(19)
`
`(12)
`
`Europäisches Patentamt
`
`European Patent Office
`
`Office européen des brevets
`
`*EP001371646A1*
`EP 1 371 646 A1
`
`(11)
`
`EUROPEAN PATENT APPLICATION
`published in accordance with Art. 158(3) EPC
`
`(43) Date of publication:
`17.12.2003 Bulletin 2003/51
`
`(21) Application number: 02705159.8
`
`(22) Date of filing: 14.03.2002
`
`(84) Designated Contracting States:
`AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU
`MC NL PT SE TR
`Designated Extension States:
`AL LT LV MK RO SI
`
`(30) Priority: 19.03.2001 JP 2001079029
`
`(71) Applicant: Dainippon Pharmaceutical Co., Ltd.
`Osaka-shi, Osaka 541-8524 (JP)
`
`(72) Inventors:
`• MORIE, Toshiya
`Matsubara-shi, Osaka 580-0024 (JP)
`
`(51) Int Cl.7: C07D 211/62, C07D 401/12,
`C07D 413/14, C07D 239/14,
`C07D 233/50, C07D 243/04,
`C07D 401/14, A61K 31/506,
`A61K 31/551, A61K 31/445,
`A61K 31/497, A61K 31/4545,
`A61P 43/00, A61P 9/00,
`A61P 19/00, A61P 9/10,
`A61P 29/00, A61P 19/02,
`A61P 35/00, A61P 27/02,
`A61P 17/06
`
`(86) International application number:
`PCT/JP02/02391
`
`(87) International publication number:
`WO 02/074743 (26.09.2002 Gazette 2002/39)
`
`• IWAMA, Seiji
`Kishiwada-shi, Osaka 596-0078 (JP)
`• NOTAKE, Mitsue
`Suita-shi, Osaka 565-0825 (JP)
`• KITANO, Tomoko
`Tondabayashi-shi, Osaka 584-0031 (JP)
`
`(74) Representative: Coleiro, Raymond et al
`MEWBURN ELLIS
`York House
`23 Kingsway
`London WC2B 6HP (GB)
`
`(54)
`
`ARYL-SUBSTITUTED ALICYCLIC COMPOUND AND MEDICAL COMPOSITION COMPRISING
`THE SAME
`
`(57)
`An aryl-substituted alicyclic compound of the
`formula (I):
`
`wherein U is 1,4,5,6-tetrahydropyrimidin-2-yl, etc., A is
`phenylene, etc., B is piperidine-1,4-diyl, etc., Z is
`
`-CONH-, etc., R3 is hydrogen, etc., R5 is hydrogen, aryl,
`etc., R6 is a mono-substituted amino (e,g., benzyloxy-
`carbonylamino), R7 is hydrogen, etc., and a process for
`preparation thereof, and a pharmaceutical composition
`containing the same. The compound of the present in-
`vention has a high selectivity for a vb 3 integrin, and ex-
`hibits a potent inhibitory activity thereto, and hence, it is
`useful as a preventive or/and a therapeutic agent for a
`disease in which a vb 3 integrin is involved.
`
`EP1 371 646A1
`
`Printed by Jouve, 75001 PARIS (FR)
`
`Par Pharm., Inc.
`Exhibit 1024
`Page 001
`
`

