(12; United States Patent
`Glombik et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,884,812 B2
`*Apr. 26, 2005
`
`USU06884-81 2B2
`
`(54)
`
`(75)
`
`l)IARYI,CYCI.0/\LKYI. l)I*lRIVA'l‘IVES,
`PROCESSES FOR THEIR PREPARATION
`AND THEIR USE As PHARMACEUTICALS
`
`lnventors: Heiner‘ Clomliik, llolheim (DE);
`.
`.
`.
`.
`Eugen Palk, 1"-ranklurt (DE); Wendelm
`Frlck, H1‘instetten—Beuerbaeh (DE);
`Stefanie Kell, H0[l'll‘.i.l'1'l (DE);
`Hans-Ludwig Scliéifer, Hochheim
`(DE); Lothar Sehwink, Stadtallendori
`(DE); Wolfgang Wendler, ldstem (DE)
`
`.
`.
`[ " ) Notice:
`
`(73) Aggigncci Awntis Pharma _De"ts‘,:hla“d GmbH’
`lrankfurl AITI Malfl
`.
`.
`,
`.
`.
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U S C 154$) byo (‘W5
`‘
`'
`'
`‘
`‘
`‘
`This patent is subject to a terminal dis-
`Claim“
`
`(21) Appl. No.: 1l]_."63l,867
`(22)
`lsilcdz
`Aug_1,2003
`
`(65)
`
`Prior Publication Data
`Us 20O_,”U122U69A1Jun,24_. 2004
`
`Related U.S. Application Data
`
`(63)
`
`(30)
`
`(Tontinuation-in-part of application No._tt1,='23t_,»132_, filed on
`A‘-'8' 30- 2002: "OW Pal‘ N‘-" 6:524.-181
`Foreign Application Priority Data
`
`WO
`W0
`W0
`W0
`
`W0
`W0
`W0
`W0
`W0
`wo
`W0
`
`00163208
`W0 130554375
`“”»’fi487f>
`UUIG 4388
`
`1032000
`1132000
`W300“
`1112000
`
`Ham“
`00366‘-385
`11/ZUUU
`[JD/T1349
`llama
`“(M8312
`2,3001
`nfmgl I1
`ll,-2001
`0L,r83451
`1142001
`n1-35r,95
`l2,r'2t)0l
`U1;'017'52
`OTHER PUB] I(,M,I0Ng
`
`English language translation of Japanese Patent Application
`NU‘
`—
`—Pr rr -
`or P
`11., W111 0
`B -k
`[__icn,::u:d Rcccfimr rétflingx l_cSSi:r:);:L,3I,I?1: Mgugsrlitgd
`,,
`P
`p
`'
`Rat, Proc. R. Soc. Lond. B_. 247:83—87 (1992).
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`of Be imvl ihe ivlureas,” Clieni. Pha ‘m. Bull., 42 1
`, 57—(1
`(1%-,4l),
`"
`I
`I‘
`I
`(
`)
`}
`l.ee et al., “lieptin Agonists as a Potential Approach to the
`Treatment of Obesity,” Drugs oi‘ the Future, 26(9), 8713-881
`(g(}{)1)_
`Salvador et al., “Perspectives in the Therapeutic Use of
`I.eptin,” Expert Opin. Pharmacothen, 2[10), 1615-1622
`(3001),
`Zunft et al., “Carob Pulp Preparation for Treatment of
`Hypercholesterolemia,’ Advanced
`in Therapy,
`18(5),
`330-335 (3001)
`Motojima, “Peroxisome Prolil"erator—/\ctivated Receptor
`(PP/\R}: Structure, Mechanisms of Activation and Diverse
`Functions," Cell Structure and Function, 18, 267-277
`(1993)-
`
`(DI.-')
`(DE)
`
`A11g.31_.2tJUl
`'May24,20fJ2
`(51)
`Int. CL7
`(52) US. Cl.
`(58) Field of Search
`
`10142734
`102 23273
`A6tK 31,1421; (T07!) 263134
`514,874; 548E236
`548E236; 514/374
`
`(Continued)
`P _
`E
`_
`T P
`_F_
`owers
`r.'.mm'y ‘xammer
`.
`iona
`(74) A,r,rm-ngyj
`,4ggmJ or F5,-m_r.inncgan,
`liarabow, Garrett, & Dunner, l_.I_.P.
