PCT
`INTERNATIONAL APPLICATION PUBLISHED UNDER TIIE PATENT COOPERATION TREAIT (PCf)
`wo 98/50028
`
`WORLD INTI:LLECfUAL PROPERTY ORGANIZATION
`International Bureau
`
`(SI) International Patent Classification 6 :
`A61K 311355, 31134, 311075, 311445,
`311495, 31150
`
`Al
`
`(11) Intematlonal Publication Number:
`
`(43) International Publication Date:
`
`12 No".ernber 1998 (12.11.98)
`
`(2i) International Application Number:
`
`PCT/US98/08269
`
`(22) International Filing Date:
`
`23 April 1998 (23.04.98)
`
`(JO) Priority Data:
`60/045,405
`
`I May 1997 (01.05.97)
`
`us
`
`BRISTOL-MYERS SQUIBB COMPANY
`(71) Applicant:
`[US/US]; P.O. Box 4000, Princeton, NJ 08543-4000 (US).
`
`(81) Designated States: AL, AM, AT, AU, AZ. BA; BB; BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE,
`GH, GM, GW, HU, ID, IL, IS, JP, KB; KG; KP, KR, KZ,
`LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW,
`MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL,TJ,
`TM, 1R, TT, UA, uo. uz, VN, Yll. zw .. ARIPO patent
`(GH, GM, KE, LS, MW, SD, SZ. UG, ZW), Eurasian patent
`(AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European patent
`(AT, BB, CH, CY, DE, DK, ES, FI, FR, GB, GR, IB, IT,
`LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, Cl,
`CM, GA, ON, ML, MR, NE,.SN, TD, TG).-'
`.
`
`(72) Inventors: GREGG, Richard, B.; 7 Linden Lane, Pennington,
`NJ 08534 (US). WEITBRAU, John, R., II; 190 Rugby Published
`With international search rep0rt.
`Drive, Langhorne, PA 19047 (US).
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`·
`amendments.
`
`(74) Agents: RODNEY, Burton et al.; Bristol-Myers Squibb Com(cid:173)
`pany, P.O. Box 4000, Princeton, NJ 08543-4000 (US).
`
`(54) Title: MTP INHIBITORS AND FAT SOLUBLE VITAMIN THERAPEUTIC COMBINATIONS TO LOWER SERUM LIPID
`LEVELS
`
`(57) Abstract
`
`A phannaceutical combination fanned of an MTP inhibitor and a fat soluble vitamin such as Vitamins E; A, Kand/or D, and:optionally
`another cholesterol lowering drug, is provided which is employed in a method for lowering serum lipids, cholesterol .and/or triglycerides
`and thereby inhibiting or treating atherosclerosis, pancreatitis, hyperglycemia and/or obesity.
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`Codes used to identify Slates party to the PCT on the front pages of pamphlets publishing international applications· under the PCT.
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`DR
`BY
`CA
`CF
`CG
`CH
`Cl
`CM
`CN
`cu
`CZ
`DE
`DK
`EE
`
`Albania
`Annenia
`Austria
`A11111111ia
`Azerbaijan
`Bomia end Herzegovina
`Barbados
`Belgium
`Burkina Paso
`Bulgaria
`Bcnln
`Brnil
`Belarus
`Caruida
`Central African Republic
`Congo
`Switu:rlend
`Cillc d'Ivoltc
`Cameroon
`China
`Cuba
`C=h Republic
`Germany
`Denmark
`Estonia
`
`ES
`Fl
`FR
`GA
`GB
`GK
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`u
`LK
`LR
`
`Spain
`Finland
`Prance
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Ismel
`Iceland
`naly
`Japan
`Kenya
`Kyrgyulan
`Democra1ic Ptople01
`Republic of Korea
`Republic of Kozea
`Ka7.ablan
`Saint Lucia
`Licchten&tein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MK
`MW
`MX
`NB
`NL
`NO
`NZ
`PL
`PT
`RO
`KU
`SD
`SE
`SG
`
`Lesalho
`Li1huania
`Luxembourg
`LalVia
`Monaco
`Republic of Moldova
`Modapscar
`1be former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Maurllanla
`Malawi
`Mulco
`Niger
`Nclherlands
`Norway
`New Zealand
`Poland
`Ponupl
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`sz
`TD
`TO
`TJ
`TM
`TR
`Tl'
`UA
`UG
`us
`uz
`VN
`YU
`zw
`
`Slovenia
`Slovakia
`Senegal
`Sw112iland
`Chiu!
