United States Patent [19]
`Fisher et al.
`
`HlllllllllllllllllllllllllIlllllllllIlllllllllllllllllllIlllllllllllllllll
`5,541,197
`Jul. 30, 1996
`
`USOO5541197A
`[11] Patent Number:
`[45] Date of Patent:
`
`[54]
`
`[751
`
`[73]
`
`[21]
`[22]
`
`[63]
`
`[51]
`[521
`
`[58]
`
`[56]
`
`SUBSTITUTED SULFONAMIDES AS
`SELECTIVE B3 AGONISTS FOR THE
`TREATMENT OF DIABETES AND OBESITY
`
`Inventors: Michael H. Fisher, Ringoes; Elizabeth
`M. Naylor; Ann E. Weber, both of
`Scotch Plains, all of NJ.
`
`Assignee: Merck & Co., Inc., Rahway, NJ.
`
`Appl. No.: 404,566
`Filed:
`Mar. 21, 1995
`
`Related U.S. Application Data
`
`Continuation-in-part of Ser. No. 233,166, Apr. 26, 1994,
`abandoned.
`
`Int. Cl.[5 ....................... .. C07D 215/04; A6lK 31/47
`U.S. Cl. ..................... .. 514/311; 546/176; 548/309.7;
`548/491; 564/80; 564/84; 564/92; 514/399;
`514/412; 514/601; 514/602; 514/604
`Field of Search ........................... .. 546/ 176; 548/491,
`548/309.7; 564/80, 84, 92; 514/311, 399,
`412, 601, 602, 604
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`0427480
`0455006
`0516349
`05 1635 0
`0068669
`0565317
`1108577
`1565080
`WO93/ 10074
`WO93/22277
`WO94/02493
`WO94/29290
`
`5/1991
`ll/l99l
`12/1992
`12/1992
`l/l993
`10/1993
`4/1968
`4/1980
`5/1993
`ll/l993
`2/1994
`l2/l994
`
`European Pat.
`European Pat.
`European Pat.
`European Pat.
`European Pat.
`.
`European Pat.
`United Kingdom .
`United Kingdom .
`
`.
`
`WIPO .
`
`WIPO .
`
`WIPO .
`
`WIPO .
`
`OTHER PUBLICATIONS
`
`A. A. Larsen, et al, Journal of Medicinal Chemistry, vol. 10,
`3 pp. 462—472, Nov. 1966.
`
`Primary Examiner—Zinna Northington Davis
`Attorney, Agent, or Firm—Mollie M. Yang; David L. Rose
`
`[57]
`
`ABSTRACT
`
`Substituted sulfonamides are selective B3 adrenergic recep
`tor agonists with very little [3, and B2 adrenergic receptor
`activity and as such the compounds are capable of increasing
`lipolysis and energy expenditure in cells. The compounds
`thus have potent activity in the treatment of Type II diabetes
`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
`in?ammation 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 compounds in the treatment of
`diabetes and obesity and for lowering triglyceride levels and
`cholesterol levels or raising high density lipoprotein levels
`or for increasing gut motility are also disclosed.
`
`3,452,037
`3,816,516
`4,000,193
`4,396,627
`4,478,849
`4,999,377
`5,017,619
`5,153,210
`5,321,036
`
`Santilli et a1. . ....................... .. 514/507
`
`Cox et al. . . . . . . .
`
`. . . .. 546/344
`
`Lunts et al. . . . . .
`
`. . . .. 546/344
`
`Ainsworth et a1. .
`Ainsworth et al. .
`
`424/309
`424/285
`
`6/ 1969
`6/ 1974
`12/ 1976
`8/1983
`10/ 1984
`3/ 1991
`5/1991
`546/344
`10/1992 Ainsworth et a1. .
`6/1994 Sher ...................................... .. 514/365
`
`Caulkett et a1. . . . .
`
`. . . .. 514/507
`
`Alig et a1. . . . . . . . . . . .
`
`. . . .. 514/653
`
`FOREIGN PATENT DOCUMENTS
`
`0007206 l/l989 European Pat. Oif. .
`
`12 Claims, N0 Drawings
`
`SAWAI EX. 1008
`Page 1 of 29
`
`

`

`1
`SUBSTITUTED SULFONAMIDES AS
`SELECTIVE B3 AGONISTS FOR THE
`TREATMENT OF DIABETES AND OBESITY
`
`5,541,197
`
`CROSS REFERENCE
`
`This is a continuation~in-part of application U.S. Ser. No.
`08/233,166 ?led Apr. 26, 1994 now abandoned, which is
`hereby incorporated by reference in its entirety.
`
`BACKGROUND OF THE INVENTION
`
`B-Adrenoceptors have been subclassi?ed as [31 and {52
`since 1967. Increased heart rate is the primary consequence
`of [SI-receptor stimulation, while bronchodilation and
`smooth muscle relaxation typically result from [32 stimula
`tion. Adipocyte lipolysis was initially thought to be solely a
`[il-mediated process. However, more recent results indicate
`that the receptor-mediating lipolysis is atypical in nature.
`These atypical receptors, later called lia-adrenoceptors, are
`found on the 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
`([33 activity) than for stimulation of atrial rate (13,) and
`tracheal relaxation (132). 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 [33-adrenoceptors could make com—
`pounds of this 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
`[33 agonists is the potential for stimulation of other B-recep
`tors and subsequent side effects. The most likely of these
`include muscle tremor (B2) and increased heart rate ([51).
`Although these phenylethanolamine derivatives do possess
`some [53 selectivity, side effects of this type have been
`observed in human volunteers. It is reasonable to expect that
`these side effects resulted from partial [31 and/or [32 agonism.
`More recent developments in this area are disclosed in
`Ainsworth et al. U.S. Pat. No. 5,153,210, Caulkett et al.,
`U.S. Pat. No. 4,999,377, Alig et al., U.S. Pat. No. 5,017,619,
`Lecount et al., European Patent 427480 and Bloom et al.,
`European Patent 455006.
