US3478026A - 6 - cycloalkylguanamines,preparations and methods for treating inflammatory conditions therewith - Google Patents

6 - cycloalkylguanamines,preparations and methods for treating inflammatory conditions therewith Download PDF

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US3478026A
US3478026A US660919A US3478026DA US3478026A US 3478026 A US3478026 A US 3478026A US 660919 A US660919 A US 660919A US 3478026D A US3478026D A US 3478026DA US 3478026 A US3478026 A US 3478026A
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grams
inflammatory
preparations
cycloalkylguanamines
inflammatory conditions
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Takashi Enkoji
Edward M Levine
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Armour Pharmaceutical Co
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Armour Pharmaceutical Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine

Definitions

  • the compounds are of the class of 6-(substituted)guanamines, also called 2,4-diamino-s-triazines, and are useful in forming preparations for the therapeutic treatment of inflammatory conditions.
  • exemplary of the compounds disclosed is '6-cyclopropylguanamine.
  • the non-toxic acid addition salts of the compounds are also therapeutically useful.
  • This invention relates to new chemical compounds, to pharmaceutical preparations containing such compounds and to therapeutic methods of using such compounds in treating inflammatory conditions.
  • the treatment of inflammatory conditions refers to the inhibition or control of various aspects of inflammation and, more particularly, to a remission of the symptoms and signs of inflammatory diseases, such for example, as rheumatoid arthritis, lupus erythematosus disseminatus, ankylosing spondylitis, psoriatic arthritis, gouty arthritis, fibromyostis, 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, pemphigus, inflammatory eye diseases including keratitis, allergis conjunctivitis, nongranulomatous ulceris, and other inflammatory
  • rheumatoid arthritis as illustrative of the inflammatory diseases, including those attended by both chronic and acute inflammatory conditons, rheumatoid arthritis is generally defined as a chronic, though nonfatal 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 afllicted patient a variety of analgesics and antipyretics and even narcotics.
  • hormones and steroids having a systemic effect, for example, ACTH, cortisone, cortisone acetate, hydrocortisone, prednisolone, and the prednisolone derivatives.
  • the hormones and steroids have been combined with analgesics and antipyretics to provide further therapeutic approaches.
  • the glucocorticoid steroids cannot be used except with extreme caution in the presence of active tuberculosis, diabetes mellitus, osteoporosis, chronic psychotic reactions, predisposition to thrombophlebitis, hypertension, congestive heart failure or renal insufficiency.
  • the 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.
  • anti-inflammatory agents be made available which may be administered orally and which are very low in toxicity.
  • the present invention is based upon our discovery of 6-cycloalkylguanamines of the type having the structural formula wherein R is cycloalky-l having a carbon content of C to C
  • these compounds when employed in pharmaceutical preparations, possess definite anti-inflammatory properties.
  • these compounds are potent anti-inflammatory agents, may be ad ministered orally, have a surprisingly low degree of toxicity, and exhibit substantially none of the side effects which characterize steroid therapy.
  • a principal object of the present invention is to provide new and useful chemical compounds which, when employed in pharmaceutical preparations for therapeusis, have anti-inflammatory properties and are especially well 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 chemical compounds which, when employed in pharmaceutical preparations for therapeusis, are effective to treat inflammatory conditions while being relatively free from adverse side effects particularly those which have heretofore characterized the use of glucocorticosteroids.
  • Still another object of the present invention is to provide new and useful chemical compounds which, when employed in pharmaceutical preparations for therapeusis, are characterized by low toxicity and permit the treatment of the signs and symptoms of chronic and acute inflammatory conditions.
  • the invention is predicated upon our discovery of 6- cycloalkylguanamines of the type indicated and upon our further discovery that our novel chemical compounds can be formulated into unique medicinal preparations having potent anti-inflammatory activity and which, when compared with known preparations for treating chronic and acute inflammatory conditions, have an unexpectedly reduced incidence of side effects.
