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`
`USU(}5968979A
`
`United States Patent
`Brusilow
`
`[19]
`
`[11] Patent Number:
`
`5,968,979
`
`[45] Date of Patent:
`
`Oct. 19, 1999
`
`Walsh et al., The Journal of Biological Chemistry, vol. 265.
`No. 8, pp. 4374-4381 (1990), sn—l ,2—Diacylgy1ccrol Kinasc
`o1‘L3cheric!tz'r.- cob‘.
`
`Newmark et al., “Butyrate and Phenylaeetate as Difl"ere-uti-
`ating Agents: Practical Problems and Opportunities", Jour.
`01‘ Cell. Biochem., Supplement 32: 24-7'—253(I995}.
`
`Chen (:1 al., "'l‘ributyrin: A Prodrug of Butyric Acid for
`Potential Clinical Applicaitn in Differentiation Therapy",
`Cancer Res, 54:3494—349‘)(1‘)‘J4).
`
`Lea et al., "Butyramide and Mortobutyrin: Growth lnhibi—
`tory and Diflerentiating Agents”, Anticancer Res., 13:
`145-150 (1993).
`
`Aedémie Des Science-5., Chimie (Jrganique, "1’réparalion tlc
`quelques glycérides phénylalipliatiques et leur réduction en
`alcools .
`.
`. ”, pp. 682-684.
`
`Brusilow et a1., Metabolism, vol. 42, No. I0 0ct., 1993,1111.
`1336-1339, "Restoration of Nitrogen Homeostasis in a Man
`with Ornithine Transcarbamylase Deficiency”.
`
`Maeslri et al.. "Prospective treatment oi‘ urea cycle disor-
`ders", pp. 923-928.
`
`Printrtrjv E).'nmim_=r—Gary Geist
`fl$S'£St‘(?."tI E.rmm'm*r—Dchora|1 D Carr
`Attorney, Agent, or Ffmt—Nikaido Marmelstein Murray &
`Dram LLP
`
`[56]
`
`References Cited
`FOREIGN PATENT DOCUMENTS
`
`94-22494
`
`|U,a'l994 WIPO .......................... ..
`
`t’\6ll\' 49,02
`
`[57]
`
`ABSTRACT
`
`OTHER l’UBl..lCATIONS
`
`Georges Darzens el al.: “Preparation ale quelques glycérides
`phénylaliphatiques ct
`leur
`reduction en alcools .
`.
`Comptes Rendus
`llebdomadaires Des Seances De
`L’academie Des Sciences, vol. 205. Oct. 18, 1937. pp.
`682-684.
`Walsh ct al., Chemical Abstract vol. 112, No. 231744.
`Cltemical Abstract, vol.
`I16, No. 46308, Sciki et al,
`"l-lomogcnous Pharmaceutical Emulsions Containing Nort-
`steriodal Analogesies and Inflammation Inhibitors".
`
`Two new forms of prndrug for phenylaeetate, of even
`congeners of phenylalkanoic acid and phenylalkcnoic acids.
`which are the phenylalkanoic or phenylalkenoic esters of
`glycerol, or
`the ethyl esters of phenylalkanoie acid or
`phertylalkenoic acids. These forms of the drugs provide a
`convenient dosage form of the drugs. The prodrugs of the
`invention are useful to treat patients with diseases of nitro-
`gen
`accumulation, patients with
`certain
`B-hemoglohinopathies, anemia, and cancer.
`
`It) Claims, No Drawings
`
`LUPIN EX. 1024
`
`[54] TRIGLYCERIDES AND ETHYL ESTERS OF
`PHIENYI .Al.l{AN()lC ACID AND
`PHENYLALKENOIC ACID USEFUL IN
`TREATMENT OI" VARIOUS DISORDERS
`
`[75]
`
`Inventor: Saul W. Brusilow, Baltimore, Md.
`
`[73] Assignee: Brnsilow Enterprises LLC, Baltimore,
`Md.
`
`|2l] Appt. N-3.: 09,t[|(|6,432
`
`[22]
`
`Filed:
`
`Jan. 13, 1998
`
`Related U.S. Application Data
`
`[63] Continuation of application No. t'l8,."384__935, Feb. 7, 1995,
`abandoned.