`(57)
`ABSTRACI,
`
`[1cnd¢,r_.-,0n,
`
`(56)
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`FOREIGN PATENT DOCUMENTS
`
`I.-‘P
`JP
`W0
`WO
`W0
`W0
`W0
`W0
`W0
`
`U 462 834
`P20C|O—72695
`97195265
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`99;‘U386l
`99;-‘ISSE
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`1U,Ug’
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`l_:''l‘J99
`4-,~"l999
`7,t2f]f[I
`
`Diaryleycloalkyl derivatives and their physiologically
`acceptable salts and physiologically functional derivatives
`.
`-
`.
`.
`i’
`.
`1.
`'
`.
`'-
`'
`'
`.
`are (lbLl0‘:6( The compounts include those 01 tormula I,
`
`R,
`
`“,4 \
`K
`-|-
`R3
`
`l
`
`0
`\
`X
`
`R4
`
`X
`
`5|-1,-‘374
`
`1
`
`R5
`
`/ /‘
`,1. \
`
`0
`
`OR,
`_
`
`in which the radicals are as defined, and their physiologi-
`eally acceptable salts and processes for their preparation.
`The compounds typically have lipid- andfor triglyceride-
`lowering properties and are suitable, for example, for the
`treatment of disorders of lipid metabolism, of type II
`diabetes and of svndrorne X
`‘
`’
`i ‘
`‘
`
`35 Claims, No Drawings
`
`lof33
`
`PENN EX. 2231
`
`CFAD V. UPENN
`IPR20l5-01836
`
`

`
`US 6,884,812 B2
`Page 2
`
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`* cited by examiner
`
`2of33
`
`PENN EX. 2231
`
`CFAD V. UPENN
`IPR20l5-01836
`
`

`
`1
`
`2
`
`US 6,884,812 B2
`
`I)IARYI,CYCI.OAI.I(YI. DERIVATIVES,
`PROCESSES FOR THEIR PREPARATION
`
`[3
`
`AND THEIR USE AS PHARMACEUTICALS
`
`CROSS—REFERENCE TO RELATED
`
`5 K \
`
`R1
`
`\z
`
`—|—
`R1
`
`0
`
`N
`
`\ I
`
`X
`
`Y
`
`O
`
`OR3
`
`APPLICATIONS
`The present application is a continuation in part of US.
`patent application Ser. No.
`l[lf?._'%l,-432 filed Aug. 30 2002,
`now U.S. Pat. No. 6,624,185. The present application claims 10
`priority under 35.U.S.C. § 119_ot German Application Nos.
`I)Ol4§73:1’.4 and \11[]Z'5.2_:%273.3,\hle_cl Aug. 31, 2801 and May
`-4- -00-: F551’-“"vl1V‘vl}’=
`lb“ (l15C1°5‘-“'35 Qt whlch am
`expressly incorporated by reference herein.
`
`‘I5
`
`whgm-n
`‘
`Ring A is cyclohcxyl;
`R1, R2 independently ol one another are II, 1-‘, Cl, Br, OII,
`N03 (;N_ (;1.‘3_ 0(;[.‘3_ (cl_QD)_,-,1},-_y1 or ()_(Cl_(_‘O]-
`alkyl;
`R3 is II or ((I,—(I,.,)-alkyl,
`X is (C —C )—alkyl where, in the alkyl group, one or more
`carboh atfoms may be replaced by oxygen atoms;
`Y is (C —(I—)-alkyl where, in the alkyl group, one or more
`rm
`by
`and its physiologically acceptable salts.
`the present invention is directed to a
`In another aspect
`pharmaceutical, comprising at least one of the above com-
`pounds or physiologically acceptable salts and 21 pharma-
`cculically ,,cccp[ab],, Carrien
`In still another aspect, the present invention is directed to
`a phannaceutical, comprising at
`least one ol‘
`the above
`compounds or physiologically acceptable salts, at least one
`further active compound, and a pharmaceutically acceptable
`carrier.
`
`DESCRIPTION
`
`1. Field of the Invention
`.
`x
`.
`x
`
`.
`
`.
`
`.