`

`EP 1 371 646 A1
`
`Description
`
`TECHNICAL FIELD
`
`[0001] The present invention relates to a novel aryl-substituted alicyclic compound having a vb 3 integrin inhibitory
`activity, etc., and a pharmaceutical composition containing the same.
`
`BACKGROUND ART
`
`[0002]
`Integrin is a family of receptors that have cell adhesion molecules as ligands, and mediate cell-to-cell and
`cell-to-extracellular matrix adhesions. Integrins directly participate in preservation of cell shape, anchorage for cell
`migration, and intra- and extracellular signal transduction. Therefore, integrins play important roles in a range of bio-
`logical events including cell survival, movement, proliferation, development and differentiation.
`Integrin is a heterodimeric transmembrane glycoprotein consisting of a and b chains. To date, various kinds
`[0003]
`of a and b chains have been known, and thus more than 20 integrins have been identified based on combination of
`the a and b chains (Trends Pharmacol., Sci., 21, 29 (2000)). In addition to the integrins, a number of cell adhesion
`molecules including, proteins that constitute extracellular matrix such as, collagen and vitronectin, proteins involved
`in immune and/or inflammatory cells adhesion such as, VCAM- 1 and ICAM-1, and proteins involved in blood coagu-
`lation such as, fibrinogen and von Willebrand factor have been identified as integrin ligands (Cell, 69, 11 (1992)).
`[0004] The a vb 3 integrin comprising a v- and b 3-chains is also known as vitronectin receptor. Although vitronectin is
`the main ligand for av b 3 integrin, some other proteins with RGD sequence such as fibronectin, fibrinogen and oste-
`opontin are also known as a vb 3 integrin ligands.
`It is known that a vb 3 integrin is expressed on a wide variety of adhesive cells. Among them, much attention
`[0005]
`has been given to the pathophysiological role of a vb 3 integrin expressed on cells where cell adhesion, migration, or
`proliferation is activated with the development of disease state. For example, after angioplasty, abnormal migration
`and proliferation of vascular smooth muscle cells often causes neointimal hyperplasia resulting in restenosis. Similarly,
`in cancer tissues, abnormal migration and proliferation of vascular endothelial cells accelerates angiogenesis. More-
`over, it has been shown in animal models of progressive diseases that the expression of a vb 3 integrin is increased in
`defective cells, and that disease symptoms can be prevented by administration of antibodies or synthetic peptides
`which inhibit a vb 3 integrin (Curr. Pharm. Des., 3, 545 (1997)). Therefore, it is suggested that a vb 3 integrin may play
`an important role in the initiation and progression of restenosis and angiogenesis. Besides these two conditions, a vb 3
`integrin has also been shown to be involved in other diseases including osteoporosis, rheumatoid arthritis, cancer
`metastasis, diabetic retinopathy, inflammatory diseases and viral infections (Curr. Biol., 3, 596 (1993); Cell. Mol. Life
`Sci., 56, 427 (1999); Drug Discovery Today, 5, 397 (2000)).
`[0006] From the information above, it is assumed that inhibition of a vb 3 integrin might cure diseases that are ac-
`companied with cells adhesion, migration or proliferation. Therefore, it is expected that av b 3 integrin inhibitors may be
`useful as a novel type of antirestenotic agents, antiarteriosclerotic agents, anticancer agents, antiosteoporosis agents,
`antiinflammatory agents, antiimmune agents, and agents for eye diseases.
`[0007] Beside av b 3 integrin, a
`IIbb 3 integrin or GPIIb/IIIa, another integrin closely related to a vb 3 integrin, has been
`shown to be highly involved in platelet aggregation. As inhibitors of anb
`3 integrin that also suppress aIIb b 3 integrin
`may cause breeding adverse effects, and may be inappropriate for repeated administration, a vb 3 integrin inhibitors
`with high selectivity for av b 3 integrin as opposed to a
`IIbb 3 integrin have long been desired.
`[0008] As far as the present inventors know, no therapeutic agent with highly selective av b 3 integrin inhibitory activity
`has, so far, been developed. Therefore, under the present situation where diseases that involve a vb 3 integrin have
`been increasing with the aging population, it is necessary to develop inhibitors with high selectivity for a vb 3 integrin
`as opposed to aIIb b 3 integrin.
`[0009] To date, quite a lot of compounds having av b 3 integrin inhibitory activity have been reported (cf. USP 5990145,
`WO 98/18461, WO 99/38849, WO99/52872, etc.)
`[0010] For example, WO 99/38849 discloses (2S)-2-benzenesulfonylamino-3-[3-chloro-4-[4-(1,4,5,6-tetrahydropyri-
`midin-2-yl)piperazin-I-yl]benzoylamino]propanoic acid represented by the following formula (A-1, Example 59), and it
`reports that this compound has a potent a vb 3 integrin inhibitory activity (IC50 value: 3.5 nM) and GPIIb/IIIa inhibitory
`activity (IC50 value: 0.2 nM or less).
`
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`Par Pharm., Inc.
`Exhibit 1024
`Page 002
`
`

`

`EP 1 371 646 A1
`
`[0011]
`In addition, WO 99/52872 discloses (2S)-2-benzenesulfonylamino-3-[3-fluoro-4-[[4-(1,4,5,6-tetrahydropyrimi-
`din-2-yl)amino]-piperidin-1-yl]benzoylamino]propanoic acid represented by the following formula (A-2, Example 52),
`and it reports that this compound has a potent a vb 3 integrin inhibitory activity (IC50 value: 1.0 nM or less) and GPIIb/
`IIIa inhibitory activity (IC50 value: 1.0 nM or less).
`
`[0012] However, the chemical structures of these compounds are completely different from those of the compounds
`of the present invention as described below, and these compounds have a potent GPIIb/IIIa inhibitory activity, which
`is also different from the compounds of the present invention.
`[0013] The present inventors have intensively studied, and have found that a novel aryl-substituted alicyclic com-
`pound of the formula (I) has a potent av b 3 integrin inhibitory activity, and that it is useful as a preventive or therapeutic
`agent for diseases with which av b 3 integrin is involved, and have accomplished the present invention.
`
`DISCLOSURE OF INVENTION
`
`[0014] The present invention provides an aryl-substituted alicyclic compound of the following formula (I), a prodrug
`thereof, a pharmaceutically acceptable salt thereof or an N-oxide derivative thereof, or a hydrate or a solvate thereof,
`a process for preparing these compounds, and a pharmaceutical composition containing the same.
`
`wherein U is a group of the following formula:
`
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`Par Pharm., Inc.
`Exhibit 1024
`Page 003
`
`

