(12) United States Patent
`
`Cheng et al.
`
`(10) Patent N0.:
`
`(45) Date of Patent:
`
`US 6,875,782 B2
`Apr. 5, 2005
`
`USU068757'82B2
`
`(54)
`
`(75)
`
`SUBS'l”l'l”U'l”El) HlC"l‘lCR()CYCLIC
`DERIVATIVES USEFUI. AS ANTIDIABETIC
`AND ANTIOBESITY AGENTS AND METHOD
`
`inventors: Peter T. W. Cheng, Princeton, NJ (US);
`Sean Chen, Princeton, NJ (US);
`Charles Z. Ding, Plano, TX (US);
`Timothy F. Herpin, Princeton, NJ (US)
`
`(73)
`
`Assignee:
`
`Bristol-Myers Squibb Company,
`Princeton, NJ (US)
`
`(*)
`
`Notice:
`
`Subject to any disclaimer, the term oflhis
`patent is extended or adjusted under 35
`USC. 154(1)) by 0 days.
`
`(31)
`
`Appl. No.: l[|,f6l6,283
`
`(22)
`
`l-‘iledz
`
`(65)
`
`Jul. 8, 2003
`Prior Publication Data
`
`US 2UO4,a’0O63762 Al Apr. 1, 2004
`
`(so)
`
`Related U.S. Application Data
`Prtwisional application No. 60,-"394,553,
`filed on Jul. 9,
`2002.
`
`(51)
`
`Int. CL7
`
`.2)
`
`US. Cl.
`
`Field of Search
`
`A6'lK 31,!’-1-245;A6lK 3u4192;
`C07D 271;’06; C071) 249,104
`514E364; 548n31, 5433255;
`514,859
`514x364, 359;
`548x131, 255
`
`(58)
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`6_.4l4_.I'JO2 Bl
`7f2C|D2 Cheng el al.
`1,-"2003 Cobb et til.
`5,506,731 B1
`6,653,314 B2
`11;‘2UU3 Clieng et al.
`l-‘()Rl_iI(}N PA['l_".N'l‘ [)UCUMl_-'N'['S
`
`W0
`
`WO 95118130
`
`12.-"1994
`
`W0
`W0
`W0
`W0
`W0
`
`W0 QTIOOES
`W0 9?;‘319(J? A1
`W0 99;‘1677O
`W0 99i‘4-6232 A1
`W0 UU38325 A1
`
`{#1996
`9,-’ 1 90?
`9,-’ I 998
`9,-’ 1 909
`‘.'J,-"2000
`
`Prirrtary Exai:tiner—Charanjit S. Aulakh
`(74) Attorney, Agent, or F:frm—Burton Rodney
`ABSTRACT
`
`(57)
`
`Compounds are provided which are useful as antidiabetic
`agents and anliohesily agents and have the structure
`
`
`
`wherein m is 0, '1 or 2; n is O,
`
`1 or 2;
`
`Q is (T or N;
`
`to 5, or A is (CI-I.,.)_,_1 where X’
`A is (CH2), where X is '1
`is l
`to 5 with an alkenyl bond or an alkynyl bond
`embedded anywhere in the chain, or A is —(Cl-l2)_,_2—
`where x2 is 0 to 5 and X3 is U to 5,
`()—{(TI 12),.-"
`provided that at least one of X2 and X3 is other than 0;
`ll is a bond or is ((7113): where x4 is l
`to 5;
`X is CH or N;
`
`X: is (T, N, {) or S;
`X3 is (T, N, {) or S;
`X4 is C, N, O or S;
`X5 is C, N, O or S;
`X5 is C, N, O or S;
`
`and A, R ' , R2, R2", R2”, R2”, R7‘ and Y are as defined herein.
`
`'15 Claims, No Drawings
`
`lof57
`
`PENN EX. 2139
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`CFAD V. UPENN
`IPR20l5-01836
`
`

`
`US 6,875,782 B2
`
`1
`SUBSTITUTED HETEROCYCLIC
`DERIVATIVES USEFUL AS ANTIDIABETIC
`AND ANTIOBESITY AGENTS AND METHOD
`
`This application claims priority from US. Provisional
`Application 60f394,553, filed Jul. 9, 2002 which is incor-
`porated herein by reference.
`liIl_".I_I) OI‘ 'l'lI]_-l INVl_-'N'l'[(}N
`
`'I'he present invention relates to novel substituted hetero-
`cyclic derivatives which modulate blood glucose levels,
`triglyceride levels,
`insulin levels and non—esterifie(| fatty
`acid (NI.-'1-‘A) levels, and thus are particularly useful in the
`treatment of diabetes and obesity, and to a method [or
`treating diabetes, especially Type 2 diabetes, as well as
`hyperglycemia, hyperinsulinemia, hyperlipidemia, obesity,
`atherosclerosis and related diseases employing such substi-
`tuted heteroeyclic derivatives alone or in combination with
`another antidiabetie agent andfor a hypolipiclemic agent
`andfor other therapeutic agents.
`DI.-'SCRIP'l"I(JN ()1-‘ 'l‘lIl_i INVEN'[‘I()N
`
`invention, substituted
`In accordance with the present
`heterocyclic derivatives are provided which have the struc-
`ture I:
`
`
`
`wherein m is 0, 1 or 2; n is 0, 1 or 2;
`Q is C or N;
`A is (CH3), where x is l to 5, or A is (CH3)_,_‘ where x1
`is l to 5 with an alkenyl bond or an alkynyl bond embedded
`anywhere in the chain, or A is —(CII2)_,.2—O—(ClI2)_3—
`where x2 is U to 5 and X3 is U to 5, provided that at least one
`of X2 and X3 is other than 0;
`13 is a bond or is (CII2]_,." where X" is I to 5;
`X is CH or N;
`X3 is C, N, O or S;
`X, is C, N, () or S;
`X, is C, N, 0 or S;
`X, is C, N, () or S;
`X‘, is C, N, O or S;
`provided that at least one of X2, X3, X4 X5 and X6 is N; and
`at least one of X2, X_,, X, X, and X, is C, and specifically
`excluding the structure(s) as shown below:
`
`R3”
`m
`R“'‘ {F
`->_ X K
`K‘ \ 3
`‘'2’; 33‘
`RA
`x'
`
`(c Ho
`
`I
`
`R]
`
`R3\/
`2
`‘g \_ /' (L-[[,),f
`X
`
`R.
