US3374145A - Preparations and method for treating inflammatory conditions - Google Patents

Preparations and method for treating inflammatory conditions Download PDF

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Publication number
US3374145A
US3374145A US439080A US43908065A US3374145A US 3374145 A US3374145 A US 3374145A US 439080 A US439080 A US 439080A US 43908065 A US43908065 A US 43908065A US 3374145 A US3374145 A US 3374145A
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inflammatory
amino
preparations
patients
phenyl
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US439080A
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Enkoji Takashi
Daniel Charles
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Armour Pharmaceutical Co
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Armour Pharmaceutical Co
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Priority to IL23723A priority patent/IL23723A/en
Priority to FR23257A priority patent/FR5033M/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C07D257/06—Five-membered rings with nitrogen atoms directly attached to the ring carbon atom

Definitions

  • This invention relates generally to pharmaceutical preparations which inhibit or control various aspects of inflammation, and more particularly, to preparations Which are especially effective in causing a remission in the symptoms and signs of inflammatory diseases such, for example, as rheumatoid arthritis, lupus erythematosus disseminatus, ankylosing spondylitis, psoriatic arthritis, gouty arthritis, fibromyosistis, osteoarthritis, bursitis, scleroderma and other inflammatory conditions such as bronchial asthma, pulmonary emphysema, pulmonary fibrosis, inflammation resulting from infection, inflammation resulting from tissue injury, inflammation resulting from allergy, skin disorders, including atopic dermatitis, contact dermatitis, dermatitis herpetiformis, angioedema, urticaria, and exfoliative dermatitis, pem-phigus, inflammatory eye diseases including keratitis
  • rheumatoid arthritis as illustrative of the inflammatory diseases, including those attended by both chronic and acute inflammatory conditions, rheumatoid arthritis is generally defined as a chronic, though non-fatal disease, of uncertain origin, which affects one or more of the patients joints by redness, pain, heat and/ or swelling. Frequently, inflammation in a joint causes deformity and loss of function.
  • inflammation shall refer to the occurrence of one or more of the symptoms: redness, pain, heat and swelling.
  • the traditional approach to therapeutic treatment of the inflammatory diseases such as rheumatoid arthritis heretofore comprised administering to the afilicted patient a variety of analgesics and anti-pvretics and even narcotics.
  • hormones and steroids having a systemic effect, for example, ACTH, cortisone, cortisone acetate, hy-
  • d'rocortisone prednisolone, and the prednisolone derivatives.
  • hormones and steroids have been and carbohydrate metabolism as well as induce moon face,
  • glucocorticoid steroids cannot be used except with extreme caution in the presence of active tu-rberculosis, diabetes mellitus, osteoporosis, chronic psychotic reaction-s, predisposition to thrombophlebitis, hypertension, congestive heart failure or renal insufliciency.
  • corticosteroids are not generally acceptable to patients in early stages of pregnancy. Further, corticosteroids should not usually be administered in the presence of infection because they inhibit fibroplasia and therefore, can mask the dissemination of the causative organism. Still further, in many cases of inflammatory disease, such as rheumatoid arthritis, the corticosteroids are ineffective, that is, the patients are resistant to steroid therapy.
  • the present invention is based upon our discovery of such a therapeutic agent in S-amino-l-phenyl tetrazole which, when prepared in suitable dosage form and appropriately administered to patients afllicted with chronic or acute inflammatory conditions, such as a rheumatoid disease, has the completely unexpected and highly beneficial property of regressing and controlling the inflammatory aspects of the rheumatoid disease and thereby reduces and substantially alleviates the greatest cause of pain and discomfort to the patient so affected.
  • our preparations achieve this result without creating the myriad of side effects heretofore characterising the pharmaceutically acceptable medicaments available for treating such diseases. Still further, our preparation is found effective in treating cases which do not respond to steroid therapy.
  • a principal object of the present invention is to provide new and useful pharmaceutical preparations having anti-inflammatory properties and which are especially suited for providing relief and comfort for patients afflicted with chronic and acute inflammatory conditions.