`

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`A is a group of the following formula:
`
`EP 1 371 646 A1
`
`B is a group of the following formula:
`
`Z is -CONR4(CH2)q-, -NR4CO(CH2)q- or -COCH2(CH2)q-,
`T is -CH2-, an oxygen atom, a sulfur atom or -NRd-,
`X is an oxygen atom or a sulfur atom,
`W1, W2, W3 and W4 are the same or different, and each is -CH- or a nitrogen atom,
`D and E are the same or different, and each is -CH- or a nitrogen atom, Ra is the same or different, and each is a
`hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkyl group, a C3-7 cycloalkyl group, a C2-6 alkenyl group, a
`C2-6 alkynyl group, an aryl group, an aralkyl group, a
`C1-6 alkyloxy group, a C1-6 alkyloxycarbonyl group, a formyl group, a C1-6 alkylcarbonyl group, a carboxyl group, a
`C1-6 alkylcarbonyloxy group, an amino group, a C1-3 alkylamino group, a di(C1-3 alkyl)amino group, a formylamino
`group, a C1-3 alkylcarbonylamino group, an arylcarbonylamino group, a nitro group, a cyano group, a trifluoromethyl
`group, a trifluoromethoxy group or a trifluoroethoxy group, or
`when two Ra groups attach to the same carbon atom, then they combine to form an oxo group or a thioxo group, or
`together with said carbon atom to form a spiro ring,
`Rb is the same or different, and each is a hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkyl group, a C3-7
`cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, an aryl group, an aralkyl group, a
`C1-6 alkyloxy group, a C1-6 alkyloxycarbonyl group, a formyl group, a C1-6 alkylcarbonyl group, a carboxyl group, a
`C1-6 alkylcarbonyloxy group, an amino group, a C1-3 alkylamino group, a di(C1-3 alkyl)amino group, a formylamino
`group, a C1-3 alkylcarbonylamino group, an arylcarbonylamino group, a nitro group, a cyano group, a trifluoromethyl
`group, a trifluoromethoxy group or a trifluoroethoxy group,
`Rc is the same or different, and each is a hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkyl group, a C3-7
`cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, an aryl group, an aralkyl group, a
`C1-6 alkyloxy group, a C1-6 alkyloxycarbonyl group, a formyl group, a C1-6 alkylcarbonyl group, a carboxyl group, a
`C1-6 alkylcarbonyloxy group, an amino group, a C1-3 alkylamino group, a di(C1-3 alkyl)amino group, a formylamino
`group, a C1-3 alkylcarbonylamino group, an arylcarbonylamino group, a nitro group, a cyano group, a trifluoromethyl
`group, a trifluoromethoxy group or a trifluoroethoxy group,
`or two Rc groups may combine to form -(CR8R9)t-,
`Rd is a hydrogen atom, a C1-6 alkyl group, a C3-7 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, an aryl
`group, an aralkyl group, a formyl group, a C1-6 alkylcarbonyl group or a C1-6 alkyloxycarbonyl group,
`R1 and R2 are the same or different, and each is a hydrogen atom, a C1-10 alkyl group, a C3-7 cycloalkyl group, a C2-6
`alkenyl group, a C2-6 alkynyl group, an aryl group, an aralkyl group, a C1-6 alkylcarbonyl group, a C1-6 alkyloxycarbonyl
`group, a C1-6 alkylsulfonyl group or an arylsulfonyl group,
`or R1 and R2 may combine to form -(CR10R11)u- or -(CH2)vY(CH2)w-,
`R3 and R4 are the same or different, and each is a hydrogen atom, a C1-6 alkyl group, a C3-7 cycloalkyl group, a C2-6
`alkenyl group, a C2-6 alkynyl group, an aryl group or an aralkyl group,
`R5 is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C3-7 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl
`
`4
`
`Par Pharm., Inc.
`Exhibit 1024
`Page 004
`
`

