United States Patent 15
`5,561,142
`[11]
`Oct. 1, 1996
`Fisheret al.
`[45] Date of Patent:
`3
`
`
`Patent Number:
`
`HACA PACAA
`
`5561142A
`
`[54] SUBSTITUTED SULFONAMIDESAS
`SELECTIVE 8, AGONISTS FOR THE
`TREATMENT OF DIABETES AND OBESITY
`.
`°
`.
`:
`Inventors: Michael H. Fisher, Ringoes; Elizabeth
`M.Naylor, Scotch Plains; Dong Ok,
`Edison; Ann E. Weber, Scotch Plains;
`Thomas Shih; Hyun Ok, both of
`Edison, all of N.J.
`
`[75]
`
`[73] Assignee: Merck & Co., Inc., Rahway, N.J.
`
`{21} Appl. No.: 445,630
`“ads
`[22]
`Filed:
`May 22,1995
`Related U.S. Application Data
`
`FOREIGN PATENT DOCUMENTS
`
`European Pat. Off.
`0091749 10/1983
`European Pat. Off
`0007206
`1/1989
`European Pat. Off.
`0427480
`5/1991
`European Pat. Off.
`0455006
`11/1991
`0516350 12/1992 European Pat. Off.
`0516349 12/1992 European Pat. Off.
`0068669
`1/1993
`European Pat. Off.
`0565317 10/1993
`European Pat. Off.
`0611003
`8/1994 European Pat. Off.
`1108577
`4/1968 United Kingdom .
`1565080
`4/1990 United Kingdom .
`WO093/10074
`5/1993. WIPO.
`W093/22277 11/1993 WIPO.
`WO094/02493
`2/1994. WIPO.
`W094/29290 12/1994 WIPO.
`OTHER PUBLICATIONS
`
`.
`.
`.
`.
`
`[63] Continuation-in-part of Ser. No. 404,565, Mar. 21, 1995,
`abandoned, which is a continuation-in-part of Ser. No.
`233,166, Apr. 26, 1994, abandoned.
`6
`[32] Unt, CIP
`cesessseseennen oeahoeSan
`[52] US. Ch cecccsssssstsneen 514/312; 546/153; 546/194;
`546/269; 546/271; 546/275, 546/276; 546/277;
`546/286; 546/338; 514/318; 514/337; 514/338;
`.
`514/340; 514/342
`[58] Field of Search occ 546/153, 194,
`546/269, 271, 275, 276, 277, 280, 338;
`514/312, 318, 337, 338, 340, 342
`.
`References Cited
`U.S. PATENT DOCUMENTS
`6/1969 Santilli et alo iccceesceeeeeeee 514/365
`3,452,037
`6/1974 Cox et al. woes we 514/653
`3,816,516
`taeGor aions antstahossessererennenscnnennsees ben09
`4478.849
`10/1984 Ainsworth et al.
`ws 424/285
`4.999.377
`3/1991 Ainsworth et al.
`.
`" ADAI2B5
`5,017,619
`5/1991 Alig etal. ........
`.. 514/653
`5,153,210
`10/1992 Ainsworth etal.
`ww 546/344
`5,321,036
`6/1994 Sher w.eesesssccssssscessecessssesseseneseee 514/366
`
`
`
`[56]
`
`A.A.Larsen,et al, Journal of Medicinal Chemistry,vol. 10,
`(3) pp. 462-472, 1967.
`.
`.
`.
`.
`.
`Primary Examiner—Zinna Northington Davis
`Attorney, Agent, or Firm-~Mollie M. Yang; David L. Rose
`57]
`ABSTRACT
`Substituted sulfonamidesare selective 8, adrenergic recep-
`tor agonists with very little B, and B, adrenergic receptor
`activity and as such the compoundsare capable ofincreasing
`lipolysis and energy expenditure in cells. The compounds
`thus have potent activity in the treatment of Type II diabetes
`p
`Pp
`and obesity. The compounds can also be used to lower
`triglyceride levels and cholesterol levels or raise high den-
`sity lipoprotein levels or to decrease gut motility. In addi-
`tion,
`the compounds can be used to reduced neurogenic
`inflammation or as antidepressant agents. The compounds
`are prepared by coupling an aminoalkylphenyl-sulfonamide
`with an appropriately substituted epoxide. Compositions and
`methods for the use of the compoundsin the treatment of
`diabetes and obesity and for loweringtriglyceride levels and
`cholesterol levels or raising high density lipoprotein levels
`OF for increasing gut motility are also disclosed.
`
`18 Claims, No Drawings
`
`SAWAI EX. 1014
`Page 1 of 35
`
`SAWAI EX. 1014
`Page 1 of 35
`
`

`

`5,561,142
`
`1
`SUBSTITUTED SULFONAMIDESAS
`SELECTIVE 8, AGONISTS FOR THE
`TREATMENT OF DIABETES AND OBESITY
`
`CROSS-REFERENCE
`
`This is a continuation-in-part of co-pending application
`U.S. patent application Ser. No. 08/404,565 filed Mar. 21,
`1995, now abandoned, which is a continuation-in-part of
`U.S. patent application Ser. No. 08/233,166 filed Apr. 26,
`1994, now abandoned these applications are hereby incor-
`porated by reference in their entirety.
