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`European Patent Office
`
`11111111111111111111111111~ 11111 ~Ill ~~I ~111~11111~ 11 ll~tlll
`EP 1 099 442 A2
`
`(11)
`
`(12)
`
`EUROPEAN PATENT APPLICATION
`
`(43) Date or publication:
`16.05.2001 Bulletin 2001/20
`
`(21) Application number: 00309907.4
`
`(22) Date of filing: 08.11.2000
`
`(51) lntCl.7: A61K 31/472, A61K 31/4725,
`A61K 31/47, A61K 31/4709,
`A61K 31/4468, A61K 31/4985,
`A61 K 31/437, A61 P 3/06
`
`(84) Designated Contracting States:
`AT BE CH CY DE DK ES Fl FR GB GR IE IT LI LU
`MC NL PT SETR
`Designated Extension States:
`AL LT LV MK RO SI
`
`(72) Inventors:
`• Chang, George, Pfizer Central Research
`Groton, Connecticut 06340 (US)
`• Vincent, John, Pfizer Central Research
`Groton, Connecticut 06340 (US)
`
`(30) Priority: 10.11.1999 US 164579 P
`
`(71) Applicant: Pfizer Products Inc.
`Groton, Connecticut 06340 (US)
`
`(7 4) Representative: Ruddock, Keith Stephen et al
`Pfizer Limited,
`European Patent Department,
`Ramsgate Road
`Sandwich, Kent CT13 9NJ (GB)
`
`(54) Methods of administering apo B-secretion/MTP inhibitors
`
`(57)
`The invention provides methods for administer(cid:173)
`ing of apolipoprotein B-secretion (Apo B)/microsomal
`triglyceride transfer protein (MTP) inhibitors which com-
`
`prise administering the inhibitor to a subject in need of
`treatment therewith prior to, or during, a period of som(cid:173)
`nolence.
`
`Printed by Jouw. 75001 PARIS (FR)
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`EP 1 099 442 A2
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`Description
`
`BACKGROUND OF THE INVENTION
`
`[0001) The invention relates to improved methods of reducing levels of total serum cholesterol and LDL-cholesterol
`in a subject in need of such reduction and to methods of administering apolipoprotein B (apo B) secretion/microsomal
`triglyceride transfer protein (MTP) inhibitors to a subject in need of treatment therewith.
`.
`·
`[0002) Microsomal triglyceride transfer protein catalyzes the transport of triglyceride, cholesteryl est~r and phospol(cid:173)
`ipids and has been strongly implicated as a mediator in the assembly of apo B-containing lipoproteins, biomolecu!es
`which contribute to the fonnation of atherosclerotic lesions. Specifically, the subcellular (lumen of the endoplasmic
`reticulum) and tissue distribution (liver and intestine) of MTP have led to speculation that it plays a role in the assembly
`of plasma lipoproteins, as these are known sites of plasma lipoprotein assembly. The ability of MTP to eatal).ze ihe
`transport of triglyceride between membranes is consistent with this speculation and suggests that MTP may catalYze
`the transport of triglyceride from its site of synthesis in the endoplasmic reticulum membrane to nascent. lipoprotein
`particles within the lumen of the endoplasmic reticulum.
`[0003) Compounds that inhibit apo B-secretion and/or inhibit MTP are accordingly useful in the treatment of diseases
`and conditions in which, by inhibiting apo B-secretion and/or MTP, serum cholesterol and triglyceride levels may :be
`reduced. Such conditions may include, for example, hypercholesterolemia, hypertriglyceridemia, panci'eatitis, athero(cid:173)
`sclerosis, diabetes and the like. For detailed discussions see,. for example, Wetterau et al., Science, 258, 999-1001
`(1992) and Wetterau et al., Biochem. Biophys. Acta., 875, 610-617 (1986).
`[0004) Specific examples of compounds having utility as apo 8-secretion/MTP inhibitors are disclosed in European
`Patent Application Publication Nos. EP O 584 446 and EP O 643 057, the latter of which discloses certain comj:>ounds
`of the generic fonnulae .
`
`and
`
`0
`
`R,~
`~\~
`Rl ••• JJ.
`~/#
`
`R••
`
`which have utility as inhibitors of MTP.