`Even though these more recent developments purport to
`describe compounds with greater B3 selectivity over the B1
`and [32 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
`B1 and [32 agonist activity when the compounds are tested in
`humans, it has become apparent that the rodent is not a good
`model for predicting human [33 selectivity.
`Recently, assays have been developed which more accu
`rately predict the effects that can be expected in humans.
`These assays utilize cloned human [33 receptors which have
`been expressed in Chinese hamster ovary cells. See Emorine
`et al, Science, 1989, 245:1118—1121; and Liggett, Mal.
`Pharmac0l., 1992, 42:634-637. The agonist and antagonist
`effects of the various compounds on the cultivated cells
`provide an indication of the antiobesity and antidiabetic
`effects of the compounds in humans.
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`SUMMARY OF 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 speci?c
`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 compounds as the
`active ingredient thereof. Further objects will become appar
`ent from reading the following description.
`
`DESCRIPTION OF THE INVENTION
`
`The present invention provides compounds having the
`formula I:
`
`(1) a 5 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 hetero
`cyclic ring with from 1 to 4 heteroatoms selected
`from oxygen, sulfur and nitrogen,
`(3) a 5 or 6-membered heterocyclic ring with from 1 to
`4 heteroatoms selected 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,
`(4) phenyl, or
`(5) a benzene ring fused to a C3—C8 cycloalkyl ring;
`R1 is
`(1) hydrOXy,
`(2) oxo,
`(3) halogen,
`
`(5) NRSRs,
`(6) SR8,
`(7) tri?uorornethyl,
`(8) CFC10 alkyl,
`
`(10) SO2R9,
`(l1) OCOR9,
`(12) NR8COR9,
`(13) COR9,
`(14) NR8SO2R9,
`(15) NRSCOZRS, or
`(16) C1—C1O alkyl substituted by hydroxy, halogen,
`cyano, NR8R8, SR8, trifluoromethyl, 0R8, c,-c8
`cycloalkyl, phenyl, NR8COR9, COR9, SO2R9,
`OCOR9, NR8SO2R9 or NRSCOZRS;
`R2 and R3 are independently
`(1) hydrogen,
`(2) C1—C10 alkyl or
`(3) C1—C1O alkyl with l to 4 substituents selected from
`hydroxy, C1—C10 alkoxy, and halogen;
`
`X is
`
`SAWAI EX. 1008
`Page 2 of 29
`
`

`

`= — or
`
`.
`
`5
`
`10
`
`3
`
`5,541,197
`
`v
`4
`from 1 to 4 of halogen, C1—C10 alkyl or C1—C10
`(1) —CH2—-,
`alkoxy;
`:CCE2—C(I€IH2_,
`R9 15
`8
`<4) —CH2O—;
`(1) R gr 8
`R4 and R5 are independently
`(2) NR R ;
`(1)hydrogen,
`R10 is
`(2) C1—C10 alkyl,
`(1) c,_c10 alkyl, or
`(3) halogen,
`(2) two R10 groups together with the N to which they
`(4) NHRs’
`.
`.
`5) CR8,
`are attached formed a 5 or 6-membered ring option
`E6) SOZRQ or
`lSllbStltUlBCL lwitt;1 tCt1h—C10falkyl; or a pharmaceu
`(7) NHSOZRI);
`tic y accepta e s
`ereo .
`5 -
`In one embodiment of the instant invention A is a 5 or
`R ([15) hydrogen or
`15 6-membered heterocyclic ring with from 1 to 4 heteroatoms
`(2) CFC10 alkyl;
`selected from oxygen, sulfur and nitrogen, a benzene ring
`R7 is Z_(R1")n;
`fused to a 5 or 6-membered heterocyclic ring with from 1 to
`-
`R111 is
`4 heteroatoms selected from oxygen, sulfur and nitrogen, or
`(1) R1, with the proviso that when A is phenyl, R1“ is
`a 5 or 6-membered heterocyclic ring with from 1 to 4
`not CFC“) alkyl,
`20 heteroatoms selected from oxygen, sulfur and nitrogen fused
`(2) CTCB cycloatkylt
`(3) phenyl optionally substituted with up to 4 groups
`to a 5 or 6-membered heterocyclic ring with from 1 to 4
`independently Selected from R8 NRsRs OR SR8
`heteroatoms selected from oxygen, sulfur and mtrogen.
`and halogen, or
`In another embodiment of the instant invention A is
`(4) 5 or 6_membered heterocycle with from 1 to 4
`heteroatoms selected from oxygen, sulfur and nitro- 25 phenyl or benzem fused to a ¢TC8 c_yc1°a-tky1 nng- _
`gen, optionally Substituted with up to four groups
`Preferred compounds of the instant invention are realized
`independently selected from oxo, R8, NRSRS, 0R8,
`when in the abOV? Structural formula I:
`SR8’ and halogen;
`R2 and R3 are hydrogen or methyl;
`
`30
`
`(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 C3—C8 cycloalkyl ring,
`(5) a benzene n'ng fused to a 5 or 6_membered ‘mercy
`cyclic ring with from 1 to 4 heteroatoms selected
`from oxygen, sulfur and nitrogen,
`(6)421?1 0r 6-tnenlbereld hetdergeyetie n'ng with tlrftiltn 1 t3
`eteroatoms se ecte
`rom ox en, su r an
`nitrogen fused to a 5 or 6-membged heterocyclic 40
`ring with from 1 to 4 heteroatoms selected from
`oxygen’ Sulfur and nitrogen, or
`(7) a 5 or 6-membered heterocyclic ring with from 1 to
`4 heteroatoms selected from oxygen, sulfur and
`nitrogen fused to a C3—C8 cycloalkyl ring;
`
`Lb) LII
`
`’
`
`.2
`_1s
`n 18 0 t0 3,
`In iS 1;
`r is 0 to 2; and
`
`_
`_
`_
`R4’ R5 and R6 are hydrogen‘
`Other preferred compounds of the instant invention are
`realized when 1n the above Structural fonnnln 11
`A is phenyl or a 6-membered heterocyclic ring with 1 or
`2 heteroatoms selected from nitrogen and sulfur;
`1 .
