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`US0064-98156132
`
`112; United States Patent
`Glombik et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,493,156 B2
`Dec. 24, 2002
`
`(54)
`
`(75)
`
`IJIPHENYLAZlCTII)IN()NI‘Ll)lCRIVA'I'IVES,
`PROCESS FOR THEIR PREPARATION,
`MI-€I)ICAMlCN'I'S COMPRISING 'l‘Hl€Sl€
`COMPOUNDS AND THEIR USE
`
`Inventors: Heiner Clombik, Ilofheim (DLE);
`Werner Kramer, IVIEIIIIZ.-l_.HUlJUl']l10IIl1
`(DE); Stefanie Illolir, Eppslein (DE);
`Wendelin Frick, Hiinslellen—Beuerhach
`(DE); Iluhert Ileuer, Schwalaenheim
`(DE); Gerhard Jaehne, Frankfurt am
`Main (DE); Andreas Lindenscllmidt,
`Bad Soclen (DE); Hans-I.udwig
`Schaefer, Hofheim (DE)
`
`(73) Assignee: Aventis Pharma Deutsellland GmhH,
`1"-ranltfurt am Main (DE)
`
`FOREIGN PATENT DOCUMENTS
`
`wo
`wo
`wo
`wo
`wo
`
`311995
`wo95.«'0s532
`1211995
`wo95_«'352??
`3;199r.
`\~'()9s,»'1)s4s4
`e;1990
`worm,»-19450
`152000
`wo00,.-01037
`(J'I"lll_-ZR PUBLICATIONS
`
`“I_’zetimil)e—I lypolipidemic (fholesterol Absorption Inhibi-
`tor”, Drugs of the Future, 25(7), pp. 6?9—085, (2000).
`Hilgers et al., "Caeo—2 Cell Monolayers as a Model for Drug
`Transport Across the Intestinal Mueosa”, Pharmaceutical
`Research, 7(9), pp. 902-910, (1990).
`
`Priri.=ar_y' Exaiiiinw Joseph K. McKane
`A.s'.s'i'.s'1’r:.r.=1' Exm.In'ne1'fi1‘\ndrea D. Small
`(74) Atrormw, Agent, or F1'rm—Finnegan, Henderson,
`I-‘arabow, Garrett & Dunner, LLP
`
`[ *) Notice:
`
`Subject to any disclaimer, the term (if this
`patent is extended or adjusted under 35
`U.S.C. 15401) by 0 days.
`
`(57)
`
`ABS'I‘RAC'l"
`
`Compounds of the formula 1,
`
`(21) App]. No.: 10,021,028
`
`(22) Filed:
`(05)
`
`Dec. 19, 2001
`Prior Publication Data
`US 200210128252 Al Sep. 12, 2002
`(30)
`Foreign Application Priority Data
`DeC.2.l. 2000
`(DE)
`100 54 402
`Nov. 7, 2001
`(DE)
`......................................... 10154 520
`(51)
`Int. CL?
`A6lK 31,897; COTD 409102;
`/\6'lP 9100
`5145/210.02; 54{),=’2[)[}
`
`(52) U.S. Cl.
`
`OH
`
`R5
`\
`E \\
`/ /
`R5
`
`N
`
`0
`
`R1
`
`/ I
`3
`\
`"'--.\ _
`R—'
`\/R“
`/ J
`’\"'
`114
`
`(58) Field of Search
`
`5401200; 514f21[|.02
`
`(56)
`
`_
`References Clted
`US. P/\'[‘l_-'N'l‘ |)()(?UMl_-'N'[‘S
`
`in which R-1, R3, R3, R4, R5, and R6 ha“; [ha meanings
`given in the description, and their physiologically aeeeptable
`salts. The compounds are suitable for use, for example, as
`"Yl’*‘“I“‘1°"‘i°*‘-
`
`5_.?5rs_.4'?r1 A
`
`551998 Yumihe et al.
`
`14 Claims, N0 Drawings
`
`1 of 23
`
`PENN EX. 2223
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`US 6,498,156 B2
`
`1
`
`DIPHENYIAZlC'I'Il]IN()NIC [)ICRIVATIVlCS,
`PROCESS FOR THEIR PREPARATION,
`Ml'Il)ICAMENTS C()Ml’RIS[NG 'I"HI£SI*I
`COMI-’()UNl)S AND THEIR USIC
`
`2
`where n=0—6. where the phenyl ring may be mono-
`to trisubstituted by F, Cl, Br, I, OH, CF3, N02, CN,
`OCF3, O—(C,—C,.,)-alkyl,
`(C,—C,,)-alkyl, NIIZ,
`NH(C,—C,)—alkyl, N[(C,—C,,)—alkyl):, SO:—CH3,
`C0011, C0O—{C,—C,,)-alkyl or CONII3;
`I. is shown connected to (C,,—C_,(,)-alkylene as follows:
`
`0\\s/O
`
`
`
`/ I
`
`(Cg—C;tg_J~alky]cJ1e]
`
`R7 is methyl, ethyl, propyl or bulyl;
`R8 is II, OII, NH: or NlI—{C,—C[,)-alkyl,
`R9 is methyl, ethyl, propyl or bulyl;
`R10 is methyl, ethyl, propyl or butyl;
`wherein at
`least one oi‘ the radicals Rl
`
`to Rd has the
`
`meaning
`{Cn—C30)—alkylene—I., where one or more carbon atoms
`of the alkylene radical may be replaced by —O—,
`(C-0)
`,
`CH—CH ,
`C:C ,
`—N((C,—C,.,)-a].kyl)- or —NlI—,
`and its pharrnaceutieally acceptable salts.
