United States Patent
`
`[19]
`
`[11] Patent Number:
`
`5,968,979
`
`Brnsilow
`
`[45] Date of Patent:
`
`Oct. 19, 1999
`
`USU{J5968979A
`
`[54] TRIGLYCERIDES AND ETHYL ESTERS OF
`PHENYLALKANOIC ACID AND
`PHENYLALKENOIC ACID USEFUL IN
`TREATMENT OF VARIOUS DISORDERS
`
`[75]
`
`Inventor: Saul W. Brusiluw, Baltimore, Md.
`
`[73] Ass.igl'Iee: Brnsilnw Enterprises LLC, Baltimore,
`Md.
`
`[21] Appl.No.:091'tH]6,432
`
`[221
`
`Filed:
`
`Jan. 13, 1993
`
`Related U.S. Application Data
`
`[63] Continuation of application No. U8r'384,935__ Feb.
`abandoned.
`
`Tr‘, I995,
`
`A0lN 37110; A61K 311235
`Int. Cl."
`[51]
`[52] U.S. Cl. ....................... 5141533; 5141532; 5141547;
`51413549; 5141552; 5141558; 5141814; 5141815;
`5141885; 5541227; 554,"22(l; 554.3218; 5541219;
`56(lr'8; 56(l;'76
`Field of Search ..................................... 5541227, 220,
`5541218, 219; 56018, 7'6; 5141532, 547,
`549, 552, 558, 814, 815, 885
`
`[58]
`
`[56]
`
`References Cited
`l7()RI£I(iN P/\'I"l_’.N'l' I)()CUMEN'l'S
`
`Walsh et al., The Journal of Biological Chemistry, vol. 265,
`No. 8, pp. 4374-4381 (1990), sn—l,2—Diacylgylcerol Kinase
`of Es'c}:ericI':ia coir".
`
`Newmark et al., “Butyrate and Phenylaeetate as Differenti-
`ating Agents: Practical Problems and Opportunities”, Jour.
`of Cell. Biochem., Supplement 22: 2-4'r'—253{l995).
`
`Chen et al., “'I'rib1ttyrin: A Prodrug of Butyric Acid for
`Potential Clinical Applicaitn in Dilrerentiation 'I'l1erapy",
`Cancer Res., 54-:3494-—3499(1994-).
`
`Lea et al., “Butyramide and Monobutyrin: (irowth Inhibi-
`tory and |)i[Terentialing Agents”, Anticancer Res., 13:
`145-150 (1993).
`
`Acclémie Des Sciences, Chimie Organique, “Preparation de
`quelques glycericles phénylaljphatiques et leur reduction en
`alcools ,
`.
`. "9 P11 682-684.
`
`Brusilow et al., Metabolism, vol. 42, No. 10 Oct, 1993, pp.
`1336-1339, “Restoration of Nitrogen Homeostasis in a Man
`with Ornithine Transcarbamylase Deficiency".
`
`Maestri et al., "Prospective treatment of urea cycle disor-
`ders”, pp. 923-928.
`
`Prirrrrrry EJt'rrrrtiner—(iary Geist
`A.s'.s'istrm.r EJt'rrririrrcr—l)eht)rah D Carr
`
`/tt."0mey, Agent, or Firm—Nikaido Marrnelstein Murray &
`Oram LLP
`
`94-22494
`
`lI'l;‘l994 WIPO .......................... .. A6lK 49,102
`
`[57]
`
`ABSTRACT
`
`OTHER PUBLICATIONS
`
`Georges Damens et al.: “Preparation dc quelques glycérides
`phénylaliphatiques et
`leur
`réduction en alcools .
`,
`.”,
`Comptes Rendus Hebdomadaires Des Seances De
`lfacademie Des Sciences, vol. 205, Oct. 18, 1937, pp.
`682-684.
`
`Walsh et al., Chemical Abstract vol. 112, No. 231744.
`Chemical Abstract, vol. 116, No. 46308, Seiki
`el al,
`“Homogenous Pharmaceutical Emulsions Containing Non-
`steriodal Analogesics and Inllammation Inhibitors”.