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trirlldad and Tobago
`Ubainc
`Uganda
`United Slalcs Of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
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`MTP INHIBITORS AND FAT SOLUBLE VITAMIN THERAPEUTIC
`COMBINATIONS TO LOWER SERUM LIPID LEVELS.
`
`5
`
`10
`
`Field of the Inyention
`
`The present invention relates to a combination· of an
`MTP inhibitor and a fat soluble vitamin such as Vitamin·E,
`Vitamin A, Vitamin K and/or Vitamin D, and optionally
`another cholesterol lowering drug, for example, ari HMG.CoA
`reductase inhibitor, such as pravastatin, lovastatin br
`simvas.tatin, and to a method for lowering serum lipids,.
`cholesterol and/or triglycerides in mammalian species by
`administering such combination.
`
`15
`
`Background of the Inyention
`The use of microsomal triglyceride transfer protein
`CMTP) inhibitors for decreasing serum lipids including
`cholesterol and triglycerides and their use in trea~i~g
`atherosclerosis, obesity and pancreatitis is disclosed in
`20 Canadian Patent Application No. 2,091,102 (corresponding to
`U.S. Application Serial No. 117~362), U.S. Application
`Serial No. 472,067, filed June 6, 1995 (file DC2le), U.S.
`Application Serial No. 548,811, filed January 11, 1996
`(file DC2lh), U.S. Application Serial No. 08/767,923,· filed
`25 December 17, 1996 (file HX79c*), U.S. provisional·
`application No. 60/017,253, (file HX82*) and U.S.
`provisional application No. 60/017,254, (file HX84*).
`All of the above U.S. applications are incorporated
`herein by reference.
`
`30
`
`Description of the Invention
`In accordance with the present invention, a novel
`combination is provided which includes an MTP inhibitor and
`a fat soluble vitamin such as Vitamin E, Vitamin A, Vitamin
`35 K and/or Vitamin D, and optionally another cholesterol
`lowering agent.
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`5
`
`In addition, in accordance with the present
`invention, a method for preventing, inhibiting or treating
`atherosclerosis, pancreatitis, hyperglycemia, or obesity is
`provided, wherein an MTP inhibitor in combination with -a
`fat soluble vitamin such as Vitamin E, Vitamin A, Vitamin:K
`and/or Vitamin D, and optionally another cholesterol
`lowering drug, is administered in therapeutically effective
`amounts to lower LDL cholesterol and triglycerides.
`Furthermore, in accordance with the present
`invention, a method is provided for lowering serum lipid
`levels, cholesterol and/or triglycerides, or inhibi~ing
`and/or treating hyperlipemia, hyperlipidemia,
`hyperlipoproteinemia, hypercholesterolemia and/or
`hypertriglyceridemia, wherein a combination of an MTP
`inhibitor and a fat soluble vitamin such as Vitamin E,
`Vitamin A, Vitamin K and/or Vitamin D, and optionally
`another cholesterol lowering drug, is administered in
`therapeutically effective amounts.
`MTP inhibitors inhibit the production of
`triglyceride rich plasma lipoproteins, very low density
`lipoproteins (VLDL) and chylomicrons. Vitamins E, A, K and
`D are fat soluble vitamins which are, in part, transported
`throughout the body on these lipoproteins, or lipoproteins
`which are metabolic products of these lipoproteins.
`25 Because MTP inhibitors block lipoprotein production,. they
`may interfere with the normal absorption and transpor;t of
`fat soluble vitamins. Abnormal absorption of fat solUble
`vitamins has been observed in abetalipoproteinemic supjects
`who lack MTP due to a genetic defect in the gene encoding
`30 MTP. Fat soluble vitamin supplements in
`abetalipoproteinemic subjects ameliorate most if not all
`the complications associated with fat soluble vitamin
`deficiencies (Kane, J.P., et al, "Disorders of the
`Biogenesis and Secretion of Lipoproteins Containing the B
`35 Apolipoproteins", Chapter 57, pp. 1853-1885, "The Metabolic
`and Molecular Bases of Inherited Disease", 7th Ed., Vol. 11
`(1995)). Thus, Vitamins E, A, K, and/or D supplements in
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`subjects .treated with an MTP inhibitor will ameliorate·
`adverse effects of MTP inhibitors associated withfat
`soluble vitamin def~ciencies.
`Cholesterol lowering drugs or drugs which ~re :
`inhibitors of cholesterol biosynthesis which may 6pt~onally ·
`be used in combination with the MTP inhibitor and.the fat.
`soluble vitamin include HMG CoA reductase inhibitors,.
`squalene synthetase inhibitors, fibric acid derivatives,
`bile acid sequestrants, probucol, niacin, niacin
`derivatives, neomycin, aspirin, and the like.