`[0005] Furthermore, commonly assigned PCT International Application Publication Nos. WO 96/40640 and WO
`98/23593, each of which designate, inter a/ia, the United States, disclose certain tetrahydroisoquinolines useful. as apo
`B secretion/MTP inhibitors. The disclosures of the aforementioned PCT International Application Publication Nos. WO
`96/40640 and WO 98/23593 are incorporated herein by reference. Additional apo B secretion/MTP inhibitors useful in
`the practice of the instant invention are known, or will be apparent in light of this disclosure, to one of ordinary skill in
`the•
`.
`[0006)
`In studies assessing the impact of various circadian dosing regimens on the efficacy of hypercholesterolemic
`drugs, only competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) have
`been investigated. For example, two studies, involving the HMG-CoA reductase inhibitors mevinolin and pravastatin
`respectively, have indicated some slight improvement in the reduction of cholesterol levels am be effected when the
`drugs are administered in the evening as compared to the morning. However, the overall influence of evening as
`opposed to morning administration on cholesterol levels was marginal at best, resulting only in decreases of between
`3 and 7%. See Illingworth, Clin. Pharmacol. Ther., 40, 338-343 (1986) and Hunninghake, et al., 85, 219-227 (1990).
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`In another study employing the HMG-CoA reductase inhibitor simvastatin, the overall reduction of serum cholesterol
`levels compared to placebo was also minimal and changes in triglyceride and HDL-cholesterol levels were not signif(cid:173)
`icantly different from placebo. See Saito, et al., Arteriosclerosis and Thrombosis, 11, 616-826 (1991). A more recent
`study of the HMG-CoA reductase inhibitor atorvastatin demonstrated no significant decrease in total cholesterol, LDL-
`cholesterol, or apolipoprotein levels compared to placebo when the drug was administered in the evening rather than ·
`in the morning. See Cilia, et al., J. Clin. Phannacol •• 36, 6~09 (1996).
`[0007]
`In direct contrast to the above results, it has now been found that a substantial reduction of total serum cho(cid:173)
`lesterol and LDL-cholesterol levels can be achieved by administering an apo B-secretion/MTP inhibitor, to a subject
`·
`in need of treatment therewith, prior to, or during, a somnolent period of the subject being treated.
`
`SUMMARY OF THE INVENTION
`
`[0008) The invention provides methods of reducing total cholesterol and LDL-cholesterol, which methods comprise
`administering to a subject in need of such reduction an effective amount of an apolipoprotein B-secretion (apo B)I
`microsomal triglyceride transfer protein (MTP) inhibitor prior to, or during, a somnolent period of the subject being
`treated.
`[0009) The invention further provides methods of administering apolipoprotein B-secretion (apo B)/microsomal trig(cid:173)
`lyceride transfer protein (MTP) inhibitors to a subject in need of treatment therewith which methods comprise admin(cid:173)
`istering an effective amount of-the inhibitor prior to, or during, a somnolent period of the subject being treated.
`[0010) The apo B-secretion/MTP inhibitor, as employed according to the methods of the instant invention, is prefer(cid:173)
`ably selected from:
`
`~.
`
`(i) a compound of fonnula (I)·
`
`(I}
`
`the stereoisomers and hydrates thereof, and the phannaceutically acceptable salts of said compounds, stereoi(cid:173)
`somers and hydrates, wherein L is as defined hereinbelow;
`
`(ii) a compound of formula (la)
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`0 II c
`
`. "-..-··
`N
`lb A
`
`(la)
`
`5
`
`10
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`15
`
`20
`
`the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoi(cid:173)
`somers, and prodrugs, wherein R1, R2,and Rb are as defined hereinbelow; and
`
`25
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`(iii) a compound selected from the group consisting of:
`
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`50
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`55
`
`9-(4-(4-(2,3-dihydro-1-oxo-1 H-isoindol-2-yl}-1-piperidinyl]butyl]-N-propyl-9H-fluorene-9-carboxamide;
`2-(1-(3,3-diphenylpropyl)-4-piperidinyl]-2,3-dihydro-1 H-isoindol-1-one;
`9-(4-( 4-(2-( 4-trifluoromelhylphenyl)benzoylamino]piperidin-1-yl)butyl]-N-2 ,2 ,2-trifluoroethyl}-9H-fluorene-
`9-carboxamide;
`9-{4-(4-(2-benzothiazol-2-yl-benzoylamino )-piperidin-1-yl)-butyl}-9H-fluorene-9-carboxylic acid-{2,2,2-trifluor(cid:173)
`oethyl}-amide;
`(11a-R)-8-((4-cyanophenyl)methoxy]-2-cydopentyl-7-(prop-2-enyl}-2,3,11, 11 a-tetrahydro-6H-pyrazino[1,2b]
`isoquinoline-1,4-dione;
`(11a-R]-cyclopentyl-7-(prop-2-enyl}-8-[(pyridin-2-yl)methoxy]-2,3,11, 11a-tetrahydro-6H-pyrazino(1,2b]-iso(cid:173)
`quinoline-1 ,4-dione;
`2-cyclopentyl-2-[4-(2,4-dimethyl-pyrido[2,3b]indol-9-ylmethyl}-phenyl]-N-(2-hydroxy-1-phenyl-ethyl}-aceta(cid:173)
`mide; and
`2-cyclopentyl-N-(2-hydroxy-1-phenyl-ethyl)-2-(4-(quinolin-2-ylmethoxy}-phenyl)-acetamide; and the pharma-
`ceutically acceptable salts thereof.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0011] The invention provides methods of reducing total serum cholesterol and LDL-cholesterol, which methods
`comprise administering to a subject in need of such reduction an effective amount of an apolipoprotein B-secretion
`(apo B)/microsomal triglyceride transfer protein (MTP) inhibitor prior to, or during, a somnolent period of the subject
`being treated.