`.
`8 8
`R 18 {:1 ydroxgy’ halosgen’ cgyano’ gn?uorgmethyl’ NR R ’
`NR_ 801R ’
`COR ’ NR COZR ’ C1-C6 alkyl
`optionally substituted by hydroxy; and
`r iS 0 0r 2
`More preferred compounds are represented by the for
`mula Ia:
`
`(R‘),.
`
`R2
`OH H
`|
`/ |
`|
`CHCH2N—(|I——(X),,,
`R3
`
`\
`N
`
`*
`
`NH___SOZ_Z_(R1H>H
`
`Ia
`
`55
`
`R8 is
`(1) hydrogen,
`(2) C1—C10 alkyl,
`(3) C3—C8 cycloalkyl,
`(4) Z optionally having 1 to 4 substituents selected
`from halogen, nitro, oxo, NRIORIO, C1—C1O alkyl,
`c,_c1o alkoxy, c,_c1O alkylthio, and cl-c10 alkyl
`having 1 to 4 substituents selected from hydroxy,
`halogen, cozn, coz-c 1-010 alkyl, s0,-c,-c,,, 60
`alkyl, C3—C8 cycloalkyl, C1—C10 alkoxy, and Z
`optionally substituted by from 1 to 3 of halogen,
`C1—C10 alkyl or C1—C1o alkoxy, or
`(5) C1—C1O alkyl having 1 to 4 substituents selected
`from hydroxy, halogen, COZH, CO2-C1—C10 alkyl, 65
`soz-cl-c10 alkyl, C3-C8 cycloalkyl, cl-c10
`alkoxy, C1—C10 alkyl, and Z optionally substituted by
`
`wherein
`n is 0 to 3;
`
`m1]? 1
`R 15
`(1) halgg? or
`2(2)3NR R ’
`R 7 R are independently hydrogen or methyl;
`R1" is
`(l) halogen,
`(2) C1—C1‘) alkyl,
`(3) NR8R8,
`(4) NRSCORQ,
`(5) NR8CO2R8,
`(6) C018,
`(7) OCOR9, or
`
`SAWAI EX. 1008
`Page 3 of 29
`
`

`

`5,541,197
`
`5
`(8) a 5 or 6-membered heterocycle with from 1 to 4
`heteroatoms selected from oxygen, sulfur and nitro-
`gen, optionally substituted with up to four groups
`independently selected from oxo, halogen, R8,
`NR8RS, CR8, and SR8;
`
`5
`
`Z is
`(1) phenyl,
`(2) naphthyl,
`(3) a 5 or 6-mernbered heterocyclic ring with from 1 to
`4 heteroatoms selected from oxygen, sulfur and 10
`nitrogen
`(4) benzene ring fused to a 5 or 6-membered hetero-
`cyclic ring with from 1 to 3 heteroatoms selected
`from oxygen, sulfur and nitrogen, or
`(5) a 5 or 6-membered heterocyclic ring with from 1 to 15
`4. heteroatoms selected from oxygen, sulfur and
`mtrogen fused [0 a C3"Cs cycloalkyl ring;
`X is —CH2—; and
`R8 and R9 are as de?ned in Claim 1,
`Even more preferred compounds are those represented by
`formula Id:
`
`20
`
`6
`(5) C1—C1O alkyl having 1 to 4 substituents selected
`from hydroxy, halogen, C1—C10 alkyl, C3—C8
`cycloalkyl, and Z optionally substituted by from 1 to
`4 of halogen, C1-C1O alkyl or CFC1O alkoxy;
`R9 is
`(1) R8 or
`(2) NRsRs;
`
`l0 '
`
`R ‘S
`_
`_
`(1) cl‘cllooalky 1’ or
`(2) two R groups together with the N to wh1ch they
`are attachfid fomwjd a 5 or amembared ring Option“
`any Substllutcd Wlth crcro alkyl; and
`
`Z is
`(1) phenyl,
`(2) a 5 or 6-m@mber¢d heterocyclic ring with from 1 to
`4 heteroatoms selected from oxygen, sulfur and
`nitrogen,
`(3) a benzene ring fused to a 5 or 6-membered hetero
`cyclic nng with from 1 to 4 heteroatoms selected
`from oxygen, sulfur and nitrogen, or
`
`.
`
`.
`
`.
`
`B
`
`Id
`
`NH-SOZ
`
`mm)”
`
`3O
`
`(4) a 5 or 6-membered heterocyclic ring with from 1 to
`4 heteroatoms selected from oxygen, sulfur and
`nitrogen fused to a C3—C8 cycloalkyl ring.
`Other more preferred compounds are represented by
`formula lb:
`
`NH—SO2——Z—-—(R1“),,
`
`‘b
`
`40
`
`‘i2
`l’
`‘(H
`SHCH2N—C-———(X)m
`is
`wherein
`n is O to 3;
`m is l
`R1 is
`(l) hydroxy,
`(2) cyano,
`(3) NRgR8 or
`(4) halogen;
`R1“ is
`(l) halogen,
`(2) NRSR“,
`(3) NRsCORQ,
`(4) NRSCOZRS,
`(5) 0C0R9, or
`(6) a 5 or 6-membered heterocycle with from 1 to 4
`heteroatoms selected from oxygen, sulfur and nitro
`gen, Optionally Substituted with 11P 10 three groups
`independently Elected from 0X0, halogen, R8,
`NRSRS, CR8 and SR8;
`
`(111)"
`
`OH H R2
`/ I
`|
`I
`CHCH2N——$—CH2
`R3
`
`\
`N
`
`=1‘
`
`n is 0 or 1;
`R1 is NRsRs;
`
`2
`
`3
`
`t
`
`R and R are mdependgn?y
`(1) hydrogen, or
`
`(111),,
`
`(2) methyl;
`B is
`(1) hydrogen,
`(2) benzene fused to the benzene ring to form naphthyl, 45
`of
`(3) a 5 or 6-membered heterocycle with l to 4 heteroa-
`toms selected from oxygen, sulfur and nitrogen atom
`fused to the benzene ring;
`R1” is
`(1) halogen,
`(2) C1-C1, alkyl,
`(3) NRBRS,
`(4) NR8COR9,
`(5) NRSCOZRS,
`(6) COR9, or
`(7) a 5 or 6-1nembercd hetefocyclg with from 1 to 4
`heteroatoms selected from oxygen, sulfur and nitro-
`gen, optionally substituted with up to four groups
`independently selected from oxo, R8, SR8, 0R8, and 60
`NRsRs; when E and the benzene ring form a fused
`ring system, R1“ is attached to either ring;
`R8 is
`(1 ) hydrogen,
`(2) CFC1O alkyl,
`(3) z optionally having 1 to 4 substituents selected
`from nitro, oxo, and NRloRw, or
`
`50
`
`55
`
`Z is
`(1) phenyl,
`(2) naphthyl or
`(3) benzene ring fused to a 5 or 6-membered hetero
`cyclic ring with from 1 to 4 heteroatoms selected
`from Oxygen, sulfur and nitrogen;
`X is —CH2—; and
`
`65
`
`SAWAI EX. 1008
`Page 4 of 29
`
`

`

`7
`
`8
`
`.