`
`I
`
`'
`
`‘
`
`P y‘
`
`g
`
`y
`
`y
`_ g_
`-‘
`I
`_
`functional d°nV‘mv°5'
`g_ Background of [ha 1m,¢mi(m
`,
`,
`Cornpounds of’ similar structure have already. been A
`d°5‘31'1_b’-id “'1 thc Prlor 311 for the ”Ca[m°m Gt hYPc1'l1P1d°m13 "5
`and dla-b°I'-35 (PCTfrUS0Uf{l149U)-
`
`SUMMARY OF THE INVENTION
`
`An object of the invention is to provide compounds 30
`having a therapeutically exploitable triglyceride-lowering
`action and a favorable eIIect on lipid and carbohydrate
`metabolism, such as [or syndromes ofdyslipidemias, type II
`diabetes and the metabolic syndrome,-"syndrome X. Another
`Objcct of the hwcmion is to provide Compounds having 35
`improved action compared with the compounds of
`PCTr'US00i’14490. The compounds of the invention may
`_
`-
`_
`activate the PPARa receptor.
`
`the present
`In one aspect,
`com ound of formula I
`P
`
`I
`
`In yet another aspect, the present invention is directed to
`a pharmaceutical, comprising at
`least one of the above
`C_U':"'PUUl"d_-‘UT Ph_}'-‘"U1"’g‘Cfi]1}’ 3Cf3cl71ab1‘7 3311-Sa 111 1651-S1 0115
`l‘l“d' "F1“3lYCCT‘dc'l"“'e“"$ 3‘3“‘*'*’ “’""l7“”“de 3"‘-l 3 Phi”
`"'”f‘f“’“l“-'3“}' 3‘-"_3‘5I’13bl5 C3_”13T-
`_
`Ihe present
`invention is also directed to a method of
`llrcmngg lllflul mtggbolllsm dfsorldcr’ ‘X136 H Fllabtiics‘ ?yu'
`(“mic
`’ (dsmr
`gucos”. l°.°“'nC"3 cmng USO“ wig’
`obesity, cardiomyopathy, cardiac insufliciency, osteoporosis,
`.
`.
`,
`.
`.
`.
`atherosclcrosis,Alzheimer s disease, or inflammation, corn-
`invention is directed to a 4“ prising administering to a host in need of such treatment an
`effective amount of at least one the above com ounds or
`P
`physiologically acceptable salts.
`In another aspect, the present invention is directed to a
`method of treating a lipid metabolism disorder,
`type ll
`diabetes, or syndrome X, comprising administering to a host
`45 in need ol‘ such treatment an effective amount of a combi-
`nation ol‘ at least one ol‘ the above compounds or physi-
`ologieally acceptable salts and at least one further active
`
`compound.
`.
`.
`K
`.
`‘
`.
`.
`.
`.
`In another aspect, the present invention is directed to a
`process tor preparing a pharmaceutical, LOI'1'1pt'1St1'1g mixing
`at least one of the above compounds or physiologically
`acceptable salts with a pharmaceutically acceptable carrier
`in which
`tovform a I"I"IlXIlI-1'0’ and. bringing this mixture IIIIIO‘ a form
`((w_3_C8)_,_.y,_.]Ualkcnyl
`Ring A is [C3_Cfi)_CyC10a1ky1 or
`Wham,
`in [ha Cycloalkyl or cyclmlkmyl rings, mm or is suitable tor administration to form the pharmaceutical.
`more carbon atoms may be replaced by oxygen atoms;
`"
`|)]_r,S(jR1[J']‘1()1\1 ()1-‘ '1‘}1]_-‘, 1Nv}_-'N'[‘1(]1\]
`R1, R2, R4, R5 independently of one another are II, 1', (TI,
`The mniculam ‘shown harem am b wa of exam 16 and
`Br, OH, NO,., CN,
`(TF3, OCF3,
`(C1-C6)-alkyl or
`'
`t..,‘,‘
`. xd.
`.
`Vt. hy
`.
`P b d.
`t.
`0_((, _C, )_ai-kyl,
`orpurposeso i ustrative 'tSCL1SS1OI'10 t cvarious em_ o i-
`R3 .‘ H "
`_C ’ lk l_
`merits ofthc present invention only and are presented in the
`.
`.15
`0r( '1
`"")_‘-I y ’
`can cause of providing what is believed to be the most useful and
`X is [C,—C,.,)—alkyl where, in the alkyl group, one or more
`_d.l
`d
`,
`dd ,_ .
`.
`f h
`.
`_.
`1
`_
`1 d
`carbon atoms may be replaced bv Oxygcn atoms;
`red 1 y un erstoo
`'es:.rip'tion o t eprineip es an conccp-
`.
`,
`,
`'
`.
`-
`tual aspects ot the invention. In this regard, no attempt is
`Y is (C.,—C.,)—alky1 where, in the alkyl group, one or more
`_
`,
`,
`.
`.