`[0012] The invention further provides methods of administering apolipoprotein B-secretion (apo B)lmicrosomal trig(cid:173)
`lyceride transfer protein (MTP) inhibitors to a subject in need of treatment therewith which methods comprise admin-
`istering the inhibitor prior to, or during, a somnolent period of the subject being treated.
`[0013] As employed throughout the instant description and appendant claims, the phrase •somnolent period" refers
`generally to the normal sleeping period of the subject being treated. Preferably, the apo B-secretion/MTP inhibitor is
`administered to the subject just prior to the normal evening sleeping event (e.g. at bedtime). It is to be specifically
`understood, however, that the somnolent period may also take place during daylight hours where required: by the
`normal sleeping schedule and/or the psychological predisposition or predilection of the subject.
`[0014] Although any apo B-secretion/MTP inhibitor may be employed in the methods of the instant invention, it is
`generally preferred that the inhibitor be selected from:
`(i) a compound of formula (I)
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`EP 1 099 442 A2
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`(I)
`
`the stereoisomers and hydrates thereof, and the pharmaceutically acceptable salts of the compounds; stereoisomers
`and hydrates, wherein L represents:
`X-Y-Z, wherein:
`
`X is a moiety selected from the group consisting of C~, CO, CS, or S02;
`Y is a moiety selected from the group consisting of a direct link, aliphatic hydrocarbylene radicals having up to 20
`carbon atoms, which radical may be monosubstituted by hydroxy, (C1-C 10)alkoxy, (C1-C10)acyl, (C 1-C 10)acyloxy,
`or (C6-C 10)aryl, NH, and 0, provided that if Xis C~, Y is a direct link; and
`Z is a moiety selected from the group consisting of:
`
`(1) hydrogen, halogen, cyano,
`(2) hydroxy, (C 1-C10)alkoxy, (C1-C 10)alkylthio, (C1-C 10)acyl, thiophenylcarbonyl, (C1-C 10)alkoxycarbonyl,
`(3) (C1-C10)alkylamino, di(C1-C10)alkylamino, (C6-C10)aryl(C1-C 10)alkylamino, provided that Y is not 0 or NH,
`(4) unsubstituted vinyl, (C6-C10)aryl, (C3-C8)cycloalkyl and fused benz derivatives thereof, (C.,-C 10)polycy(cid:173)
`cloalkyl, (C4-C8)cycloalkenyl, (CrC10)polycycloalkenyl,
`(5) (C6-C10)aryloxy, (C6-C10)arylthio, (C6-C 10)aryl(C1-C10)alkoxy, (C6-C10)aryl(C1-C10)alkylthio,. (C3-C8)cy(cid:173)
`cloalkyloxy, (C4-C8 )cycloalkenyloxy,
`(6) heterocyclyl selected from the group consisting of monocyclic radicals and fused polycyclic radicals, where(cid:173)
`in said radicals contain a total of from 5 to 14 ring atoms, wherein said radicals contain a total of from 1 to 4
`ring heteroatoms independently selected from oxygen, nitrogen, and sulfur, and wherein the individual rings
`of said radicals may be independently saturated, partially unsaturated, or aromatic, provided that if Xis c~.
