CA2179009A1 - Di-tert-butylphenol compounds useful as anti-inflammatory agents - Google Patents

Abstract

The subject invention involves compositions comprising: (a) a safe and effective amount of a compound having structure (i), wherein n is an integer from 1 to about 5, m is an integer from 0 to about 3, -R is hydrogen or straight or branched chain C1-C3 alkanyl; and (b) a pharmaceutically-acceptable carrier. The subject invention also involves methods for treating diseases characterized by inflammation and/or pain, such as rheumatoid arthritis and osteoarthritis, by administration of a safe and effective amount of this compound to a human or lower animal in need of such treatment.

Description

WO 95/16443 - :: 2 1 7 9 0 0 9 PCT/US94/14405 Dl-TERT-BUTYLPHENOL COMPOUNDS USEFUL
AS ANTI-INFLAMMATORY AGENTS

TECHNICAL FIELD
The subject invention relates to nonsteroidal anti-infla",r"alGry drugs, particularly to substituted di-tert-butylpl ,enol cGi"pounds.
BACKGROUND OF THE INVENTION
Di-tert-butylphenol compounds are a class of co",pounds known for their use as stabiliz~ s for pl~stiçs, oils and fats; see, e.g., U.S.
Patent No. 3,711,544 issued to Engelhardt, Fruhstorfer, Hesse, Dennler & Baumer on January 16, 1973.
Certain di-tert-butylp~,enol co",pounds and other compounds structurally related ll,ereto have been found to have significant anti-inflal"",alofy and/or an-lgesic activity. Such ~l~pounds, processes for making them, and uses for them are ~isçlosed in the following references: U.S. Patent Nos. 3,784,701 issued to Tomcufcik, Grassi,-~
8 Slobod~ on January 8, 1974; 3,917,672 issued to Schmidt on November 4, 1975; 4,124,725 issued to Moore on November 7, 1978;
4,130,666 issued to Moore on December ~9, 1978; 4,165,383 issued to Moore on August 21, 1979; 4,172,082 issued to Moore on October 23, 1979; 4,357,345 issued to Moore on NovemL,er2, 1982; 4,418,074 issued to Moore on November 29, 1983; 4,440,784 issued to Katsumi, Kondo, Yamasl,ila, Hidaka, Hosoe, Ariki, Yamashita & Watanobe on April 3, 1984; 4,535,165 issued to Moore on August 13, 1985;
4,677,113 issued to Bell 8 Moore on June 30, 1987; 4,708,966 issued to Lo~-"ans, Matlhews & Miller on November 24, 1987; 4,714,776 issued to Bell & Moore on Dece"ll er 22, 1987; 4,833,155 issued to Muchowski, Greenhouse, Young 8 Murthy on May 23, 1989; 4,968,710 issued to Rustad on November 6, 1990; 4,982,006 issued to Hudec on January 1, 1991; 5,086,064 issued to Capris, Conner 8 Sircar on February 4, 1992; 5,102,897 issued to Boschelli, Conner, Kostlan, Kramer, Mullican 8 Sircar on April 7 1992; European Patent Applioation No. 0,212,848 of Riker LaboratGries, published March 4 1987; PCT Patent Application Nos. WO 83/01774 and WO