`

`EP 1 371 646 A1
`
`group, an aryl group or an aralkyl group,
`R6 is a hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkyl group, a C3-7 cycloalkyl group, a C2-6 alkenyl
`group, a C2-6 alkynyl group, an aryl group, an aralkyl group, a C1-6 alkyloxy group, a C3-7 cycloalkyloxy group, a C2-6
`alkenyloxy group, a C2-6 alkynyloxy group, an aryloxy group, an aralkyloxy group, a C1-6 alkylcarbonyloxy group, a
`C3-7 cycloalkylcarbonyloxy group, a C2-6 alkenylcarbonyloxy group, a C2-6 alkynylcarbonyloxy group, an arylcarbony-
`loxy group, an aralkylcarbonyloxy group, an amino group or a monosubstituted amino group (in which the substituent
`is a formyl, a C1-10 alkylcarbonyl, a C3-7 cycloalkylcarbonyl, a C2-10 alkenylcarbonyl, a C2-10 alkynylcarbonyl, an aryl-
`carbonyl, an aralkylcarbonyl, a C7-15 polycyclo-C0-3 alkylcarbonyl, a C1-16 alkyloxycarbonyl, a polyfluoro-C1-16 alky-
`loxycarbonyl, a C3-7 cycloalkyloxycarbonyl, a C2-16 alkenyloxycarbonyl, a C2-16 alkynyloxycarbonyl, an aryloxycarbonyl,
`a C3-7 cycloalkyl-C1-6 alkyloxycarbonyl, an aralkyloxycarbonyl, a C1-10 alkylaminocarbonyl, a C3-7 cycloalkylaminoc-
`arbonyl, a C2-10 alkenylaminocarbonyl, a C2-10 alkynylaminocarbonyl, an arylaminocarbonyl, an aralkylaminocarbonyl,
`a C1-10 alkylsulfonyl, a C3-7 cycloalkylsulfonyl, a C2-10 alkenylsulfonyl, a C2-10 alkynylsulfonyl, an arylsulfonyl, an ar-
`alkylsulfonyl, a C7-15 polycyclo-C0-3 alkylsulfonyl, a
`C1-10 alkylaminosulfonyl, a C3-7 cycloalkylaminosulfonyl, a C2-10 alkenylaminosulfonyl, a C2-10 alkynylaminosulfonyl,
`an arylaminosulfonyl or an aralkylaminosulfonyl),
`R7 is a hydrogen atom, a C1-6 alkyl group, a C3-7 cycloalkyl group, an aryl group or an aralkyl group,
`R8, R9, R10 and R11 are the same or different, and each is a hydrogen atom, a C1-3 alkyl group or an aryl group,
`Y is an oxygen atom, a sulfur atom or -NR12-,
`R12 is a hydrogen atom, a C1-6 alkyl group, a C3-7 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, an aryl
`group, an aralkyl group, a
`C1-6 alkylcarbonyl group or a C1-6 alkyloxycarbonyl group,
`g is an integer of 1 to 4,
`h is an integer of 0 to 3,
`k is an integer of 1 to 3,
`m and n are the same or different, and each is an integer of 0 to 3, but the sum of m and n should be an integer of 1 to 3,
`p is an integer of 1 to 4,
`q is 0 or 1,
`t is an integer of 1 to 3,
`u is an integer of 3 to 7,
`v and w are the same or different, and each is an integer of 1 to 4, but the sum of v and w should be an integer of 2 to 6,
`provided that (i) when E is a nitrogen atom, then Z is -CONR4(CH2)q- or -COCH2(CH2)q-, (ii) in the above definition,
`the alkyl group, the cycloalkyl group, the alkenyl group, the alkynyl group, and the alkyl moiety of the aralkyl group
`may optionally be substituted by 1 to 3 atoms or groups selected from a halogen, a C1-6 alkyloxy, an amino and a
`hydroxy, and the aryl group and the aryl moiety may optionally be substituted by 1 to 5 atoms or groups selected from
`a halogen, a C1-6 alkyl, a C3-7 cycloalkyl, an aryl, an aralkyl, an amino, an amino-C1-6 alkyl, a formylamino, a C1-3
`alkylcarbonylamino, a C1-6 alkylamino, a C1-6 alkylamino-C1-6 alkyl, a di(C1-6 alkyl)amino, a di(C1-6 alkyl)amino-C1-6
`alkyl, an arylcarbonylamino, a C1-6 alkylaminocarbonylamino, an arylaminocarbonylamino, a C1-4 alkyloxy, a C1-4
`alkylthio, a C1-4 alkylsulfonyl, a
`C1-4 alkyloxy-C1-6 alkyl, a carboxyl, a carboxyl-C1-6 alkyl, a C1-4 alkyloxycarbonyl, a hydroxy, a hydroxy-C1-6 alkyl, a
`cyano, a trifluoromethyl, a trifluoromethoxy, a C1-4 alkylcarbonyloxy and a nitro.
`[0015] The prodrug of the compound of the formula (I) means a compound of the formula (I) wherein R7 is a hydrogen
`atom, and the carboxyl group is modified, said modified carboxyl group being converted into a carboxyl group by
`enzymatically or chemical cleavage in a living body, for example, such as compounds having an esterified carboxyl
`group. The esterified carboxyl group is preferably ones being used in the preparation of prodrugs in the pharmaceutical
`field, for example, a C1-6 alkyloxycarbonyl group, a C3-7 cycloalkyloxycarbonyl group, an aryloxycarbonyl group, an
`aralkyloxycarbonyl group, an optionally substituted C1-3 alkyloxycarbonyl group (the substituent is selected from a
`carboxyl, a C1-3 alkyloxycarbonyl, a C1-3 alkylaminocarbonyl, a di(C1-3 alkyl)aminocarbonyl, a C1-3 alkylamino, a di
`(C1-3 alkyl)amino, a C1-3 alkyloxy or a dioxolenyl), or a group: -COOCHReOCORf (Re is a C1-3 alkyl group, and Rf is
`a C1-6 alkyl group, a C3-7 cycloalkyl group, an aryl group, an aralkyl group, a C1-6 alkyloxy group, a C3-7 cycloalkyloxy
`group, an aryloxy group or an aralkyloxy group). Besides, it is apparent that the compound of the formula (I) wherein
`R7 is other than a hydrogen atom may fall under the category of prodrug. Suitable examples of prodrug are hereinafter
`disclosed.
`[0016] The pharmaceutically acceptable salt of the compound of the formula (I) includes a pharmaceutically accept-
`able acid addition salt of the compound of the formula (I) having a group being capable of producing an acid addition
`salt within the structure thereof or a prodrug thereof, or a pharmaceutically acceptable salt with a base of the compound
`of the formula (I) having a group being capable of producing a salt with a base within the structure thereof or a prodrug
`thereof. Suitable acid addition salts are, for example, a salt with an inorganic acid such as hydrochloride, hydrobromide,
`hydroiodide, sulfate, perchlorate, phosphate, etc., and a salt with an organic acid such as oxalate, malonate, maleate,
`
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`Par Pharm., Inc.
`Exhibit 1024
`Page 005
`
`

