(19)
(11)EP 0 904 270 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
24.09.2003 Bulletin 2003/39

(21)Application number: 97904016.9

(22)Date of filing:  30.01.1997
(51)Int. Cl.7C07D 307/79, C07D 405/12, A61K 31/415, A61K 31/34
(86)International application number:
PCT/US9701/311
(87)International publication number:
WO 9702/8145 (07.08.1997 Gazette  1997/34)

(54)

DIHYDROBENZOFURAN AND RELATED COMPOUNDS USEFUL AS ANTI-INFLAMMATORY AGENTS

ALS ENTZÜNDUNGSHEMMENDE MITTEL NÜTZLICHE DIHYDROBENZOFURANE UND VERWANDTE VERBINDUNGEN

COMPOSES DE DIHYDROBENZOFURANE UTILISES COMME AGENTS ANTI-INFLAMMATOIRES


(84)Designated Contracting States:
AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE

(30)Priority: 01.02.1996 US 595122

(43)Date of publication of application:
31.03.1999 Bulletin 1999/13

(73)Proprietor: VANDERBILT UNIVERSITY
Nashville, TN 37240 (US)

(72)Inventors:
  • RIDGEWAY, James, Madison, III
    Evendale, OH 45241 (US)
  • JANUSZ, John, Michael
    West Chester, OH 45069 (US)

(74)Representative: Goldbach, Klara, Dr. et al
Grünecker, Kinkeldey, Stockmair & Schwanhäusser Anwaltssozietät Maximilianstrasse 58
80538 München
80538 München (DE)


(56)References cited: : 
EP-A- 0 322 004
WO-A-96/07651
WO-A-96/03396
  
  • J. MED. CHEM.;90; VOL.33 (3); PP.908-18, MERCK SHARP AND DOHME RES. LAB.;DEP. MED. CHEM. IMMUNOL.; RAHWAY; 07065; NY; USA (US), XP000673907 HAMMOND M L ET AL: "Antioxidant-based inhibitors of leukotriene biosynthesis. The discovery of 6-[1-[2-(hydroxymethyl)phenyl]-1-propen-3- yl]-2,3-dihydr o-5-benzofuranol, a potent topical antiinflammatory agent"
  • J. MED. CHEM. (JMCMAR,00222623);86; VOL.29 (11); PP.2326-9, SYNTEX RES.;INST. ORG. CHEM.; PALO ALTO; 94304; CA; USA (US), XP000673908 DUNN J P ET AL: "Analgetic and antiinflammatory 7-aroylbenzofuran-5-ylacetic acids and 7-aroylbenzothiophene-5-ylacetic acids"
  • DATABASE WPI Section Ch, Week 7809 Derwent Publications Ltd., London, GB; Class B02, AN 78-16667A XP002031493 & JP 53 005 178 A (YOSHITOMI PHARM IND KK) , 18 January 1978 cited in the application & JP 53 005 178 A (...)
  • J. MED. CHEM. ;89; VOL.32 (5); PP.1006-20, MERCK SHARP AND DOHME RES. LAB.;DEP. MED. CHEM. IMMUNOL.; RAHWAY; 07065; NY; USA (US), XP000673754 HAMMOND M L ET AL: "2,3-Dihydro-5-benzofuranols as antioxidant-based inhibitors of leukotriene biosynthesis" cited in the application
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

TECHNICAL FIELD



[0001] The subject invention relates to nonsteroidal anti-inflammatory drugs, particularly to substituted dihydrobenzofuran and related compounds.

BACKGROUND OF THE INVENTION



[0002] Certain dihydrobenzofuran compounds and other compounds structurally related thereto have been found to have significant disease altering activities. Such compounds, processes for making them, and uses for them are disclosed in the following references: U.S. Patent No. 4,670,457 issued to Doria, Romeo & Como on June 2, 1987; U.S. Patent No. 4,849,428 issued to Dobson, Loomans, Matthews & Miller on July 18, 1989; Japanese Patent Publication No. 53-005178 of Yoshitomi Pharm. Ind. KK published January 1, 1978; Hammond, M. L., I. E. Kopka, R. A. Zambias, C. G. Caldwell, J. Boger, F. Baker, T. Bach, S. Luell & D. E. Macintyre, "2,3-Dihydro-5-benzofuranols as Antioxidant-Based Inhibitors of Leukotriene Biosynthesis", J. Med. Chem., Vol. 32 (1989), pp. 1006-1020; Ortiz de Montellano, P. R & M. A. Correia, "Suicidal Destruction of Cytochrome P-450 during Oxidative Drug Metabolism", Ann. Rev. Pharmacol. Toxicol., Vol. 23 (1983), pp. 481-503; Chakrabarti, J.K., R.J. Eggleton, P.T. Gallagher, J. Harvey, T.A. Hicks, E.A. Kitchen, and C.W. Smith, "5-Acyl-3-substituted-benzofuran-2(3H)-ones as Potential Anti-inflammatory Agents", J. Med. Chem., Vol. 30 (1987), pp. 1663-1668.

[0003] It is an object of the subject invention to provide compounds which have effective anti-inflammatory, analgesic and/or anti-oxidant activity.

[0004] It is a further object of the subject invention to provide such compounds which cause few adverse side effects.

