US3592898A - Nonaddictive combinations of analgetics with amphetamines having substituents on the phenyl group - Google Patents

Nonaddictive combinations of analgetics with amphetamines having substituents on the phenyl group Download PDF

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US3592898A
US3592898A US805373A US3592898DA US3592898A US 3592898 A US3592898 A US 3592898A US 805373 A US805373 A US 805373A US 3592898D A US3592898D A US 3592898DA US 3592898 A US3592898 A US 3592898A
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chloroamphetamine
combinations
analgetic
amphetamines
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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • 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
    • A61K31/33—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine

Definitions

  • This invention relates to analgetics. More particularly, this invention is concerned with a method of producing a potent analgetic effect without addiction and novel compositions useful in such treatment.
  • Potent synthetic analgetics such as meperidine, methadone, anileridine, alphaprodine, piminodine, phenampromide, and diampromide are knovvn to induce physical dependence, or addiction liability, and tolerance. This limits their usefulness even though they are relatively inexpensive.
  • a potent analgetic effect can be induced in an animal, and particularly a human, without concomitant production of tolerance, physical dependence and addiction by the simultaneous or concomitant administration of a substituted amphetamine compound or its non-toxic acid addition salts, with a synthetic analgetic such as meperidine, methadone, codeine, anileridine, alphaprodine, piminodine, phenampromide, diampromide, or pentazocme.
  • a synthetic analgetic such as meperidine, methadone, codeine, anileridine, alphaprodine, piminodine, phenampromide, diampromide, or pentazocme.
  • EBy amphetamine compound is meant a compound having a substituent on the phenyl ring of the amphetamine structure of the general formula 0 H3 R R1 wherein R is hydrogen or a lower alkyl, particularly methyl or ethyl and R is a halo group and particularly chloro or bromo, the nitro group and the trifiuoromethyl group, and nontoxic physiologically acceptable acid addition salts thereof such as the hydrochloride, hydrobromide, sulfate, phosphate, fumarate, maleate, citrate and cyclohexanesulfamate salts.
  • amphetamines which can be used are p-chloro-amphetamine, p chloro-N-methylamphetamine, m trifluoromethylamphetamine, m trifluoromethyl N- methylamphetamine, p trifluoromethyl-N-ethylamphetamine, p-nitroamphetamine and p-nitro-N-methylamphetamine.
  • the substituted amphetamine compound is capable of abolishing or markedly reducing the physical dependence and tolerance properties of the analgetic without significantly interfering with its analgetic action.
  • the range of therapeutic utility and safety of the potent but addicting synthetic anagetics can be greatly increased by the simultaneous or concomitant administration of the substituted amphetamine compound and its non-toxic acid addition salts.
  • the amount of substituted amphetamine compound, in the form of its base or a non-toxic acid addition salt, which 'ice can be administered to protect against inducing physical dependence and tolerance by an analgetic can vary over a broad range. However, enough should be administered to obtain the desired result while avoiding the administration of more than needed. Generally, from about 10 to 350 mg. of a substituted amphetamine compound and its nontoxic acid addition salts can be administered simultaneously or concomitantly with the administration of an effective dosage of an anaightic.
  • the dosage of analgetic administered can vary, since the potency of the analgetics varies considerably between drugs. However, the amount of analgetic administered will generally be from about 2 to 300 mg.
  • analgetic and substituted amphetamine compound and its non-toxic acid addition salts can be administered separately, either simultaneously or concomitantly with each other, it is much more suitable to administer them in unit dosage pharmaceutical compositions which contain an amount of each at least adequate when administered one or more dosages at a time to obtain an effective action in a human.
  • novel unit dosage pharmaceutical compositions which contain an effective amount of the analgetic, usually from about 2 to 300 mg. of such drug, and an effective amount of a substituted amphetamine compound in the form of its non-toxic acid addition salts, usually from about 10 to 350 mg. of such compound, which can be admixed, if advisable, with a pharmaceutical carrier to facilitate forming tablets, capsules, losenges and liquid formulations.