`
`10
`
`BACKGROUND OF THE INVENTION
`
`B-Adrenoceptors have been subclassified as B, and B,
`since 1967. Increased heart rate is the primary consequence
`of B,-receptor
`stimulation, while bronchodilation and
`smooth muscle relaxation typically result from B, stimula-
`tion. Adipocyte lipolysis wasinitially thought to be solely a
`B,-mediated process. However, more recentresults indicate
`that the receptor-mediating lipolysis is atypical in nature.
`These atypical receptors, later called B,-adrenoceptors, are
`found onthe cell surface of both white and brown adipocytes
`where their stimulation promotes both lipolysis (breakdown
`of fat) and energy expenditure.
`Early developments in this area produced compounds
`with greater agonist activity for the stimulation of lipolysis
`(B; activity) than for stimulation of atrial rate (B,) and
`tracheal relaxation (B,). These early developments disclosed
`in Ainsworth et al., U.S. Pat. Nos. 4,478,849 and 4,396,627,
`were derivatives of phenylethanolamines.
`Such selectivity for B,-adrenoceptors could make com-
`poundsofthis type potentially useful as antiobesity agents.
`In addition, these compounds have been reported to show
`antihyperglycemic effects in animal models of non-insulin-
`dependent diabetes mellitus.
`A major drawback in treatment of chronic diseases with
`B, agonists is the potential for stimulation of other B-recep-
`tors and subsequent side effects. The most likely of these
`include muscle tremor (B,) and increased heart rate (B,).
`Although these phenylethanolamine derivatives do possess
`some f, selectivity, side effects of this type have been
`observed in human volunteers. It is reasonable to expectthat
`these side effects resulted from partial B, and/or B, agonism.
`More recent developments in this area are disclosed in
`Ainsworth et al., U.S. Pat. No. 5,153,210, Caulkett et al.,
`USS. Pat. No. 4,999,377, Alig et al., U.S. Pat. No. 5,017,619,
`Lecountet al., European Patent 427480 and Bloom etal.,
`European Patent 455006.
`Even though these more recent developments purport to
`describe compounds with greater B, selectivity over the B,
`and B, activities,
`this selectivity was determined using
`rodents, in particular, rats as the test animal. Because even
`the most highly selective compounds, as determined by
`these assays,still show signs of side effects due to residual
`B, and B, agonist activity when the compoundsaretested in
`humans, it has become apparentthatthe rodentis not a good
`model for predicting human B, selectivity.
`Recently, assays have been developed which more accu-
`rately predict the effects that can be expected in humans.
`These assays utilize cloned human B, receptors which have
`been expressed in Chinese hamster ovary cells. See Emorine
`et al, Science, 1989, 245:1118-1121; and Liggett, Mol.
`Pharmacol., 1992, 42:634-637. The agonist and antagonist
`effects of the various compounds on the cultivated cells
`
`2
`provide an indication of the antiobesity and antidiabetic
`effects of the compounds in humans.
`
`SUMMARYOF THE INVENTION
`
`The instant invention is concerned with substituted sul-
`fonamides which are useful as antiobesity and antidiabetic
`compounds. Thus, it is an object of this invention to describe
`such compounds. It is a further object to describe the specific
`preferred stereoisomers of the substituted sulfonamides. A
`still further object is to describe processes for the prepara-
`tion of such compounds. Another object
`is to describe
`methods and compositions which use the compoundsasthe
`active ingredient thereof.
`Further objects will become apparent from reading the
`following description.
`
`DESCRIPTION OF THE INVENTION
`
`20
`
`The present invention provides compounds having the
`formulaI:
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`H R
`|
`|
`
`R
`
`RS
`
`I
`
`N—SOx{CHa)—R?
`
`RRS
`
`(ayCHCHAN—C—C0n
`
`OH
`|
`*
`
`Rn
`where
`n is
`
`m is Oto 5;
`Oor 1;
`ris Oto 3;
`Ais (1) a5 or 6-membered heterocyclic ring with from 1
`to 4 heteroatoms selected from oxygen, sulfur and
`nitrogen, 2) a benzene ring fused to a 5 or 6-membered
`heterocyclic ring with from 1 to 4 heteroatomsselected
`from oxygen, sulfur and nitrogen, 3) a 5 or 6-membered
`heterocyclic ring with from 1 to 4 heteroatomsselected
`from oxygen, sulfur and nitrogen fused to a 5 or
`6-membered heterocyclic ring with from 1
`to 4 het-
`eroatomsselected from oxygen, sulfur and nitrogen,(4)