[0005] It is also an object of the subject invention to provide methods for treating inflammation and/or pain using the subject compounds.

SUMMARY OF THE INVENTION



[0006] The subject invention compounds having the structure:

wherein

(a) n is from 1 to 3;

(b) X is selected from the group consisting of O, S, SO, or SO2;

(c) Y is independently hydrogen or straight, branched or cyclic alkyl having from 1 to 4 carbon atoms, or the Y's are bonded together to form an alkanyl ring having from 3 to 7 atoms;

(d) Z is hydrogen or straight, branched or cyclic alkyl having from 3 to 10 atoms other than hydrogen;

(e) R1 is hydrogen or straight, branched or cyclic alkyl, aryl or C(=N)-NHR4; and

(f) R2, R3, and R4, are independently hydrogen, straight, branched or cyclic alkyl having from 1 to 10 carbon atoms other than hydrogen, or aryl; R2 and R3 can be bonded together to form a ring having 5 or 6 atoms.



[0007] It is preferred that X is oxygen or sulfur and R1 is hydrogen or C(=N)-NHR4.

[0008] It is further preferred that each Y is independently selected from the group consisting of hydrogen, methyl and ethyl; and Z is selected from the group consisting of unsubstituted C4-C6 branched alkanyl having 2 branches, unsubstituted C3-C6 cycloalkanyl, and phenyl.

[0009] It is furthermore preferred that both Y are methyl, and Z is t-butyl.

[0010] Additionally, it is preferred that R2 and R3 are independently selected from C1-C6 straight or single-branched alkyl or bonded together to form a five or six-membered ring.

[0011] The compound wherein X is oxygen, and R1 is hydrogen, is preferred.

[0012] The compound wherein R2 and R3 are bonded together to form a five-membered ring, is further more preferred.

[0013] The compound wherein R1 is hydrogen or C(=N)-NHR4, wherein R4 is methyl or ethyl and R2 and R3 are selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1-methylbutyl, ethoxy, benzyl, or phenethyl, is also preferred.

[0014] It is additionaly preferred that X is oxygen, and R1 is hydrogen.

[0015] Further, it is preferred that R1 is C(=N)-NHR4, R2 and R4 are ethyl and R3 is hydrogen.

[0016] Said object is also achieved by :
  • a composition comprising a compound as above and a pharmaceutically-acceptable carrier,
  • a compound as above as a therapeutic agent.


[0017] Said object is achieved further by:
  • the use of the compound as above for the manufacture of a medicament for treating inflammation or pain, and
  • the use of the compound as above for the manufacture of a medicament for treating arthritis.


[0018] It is preferred that the daily peroral administration is 1 mg/kg to 20 mg/kg.

[0019] As used herein, unless otherwise indicated, "alkyl" or "alkanyl" means a straight, branched or cyclic hydrocarbon chain, saturated or unsaturated, unsubstituted or substituted. Preferred alkyl are C1-C10; more preferred are C1-C8; especially C1-C4. Preferred alkyl are straight chain. Preferred branched alkyl have one or two branches, preferably one branch. Preferred cyclic alkyl are monocyclic or are a straight chain with a monocyclic terminus. Preferred alkyl are saturated. Unsaturated alkyl have one or more double bonds or/and one or more triple bonds. Preferred unsaturated alkyl have one or two double bonds or one triple bond, more preferably one double bond. Preferred alkyl are unsubstituted. Preferred substituted alkyl are mono-, di-, or trisubstituted, more preferably monosubstituted. Preferred alkyl substituents include halo, hydroxy, oxo, alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy), aryloxy (e.g., phenoxy, chlorophenoxy, tolyloxy, methoxyphenoxy, benzyloxyphenoxy, alkyloxycarbonylphenoxy, acyloxyphenoxy), acyloxy (e.g., propionyloxy, benzoyloxy, acetoxy), carbamoyloxy, carboxy, mercapto, alkylthio, acylthio, arylthio (e.g., phenythio, chlorophenylthio, alkylphenylthio, alkoxyphenylthio, benzylthio, alkyloxycarbonylphenylthio), aryl (e.g., phenyl, tolyl, alkyloxphenyl, alkyloxycarbonylphenyl, halophenyl), heterocyclyl, heteroaryl, amino (e.g., amino, mono- and di- C1-C3 alkanylamino, methylphenylamino, methylbenzylamino), C1-C3 alkanylamido, ureido, N'-alkylureido, N',N'-dialkylureido, N',N',N-trialkylureido, guanidino, N'-alkylguanidino, N',N"-dialkylguanidino, or alkoxy carbonyl.

[0020] As used herein, "aryl" means a moiety having an unsubstituted or substituted aromatic ring having 6 to 10 carbon atoms. Preferred aryl are phenyl and naphthyl; most preferred aryl is phenyl. Preferred aryl are unsubstituted. Preferred substituted aryl are mono-, di-, or trisubstituted, more preferably monosubstituted. Preferred aryl substituents include hydroxy, mercapto, halo, methyl, ethyl and propyl.

[0021] As used herein, "halo" means fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo; more preferred are chloro and bromo, especially chloro.