`|
`“"‘~((;11,_],_/
`
`Y
`
`where X2=N, X_,=C, )(,,=(] or S, Z=(] or a bond
`In each of X through X5, as defined above, C may include
`(Ill.
`R1 is II or alkyl;
`R7‘ is H, alkyl, alkoxy, halogen, amino, substituted amino
`or cyano;
`
`10
`
`"I5
`
`ll]
`
`35
`
`4E]
`
`45
`
`50
`
`55
`
`an
`
`65
`
`2
`
`R2", R2” and R2" may be the same or dilTerent and are
`selected from II, alkyl, alkoxy, halogen, amino, substituted
`amino or cyano;
`R3 is selected from H, alkyl, arylalkyl, aryloxycarbonyl,
`alkyloxycarboriyl, alkynyloxycarbonyl, alkenyloxycar-
`bonyl, arylcarbonyl, alkylcarbonyl, aryl, heteroaryl,
`cycloheteroalkyl, heteroarylcarbonyl, heteroaryl-
`heteroarylalkyl, alkylcarboriylamirio, arylcarbonylamino,
`heteroarylcarboriylamirio, alkoxycarbonylamino,
`aryloxycarbonylamino, heteroaryloxycarbonylamino,
`heteroary]-heteroarylearbonyl, alkylsulfonyl,
`alkenylsulfonyl, heteroaryloxyearbonyl, cyelohetero—
`alkyloxycarbonyl, heteroarylalkyl, aminocarbonyl, substi-
`tuted aminocarbonyl, alkylaminocarbonyl,
`arylaminocarbonyl, heteroarylalkenyl, eyeloheteroalkyl—
`heteroarylalkyl; hydroxyalkyl, alkoxy, alkoxyary1oxy—
`carbonyl, arylalkyloxycarbonyl, alkylaryloxyearbony-,
`arylheteroarylalkyl, arylalkylarylalkyl, aryloxyarylalkyl,
`haloalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycar-
`bonyl, aryloxyaryluxyearbonyl, arylsulfinylarylcarbony-,
`arylthioarylcarbonyl, alkoxycarbonylaryloxycarbony ,
`arylalkenyloxycarbonyl, heteroaryloxyarylalky.,
`aryloxyarylcarboriyl, aryloxyarylalkyloxycarbonyl,
`arylalkenyloxycarbonyl, arylalkylcarbony ,
`aryloxyalkyloxycarbonyl, arylalkylsulfony ,
`arylthiocarbonyl, arylalkenylsulfonyl, heteroarylsulfonyl,
`arylsulfonyl, alkoxyarylalkyl, heteroarylalkoxycarbonyl,
`arylheteroarylalkyl, alkoxyarylcarbonyl, aryloxyheteroary-—
`alkyl, heteroarylalkyloxyarylalkyl, arylarylalky ,
`arylalkenylarylalkyl, arylalkoxyarylalkyl, arylearbonyl—
`arylalkyl, alkylaryloxyarylalkyl, arylalkoxycarbonylhetero-
`arylalkyl, heteroarylarylalkyl, arylearbonylheteroarylalkyl,
`heteroaryloxyarylalkyl, arylalkenylheteroarylalkyl,
`arylaminoarylalkyl, aminocarbonylarylarylalkyl;
`Y is COZR4 (where R4 is II or alkyl, or a prodrug ester)
`or Y is a C-linked l-tetrazole, a phosphinic acid of the
`structure P(())(()R4")R5, (where R4" is II or a prodrug ester,
`R5 is alkyl or aryl) or a phosphonic acid of the structure P((])
`(0R'M)2;
`(CH:),-- (CH2)xl’ (CH2),-2» (CH2)J'33 (CH2).-"s (C-Hal": and
`(CH2),, may be optionally substituted with 1, 2 or 3 sub-
`stituents;
`
`including all stereoisomers thereof, prodrug esters
`thereof, and pharmaeeulieally acceptable salts thereof.
`Examples of
`
`
`
`which are present in the compounds ofthe invention include,
`but are not limited to,
`
`;_N._____
`N
`\ .--‘
`N
`
`l
`
`O
`\
`N
`
`,
`
`,
`
`2 of 57
`
`PENN EX. 2139
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`
`

`
`US 6,875,782 B2
`
`4
`eycl0helemalkylalkyloxyearbonyl, eyel0heler0alkyl0xy-
`carbonyl, or polyhaloalkylaryloxyearbonyl, which may be
`optionally substituted, more preferably alk0xyaryl0xycarbc-
`uyl.
`
`Preferred compounds of the invention include the follow-
`ing:
`
`3
`
`-continued
`
`$4 H“?
`
`as well as the five—membered rings covered under
`definition of heteroaryl set out hereinafter,
`preferably
`
`the
`
`\_
`/' “""*
`N
`\ ./N
`
`O
`\
`N
`
`i
`
`N
`
`/
`N
`
`‘ %\N
`,
`N/
`
`and
`
`N
`
`I
`/
`0/X
`Preferred are compounds of formula I of the invention
`having the structure IA:
`
`[A
`
`./Y
`[C-\H'3.]n
`
`R3
`
`I
`
`xxx.