  • the compositions should generally contain about 0.5 :to by weight of the active ingredients.
  • compositions which are liquid or solid may be used.
  • the preferred liquid carrier is water. Flavoring materials may be included in the solutions as desired.
  • Solid pharmaceutical carriers such as starch, sugar, talc and the like may be used to form powders.
  • the powders may be used as such for direct administration to a patient or, instead, the powders may be added to suitable foods and liquids, including water, to facilitate administration.
  • the powders may also be used to make tablets, or to fill gelatin capsules.
  • Suitable lubricants like magnesium stearate, binders such as gelatin, and disintegrating agents like sodium carbonate in combination with citric acid may be used to form the tablets.
  • a typical tablet can have the composition:
  • a gelatin capsule can contain the following active drugs:
  • Anileridine 50 p-chloroamphetamine -H SO 25 The amount of the analgetic, and thus of a substituted amphetamine compound or its non-toxic acid addition salt, will be governed by the activity of the particular analgetic used since the activity varies from one analgetic to another. The following are typical ranges of dosages which can be used in the combinations:
  • p-chloroamphetamine or p-chloro-N-methylamphetamine can be replaced with another substituted amphetamine such as m-trifluoromethylamphetamine, m-trifiuoromethyl- N-methylamphetamine, p-trifluoromethyl-N-ethylamphetamine, p-nitroamphetamine and p-nitro-N-methylamphetamine in the form of an acid-addition salt.
  • the oral route is most suitable.
  • the number of unit dosages administered daily is to be prescribed by a physician in light of the patients general condition and the results to be sought.
  • the subject invention has primary value to humans, it can also be used in lower animals such as dogs and horses and captive wild animals such as in zoos, and particularly in large mammals.
  • the method of inducing an analgetic effect in an animal which comprises simultaneously or concomitantly administering to the animal about 2 to 300 mg. of a synthetic analgetic selected from the group consisting of meperidine, methadone, anileridine, alphaprodine, piminodine, phenampromide, codeine, or pentazocine and about to 350 mg. of a substituted amphetamine compound of the formula wherein R is hydrogen or lower alkyl and R is halo, nitro or trifiuoromethyl, or a nontoxic acid addition salt thereof.
  • a synthetic analgetic selected from the group consisting of meperidine, methadone, anileridine, alphaprodine, piminodine, phenampromide, codeine, or pentazocine and about to 350 mg. of a substituted amphetamine compound of the formula wherein R is hydrogen or lower alkyl and R is halo, nitro or trifiuoromethyl, or a nontoxic acid addition salt
  • substituted amphetamine compound is p-chloroamphetamine, pchloro N methylamphetamine, m trifluoromethylwherein R is hydrogen or lower alkyl and R is halo, nitro or trifiuoromethyl, or a nontoxic acid addition salt thereof.
  • a pharmaceutical composition according to claim 3 in which the substituted amphetamine compound is pchloroamphetamine, p-chloro-N-methylamphetamine, mtrifluoromethylamphetamine, m trifiuoromethyl N methylamphetamine, p trifiuoromethyl N ethylamphetamine, p nitroamphetamine or p nitro N methylamphetamine.
  • a pharmaceutical composition according to claim 4 containing about 50 to 300 mg. of meperidine and about 50 to 350 mg. of p-chloroamphetamine.
  • a pharmaceutical composition according to claim 4 containing about to 40 mg. of methadone and about 50 to 350 mg. of p-chloroamphetamine.
  • a pharmaceutical composition according to claim 4 containing about to 100 mg. of anileridine and about 50 to 350 mg. of p-chloroamphetamine.
  • a pharmaceutical composition according to claim 4 containing about 50 to 200 mg. of alphaprodine and about 50 to 0 mg. of p-chloroamphetamine.
  • a pharmaceutical composition according to claim 4 containing about 25 to 200 mg. of piminodine and about to 350 mg. of p-chloroamphetamine.
  • a pharmaceutical composition according to claim 4 containing about 50 to 250 mg. of phenampromide and about 50 to 350 mg. of p-chloroamphetamine.
  • a pharmaceutical composition according to claim 4 containing about 10 to 50 mg. of diampromide and about 50 to 350 mg. of p-chloroamphetamine.
  • a pharmaceutical composition according to claim 4 containing about 10 to 200 mg. of pentazocine and about 50 to 350 mg. of p-chloro-N-methylamphetamine.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