`.
`,.
`,
`._
`_
`.
`made to show details of the invention in more detail than is
`carbon atoms may be replaced bv oxygen atoms;
`_
`_
`_
`.
`_
`.
`.
`.
`-
`necessary for a lundamental understanding of the invention,
`and I15 PhY5i0l0gl‘33llY 3‘3C‘3-lflahlc Salts‘
`65 the description making apparent to those skilled in the art
`In another aspect, the present invention is directed to a
`how the several forms of the invention may be embodied in
`compound of formula Ia
`practice.
`
`RN \
`K
`—|—
`
`R2
`
`0
`\
`_\-
`
`i
`
`R4
`
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`
`Ring-‘X
`
`Y
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`I
`\\ XOR?
`
`'
`
`0
`
`5n
`
`3 of 33
`
`PENN EX. 2231
`
`CFAD V. UPENN
`IPR20l5-01836
`
`

`
`US 6,884,812 B2
`
`3
`Unless otherwise stated, a reference to a compound or
`component, includes the compound or component by itself,
`as well as in combination with other compounds or
`components, such as mixtures of compounds.
`The invention relates to compounds of formula I
`
`R1 fiIX Y OR30
`
`4
`Another embodiment of the invention relates to the com-
`
`pounds of fom1ula I and their physiologically acceptable
`salts in which:
`
`Ring A is cyclohcxyl;
`R], R2 are, independently of one another, II, I5,
`CF3, OCF3, CN, CH3, or OCH3;
`R3, R4, R5 are, independently of one another, II or CH3.
`X is (C1-C2)-alkyl where, in the alkyl group, one carbon
`atom is replaced by an oxygen atom; and
`Y is (C,—C:)-alkyl where, in the alkyl group, one carbon
`atom is replaced by an oxygen atom.
`Another embodiment of the invention relates to the com-
`
`(71, Hr,
`
`I
`
`10
`
`"I5
`
`pounds of formula I and their physiologically acceptable
`salts in which:
`
`in which
`
`Ring A is (C3-C8)-cycloalkyl or (C3-C8)-cycloalkenyl
`where,
`in the cycloalkyl or cycloalkenyl rings, one or
`more carbon atoms may be replaced by oxygen atoms;
`R1, R2, R4, R5 independently of one another are H, F, Cl,
`Br, 011, N02, CN, C153,
`()Cl"3,
`(C,—C,.,)-alkyl or
`0—(C,—C,,.)—alkyl;
`R3 is II or [C,—C,,-)—alkyl;
`X is (C1-C6)-alkyl where, in the alkyl group, one or more
`carbon atoms may be replaced by oxygen atoms;
`Y is (C,—C,,-)—alkyl where, in the alkyl group, one or more
`carbon atoms may be replaced by oxygen atoms;
`and their physiologically acceptable salts.
`The invention also includes compounds of formula I in
`which
`
`(C_,,—C,,)—cycloalkenyl
`Ring A is [C_,—C,,)—cycloalkyl or
`where,
`in the eycloalkyl or cycloalkenyl rings, one or
`more carbon atoms may be replaced by oxygen atoms;
`R1, R2, R4 independently of one another are H, F, Cl, Br,
`()lI, N03,
`(TN, CI53, OCI-‘3, (C1-C6)-alkyl or
`()—(C,—C,,.)-alkyl;
`R5 is (C,—(T,.,)-alkyl;
`R3 is II or (C1-C6)-alkyl;
`X is [(T,—(T,.,)-alkyl where, in the alkyl group, one or more
`carbon atoms may be replaced by oxygen atoms;
`Y is (C,—C,.,)—alkyl where, in the alkyl group, one or more
`carbon atoms may be replaced by oxygen atoms;
`and their physiologically acceptable salts.
`The invention further includes compounds of formula I in
`which
`Ring A is (C_,—C,,)-cycloalkyl or (C3—(f,,)-cycloalkenyl;
`R1, R2 independently of one another are H, F, Cl, Br, DH,
`N02, CN, CF3, OCF3, (C,—C,,)—alkyl or O—(C,—C,,,)—
`alkyl;
`R3 is H or [C,—C,,)—alkyl;
`X is [C,—C<,)—alkyl where, in the alkyl group, one or more
`carbon atoms may be replaced by oxygen atoms;
`Y is (C1-C6)-alkyl where, in the alkyl group, one or more
`carbon atoms may be replaced by oxygen atoms;
`and their physiologically acceptable salts.