`Another embodiment of the invention relates to com-
`pounds of the formula I, in which at least one of the radicals
`R1 to R6 has the meaning (C(,—C_,,,)-alkyletie-I., where one
`or more carbon atoms of the alkylene radical may be
`replaced by —O—, —(C=O)— or —NII—.
`Another embodiment of the invention relates to com-
`
`pounds of the formula 1, in which one of the radicals R1 or
`R3 has the meaning —{(“.._,—(“.30)—alkylene—l_, where one or
`more carbon atoms of the alkylcne radical may be replaced
`by —O—, —(C=0)— or —NH—.
`Another embodiment of the invention relates to com-
`pounds of the formula I, in which one of the radicals R1 or
`R3 has the meaning —(CII:)0_1—Nll—(C=O)0_,—
`(C3-C3,)-alkylene-(C=O)U_,—Nll—I., where one or more
`carbon atoms of the alkylene radical may be replaced by
`oxygen atoms.
`One of the radicals R1 to R6 may be, for example,
`attached to the Lradical in the meta position of ring Cofthe
`I. group.
`Owing to their increased solubility in water, compared to
`the parent compounds, pharrnaceutically acceptable salts are
`particularly suitable for medical applications. These salts
`should have a pharmaceutically acceptable anion or cation.
`Suitably pharmaceutically acceptable acid addition salts of
`the compounds according to the invention are salts of
`inorganic acids, such as hydrochloric acid, hydrobromic
`acid, phosphoric acid, rnctaphosphoric acid, nitric acid,
`sullionic acid and sulfuric acid, and of organic acids, such as
`acetic acid, benzenesulfonic acid, benzoic acid, citric acid,
`cthancstllfonic acid, fiimaric acid, gluconic acid, glycolic
`acid, isothionic acid, lactic acid, lactobionic acid, maleic
`acid, malic acid, methanesulfonic acid, succinic acid,
`p—toluenesulfonie acid, tartaric acid and trifluornaeetic acid,
`for example.
`l-‘or medical purposes, very particular prefer-
`ence is given to using the chloride salt. Suitable pharma-
`ceutically acceptable basic salts are ammonium salts, alkali
`
`10
`
`I5
`
`This application claims the benefit ol‘ priority under 35
`U.S.C. §ll9(a)
`to German patent application no.
`100644013,
`llled on Dec. 21, 2000, and German patent
`application no. 10154520},
`filed on Nov. 7, 2001. The
`contents of both priority documents are incorporated by
`reference herein.
`substituted
`to
`relates
`The
`invention
`diphenylazetidinones,
`to their physiologically acceptable
`salts and to derivatives having physiological function.
`Diphenylarietidinones (such as, for example, eretimibe)
`and their use for treating hyperlipidemia and arteriosclerosis
`and hypereholesterolemia have already been described [cf.
`Drugs of the Future 2000, ?5(7):G79—(i85)].
`It was an object oi" the invention to provide further
`compounds having a therapeutically utilizable hypolipi— -
`demic action. In particular, it was an object to find novel
`compounds which, compared to the compounds described in
`the prior art, are absorbed to a very low extent. Very low
`absorption is to be understood as meaning an intestinal
`absorption of less than 10%, preferably less than or equal to
`5%. In particular, absorption of the novel compounds should
`be less than that of czctimibc. Pharmaceutically active
`compounds which are absorbed to a very low extent gener-
`ally have considerably fewer side-elliects.
`Accordingly, an embodiment of the invention relates to
`compounds of the formula 1,
`
`30
`
`IR
`
`R5E//
`
`O
`
`N
`
`R}
`
`in which
`
`R1, R2, R3, R4, R5, R6 independently of one another are
`(C0—C_.,C,)—alkylene—I_, where one or more carbon atoms
`of the alkylene radical may be replaced by —O—,
`[(I—())
`,
`CflI—(Tll
`,
`(f_(T ,
`—N[(C,—C,,)-al.kyl)- or —Nll—; or
`II, F, Cl, Br, 1, C173, N02, CN, COOII, (“_00(C,—(“_,,)-
`alkyl,
`(T()Nll,,
`(T()NII(C,—(T,,)-alkyl,
`(TON
`[(C,—C,,)-all-:yl]3,
`(C,—(.‘,,)-al.l\'yl,
`(C2—C,,)-al.k.enyl,
`(C2—Cfi)—alkyI1yl or O—(C,—C,,}—al.kyl, where one or
`more hydrogens in the alkylene radicals may be
`replaced by fluorine; or
`S03—Nll,._, SO,._NII(C1—Cd)—alkyl, SO3N[(C,—C6)—
`alkyl]:, S—(C, —C,,]—alkyl, S—(CH3)_,—phenyl, S()—
`[t“.,—(“.o)—alkyl, S0—((“.l-I,),,—phcnyl, S02—{,—(“.O)—
`alkyl or S()2—(I 12],,-phenyl, where n=0—6 and the
`phenyl radical may be substituted up to two times by
`F, Cl, Fir, OH, (TF3, N02, CN, OCF3, O—{(“.,—(“.,,)—
`alkyl, [C.‘,—Cfi)-alkyl or NI-I2; or
`N112, NIl—(C,—C,,]-alkyl, N((C,—(T,.,)-alkyl}:,
`NH(C,—C.,,)-acyl, phenyl or 0—(Cl-I3)”-phenyl,
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2of28
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`PENN EX. 2228
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`US 6,498,156 B2
`
`4
`3
`individual dose, for example as a tablet, which can contain
`metal salts (such as sodium and potassium salts) and alkaline
`from 0.05% to 95% by weight of the active compound.