DISCLOSED ARE COMBINATIONS OF AN ANALGETIC WITH P-CHLOROAMPHETAMINE AND OTHER AMPHETAMINES CONTAINING AT LEAST ONE SUBSTITUENT ON THE PHENYL RING, AND NON-TOXIC ACID ADDITION SALTS THEREOF. WHEN SUCH COMBINATIONS ARE ADMINISTERED, TOLERANCE, PHYSICAL DEPENDENCE AND ADDITION ARE NOT INDUCED.

Description

United States Patent 3,592,898 NONADDICTIVE COMBINATIONS 0F ANAL- GETICS WITH AMPHETAMINES HAVING SUBSTITUENTS ON THE PHENYL GROUP John H. Biel, 4444 N. Murray Ave, Milwaukee, Wis. 53211 No Drawing. Filed Mar. 7, 1969, Ser. No. 805,373 Int. Cl. A6lk 27/00 US. Cl. 424-260 12 Claims ABSTRACT OF THE DISCLOSURE Disclosed are combinations of an analgetic with p-chloroamphetamine and other amphetamines containing at least one substituent on the phenyl ring, and non-toxic acid addition salts thereof. When such combinations are administered, tolerance, physical dependence and addiction are not induced.
This invention relates to analgetics. More particularly, this invention is concerned with a method of producing a potent analgetic effect without addiction and novel compositions useful in such treatment.
Potent synthetic analgetics such as meperidine, methadone, anileridine, alphaprodine, piminodine, phenampromide, and diampromide are knovvn to induce physical dependence, or addiction liability, and tolerance. This limits their usefulness even though they are relatively inexpensive.
It has now been found according to the present invention that a potent analgetic effect can be induced in an animal, and particularly a human, without concomitant production of tolerance, physical dependence and addiction by the simultaneous or concomitant administration of a substituted amphetamine compound or its non-toxic acid addition salts, with a synthetic analgetic such as meperidine, methadone, codeine, anileridine, alphaprodine, piminodine, phenampromide, diampromide, or pentazocme.
EBy amphetamine compound is meant a compound having a substituent on the phenyl ring of the amphetamine structure of the general formula 0 H3 R R1 wherein R is hydrogen or a lower alkyl, particularly methyl or ethyl and R is a halo group and particularly chloro or bromo, the nitro group and the trifiuoromethyl group, and nontoxic physiologically acceptable acid addition salts thereof such as the hydrochloride, hydrobromide, sulfate, phosphate, fumarate, maleate, citrate and cyclohexanesulfamate salts. Specific amphetamines which can be used are p-chloro-amphetamine, p chloro-N-methylamphetamine, m trifluoromethylamphetamine, m trifluoromethyl N- methylamphetamine, p trifluoromethyl-N-ethylamphetamine, p-nitroamphetamine and p-nitro-N-methylamphetamine.
The substituted amphetamine compound is capable of abolishing or markedly reducing the physical dependence and tolerance properties of the analgetic without significantly interfering with its analgetic action. Thus, the range of therapeutic utility and safety of the potent but addicting synthetic anagetics can be greatly increased by the simultaneous or concomitant administration of the substituted amphetamine compound and its non-toxic acid addition salts.
The amount of substituted amphetamine compound, in the form of its base or a non-toxic acid addition salt, which 'ice can be administered to protect against inducing physical dependence and tolerance by an analgetic can vary over a broad range. However, enough should be administered to obtain the desired result while avoiding the administration of more than needed. Generally, from about 10 to 350 mg. of a substituted amphetamine compound and its nontoxic acid addition salts can be administered simultaneously or concomitantly with the administration of an effective dosage of an analegtic. The dosage of analgetic administered can vary, since the potency of the analgetics varies considerably between drugs. However, the amount of analgetic administered will generally be from about 2 to 300 mg.
Although the analgetic and substituted amphetamine compound and its non-toxic acid addition salts can be administered separately, either simultaneously or concomitantly with each other, it is much more suitable to administer them in unit dosage pharmaceutical compositions which contain an amount of each at least adequate when administered one or more dosages at a time to obtain an effective action in a human. There are, therefore, provided by this invention novel unit dosage pharmaceutical compositions which contain an effective amount of the analgetic, usually from about 2 to 300 mg. of such drug, and an effective amount of a substituted amphetamine compound in the form of its non-toxic acid addition salts, usually from about 10 to 350 mg. of such compound, which can be admixed, if advisable, with a pharmaceutical carrier to facilitate forming tablets, capsules, losenges and liquid formulations. The compositions should generally contain about 0.5 :to by weight of the active ingredients.
Pharmaceutical carriers which are liquid or solid may be used. The preferred liquid carrier is water. Flavoring materials may be included in the solutions as desired.
Solid pharmaceutical carriers such as starch, sugar, talc and the like may be used to form powders. The powders may be used as such for direct administration to a patient or, instead, the powders may be added to suitable foods and liquids, including water, to facilitate administration.