`(CHZJDI
`
`R3‘
`
`4’
`
`1<~’
`
`“J
`
`Rm%—|—§
`/(C-”1=‘x1. / ‘ix
`X-,._
`0 ‘K
`""-.._ / H x
`_|=; x3‘
`)I('‘’
`R2;
`Kr s\R]
`where X is CH
`
`More preferred are compounds of formula I of the inven—
`tiun having the structure H3:
`
`R21;
`7‘: _\ /.x,.Xfi/IC"2Jxi0/
`RE/‘*‘:\X.x
`I
`\
`,
`)(fx5*~Rt
`
`I
`
`[I5
`
`,
`1|{'
`(C[12Jm/\“(cII::..’Y sn
`
`t
`
`in
`
`15
`
`1::
`
`35
`
`30
`
`35
`
`4::
`
`45
`
`_,zN“*--
`Ph—N\
`N‘!
`
`N
`
`l’h—!\'( E
`N!
`
`CH
`
`3
`
`.
`EH‘
`
`0
`
`0
`
`(TH
`
`‘
`
`/B"--..
`Ph—N\
`
`\/'
`
`1
`
`Ph—N
`
`/hm
`\ /
`"
`
`("T113
`
`0
`
`0
`
`\_/‘-\CO H
`3
`
`0
`
`0
`
`()(?H_.
`
`N/\coqH
`A0
`
`0
`
`051;,
`
`N/\‘(.‘o3H
`A
`
`0
`
`0
`
`0C-[13
`
` N/\C02II
`A
`
`0
`
`0
`
`OCH-‘
`
`In the above compounds, it is most preferred that R2”, R31’
`and R3" are each H; R1 is alkyl, preferably CH3; X2 is "l
`to 55
`3; R2 is H; m is 0 or (CH:),,, is CH2 or CHOH or CH—alkyl,
`X3, X3, X4, X5 and KL, represent a total of L, 2 or 3 nitrogens;
`[CH:),,
`is a bond or CH2, R3 is arylalkyloxycarbonyl,
`arylheteroarylalkyl, aryloxyarylalkyl, arylalkyl,
`aryloxycarhonyl, haloaryloxycarhonyl, alkoxyaryl0xycar-
`bonyl, alkylaryloxyearbonyl, arylnxyaryluxyearbnnyl,
`heleroaryloxyarylalkyl, helernaryluxyearbunyl,
`aryloxyarylearbonyl, arylalkenyluxycarbonyl,
`eyeloalkylaryloxyearbonyl, arylalkylarylearbonyl,
`heteroaryl-heleroarylalkyl, eyeloalkyloxyaryloxyearbnnyl,
`heteroaryl—heteroarylcarbonyl, arylalkylsulfonyl,
`arylalkenylsulfonyl, alkoxyarylalkyl, arylthiocarbonyl,
`
`an
`
`65
`
`3 of 57
`
`Eu’
`3
`
`/._\
`N
`)\
`
`0
`
`N
`[.h_<'
`
`|
`/N
`
`0
`
`0
`
`(TOQH
`
`05113
`
`PENN EX. 2139
`
`CFAD V. UPENN
`IPR20l5-01836
`
`

`
`-continued
`
`0"‘ .\'
`\ /||\/\
`N
`
`0
`
`F CO
`2
`
`US 6,875,782 B2
`
`gm
`
`N/\‘(.‘OaH
`-
`A
`
`0
`
`0
`
`5
`
`10
`
`-continued
`
`Q1 1,
`
`I /\ —
`N
`(.03!-I
`
`0
`
`O
`
`O
`
`.
`0— 5.
`\
`
`\.N
`
`OCH;
`
`gm
`
`X»/‘xcozfl
`A
`0
`
`0
`
`(_j[1_,
`E
`'
`
`N/\(x)3H
`
`0
`
`0
`
`Ph —<
`
`/N
`
`|
`/5‘
`
`o
`
`Int:
`
`O"‘x
`\ J\/\
`N
`
`0
`
`0 — N
`15 [I3C MO
`N
`
`(Tl
`
`<
`
`0— X
`> 1"
`\
`\ K/\
`N
`
`o
`
`3:1
`
`35
`
`30
`
`H;(
`
`0-N
`\ Mr)
`\
`
`OCII3
`
`E“:
`
`N /\‘co3H ,5
`A
`0
`
`0
`
`(TI
`
`4E]
`
`glla
`?
`
`N /\(T()3H
`O)\O
`
`3
`
`N /\‘(?()3H
`A
`
`0
`
`0
`
`CH:
`
`2
`
`0- x
`N /\c0gI1
`M )\
`0
`0
`
`\N
`
`0
`
`0-5‘
`\ K/\
`N
`
`O
`
`X/\(T();H
`A
`
`O
`
`O
`
`Q13
`?
`
`9”,
`
`E
`
`F-3C
`
`0-K
`\ N0
`N
`
`N/\\(.‘()1H
`A
`
`0
`
`0
`
`O—N
`H,c: _)\/0
`5
`
`in
`
`X
`
`0
`
`55 ( i
`
`N
`
`0.4""
`
`N/\‘(?o3H
`A
`o
`
`0
`
`.
`.
`3
`\'/\"c‘o H
`
`H
`
`ocr,
`
`()—x
`\_ X/O
`
` N/\m3[I fin
`A
`()
`
`0
`
`In addition, in accordance with the present invention, a
`
`method is provided for treating diabetes, especially Type 2
`diabetes, and related diseases such as Type I diabetes, insulin
`resistance, hyperglycemia, hyperinsulinernia, elevated blood
`levels of fatty acids or glycerol, hyperlipidemia, obesity,
`55 hypertriglyceridemia, inflammation, Syndrome X, diabetic
`complications, dysmetabolic syndrome, atherosclerosis, and
`related diseases wherein a therapeutically effective amount
`PENN Ex. 2139
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`4 of 57
`
`CFAD V. UPENN
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`

`
`US 6,875,782 B2
`
`7
`of a compound of structure I is administered to a patient in
`need of treatment.