`phenyl, or
`(5) a benzene ring fused to a C,-C,
`cycloalkyl ring;
`R’ is (1) hydroxy, (2) oxo, (3) halogen, (4) cyano, (5)
`NR&R8,(6) SRS,(7) trifluoromethyl, (8) C,-Cy, alkyl,
`(9) ORS, (10) SO,R®, (11) OCOR?®, (12) NR®COR?,
`(13) COR®, (14) NR8SO,R°, (15) NR®CO,R®,or (16)
`C,-C,9 alkyl substituted by hydroxy, halogen, cyano,
`NR&R®, SR®,trifluoromethyl, OR®, C;-C, cycloalkyl,
`phenyl,
`NR®COR®,
`COR®,
`SO,R°,
`OCOR’®,
`NR®SO,R° or NR°CO,R°;
`R? and R? are independently (1) hydrogen, (2) C,-C,5
`alkyl or (3) C,-Cjo alkyl with 1
`to 4 substituents
`selected from hydroxy, C\—C,, alkoxy, and halogen;
`
`X is (1)
`—CH,—,
`(2) —CH,—CH,—, (3) —CH=CH—
`or (4) —CH,O—;
`R* and R® are independently (1)hydrogen, (2) C,;-Cy9
`alkyl, (3) halogen, (4) NHR®, (5) OR®, (6) SOR? or (7)
`NHSO,R?;
`R6 is (1) hydrogen or (2) C,-Cy9 alkyl};
`R’ is Z-(R',;
`R'is (1) R', with the proviso that when A is phenyl, R14
`is not C,-Cy9 alkyl, (2) C.-C, cycloalkyl, 3) phenyl
`optionally substituted with up to 4 groups indepen-
`dently selected from R®, NR®°R®, OR®, SR® and halo-
`gen, or (4) 5 or 6-memberedheterocycle with from 1 to
`
`SAWAI EX. 1014
`Page 2 of 35
`
`SAWAI EX. 1014
`Page 2 of 35
`
`

`

`5,561,142
`
`3
`4 heteroatoms selected from oxygen, sulfur and nitro-
`gen, optionally substituted with up to four groups
`independently selected from oxo, R°, NR®R®, OR,
`SR*, and halogen;
`Z is (1) phenyl, (2) naphthyl, (3) a 5 or 6-membered
`heterocyclic ring with from 1 to 4 heteroatoms selected
`from oxygen, sulfur and nitrogen, (4) a benzene ring
`fused to a C,-C, cycloalkyl ring, (5) a benzene ring
`fused to a 5 or 6-membcred heterocyclic ring with from
`1
`to 4 heteroatoms selected from oxygen, sulfur and
`nitrogen, (6) a 5 or 6-membered heterocyclic ring with
`from 1
`to 4 heteroatomsselected from oxygen, sulfur
`and nitrogen fused to a 5 or 6-membered heterocyclic
`ring with from 1 to 4 heteroatomsselected from oxy-
`gen, sulfur and nitrogen, or (7) a 5 or 6-membered
`heterocyclic ring with from 1 to 4 heteroatomsselected
`from oxygen, sulfur and nitrogen fused to a C,-C,
`cycloalkyl ring;
`
`nis 0 to 3;
`
`mis 1;
`
`ris 0 to 2; and
`R*, R° and R® are hydrogen.
`Other preferred compoundsof the instant invention are
`realized when in the above structural formulaI:
`
`10
`
`15
`
`R'
`
`Ais phenyl or a 6-membered heterocyclic ring with 1 or
`2 heteroatoms selected from nitrogen and sulfur;
`is hydroxy, halogen, cyano, trifluoromethyl, NR®R%,
`NR®SO,R°, NR®COR®, NRSCO,R®, C.-C,
`alkyl
`optionally substituted by hydroxy; and
`ris 0 or 2.
`
`More preferred compounds are represented by the for-
`mulaIa:
`
`(Rn
`
`ao
`=
`
`N
`
`i
`*
`CHCH2N—i—On
`R3
`
`NH—S0O2—Z—(R!*),
`
`°
`
`30
`
`35
`
`(2) C,-Cyy alkyl, () C3-Cg 25 wherein
`(1) hydrogen,
`R® is
`cycloalkyl, (4) Z optionally having 1 to 4 substituents
`n is Oto 3;
`selected from halogen, nitro, oxo, NR'°R'®, C,-Cig
`m is |
`alkyl, C,-C,, alkoxy, C,;-Cy,9 alkylthio, and C,"Cyo
`R' is (1) halogen or (2) NR&R°;
`alkyl having | to 4 substituents selected from hydroxy,
`R’, R? are independently hydrogen or methyl;
`halogen, COjH, CO-C,-Cy) alkyl, SOj-C,-Ci,
`alkyl, C3;-C, cycloalkyl, C,;—C,, alkoxy, and Z option-
`R'@ is (1) halogen,
`(2) C,-Cyg alkyl, (3) NR®R8, (4)
`ally substituted by from 1 to 3 of halogen, C,-C,9 alkyl
`NR&COR’, (5) NR&CO,R%, (6) COR”, (7) OCOR?,or
`or C,—-Cyg alkoxy, or (5) C,-Cy, alkyl having 1 to 4
`(8) a 5 or 6-membered heterocycle with from 1
`to 4
`substituents selected from hydroxy, halogen, CO,H,
`heteroatomsselected from oxygen, sulfur andnitrogen,
`CO,—C,—Cj alkyl, S$O,—C,—C,) alkyl, C.-C,
`optionally substituted with up to four groups indepen-
`cycloalkyl, C,—C,, alkoxy, C,~C,, alkyl, and Z option-
`dently selected from oxo, halogen, R®, NR®R®, OR®,
`ally substituted by from 1 to 4 of halogen, C.-C, alkyl
`and SR*;
`or C,-Cy, alkoxy;
`Z is (1) phenyl, (2) naphthyl, (3) a 5 or 6-membered
`R’ is (1) R® or (2) NR&R§;
`heterocyclic ring with from 1 to 4 heteroatomsselected
`R'° is (1) C,-Cyg alkyl, or (2) two R!° groups together
`from oxygen, sulfur and nitrogen,
`(4) benzene ring
`with the N to which they are attached formed a 5 or
`fused to a 5 or 6-membered heterocyclic ring with from
`6-membered ring optionally substituted with C,-Ci9
`1
`to 3 heteroatoms selected from oxygen, sulfur and
`alkyl; or
`nitrogen, or (5) a 5 or 6-membered heterocyclic ring
`a pharmaceutically acceptable salt thereof.