`Z is Hor is selected from groups (4) and (6),
`wherein, when Z contains one or more rings, said rings may each independently bear 0 to 4 substituents
`independently selected from halo, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl,· phenoxy, phe(cid:173)
`nylthio, halophenylthio, benzyl, benzyloxy, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C1-C10)
`alkylthio, (C 1-C 10)alkylamino, (C1-C 10)alkylaminocarbonyl, di(C1-C10)alkylamino, di(C1-C10)alkylaminocarbo(cid:173)
`nyl, di(C1-C10)alkylamino(C1-C10)alkoxy, (C1-C3)perfluoroalkyl, (C1-C3)perfluoroalkoxy, (C1-C10)acyl, (C 1-
`C10)acyloxy, (C1-C10)acyloxy(C1-C10)alkyl, and pyrrolidinyl; or
`
`G, wherein G is selected from the group consisting of:
`
`(a) a phenyl or heterocyclic ring wherein said heterocyclic ring contains a total of from 3 to 14 ring atoms,
`wherein said heterocyclic ring incorporates a total of from 1 to 4 ring heteroatoms selected independently from
`oxygen, nitrogen, and sulfur, wherein the individual rings of said heterocyclic ring may be independently sat(cid:173)
`urated, partially saturated or aromatic, and wherein each of said phenyl or heterocyclic rings may have op(cid:173)
`tionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, ami(cid:173)
`nosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C1-C10)alkyl, (C1-C4)perfluoroalkyl, (C 1-
`C10)alkoxy, (C1-C4)perfluoroalkoxy, (C1-C 10)alkoxycarbonyl, (C1-C10)alkylthio, (C1-C10)alkylamino, di(C1-C:10)
`alkylamino, (C1-C 10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, (C1-C10)acyl, (C1-C10)perfluoroacyl,
`(C1-C10)acyloxy, (C1-C6)acylamino and (C 1-C6)perfluoroacylamino;
`(b}-CH2CN,
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`(c)
`
`EP 1 099 442 A2
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`(d) (CrC12)alkyl or (C2-C12)perfluoroalkyl wherein each of said (CrC12)alkyl and (C2-C12)perfluoroalkyl is
`substituted optionally with from 1-3 substituents selected independently from:
`
`(1) phenyl, halogen, nitro, cyano, hydroxy, -NR1R2, -OCQR3, (C1-C4)alkoxy, (C1-C4)perfluoroalkoxy, (C1-
`C4)thioalkoxy or (C1-C4)perfluorothioalkoxy,
`.
`where R1 and R2 in the definition of-NR1R2 are each selected independently from hydrogen, fomiyl,
`phenyl, benzyl, benzoyl, (C3-C8)cycloalkyl, (C3-C8 )cycloalkenyl, (C1-C4)alkyl, (C1-C4)perfluoroalkyl, (C1-
`C10)alkoxycarbonyl, (C1-C6)acyl, (C1-C6)perfluoroacyl, aminocarbonyl, (C1-C10)alkylaminocarbonyl, di
`(C1-C10)alkylaminocarbonyl, aminosulfonyl, (C1-C4)alkylaminosulfonyl, di(CrC4)alkylaminosulfonyl, (C1-
`C4)perfluoroalkylaminosulfonyl, di(C1-C4)perfluoroalkylaminosulfonyl, (C1-C4)alkylsulfonyl, and (C1-C4)
`perfluoroalkylsulfonyl.