`One embodiment of the invention relates to the com-
`
`pounds of formula I and their physiologically acceptable
`salts in which:
`
`Ring A is (C3—C,,)—cycloalkyl;
`R1, R2, R4, R5, independently of one another, are H, F,
`Cl, Br, CF3, OCF3, CN, CH3, or OCH3;
`R3 is II or (TII3;
`X is [C,—C2)—a1kyl where, in the alkyl group, one carbon
`atom is replaced by an oxygen atom;
`Y is (C,—C3)—alkyl where, in the alkyl group, one carbon
`atom is replaced by an oxygen atom.
`
`ll]
`
`35
`
`4E]
`
`45
`
`Sf]
`
`tit]
`
`65
`
`Ring A is cyclohexyl;
`R] is It, (711,, or o(:n_,;
`R2 is It, I-‘, (:1, Br, (7173, ()c71«‘_,, (TN, (111,, or o(?I1_,.
`R3, R4, R5 are, independently of one another, H or CH_,.
`X is (C,-C:)—alkyl where, in the alkyl group, one carbon
`atom is replaced by an oxygen atom; and
`Y is (C,—C2)—alkyl where, in the alkyl group, one carbon
`atom is replaced by an oxygen atom.
`Another embodiment of the invention relates to the com-
`
`pounds of formula 1 and their physiologically acceptable
`salts in which:
`
`Ring A is cyclohcxyl;
`R1, R3, R4, are, independently of one another, H;
`R2 is H, F, Cl, Br, CF3, OCF3, CN, CH3, or OCH3;
`R5 is (III3.
`X is (C1-C2)-alkyl where, in the alkyl group, one carbon
`atom is replaced by an oxygen atom; and
`Y is (C,—C3)—alkyl where, in the alkyl group, one carbon
`atom is replaced by an oxygen atom.
`Another embodiment of the invention relates to the com-
`
`pounds of fom1ula I and their physiologically acceptable
`salts in which:
`
`Ring A is cyclohexyl;
`R1, R3 are, independently of one another, H;
`R2 is H, F, Cl, Br, CF3, OCF3, CN, CH3, or OCH3;
`R4 is (III3; and
`R5 is (III3.
`X is (C1-C2)-alkyl where, in the alkyl group, one carbon
`atom is replaced by an oxygen atom; and
`Y is (C,—C3)—alkyl where, in the alkyl group, one carbon
`atom is replaced by an oxygen atom.
`Another embodiment of the invention relates to the com-
`
`pounds of formula I and their physiologically acceptable
`salts in which:
`
`Ring A is cyclohexyl;
`R1 is H, CH3, or OCHS;
`R2 is H, F, Cl, CF3, OCFS, CH3, or OCH3;
`R3 is H;
`R4 is H or CH3; and
`R5 is C113;
`X is (C,—C3)—alkyl where, in the alkyl group, one carbon
`atom is replaced by an oxygen atom; and
`Y is (C,—C2)—alkyl where, in the alkyl group, one carbon
`atom is replaced by an oxygen atom.
`Another embodiment of the invention relates to the com-
`pounds of l'on'nula I and their physiologically acceptable
`salts in which:
`
`4of33
`
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`
`US 6,884,812 B2
`
`Ring A is cyclohexyl;
`R1 is H or CH3;
`R2 is F, OCF3, CH3, or OCH3;
`
`6
`ammonium salts, alkali metal salts [such as sodium and
`potassium salts) and alkaline earth metal salts (such as
`magnesium and calcium salts).
`Salts with a pharmaceutically unacceptable anion such as,
`for example,
`trifluoroaeetate likewise belong within the
`R31’-SH?
`scope of the invention as useful intermediates for the prepa-
`R4 is II or (TI L‘; and
`ration or purification of pharmaceutically acceptable salts
`R5 is CH1;
`_
`in nontherapeutic,
`for example in vitro,
`xis (C1_C2)_a1kylwhcrc’ inthc alkylgmumonc Carbon
`The term “physiologically functional derivative" used
`atom is replaced by an oxygcn atom; and
`10 herein refers to any physiologically tolerated derivative of a
`Y is (C1-Cg)-alkyl WIIUIU, in 111C alkyl gruup, Um: UHIDUII
`compound of formula I of the invention, for example, an
`atom is replaced by an oxygen atom.
`ester which is able, on administration to a mammal such as,
`Another embodiment of the invention relates to the eom—
`for example, a human,
`to form (directly or indirectly] a
`pounds of formula I and their physiologically acceptable
`compound of formula I or an active metabolite thereof.
