysorbate 80 {c.g. Tween 80), Sorbitol solution, 70%, U.S.P Bufier agent to adjust pH for d 1 For injection q.s. to 1 ml. 1 Q.s. to m1.
Sterile injectable suspensions and oral liquid suspensions similarly are prepared using: N- l-hydroxyisoquinolino -N-nitroso-aminoacetonitrile; N- l-chloroisoquinolino) -N-nitroso-aminoacetonitrile; N-( l-methylisoquinolino) -N-nitroso-aminoacetonitrile; N-(I-methoxyisoquinolino)-N-nitroso-aminoacetonitrile, or N l-acetylisoquinolino -N-nitroso-aminoacetonitrile in place of N-isoquinolino-N-nitroso-aminoacetonitrile above and are used as above in treating hypertension.
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 hypertension at a dose of one tablet or capsule 2 to 4 times a day.
Weight (mg.)
Ingredient Tablet Capsule N -(l-fi-hydroxyethylisoqulnolino) -N-nitrosoaminoacetonitrile 50 50 Traamnnth Lactose 197. 5 250 Corn starch 25 Talcum Magnesium stearate 2. 5
Total 300 300 Similarly tablets and capsules are prepared using:
N- l-acetoxyisoquinolino)-N-nit1'oso-aminoacetonitrile;
N-( 1-methoxyethylisoquinolino -N-nitroso-aminoacetonitrile;
N- (4-trifluoromethylisoquinolino -N-nitrosoaminoacetonitrile, or
N- l-benzylsquinolino) -N-nitroso-aminoacetonitrile as the active ingredient in place of the N-(l-B-hydroxyethylisoquinolino)-N-nitroso-aminoacetonitrile above and are used as above in treating hypertension.
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 hypertension. The injectable suspension is suitable for administration once a day whereas the oral liquid sus pension is suitable administered 2 to 4 times per day for this purpose.
Weight (mg) Sterile Oral injectable liquid Ingredients suspension suspension N-piperazino-N-nitroso-aminoacetonitrile Sodium carboxy methyl cellulose, U.S.P Methyl cellulose Polyvinylpyrrolidone Lecithin Benzyl alcohol Magnesium aluminum Flavor Color Methyl paraben, U.S.P Propyl paraben, U.S.P Polysorbate (e.g. Tween 80), U.S.P. Sorbitol solution, 70%, U.S.P Bufier agent to adjust pH for desir 1 For injection, (1.5. to 1 ml. 1 Q.s. to 5 ml.
Sterile injectable suspensions and oral liquid suspensions are similarly prepared using:
as the active agent in place of N-piperazino-N-nitrosoaminoacetonitrile above and are used as above in treating hypertension.
EXAMPLES 25 AND 26 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 hypertension at a dose of one tablet or capsule 2 to 4 times a day.
Weight (mg.)
Ingredient Tablet Capsule N-(Mi-bydroxyethylpiperazino)-N-nitroso-aminoaeetonit 1e 50 50 'Iragaeanth. Lactose 197. 5 250 Cornstarch 25 Taleum Magnesium stearate 2. 5
Total 300. 0 300 Similarly, tablets and capsules are prepared using:
N- (3-benzylpiperazino) -N-nitroso-aminoacetonitrile; N-(4-methoxyethylpiperazino)-N-nitroso-aminoacetonitrile; N- (4-trifiuoromethylpiperazino -N-nitroso-aminoacetonitrile; N-(4-benzylpiperazino)-N-nitroso-aminoacetonitrile; or
N- (4-;8-hydroxyethylpiperazino N-nitroso-ot-methyb aminoacetonitrile;
N- (4-B-hydroxyethylpip erazino -N-nitrosox-phenylaminoacetonitrile in place of the N-(4-;3-hydroxyethylpiperazino)-N-nitroso-aminoacetonitrile above and are used as above in treating hypertension.
What is claimed is:
1. A method for treating hypertension, which comprises orally or parenterally administering to a mammal in need of said treatment an anti-hypertensive effective amount of a compound of the formula 12 where R represents hydrogen, alkyl or 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 having 1 to 4 carbon atoms substituted with 1 to 4 halogen atoms having an atomic weight between about 19 to 36; or
WHM
Where m and p each independently is 0, 1 or 2.
2. A method according to claim 1 in which the compound is N-morpholino-N-nitroso-aminoacetonitrile.
3. A method according to claim 1 wherein the compound is administered to a mammal in need of said treatment at a daily dose of from about 7 milligrams to about 200 milligrams.
4. 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 1.75 milligrams to about milligrams per unit dosage.
References Cited Derwent #30749 Abstracting Netherlands 6710945 (Feb. 12, 1968).
STANLEY J. FRIEDMAN, Primary Examiner US. Cl. X.R.
US00326405A 1971-02-04 1971-02-04 N-substituted amino-n-nitroso-aminoace-tonitriles in the treatment of hypertension Expired - Lifetime US3780180A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2594643A1 (en) * 1986-02-21 1987-08-28 Unilever Nv CONCENTRATE BUTYREUX

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2594643A1 (en) * 1986-02-21 1987-08-28 Unilever Nv CONCENTRATE BUTYREUX

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