`It is believed that the combination of MTP· inhibitor.
`and other cholesterol lowering drug, which works by a
`mechanism other than inhibiting MTP,
`together with a fat
`soluble vitamin is a surprising and unique concept in
`treating diseases involved with elevated cholesterol .and/or.
`triglycerides and atherosclerosis, hyperglycemia, obesity
`and/or pancreatitis, in that the combination may provide
`additional ant:hcholesterolemic i?ffects over that which may
`be obtained using each of the cholesterol lowering
`components of the combination alone.
`It is expected that
`reduced levels of each of the MTP inhibitor and other
`cholesterol lowering drug may be employed to achieve
`desired results, albeit with reduced side effects.
`
`Detailed Description of the Invention
`The following definitions apply to the terms as used
`throughout this specification, unless otherwise limited in
`specific instances.
`The term "MTP" refers to a polypeptide or protein
`complex that (1) if obtained from an organism (e.· g., cows,
`hwnans, etc.) , can be isolated from the microsomal f~action: .
`of homogenized tissue; and (2) stimulates the tr~sport of
`.
`.
`triglycerides, cholesterol esters, or phospholipids :f:r:om
`synthetic phospholipid vesicles, membranes or lipoproteins
`to synthetic vesicles, membranes, or lipoproteins and which
`is distinct from the cholesterol ester transfer prote~n
`
`.
`
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`:
`
`[Drayna et al., Nature 327, 632-634 (1987}) which may have
`
`similar catalytic properties.
`The phrase "treating atherosclerosis" as employe(:]
`herein includes stabilizing atherosclerosis and/or causing
`the regression of athe~osclerosis.
`The phrase "stabilizing• atherosclerosis as used
`herein refers to slowing down the development of and/or:
`inhibiting the formation of new atherosclerotic lesions.
`The phrase •causing the regression of"
`atherosclerosis as used refers to reducing and/or
`eliminating atherosclerotic lesions.
`The term "fat soluble vitamin" as employed herein
`refers to Vitamin E, Vitamin A, Vitamin K or Vitamin D,
`including combinations of any two or more of the above
`vitamins .
`The term "pancreatitis" as employed herein refers to·
`pancreatitis which is secondary to hypertriglyceridemia.
`The phrase preventing, inhibiting or treating
`hyperglycemia as employed herein refers to preventing,
`inhibiting or treating hyperglycemia or diabetes (Type I or·
`II} by
`
`5
`
`10
`
`t 5
`
`20
`
`25
`
`(l} causing reduced absorption of dietary fat .
`through MTP inhibition or
`(2) lowering triglycerides through MTP inhibition or
`(3) decreasing absorption of free fatty acids·
`through MTP inhibition.
`The term preventing, inhibiting or treating
`"obesity" as employed herein refers to preventing,
`inhibiting or treating obesity by causing reduced
`30 malabsorption of dietary fat through MTP inhibition.
`The pharmaceutical combination of the invention will.
`preferably include Vitamin E in an amount within the range
`from about 100 to about 15,000 mg/day, preferably from
`about 200 to about 5,000 mg/day.
`
`35
`
`Where present, Vitamin A will be employed in an
`
`amount within the range from about 1,000 to about 50,.000
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`R4
`
`-5-
`
`International Units ( IU) /day, preferably from a.bout 10 ,=000,
`to a.bout 35,000 IU/day.
`Where present, Vitamin K will be employed in .an .
`amount within the range from about 0.1 to about 25 mg/day,:
`5 preferably from a.bout 5 to about 15 mg/day.
`Where present, Vitamin D will be employed in an·
`amount within the range from about 50 to about l,000'
`IU/day, preferably from about 100 to about 400 IU/day~
`Preferred combinations of vitamins include Vitamin:&
`and Vitamin A in amounts of each as set out above.
`Vitamin K and Vitamin E in amounts of each as set
`out above.
`Vitamin D and Vitamin E in amounts of each as set
`out above.
`The combination of the MTP inhibitor and other·
`cholesterol lowering drug will be employed in a weight·
`ratio to each other within the range of from about 1000:1.
`to about 0.001:1 and preferably from about 100:1 to about
`0.05:1.
`MTP inhibitors to be employed in the methods of the
`invention include MTP inhibitors disclosed in Canadian·
`Patent Application No. 2,091,102 (corresponding to U.S.
`Application Serial No. 117,362), U.S. Application Serial
`No. 472,067, filed June 6, 1995 (file DC2le), U.S.
`25 Application Serial No. 548, 811 filed January 11, 1996 (file
`DC2lh), U.S. Application Serial No. 08/767,923, filed
`December 17, 1996 (file HX79c*), U.S. provisional
`application No. 60/017,253, (file HX82*) and U.S.