`
`Int. Cl.” ......................... AOIN 37,110; A61K 315235
`[5l|
`[52] U.S. Cl.
`.......................... 514E533; S'|4t'S32; 514547;
`5141549; 5141552; 5143553; 5143814; 514E815;
`514E885; 5541227; 554x220; 554213; 5541219;
`560:8; semis
`...................... . 554x227, 220,
`.19; same, 76; 5141532, 547.
`549, 552, 558, 814, 815, 885
`
`
`
`Field of Search ..... ..
`554K218.
`
`[58]
`
`1 of 5
`
`

`

`5 368,979
`
`1
`TRJGLYCERIDIES AND ETHYL ESTERS OF
`PHENYI..ALKAN0lC ACID AND
`l’Hl*lNYI.ALKENO[C ACII) USEFUL IN
`TREATMENT OF VARIOUS DISORDERS
`
`CROSS REFERENCE TO RELAIED
`Al’l’LICAl'ION
`
`This application is a continuation of Ser. No. 08,384,935.
`filed lieb. 7, 1995, now abandoned.
`
`ll!
`
`BACKGROUND OF THE INVENTION
`
`The present invention relates. to compounds, pharmaceu-
`tical compositions. and methods for treating several condi-
`tions with prodrugs for phenylacetate as therapeutic agents.
`
`15
`
`FIELD OF THE INVl:‘N’l"ION
`
`Phenylalkanoic acids are known therapeutic agents for a
`variety of disorders. Phenylacetate is used for the treatment
`of nitrogen metabolism disorders. beta-hemoglobinopathies,
`anemia and cancer. Various phenylalkenoic acids can be
`used in the treatment of the same disorders. The prodrugs
`disclosed in the present
`invention are useful
`therapeutic
`agents for a number of disorders, and possess some advan-
`tages over the forms of the drugs administered in the prior
`art.
`
`Nitrogen Metabolism Disorders
`In a healthy person.
`the potentially toxic nitrogenous
`compounds which accumulate as the body degrades proteins
`are synthesized into urea which is rapidly excreted into the
`urine. However. for those who suffer kidney failure, liver
`failure or inborn errors of urea synthesis, this pathway is
`defective. The accumulation of nitrogenous compounds
`resulting from such a blockage leads to considerable mor-
`bidity and mortality.
`In the case of an inborn error of urea synthesis, the major
`metabolic abnormality is the inability of the body to convert
`waste nitrogen into urea. As a consequence, various nitrog-
`enous metabolites accumulate in the body, the most toxic
`being ammonium, although other materials, such as
`glutamine and alanine also increase.
`Previous therapeutic approaches for treating patients with
`urea cycle enzymopathies (as well as other nitrogen accu-
`mulation diseases cited earlier) have been designed to
`reduce the requirement for urea synthesis by quantitative
`and qualitative manipulation of dietary protein, amino acids
`andfor their nitrogen free analogues. Generally speaking,
`however. the mortality of inborn errors of the urea-cycle
`remained high and success was measured in terms of
`increased survival time. Thus, for example, even with the
`above-cited therapeutic approaches, children with the neo-
`natal form of these diseases rarely survive past one year of
`age {Maestri, et al., The Journal ofPedt'rri'rt'c.s', Vol. 119, No.
`6, 923-928 (1991)).
`DESCRIPTION OF RELATED ART
`
`A more recent approach to remedy this pervasive problem
`is described in U.S. Pat. No. 4.34.64? to Saul W. Brusitow,
`wherein benzoic acid, phenylacetic acid, or the salts thereof,
`convert the waste nitrogen into amino acid acylation prod-
`ucts which the body can successfully excrete as urinary
`nitrogen. More specifically, the patent teaches that pheny-
`lacetate reacts with the nitrogen to form phenylacetyl-
`glutamine which is subsequently excreted by the body. Since
`such a reaction is in no way dependent on the urea synthesis
`or excretion, it is an eflective treatment for those sulfering
`from nitrogen accumulation diseases. See also "Treatment of
`lnborn Errors of Urea Synthesis,” New Errgfnnd Jorrrmrf of
`Medicine. 306; l38'z'—1392 (1982).
`
`-
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`U.S. Pat. No. 4,457,942, also to San] W. Brusilow. dis-
`closes that even-numbered phenylalkanoic acids can be
`advantageously used for the treatment of nitrogen accumu-
`lation diseases.