`
`In addition, in accordance with the present invention, a
`method is provided for treating early malignant lesions (such
`as ductal carcinoma in situ of the breast and lobular carci-
`
`noma in situ of the breast), premalignant lesions (such as
`fibroadenoma of the breast and prostatic intraepithelial neo-
`plasia (PIN),
`liposarcomas and various other epithelial
`tumors [including breast, prostate, colon, ovarian, gastric
`and lung), irritable bowel syndrome, Crohn’s disease, gas-
`tric ulceritis, and osteoporosis and proliferative diseases
`such as psoriasis, wherein a therapeutically effective amount
`of a compound of structure I is administered to a patient in
`need of treatment.
`
`In addition, in accordance with the present invention, a
`method is provided for treating diabetes and related diseases
`as defined above and hereinafter, wherein a therapeutically
`eifective amount of a combination of a compound of struc-
`ture I and another type antidiabetic agent andfor a hypolipi-
`demic agent, andfor lipid modulating agent andfor other type
`of therapeutic agent, is administered to a human patient in
`need of treatment.
`In the above method of the invention, the compound of
`structure I will be employed in a weight
`ratio to the
`antidiabetic agent (depending upon its mode of operation)
`within the range from about 0.01:1 to about 100:1, prefer-
`ably from about 0.5:'l to about 1011.
`The conditions, diseases, and maladies collectively refer-
`enced to as "Syndrome X” or Dysmetabolic Syndrome (as
`detailed in Johanson,J. Ciirt. Ertdocrinoi. Me."ab., 1997, 82,
`727-734, and other publications) include hyperglycemia
`andfor prediabetic insulin resistance syndrome, and is char-
`acterized by an initial
`insulin resistant state generating
`hyperinsulinemia, dyslipidemia, and impaired glucose
`tolerance, which can progress to Type II diabetes, charac-
`terized by hyperglycemia, which can progress to diabetic
`complications.
`The term "diabetes and related diseases” refers to Type II
`diabetes, Type I diabetes,
`impaired glucose tolerance,
`obesity, hyperglycemia, Syndrome X, dysmetabolic
`syndrome, diabetic complications and hyperinsulinemia.
`The conditions, diseases and maladies collectively
`referred to as “diabetic complications” include retinopathy,
`neuropathy and nephropathy, and other known complica-
`tions of diabetes.
`
`type(s) of therapeutic agents” as
`The term “other
`employed herein refers to one or more antidiabetic agents
`{other than compounds of formula I), one or more anti-
`obesity agents, andfor one or more lipid—lowering agents,
`one or more lipid modulating agents (including anti-
`atherosclerosis agents), andfor one or more antiplatelet
`agents, one or more agents for treating hypertension, one or
`more anti-cancer drugs, one or more agents for treating
`arthritis, one or more anti-osteoporosis agents, one or more
`anti—obesity agents, one or more agents for treating immu-
`nomodulatory diseases, andfor one or more agents for treat-
`ing anorexia nervosa.
`The term “lipid—modulating” agent as employed herein
`refers to agents which lower I.IJI. andfor raise IIDI. andfor
`lower triglycerides andfor lower total cholesterol andfor
`other known mechanisms for therapeutically treating lipid
`disorders.
`
`I)I_7'l‘AII_l_-ll) D].-‘.S(TRIPTI()N OI" Till.’
`IN\*'l_'lN'l'ION
`
`The compounds of the formula I of the present invention
`may be prepared according to the following general syn-
`
`10
`
`"I5
`
`ll]
`
`-
`
`35
`
`4E]
`
`45
`
`Sf]
`
`60
`
`65
`
`8
`thetic schemes, as well as relevant published literature
`procedures that are used by one skilled in the art. Exemplary
`reagents and procedures for these reactions appear herein-
`after and in the working Examples. Protection and depre-
`tection in the Schemes below may be carried out by proce-
`dures generally known in the art (see, for example, T. W.
`Greene & P. G. M. Wuts, Protecting Groups in Organic
`Synthesis, 3”‘ Edition, 1999 [Wiley]).
`Scheme "l describes a general synthesis of the amino acids
`described in this invention. An alcohol 1 [R5(C.‘H3)_Y2OH) is
`coupled with a hydroxy aryl- or heteroaryl-aldehyde 2
`(preferably 3- or 4-hydroxybenzaldehyde) under standard
`Mitsunobu reaction conditions (eg. Mitsunobu, 0.,
`Syntt'te.s't'.s', 1981, 1). The resulting aldehyde 3 is then sub-
`jected to reductive amination using procedures known in the
`literature (e.g. Abdel-Magid et al,.J'. Org. Ciieru. I996, 61,
`3849) with an ot—amino ester hydrochloride 4. PG in Scheme
`1 denotes a preferred carboxylic acid—protecting group, such
`as a methyl or tert-butyl ester. The resulting secondary
`amino-ester 5 is then subjected to a second reductive ami-
`nation using rnethods known in the literature (e.g. Abdel-
`Magid et al, J. Org. Chain. 1996, 61, 3849) with an R3“
`aldehyde 6. Final deprotection of the carboxylic acid ester
`under standard conditions known in the literature (reference:
`Greene et al supra) utilizing basic conditions (for methyl
`esters) or acidic conditions [for tert-butyl esters) then fur-
`nishes the desired amino acid products II.
`An alternative route to the aldehyde 3 is shown in Scheme
`1A. Alcohol 1 (R5(CH3)_,_0H) is treated with methanesulfe—
`nyl chloride to give the corresponding mesylate 7. The
`mesylate 7 is then alkylated under standard basic conditions
`with a hydroxyaryl or hydroxyheteroaryl aldehyde 2 to
`furnish the aldehyde 3.