`provisional application No. 60/017,254, (file HX84*).
`All of the above U.S. applications are incorporated
`herein by reference.
`The MTP inhibitors disclosed in U. s. Applicati.on
`Serial No. 472,067, filed June 6, 1995 (file DC2le) are
`piperidine compounds of the structure
`n2
`0
`n'~N-CN-R'
`V-x
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`or
`
`or
`
`or
`
`or
`
`Rs ... Q_ -G
`
`fl
`6
`R
`
`.N-R1
`
`•
`
`0
`0
`whereQls -c- or -s-
`11
`0
`
`It
`
`II
`
`X is: CHRe
`
`'
`
`- c- -CH- CH-
`I I
`I
`II
`0
`Re
`R10
`
`or
`
`-C= C- i
`I
`I
`R9 R10
`
`Ra, Rg and RlO are independently hydrogen, alkyl, alkenyl,
`alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloalkyl, or cycloalkylalkyl;
`
`Y is -(CH3)zn- or -fr(cid:173)
`o
`wherein m is 2 or 3;
`Rl is alkyl, alkenyl, alkynyl, aryl, heteroaryl,
`arylalkyl wherein alkyl has at least 2 carbons,
`diarylalkyl, arylalkenyl, diarylalkenyl, arylalkynyl,
`diarylalkynyl, diarylalkylaryl, heteroarylalkyl wherein
`alkyl has at least 2 carbons, cycloalkyl, or
`cycloalkylalkyl wherein alkyl has at least 2 carbons, all
`optionally substituted through available carbon atoms with
`l, 2, 3 or 4 groups selected from halo, haloalkyl, alkyl,
`alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto,
`
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`arylmercapto, cycloalkyl, cycloalkylalkyl, heter6aryl,
`fluorenyl, heteroarylalkyl, hydroxy or oxo;
`fluorenyl-type group of the structure
`R16
`R1s
`IR k
`
`_ R11_ z1
`
`or
`
`_ R11_ z1
`
`or
`
`5
`
`IO
`
`or
`
`-R11_ z1
`
`R12_ z2
`
`; or
`
`~
`Rl is an indenyl-type group of the structure
`
`or
`
`or
`
`(a= 2,3 or 4)
`
`.E
`
`R~13 R14
`
`- R11_z
`R -z
`12
`2
`R15a
`
`168
`
`R
`
`(CH2)a
`
`or
`
`- R11-z1
`
`H
`
`15
`
`zl and z2 are the same or different and are
`independently a bond, 0, S,
`
`-?-
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`SUBSTITUTE SHEET (RULE 26)
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`,
`
`or
`
`J
`
`II
`
`If
`
`H
`s II
`-c-
`-c-l
`, -N--C---
`-Ntt-C-
`11
`I
`II
`11
`alkyl o
`o
`0
`OH
`0
`with the proviso that with respect to~. at least one· of zl
`and z2 will be other than a bond; Rll is a bond, alkylene,
`alkenylene or alkynylene of up to 10 carbon atoms; arylene
`5 or mixed arylenealkylene; Rl2 is hydrogen, alkyl,. alke_nyl,
`aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl,
`heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cycle~
`alkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl·, with
`the provisos that
`(1) when Rl2 is H, aryloxy, alkoxy or arylalkoxy;
`-N -C - . -e-
`-Ntt-C-
`n
`l
`then z2 is
`alkyl 0
`or a bond and
`o
`o
`(2) when z2 is a bond, R12 cannot be heteroaryl or
`heteroarylalkyl;
`Z is bond, 0, S, N-alkyl, N-aryl, or alkylene or
`alkenylene from 1 to 5 carbon atoms; RlJ, Rl4, Rls, and Rl6
`are independently hydrogen, alkyl, halo, haloalkyl, aryl,
`cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, hydroxy,
`alkoxy, nitre, amino, thio, alkylsulfonyl, arylsulfonyl,
`alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy,
`arylcarbonylamino, alkylcarbonylamino, arylalkyl,
`heteroaryl, heteroarylalkyl or aryloxy;
`RlSa and Rl6a are independently hydrogen, alkyl,
`halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl,
`alkenyl, alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl,
`alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy,
`arylcarbonylamino, alkylcarbonylamino, arylalkyl, ·
`heteroaryl, heteroarylalkyl, or aryloxy;
`or Rl is a group of the structure
`
`10
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`25
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`30
`
`R17
`
`-(CH2)p-<
`R18
`
`wherein p is 1 to B and Rl7 and RlB are each independently
`H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl,
`heteroarylalkyl, cycloalkyl or cycloalkylalkyl at least one
`of Rl7 and RlB being other than H;
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`or Rl is a group of the structure
`
`R20
`
`-R'e---<
`R21
`
`5
`
`IO
`
`15
`
`wherein R19 is aryl or heteroaryl;
`R20 is aryl or heteroaryl;