`
`When administered to humans, even numbered phenyla-
`lkanoic acids, such as phenylbutyrate, can be broken down
`by betaoxidation, two carbon atoms at a time, to eventually
`yield phenylacetate which, as described above, has been
`found useful for removing waste nitrogen from the blood
`stream. The administration of even numbered phenylal-
`kanoic acids such as phenylbutyrate has the advantage that
`the higher molecular weight compounds do not have the
`offensive odor which phenylbutyrate has.
`The above treatments, although elfective, have a substan-
`tial disadvantage. The dose of sodium phenylbutyrate for an
`adult with a urea cycle disorder is 20 gramsfday. This
`requires that the patient take forty (40) tablets of 0.5 grams
`each, per day. Problems of patient compliance arise when
`such large daily doses are required. The administration of
`sodium phenylbutyrate has a second disadvantage to many
`patients—patients who should restrict their daily dose of
`sodium. The above daily dose of sodium phenylbutyrate
`provides 2.5 gm of sodium per day, every day {it is recom-
`mended that adults consume less than 2.4 gramstday total
`sodium).
`The substitution in therapy of phenylacetate or
`phenylbutyrate, by the compounds ofthe present invention,
`provides the therapeutic compound in a more convenient
`dosage l'orm.
`In addition,
`the compounds of the present
`invention may eliminate the peaks and valleys in drug levels
`since the breakdown of these higher molecular weight
`compounds by beta-oxidation is
`a gradual process.
`In
`addition. the Na component of the prior art is replaced with
`glycerol, which is a normal product of metabolism.
`Cancer
`
`Phenylbutyrate and phenylacetate are being investigated
`as a treatment for various malignant diseases. The exact
`mechanism by which this therapy causes improvement in the
`patient is not entirely clear.
`It has been observed that primary central nervous system
`tumors are reminiscent ofimrnature brain, and the immature
`brain is known to be more vulnerable to damage by pheny-
`lacetate than the mature brain (as is observed in
`phenylketonuria}. Sodium phenylacetate appears to promote
`the dilferentiation of cultured human glioblastoma cell lines
`with reduced expression of malignant phenotype.
`Systemic treatment of rats bearing intracranial gliomas
`with phenylacetate resulted in signillcant tumor suppression
`with no apparent toxicity to the host. Early clinical results
`suggest that phenylacetate may become an important tool in
`the management of certain tumors in light of its demon-
`strated eflieacy, and lack of toxicity (Samid et al., Cancer
`Resenrcii, 54, 891-895, 1994, and Cinatl et al., Cancer
`Letters, 70, 15-24. 1993).
`A similar theory may be applied in treating prostate
`cancer with phenylacetate. The phenylacetate is thought to
`act as a diflerentiation inducer of leukemic and other less
`differentiated tumor cells, such as hormone refractory pros-
`tate cancer.
`
`Cultured cells of androgen dependent prostate cell lines
`with sodium phenylacetate show inhibition of cell prolifera-
`tion. In addition, such cells show reversion to non-malignant
`phenotype by in vivo and in vitro assessments (Samid et al.,
`Hie Journal of Clinical 1rrI.>e.s'n’grrriort, Vb]. 19, 2288-2295,
`1993).
`Phenylacetate may exert an anti-tumor all'ect by another
`mechanism. Glutamine is the major nitrogen source [or
`nucleic acid and protein synthesis, and substrate for energy
`in rapidly dividing normal and tumor cells. Compared to
`normal tissue. most tumors. due to decreased synthesis of
`
`2of5
`
`2 of 5
`
`

`

`5 368,979
`
`4
`DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`
`The present invention utilizes compounds of the formula:
`
`H I
`
`H—f|‘—0—R.
`t-1—f|.‘—0—Rg
`t1—-r:——o—R_.
`H
`
`whercin R1, R2, and R3 are independently, ll,
`
`0 l
`
`l
`—c—(ct13;,.—ct-:3
`
`O
`
`or —c—c,,tt;,,..3—ctt3
`
`and n is zero or an even number, m is an even number and
`at least one of R_,, R3, and R3 is not I-I.
`The most preferred compounds are those wherein none of
`R1, R3 and R3 is H. The advantage over the prior art of
`decreased dosage is greater with such tri
`lycerides.