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`EP 1 371 646 A1
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`fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate,
`trifluoromethanesulfonate, etc., an amino acid salt such as glutamate, aspartate, etc. Suitable example of a salt with
`a base are such as an alkali metal salt or an alkaline earth metal salt (e.g., sodium salt, potassium salt, calcium salt,
`etc.), a salt with an organic base (e.g., pyridine salt, triethylamine salt, etc.), a salt with an amino acid (e.g., a salt with
`lysine, arginine, etc.). The N-oxide derivative of the compound of the formula (I) means an N-oxide derivative of the
`compound of the formula (I) having a pyridine nucleus.
`[0017] The compound of the formula (I), or a prodrug thereof, or a salt thereof, and an N-oxide derivative thereof
`(hereinafter, occasionally referred to as the compound of the formula (1)) may exist in the form of a hydrate or a solvate,
`and these hydrates and solvates are also included in the compounds of the present invention. Further, the compound
`of the formula (I) may optionally have one or more asymmetric carbon atoms, and may have isomerism. Therefore,
`the compound of the formula (I) may exist in the form of several stereoisomers, and these stereoisomers, a mixture
`thereof and racemic compounds thereof are also included in the compound of the present invention.
`[0018] The compound of the formula (I) wherein U is a group of the following formula:
`
`(wherein T, Ra, g and h are as defined above),
`and R3 is a hydrogen atom may exist in the form of a tautomer of the following formula (It), and the present compound
`also includes the tautomer thereof. In the present specification, the compound of the present invention is expressed
`by the notational system of the formula (Is).
`
`(the group A and the substructure succeeding therefrom of the compounds of the formulae (Is) and (It) are omitted in
`the above formula. T, Ra, g and h are as defined above)
`[0019] The terms in the present specification are explained below.
`[0020]
`In the present specification, the number of the carbon atoms is defined such as "C1-6 alkylcarbonyloxy", and
`the number of the carbon atoms is applied to only the group or moiety immediately following thereto. Therefore, in the
`above case, since C1-6 indicate only the number of carbon atom of the alkyl, and hence, "C1 alkylcarbonyloxy" means
`acetoxy.
`[0021] Further, groups: Ra, Ra1, Ra2, Rc, Rc1, Rc2, Rc3 and Rc4 may attach to any position, for example, when T, T1
`and T2 are -CH2-, then Ra, Ra1 or Ra2 may attach to said carbon atom in place of a hydrogen atom.
`[0022] The alkyl group and the alkyl moiety may be either a straight chain or a branched chain.
`[0023] The "halogen atom" is fluorine, chlorine, bromine, iodine, and preferable one is fluorine or chlorine, and es-
`pecially preferable one is fluorine.
`[0024] The "C1-16 alkyl" is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
`isopentyl, neopentyl, hexyl, octyl, nonyl, 3,7-dimethyloctyl, decyl, hexadecyl, etc.
`[0025] The "C3-7 cycloalkyl" is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. The "C2-16
`alkenyl" includes either straight chain, branched chain or cyclic ones, having at least one double bond, for example,
`vinyl, allyl, 1-propenyl, isopropenyl, 1-, 2- or 3-butenyl, 2-, 3- or 4-pentenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,
`5-hexenyl, 2,6-dimethyl-1,5-heptadienyl, 2-hexadecenyl, 1-cyclopentenyl, 1-cyclohexenyl, and equivalents thereof.
`[0026] The "C2-16 alkynyl" may be either straight chain, branched chain or cyclic ones, having at least one triple
`bond, for example, ethynyl, 1-or 2-propynyl, 1-, 2- or 3-butynyl, 1-methyl-2-propynyl, 2-hexadecynyl, and equivalents
`thereof.
`[0027] The "aryl" includes a monocyclic or polycyclic group consisting of 5- or 6-membered aromatic ring, which
`
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`Exhibit 1024
`Page 006
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`