83/91775 of Riker Laboratories both published May 26 1983; WO
93/07865 of The Procter 8 Gamble CGIIIPan~, published April 29 1993; Kaffenberger R.M. T.H. Eichhold 8 M.J. Doyle "Determination of Tebufelone (A New Anti-lnflammatory Drug) Strength and Stability in Bulk Drug Dosage Formulations and Feed Admixtures by Reversed-Phase High-Pe, fG""ance Liquid Chromatography" Journal of ChromatoqraPh~ Vol. 505 (1990) pp. 349-356. Such co",pounds are also disclosed and reviewed in Batt D.G. "5-Lipoxygenase Inhibitors and Their Anti-inflammatory Activities" Pro~ress in Medicinal Chemistry Vol 29 (1992) pp. 1-15 45-50 and references disclosed therein.
Although a number of di-tertbutylphenol compounds have been demonstrated to exhibit anti-inflammatory activity many such ~",pounds exhibit little or no anti-inflam",atoly activity. Thus it is generally not possible to predirt whether such cG",pounds have s~ l sl~ntial anti-infl~"""alory activity without testing for the activity.
It is an object of the subject invention to provide cG",pounds which have effective anti-inflaminato,y an^lgesic andlor anti-oxidant activity.
It is a further object of the subject invention to provide such c~",pounds which cause few adverse side effects.
It is also an object of the subject invention to provide methods for lreati,)g inll~"""dliG" and/or pain using the subject c~",pounds.
SUMMARY OF THE INVENTION
The subject invention involves c~""~ositions c~l~"~rising co""~ounds having the structure:
(CH3)3C
HO~C(O)--CHR (CH2)n--C(O)--(CH2),T,--CH3 (CH3)3C
wherein n is an integer from 1 to about 5 m is an integer from 0 to about 3 -R is h~drogen or s~ t ar bran~-ed chain C1-C3 alkanyl;
and a pl,~""ac~ti~AIly-~c~ept~hle carrier. The subject invention also involves ,neU~s for treating d;seA~s cha(acteri~e:J by innsll""alion and/or pain such as rheumatoid 8~U~ritis and Gsleoslllllitis in humans 3 ~ ~ 2 ~ 7 9 o o 9 PCT/US94/14405 or lower animals by administration of a safe and effective amount of these compounds to the human or lower animal in need of such treatment.
DETAILED DESCRIPTION OF THE INVENTION
The sl~je~t invention involves particular di-tertbutylphenol com-pounds having the following structure:
(C H3)3c HO~(O)~HR (CH2)n~(0)--(CH2)m~H3 (CH3)3C
In the above structure n is an integer of from 1 to about 5, pre-ferably from 1 to 4 more preferably 1 or 2 or 3 most preferably 2. In the above structure m is an integer of from 0 to about 3 preferably from 0 to 2 more preferably 0 or 1 most preferably 0.
In the above structure -R is hyd~gen or straight or branched chain alkanyl having from 1 to about 3 carbon atoms. -R is preferaL,ly hydfoge,) methylorethyl mostpreferablyh~drogen.
r~efe"ed ~",pounds useful in the subject invention include:

4~1 5-dioxohexyl)-26-di-tert-butylpl,enol and 4~1 4-dioxopentyl)-2j6-di-tert-butylphenyl .
In order to determine and ~ssess pha~macological activity testing of the subject compounds in animals is carried out using various assays known to those skilled in the art. The anti-innaml''atory activity of the subject c~""~ounds can be conveniently del"onsl,ated using an assay designed to test the ability of the subject cGi"pounds to antagoni~e the local edema which is char~eristic of the infla",matory response. Examples of such known tests include the rat ca"ageel.an edema test the oxæolone-induced inflamed mouse ear test and the mouse arachadon.c acid-induced irlllamed ear test. Analgesic activity may be tested in art-known models such as the phenylL,en~o~uinone-induced writhing test in mice, and the Randall & Selitto test in rats.
Another useful art-known test is the rat adjlNant a, U " ilis test which is a useful model for ~ssessing anti-irlna"""dto~y activity, anti-a,U"ilic and anti~esGi l~ti~e activity in a chronic rather than an acute model.

These and other appropriate tests for pharmacological activity are disclosed andlor 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 ~rpli~tion No. 0,059,090 of Yamanuchi Pl,a",)aceutical Company Ltd., published September 1, 1982; Opas, E.V., R.J. Bonney 8 J.L. Humes, "Prostaglandin and Leukotriene Synthesis in Mouse Ears Inflamed by Arachadonic Acid", The Joumal of Investiaative DelmatOIOqy Vol. 84, No. 4 (1985), pp. 253-256; Swingle, KF., R.L.
Bell & G.G.I. Moore, "Anti-inflai"r"atoiy Activity of Antioxidants", Anti-infla""natory and Antirheumatic Druqs. Vol. Ill, Chapter 4, KD.
Rainsrord, ed., CRC Press, Inc., (1985), pp. 105-126; Adamkiewicz, V.W., W.B. Rice 8 J.D. McColl, "Antiphlogistic Effect of Trypsin in Normal and in Adrenalectomized Rats", Canadian Joumal of Biochemistry & Phvsioloay Vol. 33 (1955), pp. 332-339; Sellye, H., "Further Studies Concerning the Particir~tion of the Adrenal Cortex in the Pathogenesis of Arthritis", British Medical Joumal. Vol. 2 (1949), pp. 1 129-1 135; and Winter, C.A., E.A Risley 8 G.W. Nuss, "Carrageenan-lnduced Edema in Hind Paw of the Rats as an Assay for Antiinfla""natoiy Drugs" Proceedinas of Societv of E)~,.eri"~ental Bioloqv and Med;c;ne. Vol. 111 (1962), pp. 544-547; Ollerness, I., &
M. L. Bliven, "Laborato~y h~etllGJs for Testing Nonsleroidal Antii"lla"""alory Drugs", NGnsleroidal A"tiinlla"""alor~ Druqs.
Cl,spter 3, J. G. LGI,lbardino, ed., John Wiley & Sons, Inc. (1985), pp. 111-252. Hitchens, J. T., S. Goldstein, L. Shemano 8 J. M. Beiler, "An ~Igesic Effects of Ir, ilanls in Three 1~,1~els of E~peri,oe,)lally-lnduced Pain", Arch. Int. Pl,a"nacodYn.. Vol. 169, No. 2 (1967) pp. 384-393; Milne, G. M. & T. M. Twomey, 'The Analgetic Properties of Piroxica." in Animals and Co"elalion with Experi",enlally Detel",ined Plas",a Levels", Aaents and Actions. Vol. 10, No. 1/2 (1980), pp. 31-37; Randall, L. O. & J. J. Selitto, "A Method for Me~s~,nent of Analgesic Activity on Irlrlctllled Tissue", Arch. Int.
~I,an"acoJYn.. Vol. 111, No. 4 (1957), pp. 409-419; Winter, C. A. & L.
Faltaker, "Ncciceptive mresl,clds as Affected by Parenteral Ad~t,inislration of l,.ilanls and of Various Antinociceptive Drugs", WO 95/16443 ~ 2 1 7 9 0 0 q PCT/US94/14405 J. Pharmacol. EXP. Ther.. Vol. 148 No. 3 (1965) pp. 373-379; the disclosure of all these references are inco,~orated herein by reference.
Many anti-inflammatory drugs particularly non-steroidal anti-inflam,nalory drugs (NSAlDs) cause undesirable gastrointestinal side 5 effects especi~'ly when dosed perorally; such side effects may include ulcers and erosions. These side effects which are often as~",pto",atic 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 10 NSAlDs even compared to many other di-tert-butylphenol derivatives.
Certain NSAlDs including certain di-tert-butylphenol derivatives when dosed systemically cause an undesirable inuease in systemic levels of certain liver enzymes. Compounds of the subjQct invention generally cause less of such liver enzyme side effects co",pared to 15 other di-tert-butylphenol cGI~pounds.
Compounds useful in the subject invention can be made using the following general reaction scheme:

\~0 ~ RMgX ~ Rl(CH2) arhydfide akyl Gfignard >( CF3C(O)OC(O)CF3 >~
H~O~(CH2)r~R neat or~Mth sol~ent ~<
>~/ R o (e.g. toluene di- >~
ch;on~- "cU ~ne) di-tbu~phenol Another reaction scheme can be used when m is 0 as depicted 20 by Example 1.