`
`5,541,197
`
`R2 and R3 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]
`ethyl]phenyl]-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)ethyl]amino]
`ethyl]phenyl]>2-naphthalenesulfonarnide
`N-[4-[2-[[2-hydr0xy-2-(6-aminopyridin-3-yl)ethyl]amino]
`ethyl]phenyl]-3-quinolinesulfonamide
`N-[4-[2-[[2-hydroxy-2—(6-aminopyridin-3-yl)ethyl]amino]
`ethyl]phenyl]-5-benzisoxazolesulfonamide
`N-[4-[2—[[2-hydroxy-2—(6-aminopyridin-3-yl)ethyl]arnino]
`ethyl]phenyl]-4-[(hexylmethylaminocarbonyl)amino]
`benzenesulfonamide
`
`N-[4—[2—[[2-hydroxy—2—(6—aminopyridin—3—yl)ethyl]amino]
`ethyl]phenyl]-4—[(dimethylaminocarbonyl)amino]benze-
`nesulfonamide
`N-[4-[2-[[2-hydroxy-2-(6-aniinopyridin-S-yl)ethyl]amino]
`ethyl]phenyl]—4-(3-hexy1-2-imidazolidon-1-yl)benzene-
`sulfonamide
`
`N-[4-[2-[[3-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]
`propy1]phenyl]-4—(hexylaminocarbonylamino)ben-
`zenesulfonamide
`
`N-[4-[2-[[3-hydroxy—2-(6-arninopyridin—3—yl)ethyl]amino]
`propyl]pheny1]—4—iodobenzenesulfonamide
`N-[4-[2-[[3-hydroxy~2—(6—aminopyridin-3-yl)ethyl]amino]
`propyl]phenyl]benzenesulfonamide
`N—[4-[2-[[3-hydroxy-2-(6—arninopyridin-3-yl)ethyl]amino]
`propyl]phenyl]-2-naphthalenesulfonamide
`N-[4-[2-[[3-hydroxy-2-(6-an1inopyridin-3—yl)ethyl]amino]
`propyl]-phenyl]-3-quinolinesulfonamide
`N-[4-[2—[[2-hydroxy-2-(3-pyridinyl)ethyl]amin0]ethyl]phe—
`nyl]-4 -(hexylaminocarbonylamino)benzenesulfonamide
`N-[4-[2-[[2-hydroxy—2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]-4 -isopropylbenzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]-2 -naphthalenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]-3 -quinolinesulfonamide
`N-[4—[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe—
`nyl]-4
`~[(hexylmethylaminocarbonyl)amino]benzene-
`sulfonamide
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4o
`
`45
`
`N—[4—[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]—4-(3
`-hexyl—2-imidazolidinon— l —yl)benzenesulf0na-
`mide
`
`50
`
`N-[4-[2-[[2—hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`ny1]-4 -iodobenzenesulfonamide
`N-[4—[2-[[2-hydroxy-2-(3—pyridinyl)ethyl]amino]ethyl]phe-
`nyl]-4—[5-(3 -cyclopentylpropyl)-[1,2,4]-oxadiazol—3-yl]
`benzensulfonamide
`
`N-[4-[2-[[2-hydroxy-2—(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]-4-[(1 -oxoheptyl)amino]benzenesulfonamide
`N-[4~[2~[[2—hydroxy-2-(3-py1idinyl)ethyl]amino]ethyl]phe-
`nyl]~4—[(l
`-oxo-4-phenylbutyl)amino]benzenesulfona-
`mide
`
`N-[4-[2-[[2-hydr0xy-2-(3~pyridinyl)ethyl]amino]ethyl]phe-
`nyl]-4 -[(propoxycarbonyl)amino]benzenesu1fonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]-4-[[[(fur-2-ylmethyl)amino]carbony1]amino]benze-
`nesulfonamide
`
`N-[4-[2-[[2—hydr0xy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]-4-[[[(2 -phenylcarbonyl]amino]benzenesulfonarnide
`
`55
`
`60
`
`65
`
`N-[4-[2—[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]—4—[[[(2-indol-3-ylethyl)amino]carbonyl]amino]ben-
`zenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]—4
`-[[(octylamino)carbonyl]amino]benzenesulfona—
`mide
`N—[4—[2-[[2—hydroxy-2-(3-pyridinyl)ethyl]amin0]ethyl]phe—
`nyl]-1 -[(hexylamino)carbonyl]-5«indolinesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3—pyridinyl)ethyl]amino]ethyl]phe—
`nyl]-1-[(octylamino)carbonyl]~5-indolinesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3—pyridinyl)ethyl]amino]ethy1]phe—
`nyl]-1-[(N—methyl—N-octylamino)carbonyl]-5-indoline-