`R21 is H, alkyl, aryl, alkylaryl, arylalkyl;
`aryloxy, arylalkoxy, heteroaryl, heteroarylalkyl,
`heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or
`cycloalkylalkoxy;
`independently hydrogen, halo, alkyl,
`R2, Rl, R4 are
`alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto,
`arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl,
`heteroarylalkyl, hydroxy or haloalkyl;
`Rs is independently alkyl, alkenyl, alkynyl, aryl,
`alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl,
`heteroarylalkyl, cycloalkyl, cycloalkylalkyl,
`polycycloalkyl, polycycloalkylalkyl, cycloalkenyl,
`cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl,
`polycycloalkenyl, polycycloalkenylalkyl,
`20 heteroarylcarbonyl, amino, alkylamino, arylamino,
`heteroarylamino, cycloalkyloxy, cycloalkylamino, all
`optionally substituted through available carbon atoms with
`1, 2, 3 or 4 groups selected from hydrogen, halo, ·alkyl,
`haloalkyl .. alkoxy, haloalkoxy, alkenyl, alkynyl,
`cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cyclohetero(cid:173)
`alkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl,
`arylalkenyl, arylalkynyl, aryloxy, aryloJCialkyl,
`arylalkoxy, arylazo, heteroaryloxo, heteroarylalJcYl,
`heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano,
`amino, substituted amino, thiol, alkylthio, arylthio,
`heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl,
`arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl,
`alkynylaminocarbonyl, alkylarninocarbonyl,
`alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
`alkylcarbonylamino, arylcarbonylamino, arylsulfinyl,
`arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl,
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`arylsulfonylamino, heteroarylcarbonylamino,
`heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl,
`alkylsulfinyl;
`R6 is.hydrogen or C1-C4 alkyl or C1-C4 alkenyl; all
`5 optionally substituted with l, 2, 3 or 4 groups which may·
`independently be any of the substituents listed i~ the
`definition of Rs set out above;
`R7 is alkyl, aryl or arylalkyl wherein alkyl by
`itself or as part of arylalkyl is optionally substituted
`with oxo ( ~ ) ;
`
`10
`
`and
`
`are the same or different arid are independently selected
`from heteroaryl containing 5- or 6-ring members; and
`0
`~'( 1
`thereof; and
`"-../ R
`N..:.oxides
`pharmaceutically acceptable salts thereof;
`with the provisos that where in the first formula X
`is CH2, and R2, R3 and R4 are each H,
`then Rl will be other
`than 3,3-diphenylpropyl, and in the fifth fonnula, where
`one of R2, R3 and R4 is 6-fluoro, and the others are H, R7
`will be other than 4-{2-methoxyphenyl).
`The MTP inhibitors disclosed in U.S. application
`Serial No. 548,811 filed January 11, 1996 {file DC2lh),
`have the structure
`
`15
`
`20
`
`25
`
`- IO-
`
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`
`including the piperidine N-oxide thereof or a
`pharmaceutically acceptable salt thereof, wherein Z is a
`bond, 0 or S;
`xl and x2 are independently selected from Hor halo;:
`x is an integer from 2 to 6;
`RS is heteroaryl, aryl, heterocycloalkyl or.
`cycloalkyl, each RS group being optionally substituted with
`1, 2, 3 or 4 substituents which may be the same or
`different.
`The MTP inhibitors disclosed in U.S. Appli,cation
`Serial No. 08/767,923, filed December 17, 1996 (file
`HX79c*) have the structure
`
`or
`
`or
`
`IB
`
`IA
`including pharmaceutically acceptable salts thereof,
`N-oxides thereof,
`wherein q is a, 1 or 2;
`A is
`(1) a bond;
`-0-; or
`( 2)
`-9 -
`15
`R
`(3)
`where Rs is H or lower alkyl or Rs together with R2 forms a
`carbocyclic or heterocyclic ring system containing 4 to 8
`members in the ring.
`B is a fluorenyl-type group of the structure
`
`5
`
`10
`
`15
`
`20
`
`25
`
`R~f... ._,
`R4'
`I ,J or
`~
`~R4
`
`R3'
`
`X
`
`Het
`
`or
`
`- 11 -
`
`13 of 59
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`
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`
`B is an indenyl-type group of the structure
`
`3
`
`3'
`
`or
`
`or "#"
`
`R3b
`
`wa
`
`R3b
`
`(a= 2,3 or 4)
`
`~··
`
`.