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`EP 1 371 646 A1
`
`contains 0 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and when it is a polycyclic
`group, then it has at least one aromatic ring. Examples of the aryl group are phenyl, naphthyl, fluorenyl, antholyl,
`biphenylyl, tetrahydronaphthyl, indanyl, phenantholyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl,
`isoxazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, quinolyl, benzo[b]-thienyl, benzimidazolyl,
`1H-imidazo[4,5-b]pyridyl, tetrahydroquinolyl, and equivalents thereof, and these aryl groups may have 1 to 5 substit-
`uents as mentioned above. Examples of the substituted aryl group are 2-, 3- or 4-methylphenyl, 2,4,6-trimethylphenyl,
`pentafluorophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2-bromo-4,6-difluorophenyl, 2,3,4-trifluorophenyl,
`4-bromo-2-fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-4-nitrophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl,
`2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 2-chloro-4-trifluoromethylphenyl, 2-fluoro-5-trifluoromethyl-
`phenyl, 2-fluoro-6-trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-
`5-nitrophenyl, 2-, 3-or 4-trifluoromethylphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-trifluoromethoxyphenyl, 4-cyano-
`phenyl, 2-difluoromethoxyphenyl, 3-fluoro-4-methylphenyl, 5-fluoro-2-methylphenyl and equivalents thereof.
`[0028] The "aralkyl" is ones having an aryl group as defined above at any position of an alkyl group having 1 to 6
`carbon atoms or an alkenyl or alkynyl chain having 2 to 6 carbon atoms, and further the alkyl moiety thereof may
`optionally have 1 to 5 substituents as mentioned above. Examples of the aralkyl group are benzyl, fluorobenzyl, chlo-
`robenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, cinnamyl, fluorocinnamyl, thienylmethyl,
`thienylethyl, thienylpropyl, pyridylmethyl, pyridylethyl, pyridylpropyl and equivalents thereof.
`[0029] Examples of the alkyl, cycloalkyl, alkenyl or alkynyl moiety having the defined number of carbon atoms, or
`the complex group containing an aryl or aralkyl moiety are ones wherein the above examples for each group are applied
`to the corresponding moieties. For example, the C1-6 alkyloxy group is methoxy, ethoxy, propoxy, isopropoxy, butoxy,
`isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy.
`[0030] With respect to the group: U of the formula (I), when two Ra groups attach to the same carbon atom and
`together with said carbon atom to form a spiro ring, said spiro ring is a 3- to 7-membered one having 0 to 2 heteroatoms
`selected from an oxygen atom, a nitrogen atom and a sulfur atom.
`[0031] Examples of the substituent of the mono-substituted amino group for R6 is ethoxycarbonyl, propoxycarbonyl,
`isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,
`neopentyloxycarbonyl, hexyloxycarbonyl, 5-methylhexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl, 3,3-dimeth-
`yloctyloxycarbonyl, (CF3)2CFCF2(CH2)2OCO, CF3(CF2)3CH2CH2OCO, CF3(CF2)2(CH2)3OCO, CF3CF2(CH2)6OCO,
`CF3(CF2)8CH2OCO, cyclopentyloxycarbonyl, 2-cyclopentylethoxycarbonyl, cyclopentylmethoxycarbonyl, 3-cyclohex-
`ylpropoxycarbonyl, 3,7-dimethyl-6-octenyloxycarbonyl, benzyloxycarbonyl, phenethyloxycarbonyl, 3-phenylpropoxy-
`carbonyl, 5-phenylpentyloxycarbonyl, 6-phenylhexyloxycarbonyl, 2-naphthylmethoxycarbonyl, 4-biphenylylmethoxy-
`carbonyl, 4-butylbenzyloxycarbonyl, 4-butoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-methoxybenzyloxycar-
`bonyl, 3,5-difluorobenzyloxycarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butylamino-
`carbonyl,
`tert-butylaminocarbonyl, hexylaminocarbonyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl, al-
`lylaminocarbonyl, phenylaminocarbonyl, 3,5-difluorophenylaminocarbonyl, 4-trifluoromethylphenylaminocarbonyl,
`3-methylphenylaminocarbonyl, 4-methoxyphenylaminocarbonyl, benzylaminocarbonyl, 4-fluorobenzylaminocarbonyl,
`phenethylaminocarbonyl, 4-methoxybenzylaminocarbonyl, 2-pyridylcarbonyl, 3-pyridylcarbonyl, 4-pyridylcarbonyl,
`2-pyridylmethylcarbonyl, 3-pyridylmethylcarbonyl, 4-pyridylmethylcarbonyl, phenylsulfonyl, 3-chlorophenylsulfonyl,
`2,6-dichlorophenylsulfonyl,
`2-chloro-6-methylphenylsulfonyl,
`4-methylphenylsulfonyl,
`2-methylphenylsulfonyl,
`2,4,6-trimethylphenylsulfonyl, 4-tert-butylphenylsulfonyl, 2-methyl-5-nitrophenylsulfonyl, 4-methoxyphenylsulfonyl,
`4-tert-butoxyphenylsulfonyl, 4-acetylaminophenylsulfonyl, 3-trifluoromethylphenylsulfonyl, 2,6-dimethyl-4-biphenylyl-
`sulfonyl, 2-naphthylsulfonyl, 1-naphthylsulfonyl, cinnamylsulfonyl, butylsulfonyl, isobutylsulfonyl, 8-quinolylsulfonyl,
`2-thienylsulfonyl, 3,5-dimethyl-4-isoxazolyl, 5-chloro-3-methyl-4-pyrazolyl, phenylaminosulfonyl, (7,7-dimethyl-2-oxo-
`bicyclo-[2.2.1]heptan-1-yl)methylsulfonyl and equivalents thereof.
`[0032] Suitable examples of U of the formula (I) are groups as described below, and equivalents thereof.
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`Par Pharm., Inc.
`Exhibit 1024
`Page 007
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`