`sulfonamide
`N-[4-[2-[[2-hydroxy-2-(3—pyn‘dinyl)ethyl]amino]ethy1]phe—
`nyl]-1-(1 -oxononyl)—5~indolinesulfonamide
`N—[4-[2-[[2—hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe~
`nyl]-1-(4 -methylthiazol-2-yl)-5-indolinesulfonamide
`N-[4-[2—[[2—hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]-1-(4 —octylthiazol-2-yl)-5-indolinesulfonamide
`N-[4—[2-[[2—hydroxy-2-(3-pyridinyl)ethyl]amin0]ethyl]phe—
`nyl]—1—(4 -ethyl-5~methylthiazol-2-yl)—5—indolinesu1fona-
`mide
`
`N—[4-[2—[[2-hydroxy-2-(3-pyn'dinyl)ethyl]amino]ethyl]phe—
`nyl]-4-(3
`-octy1-2-in1idazolidinon—1-y1)benzenesulfona—
`mide
`
`N—[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe—
`ny1]-4-[3
`-(4,4,4-trifluorobutyl)—2-imidazolidinon-1-yl]
`benzenesulfonamide
`
`N—[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]-4-[3~(3
`«phenylpropyl)—2—imidazolidinon—1-yl]ben-
`zenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]-4-[3
`-(4,4,5,5,5-pentafluoropentyl)-2-imidazolidi—
`non-1 -yl]benzenesulfonamide
`N-[4-[2—[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`ny1]-4-[3-(2
`-cyclohexylethyl)~2—imidazolidinon-1-yl]
`benzenesulfonamide
`
`N-[4-[2—[[2-hydroxy-Z-(3~pyridinyl)ethy1]amino]ethyl]phe—
`nyl]-4~[3-[3 -(4-chlorophenyl)propyl]-2-imidazolidinon~
`1-yl]benzenesulfonamide
`N-[4-[2—[[2-hydroxy—2—(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]‘-4—(3 -pentyl—2—imidazolidinon—1-yl)benzenesulfona—
`mide
`
`N-[4~[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe—
`ny1]-4-[3-(3 -cyclopentylpropyl)-2—imidazolidinon-1-yl]
`benzenesulfonamide
`
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny1)ethy1]amino]ethyl]phe—
`ny1]~4—[3-(2
`-cyclopentylethyl)-2—imidazolidinon-1-yl]
`benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`ny1]-4-[3-(3
`-cyclohexylpropyl)-2-imidazolidinon-1-yl]
`benzenesulfonamide
`
`N-[4-[2-[[2-hydroxy-2—(3-pyridinyl)ethyl]amin0]ethyl]phe-
`nyl]-4-[3-(2,2
`-dimethylhexyl)-2—imidazolidinon—1—yl]
`benzenesulfonamide
`
`N—[4—[2—[[2-hydroxy-2-(3-pyridinyl)ethyl]an1ino]ethyl]phe-
`nyl]-4-(3 —hexyl-2‘imidazolon-1-yl)benzenesulfonamide
`N—[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe—
`nyl]-4-[3
`-(4,4,4-trifluorobutyl)—2—imidazolon-1-yl]ben—
`zenesulfonamide
`
`N-[4—[2-[[2-hydroxy—2—(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]—4-(3 -octyl-2—imidazolon-1-yl)benzenesulfonamide
`N-[4-[2—[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`ny1]-4-[3-(3 -cyclopentylpropyl)—2-imidazolon-1-y1]ben-
`zenesulfonamide
`
`N—[4-[2-[[2—hydroxy—2-(3-pyn'dinyl)ethyl]amino]ethyl]phe-
`ny1]-4-(2
`-octyl-3-ox0-[1,2,4]-triazol-4-yl)benzene-
`sulfonamide
`
`SAWAI EX. 1008
`
`Page 5 of 29
`
`SAWAI EX. 1008
`Page 5 of 29
`
`

`

`9
`
`10
`
`5,541,197
`
`N—[4—[2-[[2-hydroxy—2-(3-pyridiny1)ethy1]amino]ethy1]phe-
`ny1]-4-(4 -hexy1-5-tetrazo1on-1-y1)benzenesu1fonamide
`N—[4-[2-[[2—hydroxy-2—(3-pyridiny1)ethy1]amin0]ethy1]phe-
`ny1]-4-(4 -octy1-5-tetrazolon—1-y1)benzenesulfonamide
`N-[4-[2-[[2-hydroxy—2—(3-pyridiny1)ethyl]amino]ethy1]phe—
`ny1]—4-[(3
`-cyc10penty1propy1)-5-tetrazolon—1—y1]benze-
`nesulfonamide
`
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny1)ethy1]amino]ethy1]phe—
`ny1]—4—(2 ~penty10xazol-5-y1)benzenesu1fonamide
`N-[4-[2—[[2-hydroxy-2-(3-pyn'diny1)ethy1]amino]ethy1]phe-
`ny1]—4—(2 -octyloxazol~5—y1)benzenesu1fonamide
`N-[4-[2—[[2-hydroxy-2—(3-pyridiny1)ethyl]amino]ethy1]phe—
`ny1]-4—[2-(2