`
`\
`
`R3b
`
`or
`
`5
`
`R38 (CH2)8
`
`R3
`
`R3b
`
`R3a
`
`10
`
`15
`
`20
`
`25
`
`RX is H, alkyl or aryl;
`Rl is H, alkyl, alkenyl, alkynyl, alkoxyl, (alkyl or
`aryl) 3Si (where each alkyl or aryl group is independent),
`cycloalkyl, cycloalkenyl, substituted alkylamino,
`substituted arylalkylamino, aryl, arylalkyl, arylamino,
`aryloxy, heteroaryl, heteroarylamino, heteroaryloxy,
`arylsulfonylamino, heteroarylsulfonylamino, arylthio,
`arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl,
`alkylsulfonyl, cycloheteroalkyl, heteroai:ylthio,
`heteroarylsulfinyl, heteroarylsulfonyl, -PO(Rl3) (Rl4),
`(where Rl3 and Rl4 are independently alkyl, aryl, alkoxy,
`aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy,
`heteroarylalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl,
`cycloheteroalkoxy, or cycloheteroalkylalkoxy);
`aminocarbonyl (where the amino may optionally be
`substituted with one or two aryl, alkyl or heteroaryl
`groups); cyano, 1,1-(alkoxyl or aryloxy)2alkyl (where the
`
`two aryl or alkyl substituents can be independently
`defined, or linked to one another to form a ring connected
`to L1 (or L2 in the case of R2) at the 2-position); 1,3-
`dioxane or 1,3-dioxolane connected to Ll (or L2 in the case
`of R2) at the 4-position; the R1 group may optionally be
`
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`
`substituted with l, 2, 3 or 4 substituents, which can be
`any of the R3 or Rl groups or alkylcarbonylamino,
`cycloalkylcarbonylamino, arylcarbonylamino,
`heteroarylcarbonylamino, alkoxycarbonylamino,
`aryloxycarbonylamino, heteroaryloxylcarbonylamino, uriedo ·
`(where the uriedo nitrogens may optionally be substituted
`with alkyl, aryl or heteroaryl), heterocyclylcarbony!'amino
`(where the heterocycle is connected to the carbonyl group·
`via a nitrogen or carbon atom), alkylsulfonylamino,
`arylsulfonylamino, heteroarylsulfonylamino,
`
`5
`
`IO
`
`tc.20
`
`0
`
`N-
`.
`J
`
`-~
`R21_ ,_
`.b
`,
`Rzz
`
`where J is: cBR:l3, -c- -CB-CH-
`' I
`I
`11
`o
`a:i' a:is
`
`15
`
`20
`
`R23, R24 and R25 are independently hydrogen, alkyl,
`alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,
`heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
`R20, R21, R22 are
`independently hydrogen, halo,
`alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl,
`alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalJcYl,
`heteroaryl, heteroarylalkyl, hydroxy or haloalkyl; and
`these substituents may either be directly attached to Rl,
`or attached via an alkylene at an open position;
`R2 is independently any of the groups set out for
`25 Rl, H, polyhaloalkyl, or cycloheteroalkyl, and may be
`optionally substituted with one to four of any of the
`groups defined for R3 or substituents defined for Rl;
`Ll is a linking group containing from 1 to 10
`carbons in a linear chain including alkylene, alkenylene or
`alkynylene, which may contain, within the linking chain any
`of the following: one or two alkenes, one or two alkynes,
`an oxygen, an amino group, an oxo group, and may be
`substituted with one to five alkyl or halo groups;
`
`30
`
`- l3 -
`
`15 of 59
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`
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`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`L2 may be the same or different from Ll and may
`independently be any of the Ll groups set out above or a
`singe bond;
`R3, R3', R4 and R4' may be the same or different and
`are independently selected from H, halogen, CF3, haloalkyl,
`hydroxy, alkoxy, alkyl, aryl, alkenyl, alkenyloxy,· alkyliyl,
`alkynyloxy, alkanoyl, nitro, amino, thiol, alkylthiq,
`alkylsulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl,
`aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino,
`cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar-,. P.r(cid:173)
`alkyl, Aro, Ar-amino, Ar-thio, Ar-sulfinyl, Ar-sulfonyl,
`Ar-carbonyl, Ar-carbonyloxy or Ar-carbonylamino, wher~in Ar