  • Another object of the present invention is to provide new and useful pharmaceutical preparations which are effective in the treatment of inflammatory conditions while being relatively free from adverse side effects particularly those which have heretofore characterized the use of glucocortico steroids.
  • Another object of the present invention is to provide new and useful pharmaceutical preparations which are effective in providing rheumatoid patients with relief and are characterized by low-toxicity.
  • Still a further object of the present invention is to provide a new and useful method of treating the signs and symptoms of chronic and acute inflammatory conditions.
  • Still another object of the present invention is to pro vide a new and useful method of treating rheumatoid diseases, such as rheumatoid arthritis, which provides results superior to the results heretofore obtained with glucocortico steroids while substantially eliminating the undesirable side effects inherent in glucocortico steroid therapy.
  • Still another object of the present invention is to provide new and useful pharmaceutical preparations which are useful in the treatment of inflammatory conditions which do not respond to steroid therapy, both when administered as the sole therapeutic agent and when employed in combination with the previously ineffective steroid.
  • the invention is predicated upon our discovery of novel medicinal preparations which are unique in that they are potent anti-inflammatory agents which, when compared with known preparations for treating chronic and acute inflammatory conditions, have a totally unexpected reduced incidence of side effects.
  • the preparations of this invention are most advantageously in a dosage unit form and comprise a non-toxic pharmaceutical carrier and 5-amino-l-phenyl tetrazole which has the following structural formula:
  • S-amino-l-phenyl tetrazole can be prepared by treating phenylthiourea with methyl iodide in anhydrous ethanol at reflux. This yields, after the solvent is removed by distillation and the residue crystallized and washed with anhydrous ether, 1-phenyl-S-methyl-isothiourea hydriodide.
  • the l-phenyl-S-methyl-isothiourea hydriodide is, in turn, treated with anhydrous hydrazine in ethanol to give, on heating, a vigorous evolution of methyl mercaptan and, after removing the solvent by distillation under vacuum, a heavy syrup, viz, 1-phenyl-3-amino-guanidine hydriodide.
  • the syrup is then dissolved in water and treated with an aqueous solution containing silver nitrate and concentrated nitric acid. After mixing, concentrated hydrochloric acid is added and the precipitated silver halides are removed by filtration. Additional hydrochloric acid then is added and the solution is cooled to C. A cold solution of sodium nitrite is then added and the pH is adjusted to a range of 8-9 by the addition of solid sodium carbonate. This mixture is stirred for a period of time at 10 C., heated to 50 C., and recooled to 10 C. The resulting precipitate is collected by filtration and washed with cold Water. Recrystallization of the precipitate from anhydrous ethanol yields S-amino-l-phenyl tetrazole.
  • a non-toxic pharmaceutically acceptable organic or inorganic acid addition salt of S-amino-l-phenyl tetrazole may be used in lieu of the S-amino-l-phenyl tetrazole, in the preparation of this invention.
  • the salt derived from acids such as hydrochloric, sulfuric, nitric, phosphoric, citric, acetic, malonic, lactic, tartaric, sulfamic, succinic, f-umaric, maleic, ethaneclisulfonic, hydrobromic, benzoic and similar non-toxic acids are suitable in the practice of the invention.
  • salts are best prepared by reacting the S-amino-l-phenyl tetrazole with a stoichiometric amount of the desired organic or inorganic acid in a suitable solvent such as ether, ethanol, acetone, water or various combinations of solvents.
  • a suitable solvent such as ether, ethanol, acetone, water or various combinations of solvents.
  • the 5 -amino-1-phenyl tetrazole ingredient will be present in an amount to produce an anti-inflammatory eflect.
  • the preparation in preparations to be administered orally, pancavally and otherwise than at the actual situs of the inflammation (herein called systemic administration, the preparation preferably will contain the active medicament in amounts calculated to provide daily dosages of from about 50 mg. to about 8000 mg, and, advantageously, from about 400 mg. to about 2400 mg, When the preparations are administered directly at the situs of the inflammation, e.g., topically, interarticularly and the like, amounts of medicament of as low as 1 mg. may be more than adequate to achieve the desired result.