`—cyc10pentylethy1)0xazol—5-y1]benzene-
`sulfonamide
`
`N-[4—[2-[[Z—hydroxy—Z-(B-pyridiny1)ethy1]amino]ethy1]phe-
`ny1]—4-[(4
`-ethy1-5—methy1thiazo1-2—y1)amino]benzene-
`su1fonamide
`
`5
`
`10
`
`15
`
`N—[4—[2—[[2-hydroxy-2-(3—pyridiny1)ethy1]amino]ethy1]phe—
`ny1]—4 -[(4,5,6,7-tetrahydrobenzothiazol—2—y1)amino]ben-
`zenesulfonamide
`
`20
`
`N-[4-[2-[[2-hydroxy-2-(3-pyn'diny1)ethy1]amino]ethy1]phe—
`ny1]-4-(2 —hexy1imidazoI-4-y1)benzenesu1fonamide
`N—[4-[2—[[2-hydr0xy—2—(3—pyridiny1)ethy1]amino]ethy1]phe-
`ny1]-4-(1
`-methy1-2-octy1imidazol-5-y1)benzenesu1fona-
`mide
`
`N-[4-[2-[[Z‘hydroxy-Z-(B‘-pyridinyl)ethy1]amino]ethy1]phe—
`ny1]—4—[1 —methy1-2—(2-cyc10pentylethyDimidazol-S-yl]
`benzenesulfonamide
`
`N~[4-[2—[[2-hydroxy—2—(3-pyfidinyl)ethy1]amino]ethy1]phe—
`ny1]—4-[1 -Inethy1-2—[2—(4-fluorophenyl)ethy1]imidazol-5-
`y1]benzenesulfonamide
`N—[4—[2-[[2-hydroxy-2-(3-pyridiny1)ethy1]amino]ethyl]phe-
`ny1]-4-(5 -penty1-[1,2,4]-oxadiazol-3—y1)benzenesulfona-
`mide
`
`N~[4—[2-[[Z-hydroxy—Z—(S—pyridiny1)ethy1]amino]ethyl]phe-
`ny1]—4-[5-(2
`-cyclopentylethy1)-[1,2,4]~0xadiazo1-3-y1]
`benzenesulfonamide
`
`25
`
`30
`
`35
`
`N-[4—[2-[[2—hydroxy-2-(3-pyridiny1)ethy1]amino]ethy1]phe-
`ny1]—4-(5 -heptyl—[1,2,4]-oxadiazol-3-y1)benzenesulfona-
`mide
`
`40
`
`N-[4—[2-[[2-hydroxy-2-(3-pyfidinyl)ethyl]amino]ethy1]phe—
`ny1]-4-(5
`-octy1-[1,2,4]-0xadiazol-3-y1)benzenesu1fona-
`mide
`
`N—[4-[2—[[2-hydroxy-2-(3-pyn’diny1)ethy1]amino]-2-methy1-
`propy1]pheny1]-4-(3-hexy1-2-imidazolidinon—1-y1)benze-
`nesulfonamide
`
`N-[4-[2—[[2—hydroxy-2—(3-pyridiny1)ethyl]amino]—2—methy1-
`propyl]phenyl]-4-iodobenzenesu1fonmnide
`N-[4-[2-[[2—hydr0xy-2—(3—pyridinyl)ethy1]amino]-2-methyl-
`propyl]phenyl]—4—[[(hexy1amino)carbony1]amino]benze—
`nesulfonamide
`
`N—[4—[2-[(2-hydroxy-2-phenylethy1)amino]ethyl]phenyl]—4-
`iodobenzenesulfonamide
`
`N—[4—[2—[(2-hydroxy-2-pheny1ethyl)amino]ethy1]pheny1]-2-
`naphthalenesulfonamide
`N—[4—[2-[(2-hydroxy-2—phenylethyl)amino]ethy1]phenyl]-3—
`quinolinesulfonamide
`N-[4-[2-[[2-hydxoxy-2-(3-chlor0pheny1)ethy1]amino]ethy1]
`pheny1]-3 -isopr0py1benzenesulfonamide
`N-[4-[2-[[2—hydroxy-2-(3-chlor0pheny1)ethy1]amino]ethy1]
`phenyl]-2-naphthalenesulfonamide
`N—[4—[2-[[2-hydroxy—2-(3-chlor0phenyl)ethy1]amino]ethyl]
`pheny1]-3 -quin01inesulfonamide
`N—[4—[2-[[2-hydroxy~2—(4-an1in0-3,5-dich10r0pheny1)ethyl]
`amino]ethy1]phenyl]-4-(hexylminocarbonylamino)ben-
`zenesulfonamide
`
`N-[4-[2-[[2-hydroxy-2—(4—amino-3,5-dichlorophenyl)ethy1]
`amino]ethy1]phenyl]—1-[(octy1amino)carbony1]—5-ind0-
`linesu1fonamide
`
`N-[4-[2-[[2-hydroxy-2-(4-amino—3,5-dich10ropheny1)ethy1] -
`amino]ethy1]pheny1]-4-(3-hexy1-2-imidazolidinon—1-y1—
`)benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(4—amino—3,5-dich10r0phenyl)ethy1]
`amino]ethy1]phenyl]—4-(3-octy1-2—imidazolidinon- 1 -y1-
`)benzenesulfonamide
`N—[4-[2—[[2—hydroxy—2—(4—hydroxyphenyl)ethyl]amino]
`ethyl]pheny1]benzenesu1fonamide
`N-[4-[2—[[2—hydroxy-2—(4-hydroxyphenyl)ethy1]amino]
`ethyl]pheny1]-4 —i0dobenzenesulf0namide
`N—[4—[2—[[2—hydr0xy-2—(3—cyanophenyl)ethyl]amino]ethyl]
`pheny1]-4
`-(hexylaminocarbonylamino)ben-
`zenesulfonamide
`
`N—[4—[2-[[2-hydroxy-2—(3—cyanophenyl)ethy1]amino]ethy1]
`pheny1]—3 -quinolinesu1fonamide
`N-[4-[2-[[2—hydroxy-2-(3—pyridir1yl)ethy1]amino]ethyl]phe-
`ny1]—4—(5
`-hexy1-[1,2,4]-0xadiazol-3-yl)benzenesu1fona—
`mide
`
`N-[4-[2-[[2-hydroxy-2-(3-pyn'dinyl)ethyl]amin0]ethy1]phe—