`or where R1 and R2, taken together with the nitrogen atom to which they are attached, form a sat(cid:173)
`urated, partially-saturated or aromatic heterocyclic ring, wherein said heterocyclic ring contains a.total of
`from 3 to 14 ring atoms and incorporates optionally an additional 1 to 4 ring heteroatoms selected inde(cid:173)
`pendently from oxygen, nitrogen and sulfur, wherein said heterocyclic ring may have optionally from 1 to
`4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl,
`phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C1-C10)alkyl, (C1-C4)perfluoroalkyl, (C1-C10)
`alkoxy, (C1-C4)perfluoroatkoxy, (C1-C10)alkoxycarbonyl, (C1-C10)alkylthio, (C1-C10)alkylamino, di(C1-C10)
`alkylamino, (C1-C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, (C1-C10)acyl, (C1-p10)Perfluoro(cid:173)
`acyl, (C1-C10)acylamino, and (C1-C10)acyloxy,
`where R3 in the definition of -OCQR3 is selected from -NR1R2, phenyl, (C1-C10)alkyl, (C1-C4)per(cid:173)
`fluoroalkyl, (C1-C6)alkoxy and (C1-C6)perfluoroalkoxy,
`(2) (CrC8)cycloalkyl or (CrC8)cycloalkenyl wherein each of said (C3-C8)cycloalkyl and (C3-C8)cycloalke(cid:173)
`nyl may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy. cyano,
`nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C1-C1.0)alkyl,
`(C1-C4)perfluoroalkyl, (C1-C10)alkoxy, (C1-C4)perfluoroalkoxy, (C1-C10)alkoxycarbonyl, (C1-C10)alkylthio,
`(C1-C10)alkylamino, di(C1-C10)alkylamino, (C1-C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl,
`(C1-C10)acyl, (C1-C10)perfluoroacyl, (C1-C10)acylamino, (C1-C10)perfluoroacylamino, (C1-C10)acyloxy,
`and
`.
`(3) a saturated, partially-saturated or aromatic heterocyclic ring containing a total of from 3 to 14 ring
`atoms, wherein said heterocyclic ring incorporates a total of from 1 to 4 ring heteroatoms selected inde(cid:173)
`pendently from oxygen, nitrogen and sulfur, wherein said heterocyclic ring may have optionally from 1 to
`4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, :aminosulfonyl,
`phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C1-C10)alkyl, (C1-C4)perfluoroalkyl, (C1-C10)
`alkoxy, (C1-C4)perfluoroalkoxy, (C1-C10)alkoxycarbonyl, (C,-C10)alkylthio, (C1-C10)alkylamino; di(C1-C10)
`alkylamino, (C1-C10)alkylaminocarbonyl, di(C,-C 10)alkylaminocarbonyl, (C1-C10)acyl, (C1-C10)perfluoro-
`acyl, (C1-C10)acylamino, (C1-C10)perfluoroacylamino, (C1-C10)acyloxy;
`·
`
`(e) (C3-C8)cycloalkyl or (CrC8)cycloalkenyl wherein each of said (C3-C8)cycloalkyl and (C3-C8)cycloalkenyl
`may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo;
`thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C1-C10)alkyl, (C1-C4)perfluor(cid:173)
`oalkyl, (C1-C10)alkoxy, (C1-C4)perfluoroalkoxy, (C1-C10)alkoxycarbonyl, (C1-C10)alkylthio, (C,-C10)alkylami(cid:173)
`no. di(C1-C 10)alkylamino, (C1-C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, (C1-Cuj)acyl, (C1-C10)
`perfluoroacyl, (C1-C10)acylamino. (C1-C10)perfluoroacylamino, (C1-C10)acyloxy: and
`(f) -(CH2)nCOR4, where R4 in the definition of -(CH2)nCOR4 is selected from hydroxy, phenyl, -NR1R2, (C1-
`C4)alkyl, (C1-C4)perfluoroalkyl, (C1-C4)alkoxy, (C1-C4)perfluoroalkoxy, (CrC8)cycloalkyl, and {C3'-C8)cy-
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`cloalkenyl, where n is an integer from 1 to 4;
`
`(ii) a compound of formula (la)
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`3Q
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`4Q
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`#
`N
`
`(la}
`
`the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoi(cid:173)
`somers, and prodrugs, wherein
`
`each Ra and Rb is independently hydrogen or C1-C8alkyl;
`each n is independently 0, 1, 2 or 3;
`each X is independently aryl, substituted aryl, heteroaryl, substituted heteroaryl,
`cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substitited heterocycloalkyl;
`R1 is hydrogen or C1-C8alkyl; and