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`EP 1 371 646 A1
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`[0033] With respect to the group B of the formula (I), suitable examples of -(CR8R9)t- formed by combining two Rc
`are shown below together with the carbon atoms to which they bond and a surrounding substructure thereof. Equiva-
`lents of these groups are also preferable.
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`Par Pharm., Inc.
`Exhibit 1024
`Page 008
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`

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`EP 1 371 646 A1
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`In the formula (I), the suitable examples of the substituent of the mono-substituted amino group for R6 are a
`[0034]
`C7-15 polycyclo-C0-3 alkylcarbony group or a C7-15 polycyclo-C0-3 alkylsulfonyl group, such as the formulae as shown
`below. Equivalents thereof are also preferable.
`
`[0035] Preferable examples of the esterified carboxyl group of prodrugs of the compound of the formula (I) are meth-
`yloxycarbonyl group, ethyloxycarbonyl group, propyloxycarbonyl group, isopropyloxycarbonyl group, butyloxycarbonyl
`group, isobutyloxycarbonyl group, tertbutyloxycarbonyl group, cyclopropyloxycarbonyl group, cyclobutyloxycarbonyl
`group, cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group, cycloheptyloxycarbonyl group, benzyloxycarbonyl
`group, pyridyloxycarbonyl group, carboxymethyloxycarbonyl group, methoxycarbonylmethyloxycarbonyl group, meth-
`ylaminocarbonylmethyloxycarbonyl group, dimethylaminocarbonylmethyloxycarbonyl group, 2-methylaminoethyloxy-
`carbonyl group, 2-dimethylaminocarbonylethyloxycarbonyl group, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyloxycarbo-
`nyl group, acetoxymethyloxycarbonyl group, propionyloxymethyloxycarbonyl group, isobutyryloxymethyloxycarbonyl
`group, pivaloyloxymethyloxycarbonyl group, cyclopentylcarbonyloxyrnethyloxycarbonyl group, cyclohexylcarbony-
`loxymethyloxycarbonyl group, benzoyloxymethyloxycarbonyl group, 1-acetoxyethyloxycarbonyl group, 1-ethoxycarb-
`onyloxyethyloxycarbonyl group, 1-tert-butoxycarbonyloxyethyloxycarbonyl group, 1-cyclopentyloxycarbonyloxyethyl-
`oxycarbonyl group and 1-cyclohexyloxycarbonyloxyethyloxycarbonyl group.
`[0036] The preferable compounds of the present invention are the aryl-substituted alicyclic compound of the formula
`(I), a prodrug thereof, a pharmaceutically acceptable salt thereof, or an N-oxide derivative thereof, a hydrate or a solvate
`thereof,
`wherein U is a group selected from the following group:
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`Par Pharm., Inc.
`Exhibit 1024
`Page 009
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`