`ny1]-4—(5 -hexy1thio-[1,2,4]-tn'azo1-3-y1)benzenesu1fona—
`mide
`
`45
`
`N-[4-[2-[[2—hydr0xy—2-(3-pyridinyl)ethy1]amino]ethy1]phe-
`ny1]—4—(4
`-hepty1-5-methyl-[1,2,3]-triazol-2-y1)benzene—
`sulfonamide
`
`N-[4-[2-[[2-hydroxy—2-(3-pyridiny1)ethyl]amino]ethy1]phe-
`ny1]—4-[[4-(4
`-propy1piperidin—1-y1)-1,1-di0xo—[1,2,5]—
`thiadiazol-3 -y1]amino]benzenesu1fonamide
`N-[4-[2—[[2—hydr0xy-2-(3-pyridiny1)ethy1]amino]ethy1]phe—
`ny1]—4-[[4 —(hexy1methy1amino)—1,1—dioxo-[1,2,5]-thia-
`diazol-3 -y1]amino]benzenesu1fonamide
`N-[4—[2—[[2-hydroxy-2—(3-pyfidiny1)ethy1]amin0]ethy1]phe-
`ny1]—4~[[4-(N-hepty1, N-Inethylamino)-1,1-dioxo-[1,2,5]—
`thiadiazol—3 -y1]amino]benzenesulf0namide
`N-[4-[2~[[2—hydroxy-2-(3—pyridiny1)ethy1]amino]ethyl]phe-
`ny1]—4-(1
`-octy1-2,4-imidazolidinedion-3-y1)benzene-
`sulfonamide
`
`N—[4-[2-[[2—hydroxy-2-(3-pyridiny1)ethy1]amino]ethy1]phe-
`ny1]—4-[3-(3—nitr0pheny1)-5-pyrazolon-1-y1]benzene-
`sulfonamide
`
`N-[4-[2-[[2—hydroxy-2-(3-pyridiny1)ethy1]amino]ethy1]phe—
`ny1]—4-[4-(1
`-hydroxy-1-hexylheptyl)-5—methy1-[1,2,3]—
`triazol-2—y1]benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny1)ethy1]amino]ethyl]phe~
`ny1]—4-[4—(1
`-hydroxyhepty1)-5—methyl-[1,2,3]—triazol—2—
`y1]benzenesulfonamide
`
`50
`
`55
`
`60
`
`65
`
`N-[4-[2-[[2-hydroxy—2—(3-pyridiny1)ethyl]arnino]ethyl]phe—
`ny1]—4-(3
`-hexy1-2,4—imidazolidinedion-1-y1)benzene-
`sulfonamide
`
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny1)ethy1]amino]ethy1]phe-
`ny1]—4-(3
`—octy1-2,4—imidazolidinedion-1-yl)benzene-
`sulfonamide
`
`N—[4-[2-[[2-hydroxy—2—(3-pyn'diny1)ethy1]arnino]elhy1]phe-
`ny1]-4—[3—(3
`-cyclopenty1propy1)-2,4-imidazolidinedion-
`1-y1]bcnzenesulfonamide
`N-[4-[2-[[Z-hydroxy-Z-(3—pyridiny1)ethy1]amino]ethy1]phe—
`ny1]-4-(3 —penty1—[1,2,4]—oxadiazol-5-y1)benzenesu1fona—
`mide
`
`N-[4-[2—[[2—hydroxy-2-(3—pyridiny1)ethy1]amino]ethy1]phe-
`ny1]-4-(3 -hexy1-[1,2,4]-oxadiazol—5—y1)benzenesu1fona—
`mide
`
`N—[4-[2—[[2-hydroxy-2—(3—py1idinyl)ethy1]amino]ethy1]phe-
`nyl]-4-(3 -hepty1—[12,4]-oxadiazol~5-y1)benzenesulfona—
`mide
`
`N-[4-[2-[[2—hydroxy-2—(3-pyridiny1)ethy1]amino]ethy1]phe-
`ny1]—4-(3
`-octy1-[1,2,4]-oxadiazol-5-y1)benzenesulfona-
`mide
`
`SAWAI EX. 1008
`
`Page 6 of 29
`
`SAWAI EX. 1008
`Page 6 of 29
`
`

`

`5,541,197
`
`12
`N—[4—[2-[[2-hydroxy-2—(3-pyridinyl)ethyl]amino]ethy1]phe-
`ny1]-4-[5-(2
`-cyclopentylethyl)oxazol-Z-yl]benzene-
`sulfonamide
`
`N—[4-[2-[[2-hydroxy-2-(3-pyn'diny1)ethyl]amino]ethy1]phe-
`nyl]—4—[5-(3
`-cyc10pentylpropyl)oxazol-2-y1]benzene-
`sulfonamide
`
`N—[4—[2-[[2-hydroxy-2-(3-pyridiny1)ethy1]amino]ethyl]phe-
`ny1]-4-(4 -pentyloxazol-2—yl)benzenesulfonamide
`N-[4—[2-[[2-hydroxy-2-(3-py1idjnyl)ethy1]amino]ethyl]phe-
`ny1]-4-(4 -hexyloxazol-2-y1)benzenesulfonamide
`N-[4-[2—[[2-hydroxy-2-(3—pyridinyl)ethyl]amino]ethy1]phe—
`ny1]-4-(4 -heptyloxazol-2-yl)benzenesu1fonamide
`N—[4—[2-[[2-hydony-2-(3-pyridinyl)ethyl]amino]ethy1]phe-
`nyl]-4—(4—octyloxazol-2-yl)benzenesulfonamide
`N-[4-[2—[[2-hydroxy-2—(3-pyridiny1)ethyl]amino]ethyl]phe-
`nyl]-4—[4—(2
`-cyclopentylethyl)oxazol-Z-yl]benzene-
`sulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethy1]amino]ethy1]phe-
`ny1]—4-[4-(3
`-cyc10penty1propy1)oxazol-Z—y1]benzene—
`sulfonamide
`
`N—[4-[2—[[2-hydr0xy-2—(3-pyridinyl)ethyl]amino]ethyl]phe-
`ny1]-4-(2 -hexyloxazol-5-yl)benzenesu1fonamide
`N-[4—[2-[[2-hydroxy-2-(3-pyridiny1)ethyl]amino]ethy1]phe—