`R2 is hydrogen, -(cRaR8 )o-X, C1-C8alkyl, C1-C8 substituted alkyl,
`
`x
`I
`--CH
`\
`x
`
`' or
`
`or R1 and R2 together with the nitrogen atom to which they are bonded form a 3 to 7 membered heterocycloalkyl
`ring comprising from 1 to 3 heteroatoms; and
`
`5Q
`
`(iii) a compound selected from the group consisting of:
`
`55
`
`9-(4-(4-(2,3-dihydro-1-oxo-1 H-isoindol-2-yl)-1-piperidinyl)butyl]-N-propyl-9H-fluorene-9-carboxamide;
`2-(1-(3,3-diphenylpropyl)-4-piperidinyl]-2,3-dihydro-1 H-isoindol-1-one;
`9-[4-(4-[2-(4-trifluoromethylphenyl)benzoylamino]piperidin-1-yl)butyl]-N-2,2,2-trifluoroethyl)-9H-fluorene-
`9-carboxamide;
`9-{4-[4-(2-benzothiazol-2-yl-benzoylamino )-piperidin-1-yl]-butyl}-9H-fluorene-9-carboxylic acid-(2,2,2-trifluor(cid:173)
`oethyl)-amide;
`(11a-RJ-8-((4--cyanophenyl)methoxy]-2-cyclopentyl-7-(prop-2-enyl)-2,3,11, 11 a-tetrahydro-6H-pyrazino[1,2b]
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`isoquinoline-1,4-dione;
`[11a-R]-<:ydopentyl-7-(prop-2-enyl)-8-((pyridin-2-yl)methoxyJ-2,3, 11, 11 atetrahydro-6H-pyrazino[1,2b)-isoqui(cid:173)
`noline-1,4-dione;
`2-cyclopentyl-2-[4-(2,4-dimethyl-pyrido(2,3b]indol-9-ylmethyl)-phenyl]-N-(2-hydroxy-1-phenyl-ethyl}-aceta-
`mide; and
`.
`2-cyclopentyl-N-(2-hydroxy-1-phenyl-ethyl)-2-[4-(quinolin-2-ylmethoxy)-phenyl)-acetamide; and the pharnia-
`ceutically acceptable salts thereof.
`·
`
`(0015] A preferred subgroup of formula (I) compounds are those compounds selected from the group c0nsisiing of:
`
`4'-trifluoromethyl-biphenyl-2-Carboxylic acid-(2-(1 H-( 1,2,4-triazol-3-ylmethyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)~
`~-
`.
`.
`.
`4'-trifluoromethyl-biphenyl-2-carboxylic acid-[2-(2-acetylaminoethyl)-1,2,3,4-tetrahydroisoquinolin.:S-yl amide; ·
`4' -trifluoromethyl-biphenyl-2-carboxylic acidi2-(2-methoxyethyl)-1,2 ,3, 4-tetrahydroisoquinolin-6-ylJ-amide;
`4'-trifluoromethyl-biphenyl-2-carboxylic acid-[2-(2,2-diphenylethyl}-1,2,3,4-tetrahydroisoquinolin-6~yl)-amide;
`2-{6-(4'-trifluoromethyl-biphenyl-2-carbonyl}-amino]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl}-carbamic acid.methyl
`ester;
`4'-trifluoromethyl-biphenyl-2-carboxylic acid-[2-(thiophen-2-yl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6~yl)-amide;
`4'-trifluoromethyl-biphenyl-2-carboxylic acid-(2-pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide; and
`6-[(4'-trifluoromethyl-biphenyl-2-carbonyl}-amino]-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid
`[(R)-1-phenyl(cid:173)
`ethyl]-amide; the stereoisomers and hydrates thereof, and the pharmaceutically acceptable salts of the com(cid:173)
`pounds, stereoisomers, and hydrates.
`
`(0016) Unless noted otherwise, the definitions and illustrative values set forth hereinbelow for certain substituents
`and functional groups pertain both to compounds of formula (I) and (la).
`(0017] The term "heterocyclyl" as employed within the definition of Z in the compounds of formula (I) is meant to
`embrace any single ring or fused ring system containing at least one ring heteroatom independently selected from:o,
`N. and S. Thus, a polycyclic fused ring system containing one or more carbocyclic fused saturated, partially unsaturated
`or aromatic rings (usually benz rings) is within the definition of heterocyclyl so long as the system also contains at least
`one fused ring which contains at least one of the aforementioned heteroatoms. As a substituent, such heterocyclyls
`may be attached to the remainder of the molecule from either a carbocyclic (e.g. benz) ring or from a heterocyclic ring.
`(0018] The phrase "one or more rings• when employed in the definition of Z is intended to mean any (single or fused)
`cyclic moiety or moieties contained in Z. The rings may be carbocyclic or heterocyclic, saturated or partially unsaturated
`and aromatic or non-aromatic.
`(0019) Reference to a fused polycyclic ring system or radical means that all rings in the system are fused.