  • 6-cycloalkylguanamines of the present invention are characterized by unsubstituted amino groups in the 2 and 4 positions and a cycloalkyl group in the 6 position. They may be called 2,4-diamino-6-cycloalkyl-s-triazines,
  • 6-cycloalkylguanamine for instance, 6-cyclohexylguanamine
  • 6-cyclohexylguanamine may be synthesized by the catalytic hydrogenation of 6-(3cyclohexenyl) guanamine.
  • a 6-cycloalkylguanamine having the desired cycloalkyl substitution may be prepared by reacting the corresponding substituted cycloalkyl cyanide with dicyandiamide in the presence of ethylene glycol monomethyl or monoethyl esther and a basic catalyst such as potassium hydroxide at reflux temperatures (e.g., 105- 130 C.) for about 3 to 7 hours.
  • a basic catalyst such as potassium hydroxide
  • the solvent is then removed from the reaction, as by vacuum distillation, and the residue is collected as by fi-ltration and solubilized in a concentrated mineral acid.
  • the resulting solution is then filtered and the filtrate neutralized to pH 8-9 and cooled.
  • the 6-cycloalkylguanamine precipitates, and this precipitate may be collected and purified, using conventional techniques.
  • the resulting 6-cycloalkylguanamine is a white crystalline solid.
  • the 6-cycloalkylguanamine is rendered water-soluble by converting it to its acid-addition salt upon reaction with a non-toxic mineral acid such as hydrochloric, sulfuric, phosphoric and the like.
  • a non-toxic pharmaceutically acceptable organic or inorganic acid addition salt of each of the 6-cycloalkylguanamines may be used in lieu of the guanamine in the practice of the therapeusis of this invention.
  • the salt derived from reacting 6-cycloalkylguanamine with such acids as hydrochloric, sulfuric, nitric, phosphoric, citric, acetic, malonic, lactic, tartaric, sulfamic, succinic, fumaric, maleic, ethanedisulfonic, hydrobromic, benzoic and similar non-toxic acids are suitable to use in the practice of the invention.
  • the 6-cycloalkylguanamine ingredient will be present in an amount sufficient to produce an antiinflammatory effect.
  • the guanamine is admixed with a pharmaceutically acceptable excipient which may be either solid or liquid.
  • a pharmaceutically acceptable excipient which may be either solid or liquid.
  • Suitable solid carriers include lactose, magnesium stearate, sucrose, talc, stearic acid, gelatin, agar pectin, acacia and the like.
  • Suitable liquid carries include the glycols, the polyglycols,
  • the carrier or diluent may also include a time delay material such as glycerol monostearate or glycerol distearate, either alone or with wax.
  • a Wide variety of pharmaceutical forms can be employed.
  • the preparation can be formed into a tablet, a troche, a pastille or a lozenge or it can be pulverized into a powder which may, if desired, be loaded into hard gelatin capsules.
  • the amount of solid carrier will vary according to the form selected and is well within the ordinary skill of the artisan.
  • the preparation may be used in the form of a soft gelatin capsule, a liquid suspension, an emulsion, an ointment, a suppository or a solution.
  • the amount of non-solid carrier per dose is notocritical and may be adjusted to suit convenience.
  • This form of the preparation can be administered orally, topically, intravenously, or pancavally, the carrier being preselected according to the route of administration 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, grinding, granulating, compressing, suspending and dissolving as may be deemed appropriate to the desired end product.
  • the method of using these preparations in accordance with this invention comprises administering to a patient aflicted with the inflammatory condition, 6-cycloalkylguanamines or a non-toxic organic or inorganic acid addition salt thereof, preferably combined with a nontoxic pharmaceutical carrier of the type disclosed in amount to produce an anti-inflammatory effect.
  • a nontoxic pharmaceutical carrier of the type disclosed in amount to produce an anti-inflammatory effect.
  • the active medicament in dosage units in most cases will be suflicient to provide a convenient oral or pancaval daily regimen by administering from about 10 mg. to about 2400 mg. per day, advantageously from about 50 mg. to about 800 mg. 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 rout of administration.
  • Pancavally as used herein defines administration via all of the bodys openings whether natural such as the vagina, the anus, the nares, or artificial, e.g., colostomy.