`A route to the amino acids III is shown in Scheme 2. The
`secondary amine—ester 5 is deprotected under standard con-
`ditions (basic conditions if the protecting group (PG) is
`methyl; acidic conditions if PG is tert-butyl; ref. Greene et
`al supra) to furnish the corresponding amino acid 8. Reduc-
`live amination with aldehyde 9 under analogous conditions
`as described in Scheme 1 provides the desired tertiary amino
`acid products III.
`reaction of the
`Alternatively, as shown in Scheme 3,
`secondary amine-ester 5 with an alkylating agent 10 (with an
`appropriate leaving group (LG) such as halide, mesylate, or
`tosylate) under standard conditions followed by deprotee-
`tion of the carboxylic acid ester 11 provides the desired
`tertiary amino acids III.
`As shown in Scheme 4, the tertiary amino acid III may
`also be assembled through reductive amination first of the
`R3” aldehyde 12 with an appropriate amine ester hydrochlo-
`ride 4. The resulting secondary amine—ester 13 then is
`subjected to reductive amination with appropriate alkyl, aryl
`or heteroaryl aldehydes 3 [as in Scheme 1) followed by
`deprotection of the carboxylic acid ester to give the desired
`amino acid analogs II].
`An alternative general synthesis of amino acid analogs II
`is shown in Scheme 5. A hydroxyaryl or heteroaryl aldehyde
`2 is subjected to the usual reductive amination conditions
`with an appropriate amine—ester hydrochloride 4. The result-
`ing secondary amine—ester 14 is functionalized, in this case
`by a second reductive amination with aldehyde 6 to furnish
`the corresponding hydroxy tertiary amine—ester 15. Phenol
`15 now undergoes a Mitsunobu reaction with a preferred
`alcohol "I (R5—{CII2),,OII) which is followed by the depro-
`tection of the product, ester 16, to furnish the desired amino
`acid analogs II.
`
`5of57
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`1:!
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`10
`9
`Alternatively {as shown in Scheme 12), a protected aryl or
`Scheme 6 illustrates the synthesis of the carbamate-acid
`analogs IV. The secondary amine-ester 5 can be reacted with
`heteroaryl nitrile 30 is treated with an appropriate organe-
`appropriate chloroformates 17 under standard literature con-
`metallic reagent (e.g. a Grignard reagent RmMgX 26) to
`ditions (optimally in CH_._CL_._ or CHCl_., in the presence of a
`give the corresponding imine intermediate, which is imme-
`base such as Et3N) to furnish the corresponding carbamate—
`5 diately reduced (e.g. with LiAlH4) to give the corresponding
`_
`l
`_
`prlman, amino 3-l_ Fl-hls amlnc ls lhcn rcacllxl wllll an
`esters. The requisite analogs IV are then obtained after
`appl.0p'rl-alcly Subslllulcll a_hal0_cSlcl. 28 lo cl“: lllc cOl.rc_
`deprotection of the carbamate-ester. Alternatively, the sec-
`spondina o.—amine—ester 32. ThisintermediateD32 can then be
`‘mdary aminc'”Sl”r 5 can be rflafled with phmigcnc I”
`acylatedbwith an appropriately substituted aryl or heteroaryl
`gencrale 1hs,wrIcSp0ndiI,1g Carbamyl chloride 18' _Thi53(:_ar'
`gdlgiyilihliiridc lnicrmcdidtcl 18 hm be waded Tmh R _ 10 chloroformate 17 to provide the corresponding carbamate—
`( _'
`’ optimally Sub"%mun'd phenols) to af,f°“ thc co“-C‘
`ester, whose phenolic functionality is then deprotected to
`Spending carhamamficlds IV after deprotection‘
`provide the key intermediate phenol 33. Alkylation of the
`The Secondary ‘1min°'°5t°r 5 can be funclionalizcd with
`phenol 33 with a halide or mesylate 7 followed by depro-
`substituted aryl or aliphatic carboxylic acids 20, under
`lccllon provlclcslhc mccmlc Cal.l,amalc_aCld analogs X‘ An
`Standard peptide Coupling conditions’ as ulusualcd in ‘IS analogous sequence, which involves reductive amination of
`Schcmc
`Tl“: amid‘: b°_“‘l't°rmal‘°“ r°a°‘‘°“§ “'3 C0?‘
`the secondary amine-ester 32 with an aryl or heteroaryl
`ducted using standard peptide coupling procedures known in
`aldcllydc 6, lllm Sclccllvc phenol clcprolccllons alkylallm
`the art. Optimally, the reaction is conducted in asolvent such
`wllh mcsylalc 7 and ll
`final dcprolccllonl provldcs lhc
`as DMI’ at 0° C.
`to RT using 1-ethyl-3-(3-dimethylamino-
`raccmlc amlml acid analogs Xl_
`pmpyl) Carbodiimidc (EDAC or EDCI or W8C)’
`A synthesis of chiral carbamate analogs XII and amino
`1‘hYdr°xyb°nZ0lrl“Z°1°IHOBDOI l‘h3""r°xY‘7‘aZab°"Z°‘
`acid analogs XIII
`is shown in Scheme 13. Asymmetric
`Iriazolc [HOAU and ‘1 base’ Cg‘ diisopmpylclhylaminca
`reduction (e.g. using the (Iorey oxazaborolidine reduction
`N-metliyl morpholine or triethylamiiie. Deproteetion of the
`pmlowll Tc“-cw: l_.l_ _l_ Corey & C llclalllqrlgelll Cllem ml‘
`amide—ester then furnishes the desired amide—aeid analogs V.