`salts in which;
`Physiologically lunctional derivatives also include pro-
`RingA1vS cyclohexyl;
`drugs ol
`the compounds of the invention, as described, for
`_
`example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42,
`R1 15 H?
`57-61. Such prodrugs can be metabolized in vivo to a
`R313 F, OCF3. CH3, 01' OCH3;
`compound of the invention. These prodrugs may themselves
`R3 is 11;
`1:! have activity or not.
`R4 is H Ur (TIL; and
`The compounds of the invention may also exist in various
`.
`_
`“
`,
`,
`.
`_
`_
`_
`_
`,
`R5 is CH3,
`polymorphous fomis, tor example as amorphous and crys-
`_
`_
`talline polymorphous forms. All polymorphous forms of the
`X '5 (C1,_C2)'alkyl where’ m the alkyl group’ one Carbon
`compounds of the invention belong within the scope of the
`atom 13 replaced by an Oxygen “am; and
`Y 13* (C:t_C3)'alky1 Whflea in 316 alkyl Emu?» OW 035"" 25 invention and are a further aspect of the invention.
`310m is T¢P1a‘~“‘r‘-l by 3“ 0X}‘'S°I‘- "“°m-
`All references hereinafter to "compound(s) of formula I”
`Tl“ lT1V‘=T11i“T1 3150 incllldti-‘5 ‘50"1P‘“l"d-‘* Ur f“”"“l3 13
`refer to compourid(s) of formula I as described above, and
`to the salts, solvates and physiologically functional deriva-
`lives thereof as described herein.
`
`5
`
`'5
`
`["
`
`R_
`
`\
`
`K
`‘|‘
`R2
`
`0
`
`\
`N
`
`l
`
`X
`
`30
`
`Y
`
`0
`
`“R3
`
`The amount of a compound of formula I necessary to
`achieve the desired biological effect depends on a number of
`factors, for example the specific compound chosen,
`the
`intended use, the mode of administration and the clinical
`condition of the patient. The daily dose is generally in the
`35 range from about 0.3 mg to "100 mg (typically from about 3
`mg to 50 mg) per day and per kilogram of body weight, for
`example about 3-10 rng.-"kgi’day. An intravenous dose may
`be, for example,
`in the range from about 0.3 mg to l.()
`wherein
`mgfkg, which can suitably be administered as an infusion of
`Ring A is cyclohexyl;
`R1, R2 independently of one another are H, F, Cl, Br, OH, 4t! about It) rig to I00 ng per kilogram per minute. Suitable
`N()3, (IN, C143,
`()(.‘F3, {(Il—(I5)—alkyl or {)—((?1—(35)—
`infusion solutions for these purposes may contain,
`for
`alkyl;
`example, from about 0.1 rig to 10 mg, typically from about
`R3 is H or [Cl—C5)—alkyl;
`I rig to "[0 mg, per milliliter. Single doses may contain, for
`X is [C,—(Tg)-alkyl where, in the alkyl group, one or more
`example, from about I mg to 10 g of the active compound.
`carbon atoms may be replaced by oxygen atoms;
`45 Thus, ampoules for injections may contain, for example,
`Y is (C1—CL,-)—alkyl where, in the alkyl group, one or more
`from about 1 mg to 100 mg, and single—dose formulations
`carbon atoms may be replaced by oxygen atoms;
`which can be administered orally, such as,
`for example,
`and their physiologically acceptable salts.
`capsules or tablets, may contain, for example, from about
`in the
`The invention embraces compounds of formula I
`1.0 to 1000 mg, typically from about 10 to 600 mg. For the
`form of their
`racemates,
`racemic mixtures and pure Sn therapy of the abovementioned conditions, the compounds
`enantiomers, and also their diastereomers and mixtures
`of fomiula I may be used as the compound itself, but they
`thereof.
`may be in the form of a pharmaceutical composition with an
`The alkyl radicals in the substituents R1, R2, R3, R4 and
`acceptable carrier. The carrier is acceptable in the sense that
`R5 can be straight—chain or branched.
`it is compatible with the other ingredients ofthe composition
`Pharmaceutically acceptable salts are suitable for medical 55 and is not hamiful to the patient’s health. The carrier may be
`applications because of their greater solubility in water
`a solid or a liquid or both and is often formulated with the
`compared with the starting or base compounds. These salts
`compound as a single dose, for example as a tablet, which
`must have a pharmaceutically acceptable anion or cation.