`ny1]-4-(2 -heptyloxazol-5-yl)benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny1)ethyl]amino]ethyl]phe-
`nyl]-4-[2-(3
`-cyclopenty1propyl)oxazol-S-y1]benzene-
`sulfonamide
`
`N-[4—[2-[[2-hydroxy-2-(3-pyridiny1)ethyl]amino]ethy1]phe-
`ny1]-4-[2-(4
`-cyclobutyl)oxazol—S-yl]benzenesulfona-
`mide
`
`30
`
`11
`N-[4-[2-[[2—hydroxy-2-(3-pyridiny1)ethy1]amino]ethy1]phe—
`nyl]—4-[3-(2
`-cyclopentylethy1)-[1,2,4]-oxadiazol-5-y1]
`benzenesulfonamide
`N-[4-[2-[[2-hydroxy—2-(3-pyridiny1)ethy1]amino]ethyl]phe-
`ny1]-4-[3-(3 -cyclopenty1propyl)-[1,2,4]-oxadiazol-5-yl]
`benzenesulfonamide
`N-[4-[2-[[2-hydroxy—Z-(3-pyridinyl)ethyl]amino]ethy1]phe-
`ny1]-4-(3 -pentyl-[1,2,4]—thiadiazol-5—y1)benzenesulfona-
`mide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`ny1]-4-(3 -hexy1—[1,2,4]-thiadiazol-5-y1)benzenesulfona—
`mide
`N-[4-[2-[[2-hydroxy-2—(3-pyridiny1)ethyl]amino]ethyl]phe-
`ny1]-4-(3 -hepty1—[1,2,4]-thiadiazol-5-y1)benzenesulfona—
`mide
`N-[4-[2-[[Z-hydroxy-Z-(3-pyridiny1)ethy1]amino]ethyl]phe-
`ny1]-4—(3
`-octyl-[1,2,4]-thiadiazol-5-yl)benzenesulfona-
`mide
`N-[4-[2—[[2-hydroxy—2-(3—pyridinyl)ethyl]amino]ethy1]phe-
`ny1]-4-[3—(2
`-cyclopentylethyl)—[1,2,4]—thiadiazol-5-yl]
`benzenesulfonamide
`
`N-[4-[2-[[2-hydroxy-Z-(3~pyridiny1)ethy1]amino]ethy1]phe-
`ny1]-4-[3-(3 -cyclopenty1propyl)-[1,2,4]-thiadiazol—5-y1]
`benzenesulfonamide
`
`10
`
`15
`
`20
`
`N—[4-[2-[[2-hydroxy-2-(3-pyddinyl)cthyl]amino]ethy1]phe-
`ny1]-4-(5 -pentyl-[1,2,4]-thiadiazol-3~yl)benzenesulfona-
`mide
`
`25
`
`N—[4-[2-[[2-hydroxy—2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`ny1]-4-(5 -hexyl-[1,2,4]-thiadiazol-3-yl)benzenesulfona—
`mide
`
`N-[4-[2—[[2-hydroxy-2-(3-pyn'diny1)ethyl]amino]ethyl]phe-
`ny1]-4-(5 -hepty1-[1,2,4]-thiadiazol—3-yl)benzenesulfona-
`mide
`
`N-[4-[2-[[2-hydroxy-2—(3-pyridiny1)ethy1]amino]ethy1]phe—
`ny1]-4—(5 —octy1-[1,2,4]-thiadiazol-3-y1)benzenesu1fona-
`mide
`
`35
`
`N-[4—[2~[[2-hydr0xy-2-(3-pyridinyl)ethy1]amino]ethy1]phe-
`ny1]-4-[5-(2
`-cyclopentylethyl)—[1,2,4]-thiadiazol-3-yl]
`benzenesulfonamide
`
`N-[4-[2-[[2-hydroxy-2—(3-pyridiny1)ethyl]amino]ethy1]phe-
`ny1]-4-[5-(3 -cyclopenty1propyl)-[1,2,4]—thiadiazol-3-yl]
`benzenesulfonamide
`
`N—[4-[2—[[2-hydroxy-2-(3-pyn'diny1)ethy1]amino]ethyl]phe—
`ny1]-4- (4
`-pentyl-3-oxo-[1,2,4]—triazol-2-y1)benzene-
`sulfonamide
`
`N-[4—[2—[[2—hydroxy—2—(3-pyridir1yl)ethy1]amino]ethy1]phe-
`ny1]-4-(4
`-hexy1-3—0xo-[1,2,4]—triazol—2—y1)benzene-
`sulfonamide
`
`45
`
`N-[4-[2-[[2—hydroxy-2—(3-pyridir1y1)ethyl]amino]ethy1]phe-
`nyl]—4—(4
`-heptyl-3-oxo-[1,2,4]-tfiazol-2-yl)benzene-
`sulfonamide
`
`50
`
`N-[4-[2-[[2-hydroxy-2-(3~pyridiny1)ethyl]amino]ethyl]phe-
`ny1]-4-(4
`-octy1-3-oxo-[1,2,4]-triazol-2-y1)benzene-
`sulfonamide
`
`N-[4-[2-[[2-hydroxy-2—(3-pyridinyl)ethyl]arr1ino]ethy1]phe-
`ny1]-4-[4-(2
`~cyclopentylethyl)-3-oxo-[1,2,4]-tn'azol-2-
`y1]benzenesu1fonamide
`N—[4-[2-[[2-hydroxy-2-(3—pyridinyl)ethy1]amino]ethyl]phe-
`ny1]-4-[4-(3 -cyclopenty1propyl)-3-oxo-[1,2,4]-tn'azol-2-
`yl]benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2—(3-pyddiny1)ethy1]amino]ethy1]phe—
`ny1]-4-(5 -pentyloxazol-2-yl)benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethy1]amin0]ethy1]phe-
`ny1]-4-(5 -hexyloxazol-2-yl)benzenesulfonamide
`N-[4-[2—[[2-hydroxy-2—(3-pyridiny1)ethy1]amino]ethy1]phe-
`ny1]~4~(5 -hepty10xazol-2-yl)benzenesulfonamide
`N—[4-[2-[[2-hydr0xy—2-(3-pyridiny1)ethyl]amino]ethy1]phe-
`ny1]-4-(5 -octyloxazol-2-yl)benzenesulf0n