Compounds



[0022] The subject invention involves compounds having the following structure:

wherein

(a) n is from 1 to 3;

(b) X is selected from the group consisting of O, S, SO, or SO2;

(c) Y is independently hydrogen or straight, branched or cyclic alkyl having from 1 to 4 carbon atoms, or the Y's are bonded together to form an alkanyl ring having from 3 to 7 atoms;

(d) Z is hydrogen or straight, branched or cyclic alkyl having from 3 to 10 atoms other than hydrogen;

(e) R1 is hydrogen or straight, branched or cyclic alkyl, aryl or C(=N)-NHR4; and

(f) R2, R3, and R4, are independently hydrogen, straight, branched or cyclic alkyl having from one to 10 carbon atoms, or aryl; R2 and R3 can be bonded together to form a ring having 5 or 6 atoms other than hydrogen



[0023] In the above structure, each Y is independently selected from hydrogen, straight or branched alkanyl having from 1 to 4 carbon atoms, and cyclic alkyl having 3 carbon atoms, cyclopropyl, or the Y's are bonded together to form a cyclic alkanyl ring having from 3 to 7 carbon atoms in the ring. Each Y is preferably hydrogen, methyl, ethyl or cyclopropyl; more preferably hydrogen or methyl; most preferably methyl. Preferably both Y's are the same. When the Y's are bonded together to form a cyclic ring, the ring is preferably cyclopropyl, cyclobutyl or cyclopentyl, more preferably cyclopropyl.

[0024] In the above structure, Z is preferably saturated. Z is preferably branched alkanyl having from 3 to 8 carbon atoms, more preferably from 4 to 6 carbon atoms. Z is preferably branched alkanyl having 2 or more branches, more preferably 2 branches. Preferred branched alkanyl Z include t-butyl, neopentyl, isopropyl; most preferred is t-butyl. Preferred cyclic alkanyl Z include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. Also preferred Z is unsubstituted phenyl or benzyl.

[0025] In the above structure, the identity of R1 is hydrogen, straight, branched or cyclic alkyl, aryl or C(=N)-NHR4.

[0026] In the above structure, R2, R3, and R4 are independently hydrogen, straight, branched or cyclic alkyl having from one to 10 carbon atoms. R2 and R3 may be bonded together to form a ring having 5 to 6 atoms other than hydrogen. Other preferred R2 and R3 groups include aryl and araalkyl.

[0027] Preferred compounds of the subject invention are included in the following table:

Compound No.





[0028] In order to determine and assess pharmacological activity, testing of the subject compounds in animals is carried out using various assays known to those skilled in the art. The anti-inflammatory activity of the subject compounds can be conveniently demonstrated using an assay designed to test the ability of the subject compounds to antagonize the local edema which is characteristic of the inflammatory response. Examples of such known tests include the rat carrageenan edema test, the oxazolone-induced inflamed mouse ear test, and the mouse arachadonic acid-induced inflamed ear test. Analgesic activity may be tested in art-known models such as the phenylbenzoquinone-induced writhing test in mice, and the Randall & Selitto test in rats. Another useful art-known test is the rat adjuvant arthritis test which is a useful model for assessing anti-inflammatory activity, anti-arthritic and anti-resorptive activity in a chronic, rather than an acute, model.

[0029] These and other appropriate tests for pharmacological activity are disclosed and/or referred to in U.S. Patent No. 4,130,666 issued to Moore on December 19, 1978; U.S. Patent No. 4,431,656 issued February 14, 1984 to Katsumi, et al.; U.S. Patent No. 4,440,784 issued to Katsumi, et al. on April 3, 1984; Japanese Patent Application 85/54315 of Katsumi, et al., published March 28, 1985; European Patent Application No. 0,059,090 of Yamanuchi Pharmaceutical Company Ltd., published September 1, 1982; Opas, E.V., R.J. Bonney & J. L. Humes, "Prostaglandin and Leukotriene Synthesis in Mouse Ears Inflamed by Arachadonic Acid", The Journal of Investigative Dermatology, Vol. 84, No. 4 (1985), pp. 253-256; Swingle, K. F., R. L. Bell & G. G. I. Moore, "Anti-inflammatory Activity of Antioxidants", Anti-inflammatory and Antirheumatic Drugs, Vol. III, Chapter 4, K. D. Rainsford, ed., CRC Press, Inc., (1985), pp. 105-126; Adamkiewicz, V. W., W. B. Rice & J. D. McColl, "Antiphlogistic Effect of Trypsin in Normal and in Adrenalectomized Rats", Canadian Journal of Biochemistry & Physiology, Vol. 33 (1955), pp. 332-339; Sellye, H., "Further Studies Concerning the Participation of the Adrenal Cortex in the Pathogenesis of Arthritis", British Medical Journal, Vol. 2 (1949), pp. 1129-1135; and Winter, C.A., E. A. Risley & G. W. Nuss, "Carrageenan-Induced Edema in Hind Paw of the Rats as an Assay for Antiinflammatory Drugs" Proceedings of Society of Experimental Biology and Medicine, Vol. 111 (1962), pp. 544-547; Ottemess, I., & M. L. Bliven, "Laboratory Methods for Testing Nonsteroidal Antiinflammatory Drugs", Nonsteroidal Antiinflammatory Drugs, Chapter 3, J. G. Lombardino, ed., John Wiley & Sons, Inc. (1985), pp. 111-252. Hitchens, J. T., S. Goldstein, L. Shemano & J. M. Beiler, "Analgesic Effects of Irritants in Three Models of Experimentally-Induced Pain", Arch. Int. Pharmacodyn., Vol. 169, No. 2 (1967) pp. 384-393; Milne, G. M. & T. M. Twomey, "The Analgetic Properties of Piroxicam in Animals and Correlation with Experimentally Determined Plasma Levels", Agents and Actions, Vol. 10, No. 1/2 (1980), pp. 31-37; Randall, L. O. & J. J. Selitto, "A Method for Measurement of Analgesic Activity on Inflamed Tissue", Arch. Int. Pharmacodyn., Vol. 111, No. 4 (1957), pp. 409-419; Winter, C. A. & L. Faltaker, "Nociceptive Thresholds as Affected by Parenteral Administration of Irritants and of Various Antinociceptive Drugs", J. Pharmacol. Exp. Ther., Vol. 148, No. 3 (1965), pp. 373-379; the disclosure of all these references are incorporated herein by reference.