ExamPie 1 Preparation of 4-(1.5~ioxohexY1)-2 6~i-tert-butylphenol OH OH
~+ Cl ~ ~ SnC14 , H+

O O
To a solution of 2.06 9 (10.0 mmol) of 2,6-di-tbutylphenol and 1.17 g (10.0 mmol) of 4-hexynoyl chloride in 20 mL of dichlor~",etl,ane is added, at -78C, 2.30 mL (20.0 mmol) of stannic chloride. The mixture is stirred at -78C for 30 minutes, and then let warm to room temperature and stirred for an additional 30 minutes. The reaction is added slowly to 1N HCI at 0C, and afler stirring for 5 minutes, layers are allowed to form and are separated. The ~ eo~s portion is e~lracted with ether, and the combined organic phase is washed with sat. NaHCO3 and sat. NaCI, and then dried (MgSO4). Flash chro,nal~grdphy (20% EtOAc/hex, Rf=0.25) affords 2.23 9 of product as a dark brown viscous oil. Further purification is achieved by recrystalli~alion from hexanel~er, ene to afford 1.85 9 of pure 4~1,~
dioxohexyl)-2,6-di-tert-but~lphenol, mp 100.5-101C.
Compositions of the subject invention cG",prise a safe and effective amount of the subject compounds, and a Ph8111)AC~UtjC~IIY_ ~ccept~ble carrier. As used herein, "safe and effective amount" means an amount of a cG",pound sufficient to significantly induce a positive modification in the c~lldilion to be ~ealed, but low enough to avoid serious side effects (at a reasGnable benefiVrisk ratio), within the scope of sound ",e.lical judge,nent. A safe and effective amount of a c~""~ound will vary with the particular condition being t,eated, the age and physical c~l ,dilion of the patient being l~ateJ, the severity of ths conditiGn, the duration of the lredl,nenl, the nature of concurrent lherapy, the particular pl ,s,n~utic^'ly-~c~pt~:lle carrier ! ~tili7e~:1, and like factors within the knowledge and expertise of the attending physician.
Compositions of the subject invention p(eferably cGI~plise from about 0.1% to about 99.9% by weight of a cGmpound, more pr~ferably from about 20% to about 80% and most preferably from about 40% to about 70%.
In addition to the compound the compositions of the S!~
invention contain a pharmaceutically-acceptable carrier. The term "pharmAceutic~lly-a--r~ptable carrier" as used herein means one or more cG,npalible solid or liquid filler diluents or en-~rsul^ting suhst~nces which are suitable for administration to a human or lower animal. The term "co,npatible" as used herein means that the components of the composition are capable of being cG",mingled with the subject compound and with each other in a manner such that there is no interaction which would s~ ~hstAntially reduce the pharmaceutical efncacy of the composition under ordinary use situations. Pharmaoeutically-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.
Some e~al"ples of s~ slAnces which can serve as pharmAc~uticAIly-acceptable carriers or co,npone,nls ~l ,ereof are sugars such as lActose glucose and sucrose; slarches such as co",slar~, and potato starch; cellulose and its derivatives, such as sodium ca,l,o~ymethyl cellulose ethyl cellulose cellulose ac~tAte;
powdered l,agacarltl,; malt; gelatin; talc; solid luLricants such as stearic acid magnesium stearate; calcium sulfate; vegel~hle oils such as peanut oil cotlonseed oil sess",e oil olive oil com oil and oil of U,eobro",a; polyols such as propylene glycol glycerin so,l,itol n,annitol and polyethylene glycol; alginic acid; emulsifiers suc~ as the Tweens~; wetting agents such as sodium lauryl sulfate; coloring agenls; fl~Yoring agents excipients; tableting agents; stabilizers;
antioxidAnts; preseNatives; pyrogen-free water; isotonic saline; and ~hosphate buffer solutions.
The choice of a pha""Aceutic~'ly-acceptable carrier to be used - in conjunction with a subject ~,npound is bAsi~lly determined by the way the cG".pound is to be admir,islered.
If the subject c~",pound is to be in~ected it is prdferably injected non-intravenously; the prefe"ed pl,a""aceutically-AcceptAhle carrier is sterile, physiological saline with blood col"palible suspending agent the pH of which has been adjusted to about 7.4. Such injectable co"~positions preferably co."~,,ise from about 1% to about 50% of the WO 95116443 2 1 7 9 ~ 0 9 PCT/US94/14405 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.
Suitable pharmaceutically-acceplable carriers for topical 5 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 coi-"~ositions preferably c~mprise from about 0.1% to about 50%, of the subject co",pound, more preferably from about 0.5% to about 10%, also preferably from about 5 mg to about 3500 mg per dose.
The preferred mode of administering the subject compound is perorally. The prefe"ed unit dosage form is tl ,erefore tablets, c~psules and the like, comprising a safe and effective amount of the c~mpound, v~hich 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 pl ,a""AceuticAIly~cceptAhls carriers suitable for the preparation of unit dQs~Age forms for oral administration are well-known in the art. Their selection will depend on secon-Jary 20 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.