`The present
`invention also utilizes efiiyl esters of the
`formula II
`
`(tn
`
`c_.H5-—o——c——t<,
`
`wherein R4 is
`
`3
`glutamine along with accelerated utilization and catabolism,
`operate at
`limiting levels of glutamine availability and
`consequently are sensitive to further glutamine depletion. In
`the body, phenylacetate conjugates with glutamine, with
`subsequent renal excretion of phenylacetylglutamine. This
`pathway is the reason that phenylacetate administration is
`useful in the treatment of nitrogen accumulation diseases.
`Because phenylacetate removes glutamine, administration
`ofphenylacetate may limit the growth rate of rapidly divid-
`ing cells such as tumor cells.
`By one or more of the above mechanisms, phenylacctate
`causes a decrease in tumor characteristics of a variety of
`tumor cells. Because of its known non—toxicity, phenylac—
`etate is a promising therapeutic agent, either alone or in
`combination with other anti~tunJor agents.
`Hemoglobinopathies
`Sodium phenylbutyrate is thought to cause improvement
`in certain B-hemoglobinopathies because the sodium phe-
`nylbutyrate induces the expression of fetal hemoglobin.
`Thus the absent or aberrant B-hemoglobin is substituted with
`fetal hemoglobin.
`Numerous agents which induce the expression of fetal
`hemoglobin have been used to treat sickle cell anemia and
`B-thalassemias. Some of the agents which increase the
`production of fetal hemoglobin however, have serious side
`effects that are not consistent with their use as long terrn _
`therapeutic agents.
`llovvever, sodium phenylaoetatc and
`sodium phertylbutyrate have been previously used to treat
`urea cycle disorders and are known to be very well tolerated
`and free of adverse reactions in clinical use. Preliminary
`clinical studies of patients with beta thalassemia indicate
`that
`treatment with sodium phenyllautyrate results in a
`response in many patients. The response is panicularly good
`in patients with relatively high erythropoietirt levels. Thus,
`combination therapy of the phenylbutyrate and erythropoi-
`etin may be eltective. Hydroxyurea given orally has atso
`been shown to increase hemoglobin levels in some thalas-
`semia patients. Clinical studies of thalasscmia patients
`treated with a combination of hydroxyurea and sodium
`phenylbutyrate has produced increased hemoglobin levels in
`some patients.
`
`35
`
`40
`
`it!
`
`15
`
`30
`
`SUMMARY OF THE INVENTION
`
`{CH3}7 CH _
`
`or
`
`The compounds of the present invention, triglycerides of
`phenylalkanoic acids or phcnylalkenoic acids, and ethyl
`esters of phenylalkanoic acids or phenylalkenoic acids,
`provide a more convenient dosage form of drugs for treat-
`ment of nitrogen accumulation disorders, cancer, anemia
`and hemoglobinopathies. The compounds of the invention
`are oils or soft fats. Where the prior art dose for an adult
`would have been forty (L5 g tableslday, the present invention
`provides the same amount of active compound in approxi-
`mately four {4} lcaspoonfuls per day. The dosage form of the
`present invention also decreases sodium intake in patients,
`which is advantageous in certain patients, and may also
`provide the active component of the drug,
`the phenylal-
`kanoic or phenylalkenoic acid, at a more constant level.
`The compounds of the invention may be used for the
`treatment of nitrogen accumulation disorders, portal sys-
`temic encephalopathy, and diseases involving impaired
`hepatic function. Additionally, the use of triglycerides and for
`the esters of the present invention alone or in combination
`with hydroxyurea andfor erythropoiet in, may he used for the
`treatment of beta chain hemoglobinopathies. The com-
`pounds of the invention are suitable for the treatment for
`various leukemias and solid tumors.
`
`The compounds of the invention can be produced by
`standard esterilication procedures. Additionally, many of the
`compounds of the invention are commercially available.
`
`45
`
`50
`
`55
`
`60
`
`65
`
`j(CHm—2}nT‘C-H2
`
`and n is zero or an even number, and m is an even number.
`The compounds of the invention include compounds with
`substituents of even numbered congeners of henylalltanoic
`and phenylalkenoic acids. Preferably the su stituents con-
`tain 24 or fewer carbon atoms. Most preferably, n and m are
`0, 2, 4 or 6.