`with from 1
`to 4 heteroatoms selected from oxygen,
`In one embodiment of the instant invention A is a 5 or
`sulfur and nitrogen fused to a C;-C, cycloalkylting;
`6-membered heterocyclic ring with from 1 to 4 heteroatoms
`X is —CH,—; and
`selected from oxygen, sulfur and nitrogen, a benzene ring
`R® and R?are as defined in claim 1.
`fused to a 5 or 6-membered heterocyclic ring with from 1 to
`4 heteroatoms selected from oxygen,sulfur and nitrogen, or
`Even more preferred compoundsarc those represented by
`formula Id:
`a 5 or 6-membered heterocyclic ring with from 1
`to 4
`
`40
`
`45
`
`(R}),
`
`a
`SN
`
`N
`
`H R?
`OH
`|
`i
`CHCH,;N—C—CH
`*
`|
`
`NH—S0Q?
`
`(R4),
`
`heteroatomsselected from oxygen,sulfur and nitrogen fused
`to a 5 or 6-membered heterocyclic ring with from 1
`to 4
`heteroatoms selected from oxygen, sulfur and nitrogen.
`In another embodiment of the instant
`invention A is
`phenyl or benzene fused to a C.-C, cycloalkyl ring.
`Preferred compoundsof the instant invention are realized
`whenin the above structural formulaI:
`R? and R® are hydrogen or methyl;
`X is —CH,—;
`
`60
`
`65
`
`nis 0 or 1;
`R’ is NRER®;
`R? and R?are independently (1) hydrogen, or (2) methyl;
`B is (1) hydrogen, (2) benzene fused to the benzene ring
`to form naphthyl, or (3) a 5 or 6-membered heterocycle
`with 1
`to 4 heteroatoms selected from oxygen, sulfur
`and nitrogen atom fused to the benzenering;
`R™ is (1) halogen,
`(2) C,-Cyq alkyl, (3) NR®R8, (4)
`NR&COR®, (5) NR8CO,R8, (6) COR®, or (7) a 5 or
`
`SAWAI EX. 1014
`Page 3 of 35
`
`SAWAI EX. 1014
`Page 3 of 35
`
`

`

`5,561,142
`
`5
`6-membered heterocycle with from 1 to 4 heteroatoms
`selected from oxygen, sulfur and nitrogen, optionally
`substituted with up to four groups independently
`selected from oxo, R®, SR®, OR®, and NR®R$; when B
`and the benzenering form a fused ring system, Ris 5
`attached to either ring;
`R® is (1) hydrogen, (2) C,-Cig alkyl, (3) Z optionally.
`having 1 to 4 substituents selected from nitro, oxo, and
`NR’R?®,or (5) C,-Cyo alkyl having 1 to 4 substituents
`selected from hydroxy, halogen, C,-C,9 alkyl, C;-Cg,
`cycloalkyl, and Z optionally substituted by from 1 to 4
`of halogen, C\—-Cyalkyl or C,-C,) alkoxy;
`R? is (1) R® or (2) NR&R®;
`R’° is (1) C;-Cyy alkyl, or
`(2) two R'° groups together with the N to which they are
`attached formed a 5 or 6-membered ring optionally substi-
`tuted with C,-C,, alkyl; and
`,
`Z, is (1) phenyl, (2) a 5 or 6-membered heterocyclic ring
`with from 1
`to 4 heteroatoms selected from oxygen,
`sulfur and nitrogen, (3) a benzenering fused to a 5 or
`6-membered heterocyclic ring with from 1
`to 4 het-
`eroatomsselected from oxygen,sulfur and nitrogen, or
`(4) a 5 or 6-memberedheterocyclic ring with from 1 to
`4 heteroatoms selected from oxygen, sulfur and nitro-
`gen fused to a C,-C, cycloalkyl ring. Most preferred
`compoundsare those having the formula Ie
`
`15
`
`20
`
`25
`
`6
`Z is (1) phenyl, (2) naphthyl or (3) benzene ring fused to
`a 5 or 6-membered heterocyclic ring with from 1 to 4
`heteroatoms selected from oxygen, sulfur and nitrogen;
`X is —CH,—;and
`R? and R? are independently hydrogen or methyl.
`Representative antiobesity and antidiabetic compounds of
`the present invention include the following:
`N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]
`ethyl]phenyl]-
`4-(hexylaminocarbonylamino)ben-
`zenesulfonamide
`,
`N-[4-[2-[{2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]
`ethy]]pheny]]- 4-iodobenzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]
`ethyl]phenyl]-benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyllamino]
`ethyl]phenyl]}- 2-naphthalenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethy]l]amino]
`ethyl]phenyl]- 3-quinolinesulfonamide N-[4-[2-[[2-hy-
`droxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyliphe-
`nyl]- 5-benzisoxazolesulfonamide
`N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyllamino]
`ethyl]phenyl]-
` 4-[(hexylmethylaminocarbony])amino]
`benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethy!]amino]
`ethyl]phenyl]- 4-[(dimethylaminocarbonyl)amino]benze-
`nesulfonamide
`
`H
`OH
`|
`a |
`CHCH2N —CH2—CH2
`—~
`*
`
`N
`
`NH—SOQ,
`
`(R™),
`
`Te
`
`nis Oor 1;
`R’ is (1) halogen, (2) NR®COR®,or (3) a 5-membered
`heterocycle substituted with 0 or 1 oxo selected from
`imidazolidinone,
`imidazolone, oxadiazole, oxazole,
`triazole and tetrazolone, optionally substituted with up
`to three groups independently selected from R°,
`R®is (1) hydrogen, (2) C,-Cy9 alkyl, or (3) C.-C, alkyl
`having 1
`to 4 substituents selected from hydroxy,
`halogen, C.-C, alkyl, C,-C, cycloalkyl, and Z
`optionally substituted by from 1
`to 4 of halogen,
`C.-C, alkyl or C,-C,, alkoxy;
`R® is NR®R°;
`Z is phenyl.