  • the pharmaceutically acceptable carrier may be, for example, either a solid or a liquid.
  • suitable solid carriers are lactose, magnesium stearate, sucrose, talc, stearic acid, gelatin, agar pectin, acacia and the like.
  • suitable liquid carriers are glycols, polyglycols, peanut oil, olive oil, sesame oil, and the like.
  • the carrier or diluent may include a time delay material such as glycerol monostearate or glycerol distearate alone or with a wax.
  • the preparation can be tableted, used as a pharmaceutical powder, placed in a hard gelatin capsule, or in the form of a troche or lozenge.
  • the amount of solid carrier per dosage unit will vary widely but preferably will be from about 25 mg. to about 1 gram.
  • the preparation may be in the form of a soft gelatin capsule, a liquid suspension, an emulsion, an ointment, a suppository, a gel or a solution.
  • the amount of non-solid carrier per dose is not critical and may be adjusted to suit convenience.
  • This form of the preparation may be administered orally, topically, intravenously or pancavally, the carrier being preselected according to the administration route desired.
  • All of the various dosage forms of these preparations can be made by following such of the conventional and well known manufacturing techniques of mixing, granulating, compressing, suspending and dissolving as may be appropriate to the desired end product.
  • the method of using these materials in accordance with this invention comprises administering to a patient afllicted with the inflammatory condition, S-arnino-lphenyl tetrazole or a non-toxic organic or inorganic acid addition salt thereof, preferably combined with a nontoxic pharmaceutical carrier of the type disclosed in an amount to produce an anti-inflammatory effect.
  • a nontoxic pharmaceutical carrier of the type disclosed in an amount to produce an anti-inflammatory effect.
  • the active medicament in dosage units in most cases will be suflicient to provide a convenience oral or pancaval daily regimen by administering from 50 mg. to about 8000 mg. per day, advan-tageously from about 400 mgs. to about 2400 mgs. per day.
  • administration to the direct situs of inflammation requires substantially less medicament to achieve the desired result.
  • the administration of the preparation to the patient may be intramuscularly, parenterally, topically, pancavally, or orally, the latter being the preferable route of administration.
  • Pancavally as used herein defines administration via all of the bodys openings whether natural as the vagina, the anus, the nares, or artificial, e.g. colostorny.
  • the preparation when systemic administration as indicated, is preferably administered orally one to four times daily to provide a daily regimen of from about 50 mg. to about 8000 mg. of active medicament, advantageously from about 400 mg. to about 2400 mg.
  • the preparation is preferably administered topically or interarticularly and can contain as little as 1 mg. of active medicament per dose, depending on the specific condition being treated.
  • This method of producing anti-inflammatory action by this invention is particularly effective when applied to human beings having rheumatoid diseases such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, goutyarthritis, fibromyositis, osteoarthritis and bursitis.
  • the method is also useful in the treatment of collagen diseases such as scleroderma, lupus erythematosus disseminatus and in treating other inflammatory conditions as are associated with allergic bronchial asthma, pulmonary emphysema, pulmonary fibrosis, infection, tissue injury and the like.
  • the preparations are also effective in the treatment of inflammatory conditions accompanying intractable hay fever (pollinosis); skin disorders including atopic dermatitis (eczema), contact dermatitis, poison ivy dermatitis, neuro-dermatitis, dermatitis 'herpetiformis, angioedema, urticaria, and exfoliative dermatitis, pemphigus, inflammatory eye diseases including keratitis, allergic conjunctivitis, non-granulomatous ulceris, iridocyclitis, choroiditis, uveitis, chorioretinitis, marginal corneal ulcers and secondary glaucoma complicating inflammatory eye diseases; nephrotic syndrome and adrenogenital syndrome.
  • skin disorders including atopic dermatitis (eczema), contact dermatitis, poison ivy dermatitis, neuro-dermatitis, dermatitis 'herpetiformis, angioedema,
  • Example II then compressed into tablets.