[0030] Many anti-inflammatory drugs, particularly non-steroidal anti-inflammatory drugs (NSAIDs) cause undesirable gastrointestinal side effects, especially when dosed perorally; such side effects may include ulcers and erosions. These side effects, which are often asymptomatic, can become serious enough to require hospitalization and can even be lethal. Compounds of the subject invention generally cause fewer such gastrointestinal side effects compared to other NSAIDs. Some compounds of the subject invention are even gastroprotective, protecting the stomach and intestines from ulcers and erosions, particularly those caused by ethanol or other NSAIDs.

[0031] Certain NSAIDs, when dosed systematically, cause an undesirable increase in systemic levels of certain liver enzymes. Compounds of the subject invention generally cause little or no liver enzyme side effects.

[0032] Compounds useful in the subject invention can be made using the following general reaction schemes:
The guanidines can be prepared by the reaction of the corresponding aniline with the desired amidino sulfonic acid to produce the desired guanidine in one step. This method ususally gives the desired guanidine although occassionally the first formed guanidine reacts with the sulfonic acid reagent to add another amidine group to the aniline nitrogen.


Synthesis Examples



[0033] The following non-limiting examples provide further information regarding synthesis of the subject compounds.

Example 1


2-(N-(7-tert-Butyl-2,3-dihydro-3,3-dimethylbenzo[b]furan-5-yl)-amino)imidazoline



[0034] To a 0.3 g (1.3 mmol) solution of 5-amino-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo[b]furan in 10 mL of acetonitrile at RT is added 0.2 g (1.3 mmol) of imidazoline-2-sulfonic acid, (Maryanoff et al., J. Org. Chem., 1986, 51, 1882). The reaction is then refluxed overnight. On cooling to RT, pure guanidine precipitates out of solution and is filtered from the solution to give 120 mg (32 %) of product; mp 264 °C (decomp).

Example 2


N-[7-tert-Butyl-2,3-dihydro-3,3-dimethyl-benzo[b]furan-5-yl]-N-[N-ethylamidino]-N'-ethylguanidine



[0035] A solution of 5-Amino-7-tert-Butyl-2,3-dihydro-3,3-dimethyl-benzo[b]furan (2.2 g, 10.2 mmol), N-ethylaminoiminosulfonic acid (10.2 mmol, 1.55 g) (Maryanoff et al., J. Org. Chem., 1986, 51, 1882)., and isopropanol (75 mL) is refluxed for four days. The reaction is then cooled to room temp, the isopropanol evaporated, and the crude material purified by flash chromatography (15% MeOH/CHCl3, product stains with Dragendorf's spray) to give product (210 mg, 5%) as an off-white solid, MP >290 °C.

Example 3


2-(N-(7-tert-Butyl-2,3-dihydro-3,3-dimethylbenzo[b]thiophene-5-yl)-amino)imidazoline



[0036] To a 0.33 g (1.3 mmol) solution of 5-amino-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo[b]thiophene in 10 mL of acetonitrile at RT is added 0.2 g (1.3 mmol) of imidazoline-2-sulfonic acid, (Maryonoff et al., (J. Org. Chem., 1986, 51, 1882). The reaction is then refluxed overnight. On cooling to RT, pure guanidine precipitates out of solution and is filtered from the solution to give 155 mg (40 %) of product.

Compositions



[0037] Compositions of the subject invention comprise a safe and effective amount of the subject compounds, and a pharmaceutically-acceptable carrier. As used herein, "safe and effective amount" means an amount of a compound sufficient to significantly induce a positive modification in the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. A safe and effective amount of a compound will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician.

[0038] Compositions of the subject invention preferably comprise from about 0.1% to about 99.9% by weight of a compound, more preferably from about 20% to about 80%, and most preferably from about 40% to about 70%.

[0039] In addition to the compound, the compositions of the subject invention contain a pharmaceutically-acceptable carrier. The term "pharmaceutically-acceptable carrier", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a human or lower animal. The term "compatible", as used herein, means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or lower animal being treated.

[0040] Some examples of substances which can serve as pharmaceutically-acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as comstarch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid, magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the Tweens®; wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents, excipients; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0041] The choice of a pharmaceutically-acceptable carrier to be used in conjunction with a subject compound is basically determined by the way the compound is to be administered.