`Other more preferred compounds are represented by
`formula Ib:
`
`mR
`(R),KFCHCHAN-C-X)n<\-NH—SO-Z€R™),
`*
`
`R3
`
`i
`
`wherein
`n is
`
`Oto 3;
`m is
`R" is (1) hydroxy, (2) cyano, (3) NR®R®or (4) halogen;
`R’ is
`(1) halogen,
`(2) NR®R®,
`(3) NR®COR®,
`(4)
`NR®CO,R8, (5) OCOR®, or (6) a 5 or 6-membered
`heterocycle with from 1 to 4 heteroatoms selected from
`oxygen, sulfur and nitrogen,optionally substituted with
`up to three groups independently selected from oxo,
`halogen, R®, NR®R®, OR® and SR®;
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-ylethy]l]amino]
`ethyljphenyl]- 4-(3-hexyl-2-imidazolidon- 1-yl)benzene-
`sulfonamide
`N-[4-[ 3-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]
`propyl]-phenyl]-
`4-(hexylaminocarbonylamino)ben-
`zenesulfonamide
`N-[4-[3-[[2-hydroxy-2-(6-aminopyridin-3-ylethy]]amino]
`propyl]-phenyl]- 4-iodobenzenesulfonamide
`N-[4-[3-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino}
`propyl]-phenyl}benzenesulfonamide
`N-[4-[ 3-[[2-hydroxy-2-(6-aminopyridin-3-ylethyl]amino]
`propyl]-phenyl]- 2-naphthalenesulfonamide
`N-[4-[3-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]
`propyl]-phenyl]- 3-quinolinesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]aminoJethyl]phe-
`nyl]- 4-(hexylaminocarbonylamino)benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny])ethyl]amino]ethyl]phe-
`nyl]- 4-isopropylbenzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny])ethyl]aminoJethyl]phe-
`nyl]- 2-naphthalenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny])ethyl]amino]Jethyl]phe-
`nyl]- 3-quinolinesulfonamide
`N-[4-[ 2-[[ 2-hydroxy-2-(3-pyridinyl)ethylJamino Jethyl]
`phenyl]- 4-[(hexylmethylaminocarbonyl)amino]benzene-
`sulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny!)ethyl]aminoJethyl]phe-
`nyl]-4-( 3-hexyl-2-imidazolidinon-1-yl)benzenesulfona-
`mide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny])ethyl]aminoJethyl]phe-
`nyl]- 4-iodobenzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]aminoJethyl]phe-
`nyl}-4-[5-( 3-cyclopentylpropy!)-[1,2,4]-oxadiazol-3-yl]
`benzensulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]aminoJethyl]phe-
`nyl]-4-[( 1-oxoheptyl)amino]benzenesulfonamide
`
`SAWAI EX. 1014
`Page 4 of 35
`
`SAWAI EX. 1014
`Page 4 of 35
`
`

`

`5,561,142
`
`10
`
`25
`
`30
`
`35
`
`40
`
`20
`
`8
`7
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)cthylJamino]ethyl]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]-4-[3-( 4,4,4-trifluorobutyl)-2-imidazolon- 1-yl]ben-
`nyl]-4-[G-oxo-—4-phenylbutyl)Jamino]benzenesulfona-
`mide
`zenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)cthyl]amino]ethyl]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)cthyl]amino ]ethyl]phe-
`nylJ- 4-[(propoxycarbonyl)amino]benzenesulfonamide
`nylj-4-(3-octyl- 2-imidazolon-1-yl)benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethylJaminoJethyl]phe-
`N-[4-[
` 2-[[
`2-hydroxy-2-(3-pyridinyl)ethylJamino]ethy]]
`phenyl]-4-[3-( 3-cyclopentylpropyl)-2-imidazolon- 1-yl]
`nylj-4-[{[(fur- 2-ylmethyl)amino]carbonylamino]benze-
`nesulfonamide
`benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]aminoJethyl |phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny)ethyl]amino]Jethyl]phe-
`nyl]-4-(2-octyl-
`3-oxo-[1,2,4]-triazol-4-yl)benzenc-
`nyl]-4-[[[( 2-phenylethyl)amino]carbony]lJamino]benze-
`nesulfonamide
`sulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl ethyl ]amino]ethyl]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethylaminoJethyl]phe-
`nyl]-4-( 4-hexyl-5-tetrazolon-1-yl)benzenesulfonamide
`nyl]-4-[[[( 2-indol-3-ylethyl)amino]carbony]Jamino]ben-
`zenesulfonamide
`N-[4-[2-[(2-hydroxy-2-(3-pyridinyl)ethylamino]ethy!]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethy]]phe-
`nyl]-4-(4-octyl- 5-tetrazolon-1-yl)benzenesulfonamide
`nyl]-
`4-[([(octylamino)carbonylJamino]benzenesulfona-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]Jethyl]phe-
`mide
`nyl]-4-[4-( 3-cyclopentylpropyl)-5-tetrazolon- 1-yl]ben-
`zenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)cthyl]amino]ethyl]phe-
`nyl]- 1-[(hexylamino)carbonyl]-5-indolinesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethy]]aminoJethyl]phe-
`N-[4-(2-[[2-hydroxy-2-(3-pyridinylethylamino]ethyl]phe-