`earth metal salts (such as magnesium and calcium salts).
`Further pharmaceutically active substances can also be
`The scope of the invention also includes salts having a
`present, including further compounds of the formula (I). The
`pharmaceutically unacceptable anion, which salts may be
`5 pharmaceutical compositions according to the invention can
`useful intermediates for preparing or purifying pharmaceu-
`be prepared by one of the known pharmaceutical method.s,
`tically acceptable salts andfor for use in nontherapeutic, for
`which essentially consists in mixing the constituents with
`example in vitro, applications.
`pharrnaceutically acceptable carriers andfor auxiliaries.
`Here, the term “derivative having physiological function"
`Pharmaceutical compositions according to the invention
`refers to arty physiologically acceptable derivative of a
`com pound according to the invention, for example an ester, 1e are those which are suitable for oral or peroral (e.g.
`capable of forming, upon administration to a mammal, for
`sublingual) administration, although the most suitable man-
`example man, such a compound or an active metabolite
`ner ofadministration is dependent in each individual case on
`[directly or indirectly).
`the nature and severity of the condition to be treated and on
`A further aspect of this invention are prodnlgs of the
`the type of the compound of the formula (I) 1Ised in each
`compounds according to the invention. Such prodrugs can is case. Coated fomiulations and coated delayed-release for-
`be metabolized in vivo to give a compound according to the
`mulations are also included in the scope of the invention.
`invention. These prodrugs may or may not be active in their
`Acid—resistant and enteric formulations are preferred. Suit-
`own right.
`able enteric coatings include cellulose acetate phthalate,
`The compounds according to the invention can also be
`polyvinyl acetate phthalate, hydroxypropylmethylcellulose
`present in various polymorphic forms, for example as amor— an phthalatc and anionic polymers of methacrylic acid and
`phous and crystalline polymorphous forms. The scope of the
`methylmethacrylate.
`invention includes all polymorphic forms of the compounds
`Suitable pharmaceutical compounds for oral administra-
`according to the invention, which form a further aspect of
`tion can be present in separate units, such as, for example,
`the invention. The compounds of the invention may also
`capsules, cachets, lozenges or tablets, which in each case
`exist in the form of solvates.
`15 contain a specific amount of the compound of the formula
`The compounds of the formula [ and their phan'naceuti-
`(I); as a powder or granules; as a solution or suspension in
`cally acceptable salts, esters, prodrugs and derivatives hav—
`an aqueous or nonaqueous liquid; or as an oil—in—water or
`ing physiological function are ideal medicamcnts for trcat—
`water—iu—oil emulsion. As already mentioned, these con1po—
`ing an impaired lipid metabolism,
`in particular
`sitions can be prepared according to any suitable pharma-
`hyperlipidemia. The compounds of the formula I are also so ceutical method which includes a step in which the active
`suitable for modulating the serum cholesterol concentration
`compound and the carrier [which can consist of one or more
`and for treating arteriosclerotic symptoms. The compounds
`additional constituents) are brought into contact. In general,
`ofthe invention are also suitable for the treatment ofinsulin
`the compositions are prepared by uniform and homogeneous
`resistance.
`mixing of the active compound with a liquid andfor finely
`As used here, “lrealment" or "therapy” of a condition and 35 divided solid can'ier, after which the product, if necessary, is
`"treating”a condition can mean successfullyeliminating the
`shaped. For example,
`a
`tablet can thus be prepared by
`condition, reducing the elIects associated with it, andfor
`pressing or shaping a powder or granules of the compound,
`reducing its severity.
`It also includes administering the
`if appropriate with one or more additional constituents.
`relevant compotmds to a patient to avoid recurrence of a
`Presserl tablets can be produced by tableting the compound
`condition. It also includes avoiding the onset of a condition 40 in frec—llowing form, such as, for example, a powder or
`by administering the relevant compounds to patients falling
`granules, if appropriate mixed with a binder, lubricant, inert
`into a risk group or category for developing the particular
`diluent andmr a (number of) surface-activetdispersing agent
`condition. Those skilled in the art can routinely identify
`in a suitable machine. Shaped tablets can be produced by
`patients likely to present with a given condition,
`thereby
`shaping the pulverulent compound moistened with an inert
`qualifying as candidates for treatment.
`45 liquid diluent in a suitable machine.