[0042] If the subject compound is to be injected, it is preferably injected non-intravenously; the preferred pharmaceutically-acceptable carrier is sterile, physiological saline, with blood compatible suspending agent, the pH of which has been adjusted to about 7.4. Such injectable compositions preferably comprise from about 1% to about 50% of the subject compound, more preferably from about 5% to about 25%, also preferably from about 10 mg to about 600 mg of the subject compound per dose.

[0043] Suitable pharmaceutically-acceptable carriers for topical application include those suited for use in lotions, creams, gels and the like. Topical compositions preferably contain from about 1% to about 50% of an emollient, more preferably from about 5% to about 25% of an emollient. Such topical compositions preferably comprise from about 0.1% to about 50%, of the subject compound, more preferably from about 0.5% to about 10%, also preferably from about 5 mg to about 3500 mg per dose.

[0044] The preferred mode of administering the subject compound is perorally. The preferred unit dosage form is therefore tablets, capsules and the like, comprising a safe and effective amount of the compound, which is preferably from about 5 mg to about 3500 mg, more preferably from about 10 mg to about 1000 mg, and most preferably from about 25 mg to about 600 mg. The pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well-known in the art. Their selection will depend on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be made without difficulty by a person skilled in the art.

[0045] Many of the subject compounds are hydrophobic. If it is desired to provide an aqueous-based composition or a composition soluble in or miscible with aqueous media, a solubilizing agent may be included in the composition. Nonlimiting examples of such solubilizing agents include polyethylene glycol, propylene glycol, ethanol, and polyoxyethylene (35) castor oil.

[0046] Particularly preferred oral composition carriers suitable for compositions of the subject invention are disclosed in U.S. Patent Nos. 5,189,066 of Kelm & Bruns, issued February 23, 1993, entitled "Pharmaceutical Compositions of Tebufelone", and 5,281,420 of Kelm & Dobrozsi, issued January 25, 1994, entitled "Solid Dispersion Compositions of Tebufelone", hereby incorporated herein by reference.

Methods



[0047] Another aspect of the subject invention is methods for treating or preventing diseases characterized by inflammation by administering a safe and effective amount of a subject compound to a human or lower animal in need of such treatment. The term "diseases characterized by inflammation", as used herein, means conditions which are known to involve inflammation, and may include conditions such as arthritis (e.g., rheumatoid arthritis, osteoarthritis, psoriatic arthritis, juvenile arthritis, Reiter's syndrome, infectious arthritis, and ankylosing spondylitis, systemic lupus, erythematosus and gout), as well as the presence of inflammation whether or not it is associated with an identifiable disease. Diseases characterized by inflammation further may include inflammation in the oral cavity (e.g., inflammation associated with gingivitis or periodontal disease); inflammation in the gastrointestinal tract, (e.g., inflammation associated with ulcers and irritable bowel disease); inflammation associated with dermatological diseases (e.g., psoriasis, acne, and other skin inflammation); inflammation associated with the respiratory tract (e.g., asthma, bronchitis, and allergies); and inflammation in the central nervous system (e.g., Alzheimer's disease).

[0048] Another aspect of the subject invention is methods for treating or preventing pain by administering a safe and effective amount of a subject compound to a human or lower animal in need of such treatment. Pain which can be treated or prevented by administering the subject compounds may include peripheral pain, menstrual pain, dental pain, and lower back pain.

[0049] Another aspect of the subject invention is methods for preventing oxidative damage at inflammatory sites by administering a safe and effective amount of a subject compound to a human or lower animal in need of such treatment. While not limited to a particular mechanism, it is believed that the subject compounds inhibit leukotriene synthesis, thereby decreasing neutrophil accumulation at an inflammatory site.

[0050] Another aspect of the subject invention is methods for treating or preventing gastric or duodenal ulcers or erosions by administering a safe and effective amount of a subject compound to a human or lower animal in need of such treatment. In particular, such ulcers or erosions caused by ethanol or non-steroidal antiinflammatory drugs (NSAIDs) can be treated and/or prevented by administration of preferred subject compounds.

[0051] Appropriate tests for determining the gastrointestinal safety or gastroprotective or gastric healing properties of the subject compounds are known.

[0052] Methods for determining acute gastrointestinal safety are disclosed and/or referred to in the following references: Unangst, P.C., G.P. Shrum, D.T. Connor, R.D. Dyer, and D.J. Schrier, "Novel 1,2,4-Oxadiazoles and 1,2,4-Thiadiazoles as Dual 5-Lipoxygenase and Cyclooxygenase Inhibitors", J. Med. Chem., Vol. 35 (1992), pp. 3691-3698; and Segawa,Y, O. Ohya, T. Abe, T. Omata, et al., "Anti-inflammatory, Analgesic, and Antipyretic Effects and Gastrointestinal Toxicity of the New Anti-inflammatory Drug N-{3-[3-(piperidinylmethyl)phenoxy] propyl}-carbamoylmethylthio]ethyl 1-(p-chlorobenzoyl) 5-Methoxy-2-methyl-3-indolylacetate", Arzneim.-Forsch./Drug Res., Vol. 42 (1992), pp. 954-992. In the methods disclosed therein, stomachs of the animals are typically examined two hours after dosing a compound. Methods for determining subchronic gastrointestinal safety are disclosed and/or referred to in the following references: Melarange, R., C. Gentry, et al., "Anti-inflammatory and Gastrointestinal Effects of Nabumetone or Its Active Metabolite, 6-Methoxy-2-naphthylacetic Acid (6MNA)", Dig. Dis. Sci., Vol. 37 (1992), pp. 1847-1852; and Wong, S., S.J. Lee, et al., "Antiarthritic Profile of BF-389 - A Novel Anti-inflammatory Agent With Low Ulcerogenic Liability", Agents Actions, Vol. 37 (1992), pp. 90-91.