`may contain from about 0.05% to 95% by weight of the
`Suitable pharmaceutically acceptable acid addition salts of
`active compound. Other pharmaceutically active substances
`the compounds of the invention are salts of inorganic acids so may likewise be present,
`including other compounds of
`such as hydrochloric acid, hydrobromic, phosphoric,
`formula I.The pharmaceutical compositions ofthe invention
`rnetaphosphoric, nitric and sulfuric acids, and of organic
`can be produced by one of the known pharmaceutical
`acids such as, for example, acetic acid, benzienesullonic,
`methods, which may essentially consist ofmixing the ingre-
`benmic, citric, ethanesulfonic, fumaric, gluconic, glycolic,
`dients with pharmacologically acceptable carriers and,-"or
`isethionic,
`lactic,
`lactobionic, maleic, malic,
`65 excipients.
`methanesulfonic, succinic, p—toluenesulfonic and tartaric
`Pharmaceutical compositions of the invention include
`acids. Suitable pharmaceutically acceptable basic salts are
`those suitable for oral, rectal, topical, peroral (for example
`PENN EX. 2231
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`CFAD V. UPENN
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`US 6,884,812 B2
`
`7
`(for example subcutaneous,
`sublingual) and parenteral
`intramuscular,
`intradem1al or intravenous) administration,
`although the most suitable mode of administration depends
`in each individual case on the nature and severity of the
`condition to be treated and on the nature of the compound of
`formula I used in each case. Coated formulations and coated
`
`10
`
`"I5
`
`ll]
`
`slow—release formulations also belong within the framework
`of the invention. Preference is given to acid— and gastric
`juice-resistant formulations. Suitable coatings resistant to
`gastric juice comprise cellulose acetate phthalate, polyvinyl
`acetate phthalate, hydroxypropylmethylcellulose phthalate
`and anionic polymers of methacrylic acid and methyl meth-
`acrylate.
`Suitable pharmaceutical compounds for oral administra-
`tion may be in the form of separate units such as, for
`example, capsules, wafers, suckable tablets or tablets, each
`of which contain a defined amount of the compound of
`formula I; as powders or granules, as solution or suspension
`in an aqueous or nonaqueous liquid; or as an oil-in-water or
`water-in-oil emulsion. These compositions may, as already
`mentioned, be prepared by any suitable pharmaceutical
`method which includes a step in which the active compound
`and the carrier [which may consist ofone or more additional
`ingredients) are brought into contact. The compositions are
`generally produced by uniform and homogeneous mixing of .1.
`the active compound with a liquid and,-"or finely divided solid
`carrier, after which the product is shaped if necessary. Thus,
`for example, a tablet can be produced by compressing or
`molding a powder or granules of the compound, where
`appropriate with one or more additional ingredients. Com-
`pressed tablets can be produced by tab leting the compound
`in free-flowing form such as, for example, a powder or
`granules, where appropriate mixed with a binder, glidant,
`inert diluent andfor one or more surface-activefdispersing
`agent(s)
`in a suitable machine. Molded tablets can be
`produced by molding the compound which is in powder
`form and is moistened with an inert
`liquid diluent in a
`suitable machine.
`
`35
`
`Pharmaceutical compositions which are suitable for per-
`oral (sublingual) administration comprise suckable tablets
`which contain a compound of formula I with a flavoring,
`normally sucrose and gum arabic or tragacanth, and pastilles
`
`4E]
`
`8
`which comprise the compound in an inert base such as
`gelatin and glycerol or sucrose and gum arabic.
`The pharmaceutical compositions suitable for parenteral
`administration may comprise sterile aqueous preparations of
`a compound of formula I, which may be isotonic with the
`blood of the intended recipient. These preparations may be
`administered intravenously, although administration may
`also take place by subcutaneous, intramuscular or intrader—
`ma] injection. 'I'hese preparations can be produced by mix-
`ing the compound with water and making the resulting
`solution sterile and isotonic with blood. Injectable compo-
`sitions of the invention generally contain from about [L1 to
`5% by weight of the active compound.
`Pharmaceutical compositions suitable for rectal adminis-
`tration may be in the form of single-dose suppositories.
`These can be produced by mixing a compound of formula I
`with one or more conventional solid carriers, for example
`cocoa butter, and shaping the resulting mixture.