`nylj-4-( 2-pentyloxazol-5-yl)benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny])ethy]l]aminoJethyl]phe-
`nyl]- 1-[(octylamino)carbonyl]-5-indolinesulfonamide
`nyl]-4-( 2-octyloxazol-5-yl)benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny])ethy]aminoJethyl]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethylJamino]ethyl}phe-
`nyl]-
`1-[(N-methyl-N-octylamino)carbonyl1]-5-indoline-
`sulfonamide
`nyl]-4-[2-(
`2-cyclopentylethyl)oxazol-5-yl]benzene-
`sulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethylJaminojethy!]phe-
`nyl]-1-( 1-oxonony])-5-indolinesulfonamide
`nyl]-4-{(
`4-ethy]-5-methylthiazol-2-yl)amino]benzene-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`sulfonamide
`nyl]- 1-( 4-methylthiazo-1-2-yl)-5-indolinesulfonamide
`N-[4-(2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethy!]phe-
`nyl]-4-[( 4,5,6,7-tetrahydrobenzothiazol-2-yl)amino]ben-
`nylj- 1-( 4-octylthiazol-2-yl)-5-indolinesulfonamide
`zenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethy]]amino]ethy]]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethy!]aminoJethyl]phe-
`nyl]-1-( 4-ethyl-5-methylthiazol-2-yl)-5-indolinesulfona-
`nyl]-4-( 2-hexylimidazol-4-yl)benzenesulfonamide
`mide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny]ethylamino]Jethyl]phe-
`JethylJaminoJethy]]
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl
`nyl]-4-( 1-methy]-2-octylimidazol-5-yl)benzenesulfona-
`mide
`.
`phenyl]-4-(
`3-octyl-2imidazolidinon-1-yl)benzene-
`sulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny]ethyljamino]ethyl}phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethylaminoJethyl]phe-
`nyl]-4-[
` 1-methy]-2-(2-cyclopentylethyl)imidazol-5-y1]
`benzenesulfonamide
`nyl]-4-[3-(
` 4,4,4-trifluorobutyl)-2-imidazolidinon-1-yl]
`benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]aminoJethyl]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethylJaminojethyl]phe-
`nyl]-4-[ 1-methyl-2-[2-(4-fluorophenyl)ethyl]imidazol-5-
`ny]]-4-[3-( 3-phenylpropyl)-2-imidazolidinon- 1-yl]ben-
`yl]benzenesulfonamide
`zenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny]l)ethylJaminoJethyl|phe-
`nyl]-4-( 5-pentyl-[1,2,4]-oxadiazol-3-yl)benzenesulfona-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl}ethyl]aminoethyl]phe-
`mide
`nyl]-4-[3-(4,4,5,5,5-pentafluoropenty])-2-imidazolidi-
`non-1-yl]benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]aminoJethyl]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethylJphe-
`nyl]-4-[5-(
`2-cyclopentylethyl)-[1,2,4]-oxadiazol-3-yl]
`benzenesulfonamide
`nylJ-4-[3-( 2-cyclohexylethyl)-2-imidazolidinon-
` 1-yl]
`benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]aminoJethyl]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethy! ]amino]ethyl]phe-
`nyl]-4-( 5-heptyl-[1 ,2,4]-oxadiazol-3-yl)benzenesulfona-
`mide
`nyl]-4-[3-[3-(4-chlorophenyl])propy1]-2-imidazolidinon-
`1-yl]benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny]lethyl]amino]ethyl}phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethyl]amino]ethyl]phe-
`nylj-4-(
` 5-octyl-[1,2,4]-oxadiazol-3-yl)benzenesulfona-
`mide
`ny]]-4-( 3-penty]l-2-imidazolidinon-1-yl)benzenesulfona-
`mide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethylJamino]ethy!]phe-
`)Jethyl]amino]ethyl]
`2-hydroxy-2-(3-pyridinyl
`N-[4-[2-[[
`nyl]-4-( 5-hexylthio-[1,2,4]-triazol-3-yl)benzenesulfona-
`mide
`phenyl]-4-[ 3-( 3-cyclopentylpropyl)-2-imidazolidinon-
`1-yl]benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethy]]phe-
`nyl]-4-[[4-(4-propylpiperidin-1-yl)-1,1-dioxo-{1,2,5]-
`nyl]- 4-[cyclopentylethyl)-2-imidazolidinon- 1-yl]benze-
`thiadiazol- 3-ylJamino]benzenesulfonamide
`nesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethyl]amino]ethyl]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethy]]amino]ethyl]phe-
`nyl]-4-[[4-(hexylmethylamino)-1,1-dioxo-[1,2,5]-thia-
`ny1]-4-[3-( 3-cyclohexylpropyl)-2-imidazolidinon- 1-yl]
`diazol- 3-yl]amino]benzenesulfonamide
`benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny]ethyljaminoJethy!]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl ethyl]aminoethyl]phe-
`ny] ]-4-[[4-(heptylmethylamino)-1,1-dioxo-[1,2,5]-thia-
`nylj-4-[3-( 2,2-dimethylhexyl)-2-imidazolidinon-