[0053] Methods for determining acute gastroprotection are disclosed and/or referred to in the following reference: Playford, R.J., D.A. Versey, S. Haldane, M.R. Alison, and J. Calan, "Dose-dependent Effects of Fentanyl on Indomethacin-induced Gastric Damage", Digestion, Vol. 49 (1991), pp. 198-203. In the method disclosed therein, female Lewis rats (130-175 g) are dosed perorally with the subject compound (40 mg/kg b.i.d.) or vehicle at 2 hours and immediately before administration of a gastric damaging dose of indomethacin. The rats are sacrificed 4 hours later by CO2 asphyxiation. Gastric corpus damage (millimeters of hemorrhagic lesions) is measured by digitized imaging.

[0054] The preferred mode of administration of the subject compounds is peroral, but other known methods of administration are contemplated as well, e.g., dermatomucosally (for example, dermally, rectally and the like), and parenterally (for example, by subcutaneous injection, intramuscular injection, intraarticular injection, intravenous injection and the like). Ocular administration and inhalation are also included. Thus specific modes of administration include, without limitation, peroral, transdermal, mucosal, sublingual, intranasal, intramuscular, intravenous, intraperitoneal, subcutaneous, and topical administration.

[0055] Preferred doses of the subject compounds range from about 0.2 mg/kg to about 70 mg/kg, more preferably from about 0.5 mg/kg to about 12 mg/kg. Preferred injectable doses comprise from about 0.1 mg/kg to about 10 mg/kg of the subject compound. Preferred topical doses comprise from about 1 mg/cm2 to about 200 mg/cm2 of the subject compound applied to the skin surface. Preferred peroral doses comprise from about 0.5 mg/kg to about 50 mg/kg. more preferably from about 1 mg/kg to about 20 mg/kg, more preferably still from about 2 mg/kg to about 10 mg/kg, of the subject compound. Such doses are preferably administered from about once to about six times daily, more preferably from about twice to about four times daily. Such daily doses are preferably administered for at least one week, also preferably for at least two weeks, also preferably at least one month, also preferably for at least 2 months, also preferably for at least 6 months, 1 year, 2 years, or more.

Compositions and Method Examples



[0056] The following non-limiting examples illustrate the subject invention.

Example A



[0057] Pharmaceutical compositions in the form of tablets are prepared by conventional methods, such as mixing and direct compaction, formulated as follows:
IngredientQuantity (mg per tablet)
Compound 1 200
Microcrystalline Cellulose 100
Sodium Starch Glycollate 30
Magnesium Stearate 3


[0058] When administered orally two times daily, the above composition significantly reduces the inflammation in a patient suffering from rheumatoid arthritis. A significant benefit is also achieved by twice daily administration of this composition to a patient suffering from osteoarthritis.

Example B



[0059] A pharmaceutical composition in capsule form is prepared by conventional methods, formulated as follows:
IngredientQuantity (mg per capsule)
Compound 2 200
Lactose To fill to volume of capsule


[0060] The above capsule administered orally once a day substantially reduces the symptomology of a patient afflicted with rheumatoid arthritis or osteoarthritis.

Example C



[0061] A pharmaceutical composition in liquid form is prepared by conventional methods, formulated as follows:
IngredientQuantity
Compound 2 200 mg.
EtOH 4 ml
Methyl cellulose 0.4 mg
Distilled water 76 ml
Tween 80 1.6 ml


[0062] 50 ml of the above composition administered perorally once a day substantially reduces the symptoms of a patient afflicted with rheumatoid arthritis or osteoarthritis.

Example D



[0063] A pharmaceutical composition in liquid form is prepared by conventional methods, formulated as follows:
IngredientQuantity
Microcrystalline (micronoized) Compound 1 200 mg
Avicel (microcrystatline cellulose) 50 mg
Tween 80 1.6 ml
Methyl cellulose 0.4 mg
Deionized water 80 ml


[0064] 50 ml of the above composition administered perorally twice a day substantially reduces the symptoms of a patient afflicted with rheumatoid arthritis or osteoarthritis.

[0065] While particular embodiments of the subject invention have been described, it would be obvious to those skilled in the art that various changes and modifications to the compositions disclosed herein can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of this invention.


Claims

1. A compound having the structure:

wherein

(a) n is from 1 to 3;

(b) X is selected from the group consisting of O, S, SO, or SO2;

(c) Y is independently hydrogen or straight branched or cyclic alkyl having from 1 to 4 carbon atoms, or the Y's are bonded together to form an alkanyl ring having from 3 to 7 atoms;

(d) Z is hydrogen or straight, branched or cyclic alkyl having from 3 to 10 atoms other than hydrogen;

(e) R1 is hydrogen or straight, branched or cyclic alkyl, aryl or C(=N)-NHR4; and

(f) R2, R3, and R4, are independently hydrogen, straight, branched or cyclic alkyl having from one to 10 carbon atoms or aryl; R2 and R3 can be bonded together to form a ring having 5 or 6 atoms other than hydrogen.