`The compound(s) of the formula (I) can also be admin—
`Pharmaceutical compositions which are suitable for per-
`istered in combination with other active compounds.
`oral
`(sublingual) administration include lozenges which
`The amount of a compound of the formula (I) required to
`contain a compound of the formula (I) with a flavoring,
`achieve the desired biologicalelfect depends onanumber of
`customarily sucrose and gum arabic or tragacanth, and
`factors, for example on the specific compound chosen, on 50 pastilles which include the compound in an inert base such
`the intended use, on the mode of administration and on the
`as gelatin and glycerol or sucrose and gum arabic.
`clinical condition of the patient. In general, the daily dose is
`Suitable other active compounds for the combination
`in the range from 0.1 mg to 100 mg (typically frotn 0.1 mg
`preparations include: all antidiabctics, mentioned in Role
`to 50 mg) per day per kilogram of bodyweight, for example
`Liste 2001, Chapter 12, the disclosure of which is incorpo-
`0.'l—l0 mgfkgxday. Tablets or capsules may contain, for 55 rated by reference herein. They can be combined with the
`example, from 0.01 to "100 mg, typically from 0.02 to 50 mg.
`compounds of the formula I according to the invention in
`In the case of pharmaceutically acceptable salts, the above-
`particular to achieve a synergistically enhanced action. The
`mentioned weight data relate to the weight of the diphenyl—
`active compound combination can be administered either by
`azetidinonc-ion derived from the salt. For the therapy of the
`separate administration of the active compounds to the
`abovementioned conditions, the compounds of the formula on patient or in the form of combination preparations compris-
`(I) can be used themselves as the compound, but preferably
`ing a plurality of active compounds in a pharmaceutical
`they are present in the form of a pharmaceutical composition
`preparation.
`with an acceptable carrier. The carrier must of course be
`Antidiabetics include insulin and insulin derivatives, such
`acceptable in the sense that it is compatible with the other
`as, for example, I.antus® or IIMR 1964, GLP-1 derivatives,
`constituents of the composition and is not harmful to the 65 such as, for example, those disclosed by Novo Nordisk A/"S
`health ofthe patient. The carrier can be a solid or a liquid or
`in W0 ‘)8{0887l, the disclosure of which is incorporated by
`both and is preferably formulated with the compound as an
`reference herein, and oral hypoglycemic active compounds.
`
`3 of 23
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`PENN Ex. 2223
`CFAD V. UPENN
`lPR20l5-01836
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`

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`US 6,498,156 B2
`
`5
`6
`In one embodiment of the invention, the compounds of
`The oral hypoglycemic active compounds preferably
`the formula I are administered in combination with a lipo-
`include sulphonyl ureas, biguadines, meglitinides,
`protein lipase inhibitor, such as, for example, ND-1886.
`oxadiazolidindiones,
`thiazrtlidindiiines, glucosidase
`In one embodiment of the invention, the compounds of
`inhibitors, glucagon antagonists, GI.P—l agonists, potassium
`the formula I are administered in couibiiiatioii with an ATP
`chaiiiiel openers, such as, for exaiiiple, those disclosed by 5
`citrate lyase inhibitor, such as, for example, SB-204991).
`Novo Nordisk MS in WC) 97i’26265 and WO 99303861, the
`In one embodiment of the invention, the compounds of
`disclosures of which are incorporated by reference herein,
`the formula I are administered in combination with a
`insulin sensitizers, inhibitors of liver enzymes involved in
`.‘ ua ene s n ease in i
`ior, suc
`as, or exam e,
`.‘-
`simu a in
`uconeo enesis 2Il'IL or r co eno sis, mo(u-
`so
`I
`ytht
`hbt
`h
`f
`pl BM‘:
`t
`It ggl
`g
`if
`Ely
`g
`ly
`i
`lators of glucose uptake, compounds which modulate lipid 1U 188494.
`metabolism, such as antihyperlipidcmic active compounds
`In one embodiment of the invention, the compounds of
`and antilipidemic active compounds, compounds which
`the formula I are administered in combination with :1
`reduce food intake, PPAR and l’><R agonists and active
`lipoprotcin(a) antagonist, such as, for example, CI—1(]27 or
`compounds which act on the ATP—depcndent potassium ,5 nicotinic acid. In one embodiment of the invention,
`the
`channel of the beta cells.
`compounds ofthe formulal are administered in combination
`In one embodiment of the invention, the compounds of
`with a lipase inhibitor, such as, for example, orlistat.
`the formula I are administered in combination with a IIMG-
`In one embodiment, of the invention the compounds of
`Co/\ ieductase inhibitor such as sinivastatin, fluvastatin,
`the formula I are administered in combination with insulin.
`pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvasta— an
`In one embodiment, the compounds of the formula I are
`tin.
`administered in combination with a sulphonyl urea, such as,
`In one embodiment of the invention, the compounds of
`for example, tolbutamide, glibenclamide, glipizidc or gli-
`the formula I are administered in combination with a cho—
`clazide.