`1-yl]
`diazol- 3-yl]Jamino]benzenesulfonamide
`benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethy]]amino]ethyl]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethy]]amino]ethyl]phe-
`nyl]-4-(
`1-octy]-2,4-imidazolidinedion-3-yl)benzene-
`sulfonamide
`ny]]-4-( 3-hexyl-2-imidazolon-1-yl)benzenesulfonamide
`
`45
`
`50
`
`55
`
`60
`
`65
`
`SAWAI EX. 1014
`Page 5 of 35
`
`SAWAI EX. 1014
`Page 5 of 35
`
`

`

`5,561,142
`
`*
`
`9
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny]l)ethyl]amino]ethyl]phe-
`nyl]-4-[3-(3-nitrophenyl)-5-pyrazolon-
`1-yl]benzene-
`sulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl}phe-
`nylJ-4-[4-(
` 1-hydroxy-1-hexylheptyl)-5-methyl-[1,2,3]-
`triazol-2-yl]benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny]ethylJamino]Jethyl]phe-
`nyl]-4-[4-( 1-hydroxyheptyl)-5-methyl-[1,2,3 ]-triazol-2-
`yl]benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny])ethyl]amino]-2-methyl-
`propyl]-phenyl]- 4-(3-hexyl-2-imidazolidinon- 1-yl)ben-
`zenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethy!]amino]-2-methyl-
`propyl]-phenyl]- 4-iodobenzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethylJamino]-2-methyl-
`propyl]-phenyl]-
`4-[[(hexylamino)carbony]]amino]ben-
`zenesulfonamide
`N-[4-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]phenyl]-4-
`iodobenzene-sulfonamide
`N-[4-[2-[(2-hydroxy-2-phenylethyl)aminoJethy!]pheny]]-2-
`naphthalene-sulfonamide
`N-[4-[2-[(2-hydroxy-2-phenylethyl)amino]Jethyl]pheny1]-3-
`quinoline-sulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-chlorophenyNethyl]aminoJethy]]
`phenylj- 3-isopropylbenzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-chloropheny])ethylJaminojethy!]
`phenyl]- 2-naphthalenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-chlorophenyl)ethyl]amino]ethyl]
`phenyl]- 3-quinolinesulfonamide
`N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]
`amino]ethyl]-pheny]]-
`4-(hexylaminocarbonylami-
`no)benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichloropheny])ethyl]
` aminojethyl]-phenyl]- 1-[(octylamino)carbonyl]-5-indo-
`linesulfonamide
`N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethy1]
`aminoJethyl}-phenyl]- 4-@G-hexy]-2-imidazolidinon-1-yl-
`Jbenzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyDethyl]
`aminoJethy!]-phenyl]- 4-(3-octy]-2-imidazolidinon- 1-yl-
`)benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(4-hydroxypheny]l)ethylJamino]
`ethyl]phenyl]-benzenesulfonamide
`N-[4-[2-[(2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino]
`ethyl]phenyl]- 4-iodobenzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-cyanophenyl])ethy]Jamino]Jethyl]
`phenyl]-
`4-(hexylaminocarbonylamino)ben-
`zenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-cyanophenyl)ethyl]aminojethyl]
`phenyl]]- 3-quinolinesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyfidiny)ethyl]amino]ethyl]phe-
`nylJ-4-( 5-hexyl-[1,2,4]-oxadiazol-3-yl)benzenesulfona-
`mide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethy]]aminoethyl]phe-
`nyl]-4-( 4-hepty]-5-methyl-[1,2,3]-tfiazol-2-yl)benzene-
`sulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyfidiny])ethyl]amino]ethy]]phe-
`nyl]-4-( 3-hexyl-2,4-imidazolidinedion-
`1-yl)benzene-
`sulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyfidiny])ethyljamino}ethyl]phe-
`nyl]-4-( 2,4-imidazolidinedion-1-yl)benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyfidinyl)ethyl]amino]ethyl]phe-
`nyl]-4-[3-( 3-cyclopentylpropyl)-2,4-imidazolidinedion-
`1-yl]benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyfidinyl)ethyl]amino]ethyl]phe-
`nylJ[1,2,4]-oxadiazol-5-yl)benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethyl]amino]ethyl]phe-
`nyl]-4-( 3-hexyl-[1,2,4]-oxadiazol-5-yl)benzenesulfona-
`mide
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`10
`N-[4-[2-[[2-hydroxy-2-(3-pyfidinylethyl]amino]ethyl]phe-
`nylJ-4-( 3-heptyl-[1,2,4]-oxadiazol-5-yl)benzenesulfona-
`mide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethylJamino]ethyl]phe-
`nyl]-4-(
` 3-octyl-[1,2,4]-oxadiazol-5-yl)benzenesulfona-
`mide
`N-[4-[2-[[2-hydroxy-2-(3-pyfidiny]ethylamino]ethyl]phe-
`nyl]-4-[3-(
` 2-cyclopentylethy!)-[1,2,4]-oxadiazol-5-yl]
`benzenesulfonamide
`N-[4-[