`Pharmaceutical compositions suitable for topical use on
`the skin may be in the form of an ointment, cream, lotion,
`paste, spray, aerosol or oil. Carriers which can be used are
`petrolatum, lanolin, polyethylene glycols, alcohols and com-
`binations ol‘ two or more of these substances. The active
`
`compound is generally present in a concentration of from
`about 0.1 to 15% by weight of the composition, for example
`from about 0.5 to 2%.
`
`Transdermal administration is also possible. Pharmaceu-
`tical compositions suitable for transdermal uses can be in the
`form ofsingle plasters which are suitable for long-term close
`contact with the patient’s epidermis. Such plasters suitably
`contain the active compound in an aqueous solution which
`is bulTered where appropriate, dissolved andfor dispersed in
`an adhesive or dispersed in a polymer. A suitable active
`compound concentration is about 1% to 35% by weight, or
`about 3% to 15%. A possibility is for the active compound
`to be released by electrotransport or
`iontophoresis as
`described, for example, in Pharmaceutical Research, 2(6):
`318 (1986).
`The invention furthermore provides a process for prepar-
`ing the compounds of formula I which comprises obtaining
`the compounds of formula I by proceeding in accordance
`with the reaction scheme below:
`
`()
`
`NH’:
`
`()
`+ C\)i\ ,0X,
`
`ll2U" C.
`
`W \
`
`K_
`
`|_
`R2
`
`Q81’ ,
`
`Rl\\{
`
`|
`RE
`
`0
`
`IN
`
`R4
`
`X,
`
`A
`
`Nal.
`acetone
`
`Cl
`
`/ I
`T115
`
`it “>.O
`
`OH
`
`'1. (coon;
`'3. MCOH
`
`6of33
`
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`
`

`
`US 6,884,812 B2
`
`9
`
`-continued
`
`R1
`
`,
`
`0
`
`
`_|_
`N
`RE
`
`R4
`
`v/1
`A
`
`B
`
`"”=5“"=‘7‘F 1to—(cItg)n
`
`(c11g)m—ot1
`
`(T
`
`at
`
`,
`¥ \
`_|_
`R2
`
`‘
`
`0
`
`\_\_
`
`‘*4
`
`Y/<:—(<tHg;n
`E
`
`(CIIgJrn—O[I
`\|
`
`_|_
`R2
`
`X
`
`X“/0\\((IH3)n
`F
`
`Nal-I, Nal
`om"
`
`7’
`
`/ I—R5
`I
`0
`\ J
`(c11:)nf”‘v* >\
`
`l
`ai ,It<4
`_|_
`N
`X
`
`R3
`
`t—BuOI I,
`50% KOII aq
`
`/ 5
`Y \>J\
`
`O
`
`on
`
`The compound of formula 1’ is converted into oompou nds
`To this end, compounds of formula A in which R1, R2, R4
`of formula I by hydrolyzing the ester function, for example
`and X have the meanings given above are reacted with Nal
`in acetone with healing at reflux for about 12 to E hours, 45 by healing with potassium hydroxide in an aloohol (ethanol,
`giving a compound of formula B.
`tert—butanol) and releasing the carboxylie acid group of
`The compound of formula B is reacted with a compound
`formula I by acidification. This carboxylie acid group can he
`of formula C in which n and m are each 0-5, giving a
`derivatized by customary methods to a group of the formula
`compound of formula E in which R1, R2, R4, m, n and X —((f=())—()R3, where R3 has the meaning described
`have the meanings described above. Here, (a) C is depro- Sn above.
`tonated at room temperature in an inert solvent such as
`The compounds of formula I act favorably on metabolic
`dimethylformamide or
`tetrahydrofuran using sodium
`disorders. They have a positive effect on lipid and sugar
`hydride and then reacted at about 70° C. with the halide, or
`metabolism and, in particular, reduce the concentration of
`(b) component C is initially heated with dibutyltin oxide in
`triglycerides, and they are suitable for preventing and treat-
`toluene on a water separator for a number of hours and then, 55 ing type II diabetes and arteriosclerosis.
`with addition of dimethylformamide, cesium fluoride and
`The compounds can be administered alone or in combi-
`iodide B, converted into E by stirring at room temperature
`nation with one or more further pharmacologically active
`for a number of hours, such as between about 10 and 14
`substances which, for example, act favorably on metabolic
`hours, preferably overnight.
`disorders and are selected, for example, from antidiabeties,
`The compound of formula E. is, using a compound of tin antiadipose agents, antihypcrtensivcs and active compounds
`formula I) in which Y is