`invention can be t.Lsed
`The compounds of the present
`separately or in the form of mixtures. The amount of the
`compounds of the present invention which is administered to
`patients for the present purposes can vary widely from case
`to case. Normally, however, the daily dosage for the com-
`pounds should fall in the range of 450 to 600 mgflt I body
`weight for children, and from 9.9 to 13 grams for aduli . The
`size and frequency of the dosages given at any time may be
`varied as described provided the indicated total daily does is
`not significantly modified. Preferably the compounds of the
`invention are administered orally, although in some
`circumstances. administration may be other routes such as
`topically or parentcrally.
`Metabolic Fates of the Compounds of the Invention
`Pancreatic lipase is able to hydrolyse the triglyceride
`compounds of the invention to produce glycerol and phe-
`
`3of5
`
`3 of 5
`
`

`

`5
`rtylalkanoit: acids or phenylalkenoic acids. The glycerol is
`then metabolized in the usual manner.
`
`6
`2. A compound of formula I
`
`5 368,979
`
`It—C—o—R.
`
`H——C—O—R2
`
`n—c—o—1<_.
`
`wherein R1, R2, and R3 are independently
`
`’ CIlg—C5H5_.
`
`0 l
`
`l
`jib‘?
`
`0 l
`
`l
`01' j Ci CmH_sm_3 * CH2‘ C5H5,
`
`and n and m are an even number from 2 to 24.
`
`3. A pharmaceutical composition comprising (a) a com-
`pound of formula I
`
`(I1
`
`H—C—0—R.
`
`H—C‘—0—R3
`
`H—(‘—0—R3
`
`wherein R_,. R3, and R3 are independently H,
`
`0 I
`
`I
`— c— ((113),, — cu,— cuts,
`
`0 l
`
`l
`01‘ j Ci Cm l‘l2m_3 * Cl 12* (_‘{,H5,
`
`and n is zero or an even number from 2-24, m is an even
`number from 2-24, wherein at least one of R,, R3, and R3
`is not II, and (b) a component selected from the group
`consisting of hydroxyurea and erythropoietin.
`
`4. A pharmaceutical composition suitable for the treat-
`ment
`of nitrogen metabolism disorders,
`|3—hernogIobinopathies, anemia or cancer comprising a com-
`pound of formula I
`
`(ll
`
`H—C—o—R.
`
`H—(‘—0—Rg
`
`t1—c—o—R,
`
`4of5
`
`ll)
`
`15
`
`25
`
`3-0
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`In their experiments with dogs. Raper and Wagner
`(Biochem Journal 222188 (1938)) demonstrated that pheny-
`lalkanoic acids are oxidized at
`the beta carbon during
`metabolism to cause cleavage of two carbons at a time.
`Thus, they found that 80% of the phenylbutyrate adminis-
`tered to dogs appeared in the urine as the glycine conjugate
`of phenylacetate. Unlike dogs, man only produces an acety-
`lation product of glutamine from phenylacetate. ‘thus, when
`phenylhutyratc is administered to a human as either a fatty
`acid or a salt thereof, the phenylacetate formed as a result of
`beta oxidation will acetylatc the glutamine thus causing the
`formation of phenylacetylglutamine which will be excreted
`by the kidney. The beta oxidation process is not limited to
`phenylbutyrate. In fact, any even numbered phenylalkanoate
`can be metabolized to phenylacetate. Thus phenylhcxanoate.
`phcnyloctanoate and p|:tenyldecanoate are also effective to
`control waste nitrogen levels.
`
`Unsaturated fatty acids are oxidized by the same general
`pathway as saturated fatty acids. Two additional enzymes
`may he used. one which can reversibly shift the double bond
`from cis to trans configurations, and one which hydrates the
`double bond to form hyclroxy fatty acids. The compounds
`are then substrates for the beta oxidation enzymes.
`
`The ethyl esters of formula II are thought to be metabo-
`lizcd by spontaneous degradation in the intestine.
`
`the toxicity of tri-glycerides of
`is anticipated that
`It
`phenylbutyrate and other compounds of this invention to
`patients would be low when these compounds are adminis-
`tered to patients because the fate of such compounds is
`phenylbutyrate which is beta oxidized to form phenylac-
`etate. Glycerol is also produced, but
`it
`is a normal body
`constituent which is either converted to glucose or oxidized.