 
2. The compound of Claim 1 wherein X is oxygen or sulfur and R1 is hydrogen or C(=N)-NHR4.
 
3. The compound of Claim 2 wherein each Y is independently selected from the group consisting of hydrogen, methyl and ethyl; and Z is selected from the group consisting of unsubstituted C4-C6 branched alkanyl having 2 branches, unsubstituted C3-C6 cycloalkanyl, and phenyl.
 
4. The compound of Claim 3 wherein both Y are methyl, and Z is t-butyl.
 
5. The compound of Claim 3 wherein and R2 and R3 are independently selected from C1-C6 straight or single-branched alkyl or bonded together to form a five or six-membered ring.
 
6. The compound of Claim 5 wherein X is oxygen, and R1 is hydrogen
 
7. The compound of Claim 6 wherein both Y are methyl, and Z is t-butyl.
 
8. The compound of Claim 7 wherein R2 and R3 are bonded together to form a five-membered ring.
 
9. The compound of Claim 3 wherein R1 is hydrogen or C(=N)-NHR4, wherein R4 is methyl or ethyl and R2 and R3 are selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1-methylbutyl, ethoxy, benzyl, or phenethyl.
 
10. The compound of Claim 8 wherein both Y are methyl, and Z is t-butyl.
 
11. The compound of Claim 9 wherein X is oxygen, and R1 is hydrogen.
 
12. The compound of Claim 10 wherein R1 is C(=N)-NHR4, R2 and R4 are ethyl and R3 is hydrogen.
 
13. A composition comprising a compound of claim 1, 8 or 12 and a pharmaceutically-acceptable carrier.
 
14. A compound according to any of claims 1 to 12 as a therapeutic agent.
 
15. Use of the compound of claim 1, 8 or 12 for the manufacture of a medicament for treating inflammation or pain.
 
16. Use of the compound of claim 1, 8 or 12 for the manufacture of a medicament for treating arthritis.
 
17. The use according to claim 16, wherein the daily peroral administration is 1 mg/kg to 20 mg/kg.
 


Ansprüche

1. Verbindung mit der Struktur

worin

(a) n 1 bis 3 beträgt;

(b) X ausgewählt ist aus der Gruppe bestehend aus O, S, SO oder SO2;

(c) Y unabhängig Wasserstoff oder geradkettiges, verzweigtes oder cyclisches Alkyl mit 1 bis 4 Kohlen stoffatomen ist oder die Y unter Bildung eines Alkanylrings mit 3 bis 7 Atomen aneinander gebunden sind;

(d) Z Wasserstoff oder geradkettiges, verzweigtes oder cyclisches Alkyl mit 3 bis 10 Atomen, die von Wasserstoff verschieden sind, ist;

(e) R1 Wasserstoff oder geradkettiges, verzweigtes oder cyclisches Alkyl, Aryl oder C(=N)-NHR4 ist; und

(f) R2, R3 und R4 unabhängig Wasserstoff, geradkettiges, verzweigtes oder cyclisches Alkyl mit 1 bis 10 Kohlenstoffatomen oder Aryl sind; R2 und R3 können unter Bildung eines Rings mit 5 oder 6 Atomen, die von Wasserstoff verschieden sind, aneinander gebunden sein.


 
2. Verbindung nach Anspruch 1, worin X Sauerstoff oder Schwefel ist und R1 Wasserstoff oder C(=N)-NHR4 ist.
 
3. Verbindung nach Anspruch 2, worin jedes Y unabhängig ausgewählt ist aus der Gruppe bestehend aus Wasserstoff, Methyl und Ethyl; und Z ausgewählt ist aus der Gruppe bestehend aus unsubstituiertem, verzweigtem C4-C6-Alkanyl mit 2 Verzweigungen, unsubstituiertem C3-C6-Cycloalkanyl und Phenyl.
 
4. Verbindung nach Anspruch 3, worin beide Y Methyl sind und Z t-Butyl ist.
 
5. Verbindung nach Anspruch 3, worin R2 und R3 unabhängig ausgewählt sind aus geradkettigem oder einfach verzweigtem C1-C6-Alkyl oder unter Bildung eines fünfoder sechsgliedrigen Rings aneinander gebunden sind.
 
6. Verbindung nach Anspruch 5, worin X Sauerstoff ist und R1 Wasserstoff ist.
 
7. Verbindung nach Anspruch 6, worin beide Y Methyl sind und Z t-Butyl ist.
 
8. Verbindung nach Anspruch 7, worin R2 und R3 unter Bildung eines fünfgliedrigen Rings aneinander gebunden sind.
 
9. Verbindung nach Anspruch 3, worin R1 Wasserstoff oder C(=N)-NHR4 ist, worin R4 Methyl oder Ethyl ist, und R2 und R3 ausgewählt sind aus der Gruppe bestehend aus Wasserstoff, Methyl, Ethyl, n-Propyl, i-Propyl, n-Butyl, 1-Methylpropyl, 2-Methylpropyl, 1-Methylbutyl, Ethoxy, Benzyl oder Phenethyl.
 