`
`30
`
`for example,
`
`In one embodiment, the compounds of the formula I are
`lesterol absorption inhibitor, such as,
`:5 administered in coi'nbination with a biguanide, such as, for
`cmtjmibm liquesidcj pamaquesidc‘
`example‘ mem’"T”"'
`_
`‘
`In one embodiment of the invention, the compounds of
`1 _m_
`a[.1°.t_h°_r °C_hmT)r.n’_1}.1"' "°n.]113°l" "C15 elf. l.hc. :(_lm_1u
`the formula I are administered in combination with a PPAR
`an; a II]l[l.l3:sl;i.«l'U.
`iii eloiiidiiiatioii wit I a iiieg lllt1l.lL, suei
`gamma agonisl, such as‘
`for example’ msiglilazonc’
`as or exarnp e, repag im e.
`_
`_
`,
`’In one embodiment, the compounds of the formula I are
`ploglllamnc’ JTTLSOL’ GI 263_570‘
`1
`adiiiinistcrcd in combination with a thiazolidiiidione, such
`In Or": embodlmenl Elf the lfwlimlonf ‘hf: C°":'p°”“d5 of
`as’
`for example’
`tmglnazone, Cigmazone, pioglitazone’
`the formula 1 are administered in combination with a l’l’AR
`rosi_glita7ione, or the compounds disclosed by Dr. Reddy’s
`alpha agonist, such as, for example, GW 9578, GW 7647.
`Research Foundation in W0 97.41097, the disclosure of
`In one embodiment of the invention, the compounds of
`the formulalarc administered in combination witha mixed 35 which 15 1W-'0TPUT3lCd by Tfilfiffificti hflffilfli
`111 Piirll‘-‘"11"
`PPAR alphafgamma agonist, such as, for example, GW
`5"[l:4'[_( 3 ,4-d 1 ll Yd 1'0 ' 3 ' 1'“ °lhYl' ‘ljo X‘: '_3'_
`1536, AVE 8042? AVE 8134, AVE U841
`quinazolinylmethoxy]phenyl]methyl]—2,4—thiazolidindione.
`In one embodiment of the invention, the Compounds of
`Il'l'()l-‘J6 embodiment, the compounds of the tormula-I are
`.
`.
`.
`.
`.
`.
`.
`administered in combination with an o.—gliicos.idase
`the formula I are administered in combination with a tibrate,
`.
`.
`.
`.
`.
`‘
`_h
`‘ f
`1
`I,
`rb '
`_l [,b _
`be, _[,b _
`4U inhibitor, such as, for example, miglitol or acarbose.
`Sm‘
`as” or examp 6’ W0 L rifle’ "
`I Idle’
`id 1 Rue‘
`In one embodiment, the compounds of the formula I are
`In one embodiment ol the invention, the compounds of
`administered in wmbinau-on with an active Compound
`the formula I are administered in combination with an M'I'l-’
`which ads on the /\'1‘p_dt.,pt.,m]em polassium Channel of baa
`il1l'IilJiT0f,‘e'v|Ji-‘ll
`il5- f0f t-'rX¥l|11PlUs Ba)‘ 13'9952= BMS"-M1038,
`cells, such as,
`for example,
`tolbutamide, glibenclamide,
`R—1U37"57.
`45 glipizidc, yiazide or repaglinidc.
`In om; embodiment of the invention, [hc compounds of
`In one embodiment, the compounds of the formula I are
`the formula [ are administered in combination with a bile
`admlnlslcfifd 1“ °0mbm3-U0" Wllh mom Illa“ one ‘Of Fhc
`acid absorption inhibitor, such as, for example, IIMR 1453.
`ah,"“'cmc"“]:’"cdl mmPmTdS‘ {Ur *’_xamp1cl 1; “T-'h1"“m':m
`In one embodiment of the invention, the compounds of
`mm 4 W11) Uny.u.rea ‘mt me] on-fl.m’.a W Orly Med dud
`.
`._
`.
`.
`.
`.
`.
`..
`,
`5U acarliose, repaglinide and lI1L:lIUl'II]t[], iiisulni and a sulplio—
`the formula I are administered in combination with a (J:.lP
`_
`.
`‘
`.
`_
`.
`.
`‘
`.
`1
`. H
`. h.bhOl_ Such 15 for exam IC B1
`194789
`nyl urea,
`insulin and metformin,
`insulin and troglita/ion,
`‘
`m 1
`‘
`'
`‘ "
`‘
`p _’
`‘ Y‘
`'
`insulin and lovastattn, etc.
`In‘ one cmh0d'm°m‘ ol the Hivcnnnnj lb‘? mmP0""dS 0f
`In a further eiiibodinient, the compounds of the formula I
`111“ 101'm“1*1 1 3“? *“lm1“15W“—'d 1“ Wmblnallflfl ‘-Wh 3 P01)?"
`are administered in combination with CARI‘ agonists. NPY
`merie bile acid adsorlicr, stich as,
`for example, 55 agonists,MC4 agoriists,orexin agonists,I-I3 agonists,TNF
`cholestyramine, eolesolvam.
`agonists, CRT’ agoriists, CRF TIP agonists, urocortin
`In one embodiment of the invention, the compounds of
`agonisls. B3-agonists, MSH (melarmcyte-Stimulating
`the formula I are administered in combination with an IDI.