`
`Two new l‘on'ns ol‘ prodrug for phenylacetate, ol‘ even
`congeners of phenylalkanoic acid and phenylalkenoic acids,
`which are the phenylalkanoic or phenylalkenoic esters of
`glycerol, or the ethyl esters of phenylalkanoic acid or
`phenylalkenoic acids. These forms of the drugs provide a
`convenient dosage form of the drugs. The prodrugs ol‘ the
`invention are useful to treat patients with diseases of nitro-
`gen
`accumulation, patients with certain
`]3—hemoglobinopathies, anemia, and cancer.
`
`10 Claims, No Drawings
`
`1
`
`PAR PHARMACEUTICAL, INC.
`PAR PHARMACEUTICAL, INC. EX. 1026
`EX. 1026
`
`

`
`5,968,979
`
`1
`TRIGLYCERIDES AND ETHYI. ESTFIRS OF
`PHENYIALKANOIC ACID AND
`PHENYLALKENOIC ACID USEFUL IN
`TREATMENT OF VARIOUS DISORDERS
`
`CROSS Rl:ll7l£REN(_'l.l TO REl.I\Tl3l)
`APPLICATION
`
`This application is a continuation of Ser. No. U8;’384,935,
`filed Feb. 7, 1995, now abandoned.
`
`BACKGROUND OI‘ 'l‘IlI_-I INVENTION
`
`The present invention relates to compounds, phannaceu-
`tical compositions, and methods for treating several condi-
`tions with prodrugs for phenylacetate as therapeutic agents.
`
`I5II£l.D OI" TIIE. INVI_-'.NTI()N
`
`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. Ilowever, for those who sulfer 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-
`mulatifllt 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, ct al., T!teJoumm’ ofPediarr.€c.s', Vol. 119, No.
`6, 923-928 (1991)).
`DESCRIPTION OF RELATED ART
`
`/\ more recent approach to remedy this pervasive problem
`is described in U.S. Pat. No. 4,284,647 to Saul W. Brusilow,
`wherein benzoic acid, phenylacetie 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 etfective treatment for those sulfering
`from nitrogen accumulation diseases. See also "Treatment of
`I nborrl Errors of Urea Synthesis,” New f‘§rigi'(rrt(t'.Ir)nrnrrI of
`Medicine, 306; 1387-1392 (1982).
`
`‘Ill
`
`15
`
`10
`
`30
`
`40
`
`2
`U.S. Pat. No. 4,457,942, also to Saul 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 dow'n
`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
`olfensive odor which phenylbutyrate has.
`The above treatments, although effective, have a substan-
`tial disadvantage. The dose of sodium phenylbutyrate for an
`adult with a urea cycle disorder is 20 grarnstday. This
`requires that the patient take forty (44)) tablets of 0.5 gran1s
`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 gramsfday total
`sodium).
`The substitution in therapy of phenylacetate or
`phenylbutyrate, by the compounds of the present invention,
`provides the therapeutic compound in a more convenient
`dosage form. 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 of immature 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 differentiation of cultured human glioblastoma cell lines
`with reduced expression of malignant phenotype.
`Systemic treatment of rats bearing intracranial gliomas
`with phenylacetate resulted in significant 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 efficacy, and lack of toxicity (Samid et al., Cancer
`Re.s'ca'r(:!r, 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 ditferentiation inducer of leukemic and other less
`dilferentiated tumor cells, such as hon'none refractory pros-
`tate cancer.
`
`60
`
`65
`
`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.,
`The Jazmin! of Ctinieaf Investigation, Vol. 1 9, 2288-2295,
`1993).
`Phenylacetate may exert an anti-tumor atfect by another
`mechanism. Glutamine is the major nitrogen source for
`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
`
`2
`
`

`
`5,968,979
`
`3
`glutamine along with accelerated utilization and catabolism,
`operate at
`tuniting 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
`of phenylacetate may limit the growth rate ol‘ rapidly divid-
`ing cells such as tu mor cells.
`By one or more of the above mechanisms, phenylacetate
`causes a decrease in tumor characteristics of a variety of
`tumor cells. Because of iLs known non-toxicity, pheny1ac-
`etate is a promising therapeutic agent, either alone or in
`combination with other anti—tumor agents.
`Ilemoglobinopathies
`Sodium phenylbutyrate is thought to cause improvement
`in certain [i—hemoglobinopathies because the sodium phe-
`nylbutyrate induces the expression of fetal hemoglobin.