`Ed, Ellglu 1998, 37’
`l986_20l2) of lllc aryl_kclOnC 34
`TI“ liwillldal)’ a"ll"l‘v"75i°lcT 5 ‘-7111 315“ be T53‘-'1"d Will‘ 25 provides each of the two desired enantiomeric alcohols 35
`allphalic OT aT}’1i3°C}‘'a"ai°521 7-0 PI"~“'id5 the C°"“v5P°“‘-ling
`{although only one enantiomer
`is represented in the
`urea-esters. Deprotection of this product provides the
`Schcmcy Tl-calmcnl oflhc chiral alcohol 35 will-l azldc in a
`dc-‘iircd I-l“3a'a‘3id 3“31'5‘g5 Via 35 -‘*h'5‘W“
`in S‘-'h"3"""’ 8-
`Mitsunobu-like reaction (ref: A. S. Thompson et. al.,J. Org.
`Ali“-1'“?-l‘l"'3lYa 35 Show“ in Scheme 9: the Carbamyl Chlmide
`Clrcrtr. I993, 58, 5886-5888) gives the corresponding chiral
`intermediate 18 described in Scheme 6 can be reacted with 30 azidc (wilh {mm-led Sm-cochcmislry from lhc Sm-ling
`appraiariatciarimary arsccandary aliphatic ararylaminaa 23
`alcohol). This azide is then reduced to the amine 36 by
`and 23 in lh’-3 Prcscncc of 3 tertiary amlflc (9-Er E131“ [0
`standard methods [e.g. hydrogenation or Ph1P,="I'III‘}’II..()).
`furnish tri— or tetrasubstituted urea—acid analogs VII or VIII
`Tl-calmml of mg chiral amine, 36 with an a'_hal0_¢5l¢f 33
`“fl” dcprolccllon of ii“: °5i°1'~
`provides the secondary amine-ester 37. Acylation of amino-
`The secondary amine-ester 5 can also be reacted with 35 ester 36 with an aryl or heteroaryl chloroformate 17 lol-
`appropriate sulfonyl chlorides 24 under standard literature
`lowed by deprotection provides the chiral carbamate—acid
`Cllndllliml-‘i Illlllilllillly in “'13 PT‘?-‘Will-‘fl Oi 3 53-‘ifl
`-‘illiih 35
`analogs XII (which may be either enantiomer depending
`pyridine. either meat or using chloroform as :1 ewsulvenl),
`upon the stereochemistry of 36). Reductive amination of
`followed by deprotection,
`to provide the corresponding
`ajkyl amjn0_;_-,5“-,; 37 with aryl aldchydcs 6 f0ll0wc(I by
`Sllirtlfliimidfi-2iCidS IX, El-S 5-'sh0Wl'| ill 5L‘h€|'|'|fl
`10.
`4:1 deprotection provides the chiral amino-acid analogs XIII
`The different approaches to the preparation of the pre—
`(which may be either enantiomer depending upon the ste-
`ferred raeemic oL—alkylbenzyl carbamate—acid and amino
`reochemistry of 36).
`acid analogs X and XI
`respectively are exemplified in
`An alternative synthesis of analogs XII and XIII is shown
`synthetic Schemes 11 and 12. In Scheme 11 a substituted
`in Scheme I4./\n appropriately protected oxyaryl ketone 38
`aryl nitrile (with a suitable aromatic heterocycle R5 already 45 undergoes asymmetric reduction to give the chiral alcohol
`appended) is treated with an appropriate organometallic
`39. This is converted to the chiral amine 40 via the identical
`reagent (e.g. a Grignard reagent R10MgX 26 or an organo-
`sequence as in Scheme I3 (via the chiral azide). Treatment
`lithium reagent RmI_i) under standard conditions to give the
`of the chiral amine 40 with an ester 28 (I.G=halogen or
`corresponding imine intermediate, which is immediately
`mesylate) gives the corresponding secondary amine-ester
`reduced [e.g. with I.iAlH,,] to give the corresponding pri- Sn 4'1. Acylation of 4'1 with an aryl or heteroarylchloroformate
`mary amine 27. Amine 27 is then reacted with an appropri-
`17 provides the coiTesponding carbamate-ester. Selective
`ately substituted ot—halo—ester 28 to provide the oorrespond—
`deprotection furnishes the free phenol carbamate—ester 42.
`ing ot-amine-ester 29.
`It will be understood that
`in the
`Alkylation of the phenol 42 with a halide or mesylate 7
`amine-ester 29, the moiety
`followed by deprotection provides the chiral carbamate-acid
`55 analogs XII. An analogous sequence which involves reduc-
`live amination of the secondary amine-ester 41 with an aryl
`or heteroaryl aldehyde 6, then selective deprotection, alky-
`lation with 7 and a final deprotection, provides the chiral
`amino acid analogs XII]. ltwillbe appreciated that either the
`an (R)- or (S)-enantiomer of X or XI may be synthesized in
`Schemes 13 and 14, depending upon the ehirality of the
`does not necessarily represent two repeating units.
`reducing agent employed.
`Acylation of the amine-ester 29 with an appropriately
`A preferred alternative asymmetric synthesis of
`substituted aryl or heteroaryl chlor-ol‘ormates 17 followed by
`carbamate—acids XII is shown in Scheme '15. Protection of a
`deprotection provides the racemic carbamate—aeid analogs
`X. Reductive amination ofalkylbenxyl amine-ester 29 with 65 chiral amine 43 (with the phenol differently protected),
`aryl aldehyde 6 followed by deprotection provides the
`preferably as a carbamate, provides intermediate 44. Selec-
`racemic amino-acid analogs XI.
`live removal of the phenolic protecting group of 44 provides
`PENN EX. 2139
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`carbamate-ester, which is then deprotected to furnish the
`Zralkenyl aryl carbamate acid analogs XVIII (Scheme 18).
`Alternatively, this sequence can be reversed, i.e. the initial
`step being the deprotection of acetylenic ester 58 to the
`acetylenic acid, followed by stereoselective reduction of the
`acetylene moiety to provide the Z—alkene—acid analogs
`XVIII.