`is aryl or heteroaryl and Ar may optionally include l, 2 or
`3 additional rings fused to Ar;
`R3a and R3b are the same or different and are
`independently any of the R3 groups except hydroxy, nitre,
`amino or thio;
`
`and
`
`are the same or different and independently represent
`a 5 or 6 membered heteroaryl ring which contains l, 2, 3 or
`4 heteroatoms in the ring which are independently N, S or
`0; and including N-oxides;
`X is a bond, or is one of the following groups:
`(1) - s -
`1
`(O)zi•
`-o-
`
`(2)
`
`(3) -H -
`I
`R'
`
`(4)
`
`-,c,
`R7
`RB
`
`,,
`(5) -c ~
`/
`Rg
`RlORg•
`RlO'
`
`- 14 -
`
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`
`(6)
`
`or
`
`(7) - c - - -Y -
`R9
`a10
`
`,,'
`
`5
`
`10
`
`15
`
`wherein
`Y is 0, N-R6 or S;
`n' is 0, 1 or 2;
`R6 is H,
`lower alkyl, aryl, -C (0) -Rll or
`-C (0) -0-Rll;
`R7 and Ra are the same or different and are
`independently H, alkyl, aryl, halogen, -o-R12, or·
`R7 and RB together can be oxy~en to fonn a ketone;
`R9, RlO, R9' and RlO' are the same or different and
`are independently H, lower alkyl, aryl or -O-Rll;
`R9" and Rio· are the same or different and are·
`independently H,
`lower alkyl, aryl, halogen or
`-0-Rll;
`
`.
`
`20
`
`25
`
`structure R
`A
`B
`R
`(a) when Rl is unsubstituted alkyl or unsubstituted
`arylalkyl, Ll cannot contain amino;
`(b) when Rl is alkyl, Ll cannot contain amino and
`oxo in adjacent positions (to form an amido group);
`(c) when R2L2A- is H2N-, RlLl cannot contain amino;
`(d) when Rl is cyano, Ll must have more than 2
`carbons;
`(e) RlLl must ~ontain at least 3 carbons;
`with respect to compounds of formulas I, IA and IB,
`30 where Rl or .R2 is cycloheteroalkyl, Rl or R2 is exclusive
`of 1-piperidinyl, 1-pyrrolidinyl, 1-azetidinyl or 1-(2-oxo(cid:173)
`pyrrolidinyl);
`
`Rll is alky or aryl;
`Rl2 is H, alkyl or aryl;
`with the following provisos for compound of the
`
`2_...L~ 5 _...L~ 1
`
`- 15 -
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`
`with respect to the sulfur containing compounds and
`alcohols, R2L2 cannot have an O or N atom directly at.tached
`to S=(O)q or CRX(QH), and for IA, R2L2 cannot be H.
`The MTP inhibitors disclosed in U.S. provisional
`application No. 60/017,253, filed May 10, 1996, (file
`HX82*) are pyrrolidine compounds and have the structure
`:r
`
`:r :r
`
`0
`0
`"
`II
`where a ls -c- or -s-
`II
`0
`
`w is H,H or 0;
`
`X Is: CHR8
`
`'
`
`- C-
`II
`0
`
`-CH- CH· or
`I
`I
`R'
`R10
`
`'
`
`Ra, R9 and RlO are independently hydrogen, alkyl, alkenyl,
`alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloalkyl, or cycloalkylalkyl;
`Rl is alkyl, alkenyl, alkynyl, aryl, heteroaryl,
`arylalkyl (wherein alkyl preferably has at least 2 carbons,
`more preferably at least 3 carbons), diarylalkyl,
`arylalkenyl, diarylalkenyl, arylalkynyl, diarylalkynyl,
`diarylalkylaryl, heteroarylalkyl (wherein alkyl preferably
`has at least 2 carbons, more preferably at least 3
`carbons), cycloalkyl, or cycloalkylalkyl (wherein alkyl
`preferably has at least 2 carbons, more preferably at least
`3 carbons) i. all of the aforementioned R.1 groups being
`optionally substituted through available carbon atoms with
`1, 2, 3 or 4 groups selected from halo, haloalkyl, alkyl,
`alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto,
`
`- 16-
`
`5
`
`IO
`
`15
`
`20
`
`25
`
`30
`
`18 of 59
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`
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`
`arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl,
`fluorenyl, heteroarylalkyl, hydroxy or oxo; or
`Rl is a fluorenyl-type group of the structure
`R15
`R1&
`R1s
`';fa..k
`'IRk
`
`R16
`
`or
`
`5
`
`or
`
`z
`
`R13
`u
`Rl is an indenyl-type group of the structure
`
`; or
`
`or
`
`or
`
`10
`
`(a= 2,3 or4)
`
`E
`
`R~13 R14
`
`- R11-Z
`R12_ z2
`Rtsa (C"2)a
`
`R1sa
`
`or
`
`g
`
`tl
`zl and z2 are the same or different and are
`independently a bond, 0, S,
`
`R1sa
`
`15
`
`s II
`0
`
`t
`
`-NH-C-
`II
`0
`
`•
`
`-N--C- ,
`I
`11
`alkyl 0
`
`-c-11
`0
`
`or