`Thus the absent or aberrant [3-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 lietal hemoglobin however, have serious side
`effects that are not consistent with their use as long term
`therapeutic agents. However, sodium phenylacetate and
`sodium phenylbutyrate 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 phenylbutyrate results in a
`response in many patients. The response is particularly good
`in patients with relatively high erythropoietin levels. Thus,
`combination therapy of the phenylbutyrate and erythropoi—
`etin may be elTective. Ilydroxyurea given orally has also
`been shown to increase hemoglobin levels in some thalas-
`semia patients. Clinical studies of thalassemia patients
`treated with a combination of hydroxyurea and sodium
`phenylbutyrate has produced increased hemoglobin levels in
`sorrle patienLs.
`
`‘IE!
`
`‘IS
`
`10
`
`30
`
`40
`
`4
`DIJSCRIPTION 01"‘ Tl-IE PREFl.i.RREI)
`EMBODIMENTS
`
`The present invention utilizes compounds of the formula:
`
`[I
`I
`H—(|?—()—R1
`[I—t|Z‘—0—Rg
`[I—C—0—R,
`H
`
`wherein R1, R2, and R3 are independently, H,
`
`O
`
`— c— (C[I.3],, — ct-1,
`
`:
`
`0
`
`or — c — C,,,H«_,,,,_-3 — es,
`
`and n is zero or an even number, m is an even number and
`at least one of R], R2, and R3 is not II.
`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 triglycerides.
`The present
`invention also utilizes ethyl esters of the
`formula II
`
`(ll)
`
`:,H5-—o—c—It1
`
`wherein R, is
`
`()l
`
`SUMMARY OF THE INVENTION
`
`(( '‘H‘2.l|t
`
`The compounds of the present invention, triglycerides of
`phenylalkanoic acids or phenylalkenoic acids, and ethyl
`esters of phenylalkanoic acids or phenylalkenoic acids,
`provide a more convenient dosage fonn 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 0.5 g tables.r‘day, the present invention
`provides the same amount of active compound in approxi-
`mately four (4) teaspoonfuls 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-
`kanoie 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 andior
`the esters of the present invention alone or in combination
`with hydroxyurea andfor erythropoietin, may be 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 ol‘ the invention are commercially available.
`
`T(C[1.~m.2)...
`
`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 phenylalkanoic
`and phenylalkenoic acids. Preferably the substituents con-
`tain 24 or fewer carbon atoms. Most preferably, in and m are
`U, 2, 4 or 6.
`The compounds of the present invention can be used
`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 mgfkg body
`weight for children, and from 9.9 to 13 grams for adults. 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 parenterally.
`
`Metabolic liates of the Compounds of the Invention
`Pancreatic lipase is able to hydrolyse the triglyceride
`compounds of the invention to produce glycerol and phe-
`
`60
`
`3
`
`

`
`5
`nylalkanoic acids or phenylalkenoic acids. The glycerol is
`then metabolized in the usual manner.
`
`6
`2. A compound of formula I
`
`5,968,979
`
`(ll
`
`[I—C—0—R1
`
`H—(?—O—Rg
`
`H—c—o—1<,
`
`wherein R,, R2, and R3 are independently
`
`0 l
`
`l
`jcj(ClI'3]n’C'lI'3’C5[I5,
`
`0 l
`
`l
`01‘ T CT CmlI2m_3T C[I3— Cfillg,
`
`and n and m are an even number from 2 to 24.
`
`3. A pl'lalTnaceutical composition comprising (a) a com-
`pound of formula I
`
`U}
`
`II—C—0—R1
`
`H—(:—o—t<g
`
`I-I—C—O—R;.
`
`wherein R1, R2, and R3 are independently Ii,
`
`0 l
`
`l
`j C? (C113,. ’ C11] — CfiI'I5,
`
`0 l
`
`l
`01‘ T CT Cull 13”“: T Cl Ig— Cal [5,
`
`and n is zero or an even number from 2—24, m is an even
`number from 2-24, wherein at least one of R1, R2, and R3
`is not H, and (b) a component selected from the group
`consisting 0|‘ hydroxyurea and erythropoietin.