`
`11
`the free phenol 45. Alkylation of phenol 45 with the mesy-
`late 7 furnishes the protected amine 46. Deprotection of the
`amine of 45 then furnishes the key intermediate, the primary
`amine-ester 36, which then undergoes alkylation with a
`o.—halo—ester 28 in the presence of base to provide the
`secondary amine 37. Reaction of amine 37 with a chloro-
`formate 17 provides the chiral carbamate acid analogs XII.
`Apreferred asymmetric synthesis of analogs XIV and XV
`is shown in Scheme 16. The aldehyde 3 is subjected to
`The corresponding trans—all<enyl aryl carbamate acids
`standard Wittig reaction conditions (ref: Preparation of ID xlx am Synthesized according to the gene,-a1 mum in
`Alkenes, a Practical Approach, .1. J. Williams, lJ.d., (fhapter
`Schcmfi 19_ A hetcmaryl (R5)_accIy1cnc 57 is halogmaled
`2’ Pp 19_5.8) 10 liurnish [he a1kcnfl.47' Aqymmflmc ami"°'
`under standard conditions (ref: Boden, C. D. J. ct al., J.
`h}:dnixylamm accmdmg [0 known lltcraiurc pmccdums (ml:
`Clrcrir. Soc. i"erkiri 'i"i'rrri.s'. I, 1996, 2417; or Lu, W. et. al.,
`O Brien, P., /trtgew, Cfiem.
`Int. Ed, 1999, 38, 326 and
`_
`,
`,
`Reddy, K. I.., and Sharpless, K. I3.,J. Am. Chem. Soc, 1998,
`‘I5 Tefraiiedrofl Len‘ 1_998_’ 39’ 952” to gwc the Corresponding
`130’ 1207) furnishes the dcsircd amm0_a1c0h01 43 as a
`halo—acetylene,which is then converted tothe corresponding
`single enantiomer.
`It
`is understood that
`this reaction can
`“'3“5'3lk"~“1Y15”‘“fl““° 59 (Wt B0909: 9- Dv J-,J- U19“!-
`produce either enantiomer (of which only one is shown
`500-, 1”i"ki?1 3'i"I1??-5'- 1.1995: 3417)-T915 aryl‘ UT h*>1€F03TY1'
`here). Selective protection of the amine 48 provides the
`substituted trans-alkenyl stannane 59 is then coupled with
`alcohol 49. Alcohol 49 is then converted by standard meth-
`the [1;11g.ary] carban-.a1e ester 56 undgf Standard Sting mu-
`99519 lh°_ inlcrmcdlfiilc 50a which "‘-“wins 3 5"i‘3"]° ]°3"'l"8
`pling conditions (ref: Farina, V. ct. al., “The Stille Reaction",
`gm”? fallhsr 3 hahdc Ur
`2} mcsylaltii T” the Subscqlfcnl
`()rga'rric Rea'ci’i'r)rr.s', 1997, 50, l)to furnish the corresponding
`Climate dlsplacsmsm r_sam(,m' Rcacum of an appmPnal_c
`trans—alkenyl aryl carbamate ester 60. This carbam ate—ester
`hlghcpordcr Cupmtc 51 (mt: L‘ A‘ Paqucuc’ Ed" Orgamc
`is then deprotected under standard conditions to give the
`Reacfioris, 1992, Vol. 41, J. Wiley & Sorts) with the pro— 25
`‘
`.
`i
`.
`”
`tected amine substrate 50 provides the coupled, protected
`dcslwd lransfllkcnyl aryl Carbamaw and analogs XIX‘
`amine 52. Dcprotcction of the amine functionality of 52,
`In Scheme 20, treatment ofa suitably protected halo—aryl
`followed by reaction with an ester 28 (I.(i=halogen or
`ca,-|,ama[c_cS[cr 56 with a mmallam-lg agcm(c_g_iS0pmpy1
`mesylale)! liurnifihss the Sorrtispflllding Sccundary ar"i""'
`magnesium bromide, reference: P. Knochel et al., Syni‘i’ie.s'i:'.s',
`ester 53. Acylation of amine 33 with an aryl or heteroaryl 30 700., 565469) rumighfltha wrrcgpmding arylmagnfiium
`chloroformate 17 provides the corresponding carbamate-
`[Tea 211-‘
`;Vh_l.ch .5 Ihcril rcértxd whhiformrlldch d‘ to K;V.dc
`ester, which is then deprotected to furnish the carbamate-
`b g ['1 h lL.1 T
`L b
`f
`11 h ‘1 6 y Sh
`pg
`11
`acid analogs XIV
`enzy aoo o 6 ,
`reatment o a co 0
`1 wit mesy ate
`Alternatively, reductive amination of amine 53 with an
`VIII 1"
`thc pmscncc of Page: provides the Corrcspcfnflfng
`aldehyde 6 followed by deprotection provides the tertiary 35 ClhC‘''C3''h-'im-'itC 95101’: which 15 th'31'1 d9P"9‘9‘3"3d 10 h1ml5h
`amino acid analogs XV,
`the ether—acid XX of the invention.
`I
`_
`lh 1
`I. t
`The synthesis of carbon—linked analogs are shown in
`I S h
`-,1 I
`I
`I
`f
`-I bl
`Schemes 17-19. Scheme 17 describes a general synthesis of
`Cafl[)1an:al:I_::l;r lsgcivriffinafi aa
`iriaficpfigcl can is: 1
`the acetylene—linked acids XVI and the alkyl—linked acids
`.b
`‘I
`.
`'1 .
`d
`P; .111
`_
`1. y
`_
`‘If’
`‘
`XVII./\halo-substituted aryl aldehyde 54 (preferably iodide 4:1 (c‘g' m my Vin}! lm) 1”} er
`[1 6 “mp mg um mom’
`‘
`or bromide) is subjected to reductive amination using pro—
`(rcfcmflcci Farina! V‘! Knshnamuflh-lit V1 and Scotti w'_J‘=
`cedures known in the literature (e.g. Abdel—Magid et al, J.