  • the preparation when systemic administration as indicated, is preferably administered orally one to four times daily to provide a daily regimen of from about 10 mg. to about 2400 mg. of active medicament, advantageously from about 50 mg. to about 800 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 antiinflammatory action by this invention is particularly effective when applied to human beings having rheumatoid diseases such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, gouty arthritis, fibromyositis, osteoarthritis and bursitis.
  • the method is also useful in the the treatment of collagen diseases such as scleroderma, lupus erythmatosus disseminatus and in treating other inflammatory conditions as are associated with allergic bronchial asthma, pulmonary emphysema, pulmonary fibrosis, in. fection, 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, neurodermatitis, dermatitis herpetiformis, angioedema, urticaria, and exfoliative dermatitis; pemphigus; inflammatory eye diseases including keratitis, allergic conjunctivitis, non-granulomatous ulceris, iridocyclitis, chloroditis, uveitis, chlorioetinitis, 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, neurodermatitis, dermatitis herpetiformis, angioedema, urticaria,
  • Example I 6-cyclopropylguanamine is prepared by forming a mixture of 7.37 grams (0.11 mole) of cyclopropyl cyanide, 23.4 grams (0.26 mole) of dicyandiamide, 1.16 grams of 85% potassium hydroxide pellets, and 100 ml. of ethylene glycol monomethyl ether. The mixture is then refluxed and stirred for about 6 hours. The ether solvent is then removed by distillation under vacuum, and the residue is washed with 50 ml. of water. The insoluble product is thereafter collected by filtration, and the filter cake is dissolved in a solution of 150 ml. of water and ml. of concentrated hydrochloric acid.
  • the solution is then filtered and the filtrate is neutralized to pH 89 by the addition of concentrated ammonium hydroxide.
  • the precipitate is then collected by filtration, washed with water, and dried in a vacuum oven to yield 20.0 grams of white solid.
  • the solid is then recrystallized from 50% aqueous methanol to yield 11.6 grams of 6-cyclopropylguanamine (2,4-diamino 6-cyclopropyl-s-triazine) which melts at 296-8 C.
  • Example II 6-cyclobutylguanamine is prepared by following the procedure of Example I, while employing 6.8 grams (0.05 mole) of cyclobutyl cyanide, 6.5 grams (0.077 mole) of dicyandiamide, 1.10 grams of 85% potassium hydroxide pellets, and 95 ml. of ethylene glycol monoethyl ether. 10.0 grams of 6-cyclobutylguanamine (2,4- diamino-6-cyclobutyl-s-triazine) is obtained after recrystallization from 50% aqueous methanol. The product melts at 238.41 C.
  • Example III 6-cyclopentylguanamine is prepared by forming a mixture of 20.0 grams (0.22 mole) of cyclopentyl cyanide, 9.25 grams (0.11 mole) of dicyanidiamide, 1.16 grams of 85% potassium hydroxide pellets and 100 ml. of ethylene glycol monethyl ether. The mixture is refluxed, with stirring, for 6 hours. The solvent is removed by distilla tion under vacuum, and the residue is Washed with 50 ml. of water. The insoluble product is then collected by filtration and washed with cold water.
  • the filter cake is next recrystallized from 50% aqueous methanol to obtain 6-cyclopentylkuanamine (2,4-diamino-6-cyclopentyls-triazine) (14.9 grams), which melts at ISO-3 C.
  • Example IV 6-(1'-cyclohexenyl)guanamine is prepared by following the procedure of Example III, while employing 23.6 grams (0.22 mole) of l-cyanocyclohexene in place of cyclopentyl cyanide. 6(1'-cyclohexenyl)guanamine (11.4 grams) obtained and upon recrystallization, melts at 257-61 C.
  • Example V 6-(3'-cyclohexenyl)guanamine is prepared by following the procedure of Example III, and employing 23.6 grams (0.22 mole) of 3-cyanocyclohexene. 6(3-cyclohexenyl)guanamine obtained and upon recrystallization, melts at 1968 C.
  • Example VI 6-cyclohexylguanamine is prepared by forming a mixture of 5.74 grams (0.03 mole) of 6-(3-cyclohexenyl)- guanamine, 0.2 grams of platinum oxide catalyst and 50 ml. of glacial acidic acid. The mixture is then hydrogenated under 3 atmospheres of hydrogen until the calculated amount of hydrogen is taken up. Next, the mixture is heated to dissolve the product and filtered to remove the catalyst. The solvent is then removed by distillation under vacuum and, after recrystallization of the residue from water, the 6-cyclohexylguanamine product (1.4 grams) is obtained which, upon recrystallization, melts at 207-9 C.
  • Example VII 6-cycloheptylguanamine is prepared by forming a mixture of 25.0 grams (0.20 mole) of cycloheptyl cyanide, 8.58 grams (0.102 mole) of dicyandiamide, 2.10 grams of potassium hydroxide pellets and ml. of ethylene glycol monomethyl ether. The mixture is refluxed with stirring. At two hour intervals, 4.29 grams (0.051 mole) of dicyandiamide and 2.18 grams (0.026 mole) of dicyandiamide are added. Stirring under reflux is continued for a total of 6 hours. The solvent is then removed by distillation under vacuum, and the residue is washed with 50 ml. of water. The precipitate is then collected by filtration, and the filter cake is recrystallized from 50% aqueous ethanol. The 6 cycloheptylguanamine (20.3 grams) product melts at 208-10 C.