`2-[[2-hydroxy-2-(3-pyfidinylethyl]aminoJethyl]
`phenyl]-4-[3-( 3-cyclopentylpropy])-[1,2,4]-oxadiazol-5-
`yl]benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethy!}phe-
`nyl]-4-( 3-pentyl-[1,2,4]-thiadiazol-5-yl)benzenesulfona-
`mide
`N-[4-[2-[[2-hydroxy-2-(3-pyfidinylethylamino]ethyl]phe-
`nyl]-4-( 3-hexyl-[1,2,4]-thiadiazol-5-yl)benzenesulfona-
`mide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny])ethy]]amino]ethyl]phe-
`nyl]-4-( 3-heptyl-[1,2,4]-thiadiazol-5-yl)benzenesulfona-
`mide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]-4-(
`3-octyl-[1,2,4]-thiadiazol-5-yl)benzenesulfona-
`mide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]-4-[3-(2-cyclopentylethyl)-[1,2,4]-thiadiazol-5-yl]
`benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyfidiny]ethylamino]ethy!]phe-
`nyl]-4-[3-(3-cyclopentylpropyl)-[1,2,4]-thiadiazol-5-yl}
`benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]Jethyl}phe-
`nyl]-4-( 5-pentyl-[1,2,4]-thiadiazol-3-yl)benzenesulfona-
`mide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethylJamino]ethyl]phe-
`nyl]-4-( 5-hexy]-[1,2,4]-thiadiazol-3-yl)benzenesulfona-
`mide
`
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]-4-( 5-heptyl-[1,2,4]-thiadiazol-3-yl)benzenesulfona-
`mide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethyl]amino]ethyl]phe-
`nyl]-4-(
`5-octyl-[1,2,4]-thiadiazol-3-yl)benzenesulfona-
`mide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`nylj-4-[5-( 2-cyclopentylethyl)-[1,2,4 ]-thiadiazol-3-yl]
`benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethy]lJamino]ethy]]phe-
`nyl]-4-[ 5-( 3-cyclopentylpropyl)-[1,2,4]-thiadiazol-3-yl]}
`benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethy]]amino]ethyl}phe-
`nylJ-4-(
`4-pentyl-3-oxo-[1,2,4]-triazol-2-yl)benzene-
`sulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethy!]phe-
`nylj-4-(
`4-hexy]-3-oxo-[1 ,2,4]-triazol-2-yl)benzene-
`sulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny]ethyl]amino]ethyl]phe-
`nyl]-4-(
`4-heptyl-3-oxo-[1,2,4]-triazol-2-y)benzene-
`sulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethyl]amino]ethyl]phe-
`nyl]-4-(4-octyl-
`3-oxo-[1,2,4]-triazo]-2-yl)benzene-
`sulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethylJaminoJethyljphe-
`ny}]-4-[4-(
` 2-cyclopentylethyl)-3-oxo-[1,2,4]-triazol-2-
`yl]benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny])ethyl]amino]Jethy!]phe-
`nyl]-4-[4-( 3-cyclopentylpropyl)-3-oxo-[ 1,2,4]-triazol-2-
`yljbenzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny)ethyl]amino]ethyl]phe-
`nyl]-4-( 5-pentyloxazol-2-yl)benzenesulfonamide
`
`SAWAI EX. 1014
`Page 6 of 35
`
`SAWAI EX. 1014
`Page 6 of 35
`
`

`

`5,561,142
`
`ta
`
`15
`
`20
`
`25
`
`11
`12
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethylJaminoethyl]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]cthyl]phe-
`nyl]-4-( 5-hexyloxazol-2-yl)benzenesulfonamide
`nyl]-4-( 4-pentylthiazol-2-yl)benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethyl aminojethyl]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethyl]amino]ethyl]phe-
`nyl]-4-( 5-heptyloxazol-2-yl)benzenesulfonamide
`nyl]-4-( 4-hexylthiazol-2-yl)benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny])ethy!]amino]Jethyl]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethylJamino]ethyl]phe-
`nyl]-4-( 5-octyloxazol-2-yl)benzenesulfonamide
`nyl]-4-( 4-heptylthiazol-2-yl)benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl ethylamino]ethyl]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethyl]amino]ethyl}phe-
`nyl]-4-[5-(
`2-cyclopentylethy])oxazol-2-yl]benzene-
`nylj-4-( 4-octylthiazol-2-yl)benzenesulfonamide
`sulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethyl]amino]ethyl]phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny])ethyl]amino]ethy!]phe-
`nyl]-4-[4-¢
`2-cyclopentylethyl)thiazol-2-yl]benzene-
`sulfonamide
`nyl]-4-[5-(—3-cyclopentylpropyl)oxazol-2-yl]benzene-
`sulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethyl]aminoJethyl}phe-
`N-[4-[2-[[2-hydroxy-2-(3-pyridinylethyl]amino]ethyl]phe-
`nyl]-4-[4-(
` 3-cyclopentylpropyl)thiazol-2-yl]benzenc-
`sulfonamide
`ny!]-4-( 4-pentyloxazol-2-yl)benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl}amino]ethyl]phe-
`N-