`

`EP 1 371 646 A1
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`(T1 is -CH2-, an oxygen atom or -NRd1-, Ra1 is the same or different, and each is a hydrogen atom, a halogen atom,
`a hydroxy group, a C1-6 alkyl group, a C3-7 cycloalkyl group, an aryl group, an aralkyl group, a C1-6 alkyloxy group, a
`C1-6 alkyloxycarbonyl group, a carboxyl group, a C1-6 alkylcarbonyloxy group, an amino group, a di(C1-3 alkyl)amino
`group, a C1-3 alkylcarbonylamino group, a nitro group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group
`or a trifluoroethoxy group, or when two Ra1 groups attach to the same carbon atom, then they combine to form an oxo
`group or a thioxo group, or together with said carbon atom to form a spiro ring, Rd1 is a hydrogen atom, a C1-3 alkyl
`group, a C1-3 alkylcarbonyl group or a C1-6 alkyloxycarbonyl group, R1' and R2' are the same or different, and each is
`a hydrogen atom, a C1-5 alkyl group, a C3-7 cycloalkyl group, an aryl group or an aralkyl group, or R1' and R2' may
`combine to form -(CH2)u- or -(CH2)vY1(CH2)w-, and Y1 is an oxygen atom, a sulfur atom or -NR12'-, R12' is a hydrogen
`atom, a methyl group, a C1-4 alkyloxycarbonyl group or an acetyl group, X, g, h, u, v and w are as defined above),
`A is a group selected from the following group:
`
`(Rb1 is the same or different, and each is a hydrogen atom, a halogen atom, a hydroxy group, a C1-3 alkyl group, an
`aryl group, a C1-3 alkyloxy group, a C1-3 alkyloxycarbonyl group, a carboxyl group, a C1-3 alkylcarbonyloxy group, an
`amino group, a di(C1-3 alkyl)amino group, a C1-3 alkylcarbonylamino group, a nitro group, a cyano group, a trifluor-
`omethyl group or a trifluoromethoxy group, k is as defined above),
`B is a group selected from the following group:
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`Par Pharm., Inc.
`Exhibit 1024
`Page 010
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`

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`EP 1 371 646 A1
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`(Rc1 is the same or different, and each is a hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkyl group, a
`C3-7 cycloalkyl group, an aryl group, an aralkyl group, a C1-6 alkyloxy group, a C1-6 alkyloxycarbonyl group, a formyl
`group, a carboxyl group, a C1-6 alkylcarbonyloxy group, an amino group, a di(C1-3 alkyl)amino group, a C1-3 alkylcar-
`bonylamino group, a cyano group or a trifluoromethyl group, or two Rc1 groups may combine to form -(CH2)t-, m, n, p
`and t are as defined above),
`R3 is a hydrogen atom,
`R4 is a hydrogen atom or a C1-3 alkyl group,
`Z, R5, R6 and R7 are as defined above.
`[0037] Among the above-mentioned preferable compounds, a compound wherein R6 is a group other than a hydrogen
`atom is more preferable.
`[0038] More preferable compound is the aryl-substituted alicyclic compound of the formula (I), a prodrug thereof, a
`pharmaceutically acceptable salt thereof, or an N-oxide derivative thereof, or a hydrate or a solvate thereof, wherein
`U is a group selected from the following group:
`
`(T2 is -CH2-, an oxygen atom or -NRd2-, Ra2 is the same or different, and each is a hydrogen atom, a fluorine atom, a
`hydroxy group, a C1-4 alkyl group, an aryl group, a C1-3 alkyloxy group, a C1-3 alkyloxycarbonyl group, a di(C1-3 alkyl)
`amino group, a C1-3 alkylcarbonylamino group, a hydroxy-C1-3 alkyl group, a carboxyl group, a C1-3 alkylcarbonyloxy
`group, a trifluoromethyl group or a trifluoromethoxy group, Rd2 is a hydrogen atom, a methyl group, an acetyl group,
`a propionyl group, a methoxycarbonyl group, an ethoxycarbonyl group or a