  • Example VIII 6-(2' -norbornyl)guanamine is prepared by following the procedure of Example III and employing 26.7 grams (0.22 mole) of Z-cyanonorbornane. The 6-(2'-norbornyl)guanamine is obtained and, upon recrystallization, melts at 20810 C.
  • Example IX 6(2'-trans-phenylcyclopropyl)guanamine is prepared by the procedure of Example I, when 15.7 grams (0.11 mole) of trans-1-cyano-2-phenylcyclopropane is used in lieu of cyclopropyl cyanide.
  • the 6-(2'-trans-phenylcyclopropyl)guanamine product (18.5 grams) is obtained and, upon recrystallization, melts at 194-5 C.
  • Example X To prepare an acid addition salt, 50 grams of 6-cyclopentylguanamine (2,4-diamino-6-cyclopentyl-1,3,5 triazine) was prepared according to Example I and then dissolved into a mixture of 30 ml. concentrated hydrochloric acid and 1 liter of anhydrous 3A ethanol on a hot plate with stirring. The solution was then filtered by gravity and the filtrate was cooled in the refrigerator. The crystaline hydrochloride was collected by filtration in a Buchner funnel and dried in a vacuum oven to yield 41.4 g. M.P. 2958 C., dec.
  • Example XI Two hundred mg. of 6-cyclopropylyguanamine, mg of sorbitol and 85 mg. of mannitol were milled to uniform powder and granulated into 6 mg. of gelatin as a 10% solution. The mixture was then screened onto trays and dried 60 C., the dried granules were then sized and mixed with mg. of cornstarch and 4 mg. of magnesium stearate. The mixture was then compressed into tablets.
  • Example XII Ingredients: Weight mg. 6-cyclopentylguanamine hydrochloride 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 XIII Ingredients: Weight mg. 6-cyclopentylguanamine 200 Lactose 175 Magnesium stearate 5 The above ingredients were screened through a U.S. mesh screen or mill to a uniform powder, transferred to a mixer, mixed Well and filled into #1 hard gelatin capsules.
  • Example XIV Ingredients: Weight mg. 6-cyclopropylguanamine Sesame oil 50 The ingredients are mixed into a thick slurry and filled into soft gelatin capsules.
  • Example XV Ingredients: Weight mg. 6-cyclopentylguanamine hydrochloride 300 Polyethylene Glycol 400 240 The ingredients are mixed into a thick slurry and filled into soft gelatin capsules.
  • Example XVI Ingredients Weight 6-cyclobutylguanamine 200 gms. Polyethylene Glycol 200 q.s. up to 1 liter The ingredients are added together and warmed to about 50 C. 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 XVII A suppository having a melting point of about 60 F. was prepared having the following ingredients in the amounts indicated:
  • Example XVIII An ointment embodying the present invention was prepared from the following ingredients in the amounts indicated:
  • the dorsal area of each animal was shaved with an electric clipper and the animals were placed under light ether anesthesia.
  • the shaved regions were wiped with 70% ethanol, and 25 ml. of air was injected at the approximate center of each animals shaved portion using a syringe and 24 gauge needle.
  • the phlogistic agent (a killed and dried preparation of Mycobacterium butyricum (was suspended to provide 0.125 mg. of agent in 0.4 ml. sesame oil. This suspension was then injected using a 22 gauge needle into the formed air pouch at a situs different from that of the air injection. ll syringe needles were immersed in 70% ethanol between uses in successive animals. To insure accurate dosage, the phlogistic-agent suspension was continuously mived with a magnetic stirrer. In all instances, air was removed 48 hours after formatoon of the pouch. The test compounds were triturated in a mortar and pestle with 1% pectin, and the resulting suspension was administered by gavage in a volume of 1 ml./ 100 g. body weight. All test animals were administered test compounds once per day for 4 consecutive days, beginning on the day of pouch formation. The animals were necropsied on the 5th day.
  • volume of exudate formed in each animal treated by the drug is then compared with the volume of exudate formed in the untreated control animals.
  • a reduced volume of exudate is an accepted measure of antiinflammatory activity.
  • Percent Inhibition The relationship of the difference between the volume of exudate in the test animal and that of the control animal compared to the value of the control animal is reported below as Percent Inhibition. The higher this value, the more effective a test compound is as an anti-inflammatory drug.
  • a compound according to claim 1 denominated 6- cyclopropylguanamine.
  • a compound according to claim 1 denominated 6- cyclobutylguanamine.
  • a compound according to claim 1 denominated 6- cyclopentylguanamine.