  • Example III Ingredients: Weight, mg. 5-amino-l-phenyltetrazole 200 Avicel (microcrystalline cellulose) 150 Polyvinyl pyrrolidone 5 Magnesium stearate 4 The first three ingredients were mixed to uniformity and lubricated with a portion of the magnesium stearate. The mixture was compressed into slugs, and the slugs were reduced to uniformity and granulated. The powder was then lubricated with the remainder of the magnesium stearate and compressed into tablets.
  • Example IV Ingredients: Weight, mg. S-aniino-l-phenyltetrazole 200 Lactose 175 Magnesium stearate 5 The above ingredients were screened through a #40 US.
  • Example V Ingredients: Weight, mg. 5-aminol-phenyltetrazole 50 Sesame oil 50 The ingredients are mixed into a thick slurry and filled into a soft gelatin capsule.
  • Example VI Ingredients: Weight, mg. S-amino-l-phenyltetrazole 300 Polyethylene glycol 400 240 The ingredients are mixed into a thick into a soft gelatin capsule.
  • Example slurry and filled Ingredients Amount S-amino-l-phenyltetrazole grams -'-200 Polyethylene glycol 200, q.s. up to 1 liter.
  • the ingredients are added together and warmed to about 50 C.-60 C. to effect solution and stirred.
  • the solution was then sterile filtered, cooled to room temperature, packaged in sterile vials and stored until needed.
  • Example VIII A suitable suppository having a melting point of about 60 F. was prepared having the following ingredients in the amounts indicated. 1
  • Example IX An ointment embodying thepresent invention was prepared from the following ingredients in the amounts indicated. 1
  • Amount mg. S-amino-l-phenyltetrazole 200 Polyethylene glycol 1540' 500 Polyethylene glycol 4000 Propylene glycol 200 Cetyl alcohol a' 20 5-amino- 1-phenyltetrazole was administered orally to patients with definite rheumatoid arthritis by A.R.A. criteria. The majority of the patients had'failed to previously respond to gold, corticosteroids or both. A total of thirty-two (32) patients were so treated for intervals varying from two (2) to sixty-eight (68) weeks for a mean treatment period of. twelve (12).weeks.
  • Table II summarizes our results. Fifteen point six percent (15.6%) of the patients treated obtained complete suppression of disease while sixty-eight point seven percent (68.7%) obtained major improvement. Fifteen point six percent (15.6%) obtained only minor improvement.
  • S-amino-l-phenyltetrazole has the ability to obtain excellent response in patients not controlled previously on corticosteroids and gold, and that the response of S-arnino-l-phenyltetrazole persisted for long periods when the administration of the drug was stopped for skin rash.
  • Example XI Several case histories of therapy with S-amino-l-phenyltetrazole have been compiled from the records of the Brooklyn Hospital, Brooklyn, N.Y., and are reported below. Each patient was treated on an out-patient basis and upon admittance to the program, was given a serum glucose oxidase transaminase (SGOT), a serum glutamic pyruvate transaminase (SGPT), a complete blood count (CBC), a blood urea analysis (BUN) and urine analysis. The incoming patients afflicted with rheumatoid arthritis were classified according to the standards promulgated by the American Rheumatism Association (ARA) and the response of the patient was measured by joint score.
  • ARA American Rheumatism Association
  • Joint score refers to a rating obtained by evaluating the degree of joint involvement on the basis of heat, swelling, tenderness and pain. The criteria is 0 for no involvement and actual involvement ismeasured in increments of from 1 to 4 pluses, 4 pluses (i.e., being maximal involvement. Each comprises one unit of score. A further symbol :L, treated as 0.5 unit of score, is used to reflect a very slight involvement. Obviously, a certain amount of joint score cian doing the rating. The physician who rated these tests is highly skilled in treating inflammatory conditions and especially the rheumatoid diseases.
  • the final joint score is the summation of forty (40) separate evaluations.