`
`4. A pharmaceutical composition suitable for the treat-
`ment
`of nitrogen metabolism disorders,
`[3-hemoglobinopathies, anemia or cancer comprising a con‘!-
`pound of formula I
`
`(J)
`
`H
`
`II*C—0—R1
`
`I-I—C‘.—0—R3
`
`I-l—(T—()—R3
`
`[I
`
`‘Ill
`
`15
`
`10
`
`30
`
`40
`
`60
`
`65
`
`In their experiments with dogs, Raper and Wagner
`(Biochem Journal 222188 (1928)) demonstrated that pheny-
`lalkztnoic acids are oxidized at
`the beta carbon during
`metabolism to cause cleavage ol’ two carbons at a time.
`Thus, they found that 8{)% 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
`phenylbutyrate is administered to a human as either a fatty
`acid or a salt thereof, the phenylacetate formed as a result of
`beta oxidation will acetylate 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 phenylhexanoate,
`phenylnctanoate and phenyldecannate are also elTeclive to
`control waste nitrogen levels.
`
`Unsaturated fatty acids are oxidized by the same general
`pathway as saturated fatty acids. Two additional enzymes
`may be used, one which can reversibly shift the double bond
`from cis to trans configurations, and one which hydrates the
`double bond to form hydroxy fatty acids. The compounds
`are then substrates for the beta oxidation enzymes.
`
`The ethyl esters of formula II are thought to be metabo-
`lized 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 patienLs because the late 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 phenylacetate meta-
`bolic product, on the other ha nd, 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 etfective amount of a compound of
`formula (I)
`
`(U
`
`H—c:—o—R,
`
`II—C—O—Rg
`
`n—c—o—R,
`
`wherein R1, R3 and R3 are independently H,
`
`0 I
`
`I
`— C— (CH;,1, — cH2— c:,«,H_,,
`
`0 I
`
`or
`
`I
`(.f:(T,_,,H_-;m__1,—'(fH3—(f¢-H5,
`
`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
`R3 is other than H.
`
`4
`
`

`
`wherein R1, R3, and R3 are independently
`
`7
`
`8
`R3 is a compound of the formula
`
`5,968,979
`
`0 |
`
`|
`* C— (311.11-gm-2* CII-3 — Q5115,
`
`and a pharmaceutically acceptable excipient.
`7. A compound of the fonntlla I
`
`U)
`
`11—c—o—R1
`
`H—C—o—R3
`
`H—c—o—1<_1
`
`wherein R1, R3, and R3 are independently H,
`
`0 I
`
`I
`— (I—((?t-13),, — CH3 — c,H,_,
`
`0 |
`
`|
`01‘ H C : C"-1['Ig,-",3 ? Cl 13’ Cd 15,
`
`ii
`—u:*—(Ct13),,—r:113—c1,t1._,,
`0
`
`0|‘ j C: C1111 I3m_gT CH2 — C6115,
`
`n is Hero or an even number from 2-24, and m is an even
`number from 2—24 and a pharmaceutically acceptable
`exeipient.
`5. A pharmaceutical composition suitable for the treat-
`ment of nitrogen metabolism disorders,
`[5—hern0globin0pathies, anemia and cancer comprising ethyl
`esters of the formula ll
`
`(11)
`
`it
`c3H_.-,—o—c:—R..
`
`‘ll!
`
`15
`
`10
`
`wherein R3 is (_‘mIl1._m_,_,d—(_'lI3-—('T6II5 and m is an even
`number from 2-24, together with at least one pharmaceuti-
`cally acceptable exeipient.
`6. A pharmaceutical composition suitable for the treat-
`ment of nitrogen metabolism disorders,
`B-hemoglobinopathies, anemia or cancer comprising a com-
`pound of formula I
`
`30
`
`(I:
`
`and fl 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,
`R3, and R3 is not H, and that when n is (I or 2, then one of
`R1, R3, and R3 is a compound of the formula
`
`0 l
`
`l
`— t::— c,,.H-3.,,.;— CH3 — (:1, H3,
`
`H
`
`II—C—O—R.
`
`II—C—O—R3
`I
`H~c:—o—R_.
`
`['1
`
`40
`
`8. The compound ofelaim 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—hcm0gl0binopathies, 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 m is 2, 4, or 6.
`
`wherein R1, R3, and R3 are independently H,
`
`— (ct-I3), — CH3 — C,-,[I5,
`
`0 H
`
`or T(f:{fmH3,,1_g’CH3—(f(,H5,
`
`n is zero or an even number from 2-24, and rn is an even
`number from 2-24, provided that at least one of R1, R3, and
`
`5