`l‘°’f“f‘"°l 330711515: C-(‘K agflnlsl-‘B 5C1'0l'T}"l1’1 mllplake
`receptor induccr, Such as, for Cxamplc, HMR 1171, HMR
`inhibitors, mixed serotonin and noradrenergpc compounds,
`1586
`an SIIT agonists, bombesin agonists, galanin antagonists,
`_
`.
`.
`.
`.
`'
`growth honrione, growth hormone-releasing compounds,
`In one embodiment ol the invention, the compounds of
`.
`.
`.
`.
`d.
`. h ACAY
`TRH agonists, decoupling protein 2- or3 modulators, leptin
`h E
`1
`I‘
`I
`.
`.‘
`‘
`b.
`1
`.
`l efrmu 5”‘
`‘"6 3‘ mlnmere 1“ ‘Om, m_‘m°" W" an
`'
`agonists, DA agonists (bromoeriptin, doprexin),
`tipasei
`lnhlbumv Such as?! R” exampltb avaglmlhc‘
`amylase inhibitors, PPAR modulators, RXR modulators or
`In one embodiment of the invention, the compounds of 65 '1-R43 agonisls,
`the toriiiula I are administered in combination with an
`In one embodiment of the invention the further 'lC[t\C
`antioxidant, such as, for example, (JPC—14117'.
`compound is leptin.
`
`4 of 23
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`

`
`7
`In one embodiment, the further active compound is dex-
`amphetamine or amphetamine.
`
`8
`Preference is given to both racemic and enantiomerically
`pure compounds of the formula 1 of the following structure:
`
`US 6,498,156 B2
`
`()H
`
`Preference is furthermore given to compounds of the
`formula I
`in which the L radicals have the following
`meaning:
`
` i
`
`(Cg—C_1g,1-alkyleiiel
`
`The invention furthermore provides a process for prepar-
`ing the compounds of the formula I. which comprises
`obtaining the compounds of the formula I by proceeding
`analogously to the reaction scheme below.
`
`R!
`
`//a
`"'--..\R2
`
`~
`
`_,\«F
`R-4
`
`fl
`
`RIO..,\ N
`
`R9
`
`//
`0
`O
`\s//
`
`Ki
`
`0
`
`R7
`
`R8
`
`|\
`,\f‘
`it
`
`L
`
`In one embodiment, the further active compound is ten-
`Iluramine or dexfentluramine.
`
`In yet another embodiment, the further active compound
`is sibutramine.
`
`1U
`
`In one embodiment, the further active compound is Orl-
`istat.
`
`the further active compound is
`In one embodiment,
`mazindol or phentermine.
`
`I5
`
`In one embodiment, the compounds of the formula I are
`administered in combination with fibers, preferably
`insoluble fibers, such as,
`for example, Caromax®. The
`combination with Caromaxe® can be given in one prepa-
`ration or by separate administration of compounds of the
`formula I and Caromax®. Ilere, Caromax® can also be
`administered in the form of food, such as, for example, in
`bakery goods or muesli bars. Compared to the individual
`active compounds, the combination of compounds of the
`formula I with Caromax® is, in addition to an enhanced
`action, iI1 particular with respect to the lowering of LDL
`cholesterol, also characterised by its improved tolerability.
`
`It is to be understood that each suitable combination of the
`compounds according to the invention with one or more of
`the compounds mentioned above and optionally one or more
`further pharmacologieally active substances is included in
`the scope of the present invention.
`
`The invention furthermore provides both stereoisomer
`mixtures of the formula I and the pure stereoisomers of the
`formula I, and diastereomer mixtures ol‘ the formula I and
`the pure diastereomers. The mixtures are separated by
`chromatographic means.
`
`30
`
`35
`
`4U
`
`R]
`
`/‘X
`"'--.\R2
`
`..\—r
`R4
`
`//
`
`RS
`
`0
`
`5 of 23
`
`PENN EX. 2223
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`US 6,498,156 B2
`
`9
`R4" is (C[,—C,0)—a]kylene in which one or more carbon
`atoms of the alkylene radical may be replaced by
`0
`5
`(C_—('))
`,
`(j1[—(j[1
`,
`C:('_‘
`,
`_N[(C]_Ch_)_a]_ky1)_ or _NH_l
`Alternatively. attachment to the L group is via ring Am 5
`ring C.
`The examples below serve to illustrate the invention in
`more delails “"ilh°‘-ll limiling the i“V°mi01'1 '0 ‘he P“XlU°l5
`and einbotlitncnts described in the examples.