`(0020] The term "acyl" when employed in the description of a substituent refers to an aliphatic or hydrocarbon moiety
`attached to a carbonyl group through which the substituent bonds. Representative of such acyl moieties are acetyl,
`·
`propionyl, butyryl, isobutyryl, and the like.
`(0021) The term "alkoxy" means an alkyl group bonded to an oxygen atom. Representative examples of.. alkoxy
`groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy. Preferred alkoxy groups in formula (la) compounds
`are C1-C8alkoxy.
`·
`[0022) The term "alkyl" means a straight or branched chain hydrocarbon. Representative examples of alkyl groups
`include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl. sec-butyl, pentyl, and hexyl. Preferred alkyl·groups
`in formula (la) compounds are C 1-C8alkyl. It is to be understood that references to individual radicals, for example
`"propyl" or "propoxy", embrace only the straight chain radical, branched chain isomers such as "isopropyl" or "isopro(cid:173)
`poxy" being referred to specifically.
`[0023] The term "aliphatic hydrocarbylene radical" in reference to formula (I) compounds means a divalent, open(cid:173)
`chain organic radical containing carbon and hydrogen only. The radical serves as a linking group, denoted hereinabove
`as Y. The radical may be straight chain or branched and/or saturated or unsaturated, containing up to three unsaturated
`bonds, either double, triple or a mixture of double and triple. The two valences may be on different carbon atoms or
`on the same carbon atom, and thus the term "alkylidene" is subsumed under this definition. The radical will typically
`be classified as a (C1-C20)alkylene radical, a (C2-C20)alkenylene radical or a (C2-C20)alkynylene radical. Typically, the
`radical will contain 1-1 O carbon atoms, although longer chains are certainly feasible and within the scope of this inven(cid:173)
`tion.
`[0024) The term "aryl", e.g. (C6-C10)aryl, when employed in the description of a substituent means the ring or sub(cid:173)
`stituent is carbocyclic. Aromatic moieties which contain one or more heteroatoms are included as a subset of of the
`term "heterocyclyl" as discussed hereinabove.
`[0025] The term "cycloalkyl" means a cyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cy-
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`clobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred cycloalkyl groups are Ca-C8cyloalkyl. It is aiso possible for
`the cycloalkyl group to incorporate one or more double bonds or triple bonds, or a combination of double bonds and
`triple bonds, but not be aromatic. Examples of cycloalkyl groups having a double or triple bond include: cyclopentenyl,
`cyclohexenyl, cyclohexadienyl, cyclobutadienyl, and the like.
`·
`(0026] The term "halogen" as employed throughout the description and appendant claims is inclusive offluoro;chloro,
`·
`.
`bromo and iodo, unless noted otherwise.
`[0027] The term "heteroaryl" as employed in formula (la) compounds means a cyclic, aromatic hydrocarbon in which
`one or more carbon atoms have been replaced with a heteroatom. If the heteroaryl group contains .more than qne
`heteroatom, the heteroatoms may be the same or. different. Examples of heteroaryl groups include pyridyl; pyrimidinyl,
`imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, indolyl, isoindolyl, indoliz(cid:173)
`inyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxaliriyl,
`isothiazolyl, and benzo[b)thienyl. Preferred heteroaryl groups are five- and six-membered rings and c0ntain from c)ne
`to three heteroatoms. Further exemplary heteroaryl groups are illustrated in greater detail hereinbelow.
`·
`(0028] The term "heterocycloalkyl" In formula (la) compounds denotes a cycloalkyl group in which one. or more of
`the carbon atoms has been replaced with a heteroatom. If the heterocycloalkyl group contains more t.han one heter(cid:173)
`oatom, the heteroatoms may be the same, or different. Examples of heterocycloalkyl groups include tetrahydrofuryl,
`morpholinyl, piperazinyl, piperadyl, and pyrrolidinyl. Preferred heterocycloalkyl groups are five- and six-membered
`rings and contain from one to three heteroatoms. It is also possible for the heterocycloalkyl group to have one or more
`double bonds or triple bonds or a combination of double bonds and triple bonds, but is not aromatic. Examples of
`heterocycloalkyl groups containing double or triple bonds include dihydrofuran, and the like.
`(0029] The term "perfluoro", when employed in conjunction with a specified hydrocarbon radical, is meant to include
`a substituent wherein the individual hydrogen atoms thereof may be substituted therefor with one or more, and pref(cid:173)
`erably, from 1 to 9 fluorine atoms. Exemplary of such radicals are trifluoromethyl, pentafluoroethyl, heptafluoropropyl,
`·
`·
`and the like.