10. Verbindung nach Anspruch 8, worin beide Y Methyl sind und Z t-Butyl ist.
 
11. Verbindung nach Anspruch 9, worin X Sauerstoff ist und R1 Wasserstoff ist.
 
12. Verbindung nach Anspruch 10, worin R1 C(=N)-NHR4 ist, R2 und R4 Ethyl sind und R3 Wasserstoff ist.
 
13. Zusammensetzung, umfassend eine Verbindung nach Anspruch 1, 8 oder 12 und einen pharmazeutisch annehmbaren Träger.
 
14. Verbindung nach einem der Ansprüche 1 bis 12 als Heilmittel.
 
15. Verwendung der Verbindung nach Anspruch 1, 8 oder 12 zum Herstellen eines Arzneimittels zum Behandeln einer Entzündung oder von Schmerzen.
 
16. Verwendung der Verbindung nach Anspruch 1, 8 oder 12 zum Herstellen eines Arzneimittels zum Behandeln von Arthritis.
 
17. Verwendung nach Anspruch 16, worin die tägliche perorale Verabreichung 1 mg/kg bis 20 mg/kg beträgt.
 


Revendications

1. Composé de structure :

dans laquelle :

(a) n vaut de 1 à 3 ;

(b) X est choisi dans le groupe constitué de O, S, SO ou SO2

(c) Y est indépendamment l'hydrogène ou un alkyle à chaîne droite, ramifiée ou cyclique ayant de 1 à 4 atomes de carbone, ou les Y sont liés l'un à l'autre pour former un cycle alcanyle ayant de 3 à 7 atomes de carbone ;

(d) Z est l'hydrogène ou un alkyle à chaîne droite, ramifiée ou cyclique ayant de 3 à 10 atomes autres que l'hydrogène ;

(e) R1 est l'hydrogène ou un alkyle à chaîne droite, ramifiée ou cyclique, aryle ou C(=N)-NHR4 ; et

(f) R2, R3 et R4 sont indépendamment l'hydrogène, un alkyle à chaîne droite, ramifiée ou cyclique ayant de 1 à 10 atomes de carbone ou un groupe aryle ; R2 et R3 peuvent être liés l'un à l'autre pour former un cycle ayant de 5 à 6 atomes autres que l'hydrogène.


 
2. Composé selon la revendication 1, dans lequel X est l'oxygène ou le soufre et R1 est l'hydrogène ou C(=N)-NHR4.
 
3. Composé selon la revendication 2, dans lequel chaque Y est indépendamment choisi dans le groupe constitué de l'hydrogène, des groupes méthyle et éthyle ; et Z est choisi dans le groupe constitué d'un alcanyle ramifié en C4 à C6 non substitué ayant 2 ramifications, d'un cycloalkanyle en C3 à C6 non substitué et d'un groupe phényle.
 
4. Composé selon la revendication 3, dans lequel les deux Y sont un méthyle et Z est un t-butyle.
 
5. Composé selon la revendication 3, dans lequel R2 et R3 sont indépendamment choisis parmi un alkyle à chaîne droite ou à une seule ramification en C1 à C6 ou liés l'un à l'autre pour former un cycle pentagonal ou hexagonal.
 
6. Composé selon la revendication 5, dans lequel X est l'oxygène, et R1 est l'hydrogène.
 
7. Composé selon la revendication 6, dans lequel les deux Y sont un méthyle, et Z est un t-butyle.
 
8. Composé selon la revendication 7, dans lequel R2 et R3 sont liés l'un à l'autre pour former un cycle pentagonal.
 
9. Composé selon la revendication 3, dans lequel R1 est l'hydrogène ou C(=N)-NHR4, dans lequel R4 est un méthyle ou un éthyle et R2 et R3 sont choisis dans le groupe constitué de l'hydrogène, d'un méthyle, éthyle, n-propyle, i-propyle, n-butyle, 1-méthylpropyle, 2-méthylpropyle, 1-méthylbutyle, éthoxy, benzyle ou phénéthyle.
 
10. Composé selon la revendication 8, dans lequel les deux Y sont un méthyle, et Z est un t-butyle.
 
11. Composé selon la revendication 9, dans lequel X est l'oxygène, et R1 est l'hydrogène.
 
12. Composé selon la revendication 10, dans lequel R1 est C(=N)-NHR4, R2 et R4 sont un groupe éthyle et R3 est l'hydrogène.
 
13. Composition comprenant un composé selon la revendication 1, 8 ou 12 et un véhicule pharmaceutiquement acceptable.
 
14. Composé selon l'une quelconque des revendications 1 à 12, sous forme d'agent thérapeutique.
 
15. Utilisation du composé selon la revendication 1, 8 ou 12, pour la fabrication d'un médicament destiné à traiter les inflammations ou les douleurs.
 
16. Utilisation du composé selon la revendication 1, 8 ou 12, pour la fabrication d'un médicament destiné à traiter l'arthrite.
 
17. Utilisation selon la revendication 16, dans laquelle l'administration perorale journalière est de 1 mg/kg à 20 mg/kg.