`
`EXAMPLEI
`
`10
`N—[3—(3—Buty1-7-dimethylamino—3—ethyl—4—hydroxy—
`"I.1-Cli0X0-3,3.4a5-l0T1'3hYdT0-1H-l3C1'1Z0[l3]1hi9PiI1-5-
`yl}phenyl]-N‘-4-[l -(4-fluoroph‘cnyl)-3-(3-hydroxy-3-
`phenylpnJppjl)-ft-o1éoaze:d11§2-yl]ben;1yl-
`a) 1_(,,_(3x[]_4_phcnV]::::?1i$:-:13_:fi_%_pheny1pcmanc_1 S_
`1-
`” .3
`'
`'
`'
`"
`Uq1l3:g(;))fbcnzoy]buI),ric acid and 115 ml of tricthvlaminc
`are dissolved in 55 ml of dichloroniethane. After 5 min at
`mum Lcmpcramre, 53 ml d1‘ pivaloyl chlm-[dc are added
`over a period of 30 min, and the mixture is stirred for 2
`hours. 5.9 g of 4—pheny1oxazoIidin—2-one in 6 ml of dim-
`
`OH"
`
`0
`
`0
`
`on Q
`
`~
`
`\N
`I
`
`\\s//
`
`
`
`N/\Z\)J\N
`
`H
`
`H
`
`N-[3-[3-l5utyl-T-dirnethylamino-3-ethyl-4-hydroxy-
`'t,t-dioxo—2,3,4,5-tetrahydro-1H-bcnzo[b]thicpin-5-
`Y1)_phmy1]_5_{4_[3.(3_hyd1-ox}._3_phcny1pmpy1)_2_
`[4-methoxyphenyl]-4-oxoazetidiml -yl]
`benzylamino}pentr|namide ('1)
`
`ethyllon'namiLle and [L9 g of 4-(dirnethylamino]pyridine are
`then arlderl. The mixture is heated at reflux for about 7 hours
`(monitored by TI After the reaction has ended,
`the
`30 mixture is put into 15 ml of 2N sulfuric acid and stirred
`brielly, and the phases are then separated. The org. phase is
`washed with 5 percentstrength bicarboriate solution and,
`after dryillilg, concenltratingiand rtiierysiall17l.at1on l_‘rtli1n1q‘e’§l_}y4l
`100 mg of N_[3_(3_buIy1_7-6imett-13,1amin0_3_¢]hy1_4_
`£Dflci§:L FM_TI_?+:,L:3 :rbt\:;11§d‘l “'10
`hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-lII-henzo[h]thiepin- as
`3‘Y1iPh°"Y1l'5'bT0m0P°““l“?1m1d¢ and 70 mt; Of H4" " same route, optically activefenantiomcrieally enriched 2 is
`aminomethylphenyl)-3-(3-hydroxy-3-phenylpropy])-4-(4-
`obtained when optically activefenantiomerically enriched
`4—phenyloxa2ol id in—2—one is 11 sod.
`niethoxyphenyl)azetidi11—2—one are dissolved i11 5 1111 of
`dimethylforrnamide and, with stirring, heated at 80° C. for
`Eg0:c(f3;Iy( wxy 5 Phmylpbmdnoyl) 4 phgnyloxdwhdm
`about 2 to 3 hours. Alter the reaction has ended (monitored 4”
`Under argon and at a lcmpcraturc between 00 and _So C“
`by thin—layer chromatogram or HPI.C—MS), the solvent is
`S gof l—(2-oxo-4—phenyloxazolidin—3—yl)—S—phenylpentane—
`mmnved under reduced pressure and the residuc 1'5 purmcd
`1,5-'d10nc‘ in 20 ml oi dicliloromctliane are slowly, over a
`period ol about 3 hours, added to a solution of 1.5 ml of
`by chromatography. This gives product
`1 of molecular
`boron—dimethylsu]fide—complex in 25 ml of diehlo
`_
`Wclghl 92924 (C5sHauN407S)3 MS (FAB): 929 (M+H+i-
`45 roniethane. The mixture is stirred at the same temperature
`for another 2 hours. the reaction being monitored by thin-
`layer chromatography. After the reaction has ended, 2 ml of
`
`EXAMPLE N
`
`(J\S//U
`
`
`
`NH
`
`\ N
`/
`
`it
`
`on O ' N/K 011
`
`N
`
`O
`
`1?
`
`6 of 23
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`PENN EX. 2223
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`
`US 6,498,156 B2
`
`11
`methanol and 1.5 ml of 35 percent strength hydrogen
`peroxide solution and 1.1 ml of 3N sulfuric acid are added
`at below 0° C., and the mixture is stirred at room tempera-
`ture for another 15 min. After phase separation, the organic
`phase is washed successively with EN sulfuric acid, 59?.
`strength sodium bisullite solution and 10 percent strength
`sodium chloride solution and then dried and concentrated.
`
`After chromatography (SiO2, ethyl acetatetn—heptane=1:1,
`the product of molecular weight 339.4 (C20II2,N()_,); MS
`(DCl+): 322 (M+lI"—II2O); (L-LSl+):403 (M-t-Na"+Cll3CN),
`362 (M+Na")
`is obtained. By adding optically active
`1—methyl-3,3—diphenyltetrahyc1ropyrrolo[1,2—e][1,3,2]
`oxazaborole (S or R, 0.75 ml) at from 0° to -5” (T, to the
`reaction mixture prior
`to the addition of
`1—(2—oxo—4—
`phenyloxazolidin-3—yl)—5—pl1enylpet1tai1e—1,5—dione, by tile
`same route, 3 is obtained in diastereornerically enriched
`form.