`For the ethyl esters, ethanol is produced, but in such small
`quantities as to be non-harmful. The phenylaoctate meta-
`bolic product, on the other hand, has no known toxicity and
`is approved for investigational use in humans (IND #17123).
`We claim:
`1. A method of treating a nitrogen metabolism disorder in
`a patient in need of such treatment. comprising administer-
`ing to said patient an effective amount of a compound of
`formula (I)
`
`(I1
`
`[I
`
`H—c—o—1<,
`l
`II—T—0—Rg
`H—up—o—R,
`[-1
`
`wherein R, R2 and R3 are independently H.
`
`0 l
`
`l
`mC: (CI‘I3},.*ClI3— C5H5,
`
`0 l
`
`l
`or —C—c...tI;.,..3—t':ttg—C,,tt5,
`
`n is zero or an even number from 2-24 and m is an even
`number from 2-24, provided that at least one of R,, R2 and
`R3 is other than II.
`
`4 of 5
`
`

`

`7
`wherein R” R2. and R3 are independently
`
`8
`R3 is a compound of the formula
`
`5 368,979
`
`0 |
`
`|
`'* C‘—' C‘.mH3m.;‘—'CH;—' C]5H5_.
`
`and a pharmaceutically acceptable excipient.
`7. A compound of the formula I
`
`(11
`
`H I
`
`n—ri‘—o—R.
`n—T—o—1<2
`H—c—o—1<,
`IH
`
`wherein R], R2, and R3 are independently H,
`
`0 I
`
`I
`jC?(ClI3)n:CHg"‘C5iI5_.
`
`0 l
`
`l
`OT j C * Fm Hgm:_s 1 CH-_I,_ C5H5_.
`
`and n is zero or an even number from 2-24, and m is an even
`number from 2-24, with the provisos that at least one of R1,
`R2, and R3 is not I-I, and that when n is 0 or 2, then one of
`R1, R2, and R3 is a compound of the formula
`
`0
`
`“— C“ CmH2u..1—(-‘H2‘“ CsHs=
`
`8. The compound ofclaim 7, wherein n is 0, 2, 4. or 6, and
`m is 2, 4, or 6.
`9. A pharmaceutical composition suitable for the treat-
`ment
`ol' nitrogen metabolism disorders,
`|3-hentoglobinopathies, anemia or cancer, comprising the
`compound of claim '7, and a pharmaceutieally acceptable
`excipient.
`10. The composition of claim 9, wherein n is 0, 2, 4, or 6,
`and to is 2, 4, or 6.
`
`5of5
`
`0 |
`
`|
`jC*(CH3‘]n—’C‘H3—C5H5_.
`
`0 N
`
`or ? C — C... H2n|-3 — C'H3— C(,[‘I5_.
`
`IE)
`
`15
`
`3-0
`
`3-5
`
`40
`
`45
`
`It is zero or an even number from 2-24, and In is an even
`number from 2~24 and a pharmaceutically acceptable
`excipient.
`5. A pharmaceutical composition suitable for the treat-
`ment
`of nitrogen metabolism disorders,
`|3—hemogIolJinopathies, anemia and cancer comprising ethyl
`esters of the formula I1
`
`(I U
`
`C3H5:0?C‘jR.|
`
`is C,,,H,_.,,,_:—CH:—-C.‘fiI-L and m is an even
`wherein R_,
`number from 2-24, together with at least one pharmaceuti-
`cally acceptable excipient.
`6. A pharmaceutical composition suitable for the treat-
`ment
`of nitrogen metabolism disorders,
`|3-hemoglobinopathies, anemia or cancer comprising a com-
`pound of formula 1
`
`fl]
`
`[-1
`
`H—C—O-—R.
`
`tt—C—O—R2
`
`n—c|-—o—r<3
`H
`
`wherein R,, R3, and R3 are independently H,
`
`— (CH3), — C‘.tt;— Q«,tt_r._.
`
`0 I
`
`I
`01‘ j C: Cm Hgm__I" CH-2* C5! 15,
`
`n is zero or an even number from 2~24, and m is an even
`number from 2-24, provided that at least one of R1, R3, and
`
`5 of 5
`
`