`
`- 17 -
`
`19 of 59
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`
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`
`with the proviso that with respect to a, at least one of zl
`and z2 will be other than a bond;
`Rll is a bond, alkylene, alkenylene or alJcYnylene of
`up to 10 carbon atoms, arylene (for example
`
`-©-
`
`or mixed arylene-alkylene (for example
`~
`-g(CH2)n-
`
`where n is 1 to 6;
`R12 is hydrogen, alkyl, alkenyl, aryl, haloalJcYl,
`trihaloalkyl, trihaloalkylalkyl, heteroaryl,
`heteroarylalkyl, arylalkyl, arylalkenyl •. cycloalkyl,
`aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl; with the
`provisos that (1) when R12 is H, aryloxy, alkoxy or
`-c-
`-NH-C-
`,
`·-N--C-
`1
`u
`II
`alkyl 0
`0
`o
`
`II
`
`or a
`
`arylalkoxy, then z2 is
`bond;
`
`5
`
`IO
`
`15
`
`20
`
`25
`
`and (2) when z2 is a bond, R12 cannot be heteroaryl
`or heteroarylalkyl;
`z is a bond, 0, s, N-alkyl, N-aryl, or alkylene or
`alkenylene of from 1 to 5 carbon atoms;
`R13, R14, R15, and R16 are independently hydrogen,
`alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl,
`alkenyl, alkynyl, hydroxy, alkoxy, nitre, amino, thio,
`alkylsulfonyl, arylsulfonyl, alkylthio, arylthio,
`aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino,
`alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl,
`or aryloxy;
`RlSa and R16a are independently any of the ·R15 or R16
`groups except hydroxy, nitre, amino or thio;
`or Rl is
`
`·R17
`
`~
`
`-(CB:z)p-<
`~
`wherein p is 1 to 8 and R17 and R18 are each indepe~dently
`H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl,
`
`- 18 -
`
`20 of 59
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`
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`
`heteroarylalkyl, cycloalkyl or cycloalkylalkyl, at least
`one of R17 and RlB being other than H;
`
`- 19 -
`
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`
`or Rl is
`
`ff20
`-n•e--<
`ff21
`
`5
`
`IO
`
`15
`
`wherein Rl9 is aryl or heteroaryl;
`R20 is aryl or heteroaryl;
`R21 is H, alkyl,. aryl, alkylaryl, arylalkyl,
`aryloxy, arylalkoxy, heteroaryl, heteroarylalkyl,
`heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or
`cycloalkylalkoxy;
`R2, R3, R4 are independently hydrogen, halo, alkyl,
`alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, ·
`arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl,
`heteroarylalkyl, hydroxy or haloalkyl;
`Rs is alkyl , alkenyl, alkynyl, aryl, alkoxy,
`aryloxy, arylalkoxy, heteroaryl, arylalkyl,
`heteroarylalkyl, cycloalkyl, cycloheteroalkyl,
`heteroaryloxy, cycloalkylalkyl, polycycloalkyl,
`polycycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl,
`polycycloalkenyl, polycycloalkenylalkyl,
`heteroarylcarbonyl, amino, alkylamino, arylamino,
`heteroarylamino, cycloalkyloxy, cycloalkylamino, all of the
`Rs substituents and R6 substituents (set out hereinafter)
`being optionally substituted through available carbon atoms
`with l, 2, 3 or 4 groups selected from hydrogen, halo,
`alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl,
`cycloalkyl, cycloalkylalkyl, cycloheteroalkyl,
`cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl,
`arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy ..
`aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo,
`heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy,
`30 nitre, cyano, amino, substituted amino (wherein .the amino
`includes 1 or 2 substituents which are alkyl, aryl or
`heteroaryl, or any of the other aryl compounds mentioned in
`the definitions), thiol, alkylthio, arylthio,
`heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl,
`arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl,
`alkynylaminocarbonyl, alkylaminocarbonyl,
`
`20
`
`25
`
`35
`
`- 20-
`
`22 of 59
`
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`
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`
`PCTIUS98/08269
`
`alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
`alkylcarbonylamino, arylcarbonylamino, ar