Many of the subject c~,npounds are hydrophobic. If it is desired to provide an ~q~eolJs-based COlllpOSitiGIl or a co"~osition so~ble in 25 or miscible with a~leous media, a solubilizing agent may be included in the con,position. Non-limiting examples of such soMhili~ing agents indude polyethylene glycol, propylene glycol, etl ,anol, and polyoxyethylene (35) castor oil.
Particularly prefe,.ed oral ~"~position carriers suitable for 30 c~"~po~itions of the subject invention are d;sclQse-J in pending U.S.
Patent ~ppli~tion Serial Nos. 07/732,951 of Kelm & Bruns, filed July 19, 1991, entitled "Pl,al..,Ac~uti~l Compositions of Tebufelone", and 071885,932 of Kelm 8 DolroLsi, filed May 19, 1992, entitled "Solid Disp~rsion Compositions of Tebufelone", hereby inco",orated herein 35 by reference.
Another aspect of the subject invention is Il~Ulods for trealin~ or preventing ~iseAses c~,aracteri~ed by infla""-,ation by admifiisterin~ a 2~ 7900~
WO 9S/16443 . ~ PCT/US94/14405 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., 5 rheumatoid arthritis, osteoa, tl ,ritis, psoriatic a, ll ,rilis, 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 Asso~ tecl with an identifiable diseAse. DiseAses characteri~eJ by inna""nalion further may include 10 inflammation in the oral cavity (e.g., inna""nation ~ssoci^ted with gingivitis or periodontal diseAse); inflalY~Illdtion in the gaslrc..-testinal tract, (e.g., infla")"~alion associated with ulcers and irritable bowel diseAse); inflammation Associ~ted with dermatological diseAses (e.g., psoriasis, acne, and other skin infla"""ati~n); and inflammation Associ~ted with the respiratory tract (e.g., a~U""a, br~n~,itis, and allergies).
Another aspect of the subject invention is ")etl ,ods for treating or preventing pain by administering a safe and effective amount of a subject ~",pound to a human or lower animal in need of such treat",en~. Pain which can be treated or prevented by administering the subject c~l"pounds may include peripheral pain""enst,ual pain, dental pain, and lower back pain~
Another aspect of the subject invention is met h~Js for protecting against free radical damage resulting from oxidative stress and ischemic conditions by administering a safe and effective amount of a subject cGl"pound to a human or lower animal in need of such lleat",et)t. Such treatment may include prote~ting against ischemic heart diseAse, a~l,erosclerosis, stroke, and ischemic cell Js",age of heart.
The prefe"ed mode of administraliGn of the subject cGI"pounds is peroral, but other known ",ethods of administration are contel"plated as well, e.g., delll~atGIll~cos~lly (for example, dermally, rectally and the like), and ~arenlerally (for example, by s~ ~hcut~neous injection, intramusc~ injection, irlt,a~"icular injection, intravenous injection and the like). Ocular admir,ist~ation and inhalatiGn are also incl~.~de~
Thus specific modes of administlatiGI~ include, without li",itdtiGn, peroral transdermal m~ IcosAI sublingual inlranasal intraml ~sc~
intravenous intraperitoneal subcutaneous and topical administration.
rreferled doses of the sl~h~act co",pounds range from about 0.2 mg/kg to about 70 mgAcg more preferably from about 0.5 mgll<g to about 12 mg/kg. rlefer,ed in,ec~ le doses co",prise from about 0.1 mglkg to about 10 mg/kg of the subject co",pound. Preferred topical doses comprise from about 1 mg/cm2 to about 200 mg/cm2 of the subject co",pound applied to the skin surface. Preferred peroral doses comprise from about 0.5 mg/l<g to about 25 mgAca of the subject co",pound. Such doses are preferably sdl"inislered from about once to about six times daily more preferably from about twice to about four times daily.
The following nonlimiting examples illustrate the subject invention.
E~ 2 Phslln~ce!ltic~l co",positions in the form of tablets are prepared by conventional Illetll~ls such as mixing and direct cG""~action formulated as follows:
Inaredient QuantitY (ma Per tablet) 4~1 5-dioxohexyl)-2 6-di-tert-butylphenol) 200 Microcrystalline Cellu!ose 100 Sodium Starch Glycollale 30 Mag.,esium Stedrale 3 When administered orally hvo times daily, the above co",position sigr,ificarltly re~uces the infla"~ ation in a palient suffering from rheumatoid a,ll-ri~is. A significant benefit is also achieved by twice daily admirislralio-, of this ~"~position to a patient suffering from osleo~- U-ritis.
ExamPle 3 A pha""aceutical c~"",osition in capsule form is prepareJ by conve,ltional l-.eU.ods formulated as follows:
în~l~ ed:ent Quantit~ (mq Per ~r~su'~) 4~1 4-dioxopentyl)-2 6-di-tert-butylpl ,enol 200 I ~tose To fill to volume of capsule The above capsule administered orally once a day s~hstAntially reduces the sy,nptomology of a patient afflicted with rheumatoid arthritis or osteoarthritis.
While particular embodiments of the subject invention have 5 been described, it would be obvious to those skilled in the art that various changes and ~ ifications to the compositions disclosed herein can be made without depa,lin~ 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 (8)