`[0030] The central benz-heterocyclic ring system of formula (1), i.e. the fused bicyclic ring system attached through
`its single ring nitrogen to L, is referred to herein as a "1,2,3,4-tetrahydroisoquinoline" for convenience in nomenclatu.re,
`and this is the convention most commonly employed when naming compounds according to the invention as 2-sub(cid:173)
`stituted-1,2,3,4-tetrahydroisoquinolin-6-yl amides. It is noted that, less frequently, when named as a substituent in a
`compound, this central ring system is also denoted as a 6-substituted "3,4-dihydro-1 H-isoquinolin-2-yl" moiety.
`(0031]
`It will be appreciated by one of ordinary skill in the art that certain formula (I) and (la) compounds may contain
`an asymmetrically substituted carbon atom and accordingly may exist in, and be isolated in, both optically-active and
`racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the instant invention encom(cid:173)
`passes any racemic, optically-active, polymorphic, stereoisomeric, or mixture thereof, forms of formula (I) and (la)
`compounds which forms possess properties useful in the methods of this invention. It is well known, or will be apparent
`in light of the instant disclosure, to one of ordinary skill in the art how to prepare such optically-active forms (for example,
`by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials,
`by chiral synthesis or by chromatographic techniques) and how to determine the efficacy of such.forms in carrying out
`the objectives of the present invention by the standard protocols described in detail hereinbelow.
`[0032) Furthermore, one of ordinary skill in the art will recognize that certain combinations of substituents or moieties
`listed in this invention define compounds that may be less stable under physiological conditions (e.g., those compounds
`containing aminal or acetal linkages). Accordingly, such compounds are less preferred.
`[0033] Alkylene radicals include those saturated hydrocarbon groups having 1-20, preferably 1-10 carbon atoms,
`derived by removing two hydrogen atoms from a corresponding saturated acyclic hydrocarbon. Illustrative values hav(cid:173)
`ing 1-10 carbon atoms include straight chain radicals having the formula (C~}n wherein n is 1 to 10, such as methylene,
`dimethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene nonam(cid:173)
`ethylene and so forth. Also included are alkylidene radicals such as ethylidene, propylidene, butylidene•and sec-butyli(cid:173)
`dene. Also included are branched isomers such as 1,1-dimethyldimethylene, 1, 1-dimethyltetramethylene, 2,2-dimeth(cid:173)
`yltrimethylene and 3,3-dimethylpentamethylene.
`(0034] Alkenylene radicals include those straight or branched chain radicals having 2-20 carbon atoms, preferably
`2-10 carbon atoms, derived by removal of two hydrogen atoms from a corresponding acyclic hydrocarbon group con(cid:173)
`taining at least one double bond. Illustrative values for alkenylene radicals having one double bond include ethenylene
`(vinylene}, propenylene, 1-butenylene, 2-butenylene and isobutenylene. Alkenylene radicals containing two double
`bonds (sometimes referred to in the art as alkadienylene radicals) include 3-methyl-2,6-heptadienylene, 2-methyl-
`2,4-heptadienylene, 2,8-nonadienylene, 3-methyl-2,6-octadienylene and 2,6-decadienylene. An illustrative value for
`an alkylene radical containing three double bonds (an alkatrienylene radical) is 9, 11, 13-heptadecatrienylene. ·
`[0035] Alkynylene radicals include those straight or branched chain radicals having 2-20 carbon atoms, preferably
`2-10 carbon atoms, derived by removal of two hydrogen atoms from a corresponding acylic hydrocarbon,group con(cid:173)
`taining at least one triple bond. Illustrative values include ethynylene, propynylene, 1-butynylene, 1-pentynylene; 1-hex- .
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`ynylene, 2-butynylene, 2-pentynylene, 3,3-dimethyl-1-butynylene and so forth.
`[0036) The following are exemplary values for certain moieties and substituents named hereinabove for compounds
`of formula (I) and (la), which are not to be construed as limiting in any respect. It is noted that throughout the instant
`description and appendant claims, if a cyclic or polycyclic radical which can be bonded through differing ring atoms is
`referred to without noting a specific point of attachment, all possible points are intended, whether through a carbon
`atom, or a trivalent nitrogen atom. For example. reference to (unsubstituted) •naphthyl" means n