`Organic R900-'3’-0115, 1997. 50- 1) P1‘0V1(l°5 lhc C0“'°5P0T1"1T1£-E
`Org Chem 1996,
`(11, 3849) with an a_amino acid ester
`vinyl intermediate, which can then undergo hydroboration
`hydrochloride V. The resulting secondary amino-ester 55 is
`(eg. borane-TIII-‘) to give the alcohol 62. Treatment of
`then reacted with an aryl or heteroaryl chloroformate 17 in 45 alcohol 62 with mesylate VIII
`in the presence of base
`199 P1'°5°"_°° Of an '<1I3_P1'0P1'i«'l“3
`'3a3¢ (0-8; PYFWUC 01’
`provides the corresponding ether carbamate—ester, which is
`triethylamine)
`to furnish the corresponding halo-aryl
`than deprotected to provide the ether acid XXI of the
`carbamate-ester 56. Aryl halide 56 is then reacted with an
`invcnu-on
`i
`appropriate heteroaryl (R5)—substituted acetylene 57 in the
`The synthesis Of N—aryl acids XXII Of the i1’1VC1'11i01'1 iS
`presence of an appropriate palladium (:a[:[[ys1 {c_g_ (Ph3P)
`shown in Scheme 22. Reductive amination of protected
`2]-’d(Tl2i‘and a copper (I) salt (e.g. (ful) in a Sonogashira
`phenol—aldehyde 2 with an appropriate aniline 63 (or other
`coupling reaction (ref: Organocopper Reagents, a Practical
`heteroarylamine) provides the siibstituted aromatic amine
`Aiiproach. R- -l- K- '1‘3.\"1'1‘Ta _]—“«‘-l‘a_Ch‘1Pl‘3T 10: PP 217-2-'_§6s
`intermediate 64. N—alkylation of the aromatic amine 64 with
`(:‘”"pbe1_1' 1' B“ [_)xf“rd Unwcrsuy Pram} 1994) 1" I-“”""h _
`Ihc kcy lillcrmcdldlc‘ ary1‘“'cIy1.cnc 58'
`lhc dryldfxlylcflc 35 an appropriate halo—substituted ester 65 in the presence of
`ester 58 is deprotected to provide the corresponding ary-
`base (ca Sodium hcxamxth ldisihzidx)
`rovidxs the N_ar I
`lacetvlene acid analogs XVI. The acetvlene moiety of58 can
`‘C’
`b Y
`(
`.L p
`M
`Y.
`b
`‘
`“
`.
`,
`(or heteroaryl) ester 66. Deprotection of the phenol of
`e reduced by standard methods (e.g. hydrogenation, ref. M.
`‘
`1.
`1 67
`h. ‘h h
`1
`.
`66
`.d ‘
`h
`d
`Iludlicky, Reductions in ()rganic (fhemistry, 2"": Edition,
`‘imlnwfihjlcr
`pm“ eh, ms P m0 ,
`’ wglt
`1 en U” “-
`ACS‘ 1996’ Chapter .1] to furnish the Corresponding fully fin goes Mitsunobu reaction (e.g. usiiig cyaiioinetliyleiie
`saturated alkyl aryl carbamate esters, which are then depro—
`lrfbulylphosphofanc) with an apP"°1?“al° alcohol 1 to Pm"
`tected to give the alkyl aryl carbamate acid analogs XVII.
`‘f‘d" ll“ “]k}']‘“"d_ Ph"“"l N"”3’l “""‘""'°"""r 68‘ D“P““‘f“'
`Stereoselective reduction of the acetylene ester 58 by
`U011 0f ‘[10 °5"'~:r1' 93 P'1'0"'1d'-35 N'aI'}’1 (0? N'h¢l51'05U'Y1) 30193
`standard methods (cg. Lindlar’s catalyst; ref: Preparation of
`XX“ Of ‘[19 1f1V'*'~‘«T1110Y1- A1l_°1'fl'<1l1V°1Y. Phcml 57 can '39
`Alkenes, /\Practical Approach, J. J. Williams, Ed., Chapter 65 ‘til-K)/13100 W111‘! 1'l‘K3S)'1fl1C 7 11'!
`11115 PTCSCUCC Of 95159 (9-2,-
`6, pp 117-136, Oxford University Press, 1996) can be
`K2C03)
`followed by acid deprotection to also provide
`achieved to provide the corresponding cis-alkenyl aryl
`N-aryl (or N-heteroaryl) acids XXII of the invention.
`PENN EX. 2139
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`US 6,875,782 B2
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`R2\
`/\ (110
`/[ 2 111-}
`E j
`
`I10
`x
`3
`Mitsunohu reaction
`
`S,(~)\
`R
`K; OH
`1
`
`_
`,
`.
`C.IH.H_g\
`,. (.03P(J
`»
`ReductivAnimation
`
`4T
`
`R3
`\/N CHO
`4* i _1
`I
`.
`7‘; O
`K
`
`5
`
`R
`
`3
`R)
`\/\ Hx
`E
`i
`m
`
`l
`
`X
`
`5
`
`5/fix
`R
`X; 0
`
`(T031-’(}
`n
`1; It-“'—c110
`
`Rcduclix-‘c Aminalion
`R“ = any of the R3 group
`‘”5‘-"Tl H: ""d c|—(-‘S Mk)"
`
`w
`
`C03”
`
`
`
`Alternative Scheme 1A for Preparing Aldehyde IV
`
`R5/E~):()H
`1
`
`
` (TH SO C],-“I'LL N
`3
`3
`3
`
`C110
`
`R"-’\
`/-§|
`l
`2
`
`x
`7
`_
`Base
`
`0
`0
`{% \\Sfy
`‘ Z "Wu.
`X, 0
`T
`
`5
`
`