The powders may also be used to make tablets, or to fill gelatin capsules. Suitable lubricants like magnesium stearate, binders such as gelatin, and disintegrating agents like sodium carbonate in combination with citric acid may be used to form the tablets.
A typical tablet can have the composition:
Mg. l) Meperidine (2) p-chloroamphetamine -HCl 10 (3) Starch, U.S.P. 57 (4) Lactose, U.S.P. 73 (5 Talc, U.S.P 9 (6) Stearic acid 6 Powders 1, 2, 3 and 4 are slugged, then granulated, mixed with 5 and 6, then tableted.
A gelatin capsule can contain the following active drugs:
Mg. Anileridine 50 p-chloroamphetamine -H SO 25 The amount of the analgetic, and thus of a substituted amphetamine compound or its non-toxic acid addition salt, will be governed by the activity of the particular analgetic used since the activity varies from one analgetic to another. The following are typical ranges of dosages which can be used in the combinations:
A: Mg. Meperidine 50-300 p-chloroamphetamine -H PO 50-350 Mg. Methadone 2-40 p-chloroamphetarnine fumarate 50-350 Anileridine 25-100 p-chloroamphetamine maleate 50-350 Alphaprodine 50-200 p-chloroamphetamine cyclhexar1esulfamate 75-350 Piminodine 25-200 p-chloroamphetamine citrate 75-350 Phenampromide 50-250 p-chloroamphetamine -HCl 50-350 Diampromide 10-50 p-chloroamphetamine sulfate 50-350 Pentazocine 10-200 p-chloro-N-methylamphetamine 0-3 50 Such combinations can be formulated into unit dosage forms with or without carriers. They are particularly useful in tablet form. In each of these formulations, or others that will be obvious to one skilled in the art, p-chloroamphetamine or p-chloro-N-methylamphetamine can be replaced with another substituted amphetamine such as m-trifluoromethylamphetamine, m-trifiuoromethyl- N-methylamphetamine, p-trifluoromethyl-N-ethylamphetamine, p-nitroamphetamine and p-nitro-N-methylamphetamine in the form of an acid-addition salt.
Although the drugs might be administered by other routes, the oral route is most suitable. The number of unit dosages administered daily is to be prescribed by a physician in light of the patients general condition and the results to be sought.
Although the subject invention has primary value to humans, it can also be used in lower animals such as dogs and horses and captive wild animals such as in zoos, and particularly in large mammals.
Various changes and modifications of the invention can be made and, to the extent that such variations incorporate the spirit of this invention, they are intended to be included within the scope of the appended claims.
What is claimed is:
1. The method of inducing an analgetic effect in an animal which comprises simultaneously or concomitantly administering to the animal about 2 to 300 mg. of a synthetic analgetic selected from the group consisting of meperidine, methadone, anileridine, alphaprodine, piminodine, phenampromide, codeine, or pentazocine and about to 350 mg. of a substituted amphetamine compound of the formula wherein R is hydrogen or lower alkyl and R is halo, nitro or trifiuoromethyl, or a nontoxic acid addition salt thereof.
2. The method of claim 1 in which the substituted amphetamine compound is p-chloroamphetamine, pchloro N methylamphetamine, m trifluoromethylwherein R is hydrogen or lower alkyl and R is halo, nitro or trifiuoromethyl, or a nontoxic acid addition salt thereof.
4. A pharmaceutical composition according to claim 3 in which the substituted amphetamine compound is pchloroamphetamine, p-chloro-N-methylamphetamine, mtrifluoromethylamphetamine, m trifiuoromethyl N methylamphetamine, p trifiuoromethyl N ethylamphetamine, p nitroamphetamine or p nitro N methylamphetamine.
5. A pharmaceutical composition according to claim 4 containing about 50 to 300 mg. of meperidine and about 50 to 350 mg. of p-chloroamphetamine.
6. A pharmaceutical composition according to claim 4 containing about to 40 mg. of methadone and about 50 to 350 mg. of p-chloroamphetamine.
7. A pharmaceutical composition according to claim 4 containing about to 100 mg. of anileridine and about 50 to 350 mg. of p-chloroamphetamine.
8. A pharmaceutical composition according to claim 4 containing about 50 to 200 mg. of alphaprodine and about 50 to 0 mg. of p-chloroamphetamine.
9. A pharmaceutical composition according to claim 4 containing about 25 to 200 mg. of piminodine and about to 350 mg. of p-chloroamphetamine.
10. A pharmaceutical composition according to claim 4 containing about 50 to 250 mg. of phenampromide and about 50 to 350 mg. of p-chloroamphetamine.
11. A pharmaceutical composition according to claim 4 containing about 10 to 50 mg. of diampromide and about 50 to 350 mg. of p-chloroamphetamine.
12. A pharmaceutical composition according to claim 4 containing about 10 to 200 mg. of pentazocine and about 50 to 350 mg. of p-chloro-N-methylamphetamine.
References Cited UNITED STATES PATENTS 3,284,298 11/1966 Fujimura et a1. 424330 OTHER REFERENCES Merck Index, 7th ed. (1960), pp. 39, 81, 336, 646, 662 and 791.
Analgetics, De Stevens (1965), pp. 172, 187 and 818.
Chem. Abst. (1), 67, 4236lg (1967).
Chem. Abst. (2), 67, 42234t (1967).
STANLEY I FRIEDMAN, Primary Examiner U.S. Cl. X.R. 424267, 330
US805373A 1969-03-07 1969-03-07 Nonaddictive combinations of analgetics with amphetamines having substituents on the phenyl group Expired - Lifetime US3592898A (en)

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