  • the joints considered are: (1) the proximal interphalangeal (PIP); (2) the metacarpophalangeal (MCP); (3) the right wrist (RW); (4) the left wrist (LW); (5) the right elbow (RE); (6) the left elbow (LE); (7) the right knee (RK); (8) the left knee (LK); (9) the right angle (RA); and (10) the left angle (LA).
  • PIP proximal interphalangeal
  • MCP metacarpophalangeal
  • LW left wrist
  • RE right elbow
  • LE left elbow
  • RK right knee
  • LK left knee
  • RA right angle
  • LA left angle
  • a pharmaceutical preparation having anti-inflammatory activity comprising a pharmaceutically acceptable carrier and from about 1 mg. to about 8000 mg. of a member selected from the group consisting of S-aminol-phenyl tetrazole and its non-toxic pharmaceutically acceptable acid addition salts.
  • a preparation according to claim 2 containing from about 50 to about 8000 mg. of S-amino-l-phenyl tetrazole.
  • a preparation for the treatment of a patient having rheumatoid arthritis containing a pharmaceutically acceptable carrier and as an essential therapeutic agent from about 1 mg. up to about 8000 mg. of S-amino-lphenyl tetrazole effective to obtain a control on the overt manifestations of rheumatoid arthritis as evidenced by the patients joint score.
  • a method of providing anti-inflammatory action in animals comprising administering to an animal suffering from an inflammatory condition a compound selected from the group consisting of S-aminol-phenyl tetrazole and its non-toxic pharmaceutically acceptable acid addition salts in an amount sufficient to provide anti-inflammatory action.
  • the method of controlling an inflammatory condition in animals comprising administering to an animal so afiiicted, a daily dose of up to about 8000 mg./daily of a compound selected from the group consisting of S-amino-l-phenyl tetrazole and its nontoxic pharmaceutically acceptable acid addition salts.
  • said daily dose comprises at least about 200 mg. of said compound and the administration is systemic.
  • said daily dose comprises at least about 1 mg. of said compound and said administration is directly to the situs of the inflammatory condition.
  • the method of controlling and suppressing the inflammatory aspects of rheumatoid arthritis in man comprising administering to a man afllicted with rheumatoid arthritis via the oral route a small but effective amount up to about 80000 mg./daily of a compound selected from the group consisting of S-amino-l-phenyl tetrazole and its non-toxic pharmaceutically acceptable acid addition salts.
  • the method of controlling and reducing in an afflicted patient the overt manifestations of rheumatoid arthritis as measured by joint score comprising administering to said patient a drug containing as an essential active ingredient a compound selected from S-amino-l-phenyl tetrazole and its non-toxic pharmaceutically acceptable acid addition salts on a daily regimen.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US439080A 1965-03-11 1965-03-11 Preparations and method for treating inflammatory conditions Expired - Lifetime US3374145A (en)

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US439080A US3374145A (en) 1965-03-11 1965-03-11 Preparations and method for treating inflammatory conditions
IL23723A IL23723A (en) 1965-03-11 1965-06-14 Preparations containing 5-amino-1-phenyl tetrazole for treating inflammatory conditions
FR23257A FR5033M (en:Method) 1965-03-11 1965-07-02

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4185100A (en) * 1976-05-13 1980-01-22 Johnson & Johnson Topical anti-inflammatory drug therapy
EP0035046A1 (en) * 1978-09-07 1981-09-09 Otsuka Pharmaceutical Co., Ltd. Novel tetrazole derivatives, process for the preparation thereof, and anti-ulcer composition containing the same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4185100A (en) * 1976-05-13 1980-01-22 Johnson & Johnson Topical anti-inflammatory drug therapy
EP0035046A1 (en) * 1978-09-07 1981-09-09 Otsuka Pharmaceutical Co., Ltd. Novel tetrazole derivatives, process for the preparation thereof, and anti-ulcer composition containing the same

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Publication number Publication date
IL23723A (en) 1969-02-27
FR5033M (en:Method) 1967-05-02

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