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US660919A 1967-08-16 1967-08-16 6 - cycloalkylguanamines,preparations and methods for treating inflammatory conditions therewith Expired - Lifetime US3478026A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6150362A (en) * 1997-12-12 2000-11-21 Henkin; Jack Triazine angiogenesis inhibitors

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59106473A (ja) * 1982-12-10 1984-06-20 Nippon Shinyaku Co Ltd トリアジン誘導体

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2305217A (en) * 1942-12-15 Process of cubing surface covering
US2385765A (en) * 1941-08-30 1945-09-25 American Cyanamid Co Textile finishing
US2527314A (en) * 1950-10-24 Production of guanamines
US2859188A (en) * 1956-11-26 1958-11-04 Monsanto Chemicals Hexahydrobenzoguanamine oil modified alkyd coating compositions

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2305217A (en) * 1942-12-15 Process of cubing surface covering
US2527314A (en) * 1950-10-24 Production of guanamines
US2385765A (en) * 1941-08-30 1945-09-25 American Cyanamid Co Textile finishing
US2859188A (en) * 1956-11-26 1958-11-04 Monsanto Chemicals Hexahydrobenzoguanamine oil modified alkyd coating compositions

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6150362A (en) * 1997-12-12 2000-11-21 Henkin; Jack Triazine angiogenesis inhibitors

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