What is claimed is:

1. A pharmaceutical composition comprising:
(a) a safe and effective amount of a compound having the structure:

wherein n is an integer from 1 to 5, m is an integer from 0 to 3;
and -R is hydrogen or straight or branched chain C1-C3 alkanyl:
and (b) a pharmaceutically-acceptable carrier.

2. A pharmaceutical composition in dosage unit form comprising:
(a) from 5 mg to 3500 mg, preferably from 25 mg to 600 mg, of a compound having the structure:

wherein n is an integer from 1 to 5, preferably 1 or 2; m is an integer from 0 to 3, preferably 0 or 1; and -R is hydrogen or straight or branched chain C1-C3 alkanyl, preferably hydrogen;
and (b) a pharmaceutically-acceptable carrier.

3. The composition of Claim 1 or 2 wherein n is 2 and m is 0

4. Use of a compound for manufacture of a medicament for treating a disease characterized by inflammation, the compound having the structure:

wherein n is an integer from 1 to 5, m is an integer from 0 to 3, and -R is hydrogen or straight or branched chain C1-C3 alkyl.

5. The use of Claim 4 wherein n is from 1 to 4, preferably 1 or 2; m is from 0 to 2, preferably 0 or 1; -R is hydrogen; and from 0.2 mg/kg to 70 mg/kg, preferably 0.5 mg/kg to 12 mg/kg, of the compound is administered to a human from 1 to 6 times, preferably 1 to 4 times, per day.

6. The use of Claim 4 or 5 wherein the disease is rheumatoid arthritis or osteoarthritis.

7. Use of a compound for manufacture of a medicament for treating pain, the compound having the structure:

wherein n is an integer from 1 to 5, m is an integer from 0 to 3, and -R is hydrogen or straight or branched chain C1-C3 alkyl.

8. The use of Claim 7 wherein n is from 1 to 4, preferably 1 or 2; m is from 0 to 2, preferably 0 or 1; -R is hydrogen; and from 0.2 mg/kg to 70 mg/kg, preferably 0.5 mg/kg to 12 mg/kg, of the compound is administered to a human from 1 to 6 times, preferably from 1 to 4 times, per day.