`c)
`4—[ 1 —(4—Fluorophenylamino)—2—{2—oxo—4—
`phenyloxazolidir1e-3-carbonyl)-5-phenyl-5-
`trimethylsilanyloxypentyl]ben2onitrile (4) 3.3 g oi 3-(5-
`hydroxy—5-phenylpentanoyl)—4—phenyloxazo|idin—2—one and
`3.93 g of 4—[(4-fluorophenylimino)methyl]benzonitrile, dis-
`solved in 55 ml of dichlorometllalie, are cooled to —l0° (L,
`and 8.5 ml of diisopropylethylamine are added slowly. Over
`a period of 30 min, 5.3 ml of chlorotrimethylsilane are then
`added such that the temperature remains below —5° C. After
`one hour, the Inixture is cooled to -30° C., 1.1 ml olititanium
`tetrachloride are added at below -25° (.'. and the mixture is
`then stirred at this temperature overnight. After the reaction
`has ended, 4 ml of glacial acetic acid are added dropwise at
`—_5° C., the mixture is stirred for another 15 min, added, at
`U” (.1, to 50 ml of 7 percent strength tartaric acid and stirred
`for another hour, and 25 ml of 20 percent strength sodium
`bisullite solution are then added and stirring is continued for
`another 45 min. After phase separation, the organic phase is
`washed with about 40 ml of water, dried and concentrated to
`about 15 ml. 2.7 ml of bisrrimerhylsilylacetamirle are then
`added, and the mixture is heated at reflux for 30 min. After
`cooling to room temperature, the mixture is concentrated,
`giving, alter crystallization oi" the residue from ethyl aoetatei
`n—heptane,
`the product of molecular weight 635.8
`(C3—,.II_.,,3FN3O_,Si); MS (ES[+): (336 (M+II*).
`d) 4-[1-[4-Fluoropheny1)-3-(3-hydroxy-3-phenylpropyl)-4-
`oxo-axetidin-2-yl]benzonitrile (5)
`2.7 g of 4-[1-(4-fluorophenylamino)-2-(2-oxo-4-
`phenyloxazolidine—3—carbonyl)—5—phenyl—5—
`trimethylsilanyloxypentyl]benzonitrile in 30 ml of tert—butyl
`methyl ether, 1.6 ml of bistrimethylsilylaoetamide and 0.2 g
`of tetrabutylam nztoniunzt fluoride trihydrate are heated at
`reflux for 3 hours. The mixture is allowed to stand overnight,
`0.3 ml of glacial acetic acid are added, and the mixture is
`stirred for 15 min and then substantially concentrated. 15 ml
`
`1U
`
`I5
`
`30
`
`35
`
`40
`
`45
`
`12
`ofa mixture of isopropanolr'2N sulfuric acid=10:1 are added,
`and the mixture is stirred at room temperature for 1 hour.
`The mixture is then treated with a
`little solid sodium
`bicarbonate and again substantially concentrated and the
`residue is taken up in ethyl acetate and washed with water.
`The residue of the dried organic phase is purified by column
`filtration (Si02, ethyl acetatefn-heptane='l:1). This gives the
`product of molecular weight 400.5 (C:_.,H2,FN2O2]; MS
`(|)(Il+): 401 (M+lI*), 383 (M+II+—II;._O).
`e) 4-(4-Aminomethylphenyl)-l-(4-iluorophenyl)-3-(IL
`hydroxy—3—pheny1propyl)—azetidin—2—one (6)
`930 mg of 4—[1—(4—fluorophenyl)—3—(3—hydroXy—3—
`phenylpropyl)—4—oxo—azetidin—2—yl]—benzonitrile, dissolved
`in 100 ml of ethanol, are admixed with 4 ml of cone.
`ammonia and hydrogenated for 30 hours over Raney Ni, at
`room temperature and a hydrogen pressure ol‘ 20 bar. The
`catalyst is filtered off and the filtrate is concentrated under
`reduced pressure, giving, after chromatography (SiO2,
`diehloromethane;’methanol=0:1),
`the product of molecular
`weight 404.5 ((I_._,ll,_,jl-‘N2Og)l MS ([)(Tl+): 405 (M+l["),
`387 (M+H*—l-I20).
`f) S-[3-(3-Butyl-7-dimethylamino-3-ethyl-4-hydroxy-l,'I-
`dioxo-2,3,4,5-tetrahydro-'1H-benzo[b]thiepin-5-yl)-
`phenylcarhamoyl]pentanoic Acid (7)
`2 g of S-(3-aminophenyl)-3-butyl-7-dimethylamino-3»
`ethyl-1,'l-dioxo-2,3,4,5-tetra-hydro-1II-benzo[b]thiepin-4-
`ol, 3.4 g of hexanedioic acid, 1.04 g oi‘ dicyclohexylcarbo-
`diimidc and 640 mg of benzotria7nl—1—ol
`in 80 ml of
`tetrahydrofuran are stirred at room temperature overnight.
`The mixture is concentrated, the residue is taken up in ethyl
`acetate, excess urea is removed by filtration and the mixture
`is washed with water. The residue of the dried organic phase
`is purilicd by column filtration [SiO3, dichloromethancf
`methanol=20:1). This gives the product of molecular weight
`558.7 (C_-,nH_,2N3O,,S); MS (ESI+): 559 (M+H+].
`g) N-[3-{3-Iiutyl-7'-dimethylamino-3-ethyl-4-hydroxy-1,1-
`clioxo-2,