ZA200500371B - Benzothiazole derivatives having Beta-2-adrenoreceptor agonist activity - Google Patents
Benzothiazole derivatives having Beta-2-adrenoreceptor agonist activity Download PDFInfo
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- ZA200500371B ZA200500371B ZA200500371A ZA200500371A ZA200500371B ZA 200500371 B ZA200500371 B ZA 200500371B ZA 200500371 A ZA200500371 A ZA 200500371A ZA 200500371 A ZA200500371 A ZA 200500371A ZA 200500371 B ZA200500371 B ZA 200500371B
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- ZA
- South Africa
- Prior art keywords
- cio
- alkyl
- alkoxy
- halo
- substituted
- Prior art date
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- 229940121786 Beta 2 adrenoreceptor agonist Drugs 0.000 title description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 title description 2
- 230000000694 effects Effects 0.000 title description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 75
- 125000005843 halogen group Chemical group 0.000 claims description 55
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 54
- 239000001257 hydrogen Substances 0.000 claims description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims description 49
- 125000000623 heterocyclic group Chemical group 0.000 claims description 32
- 229910052757 nitrogen Inorganic materials 0.000 claims description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 17
- 150000003839 salts Chemical group 0.000 claims description 17
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 14
- 239000012453 solvate Substances 0.000 claims description 13
- 125000004429 atom Chemical group 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 10
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 9
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 8
- 239000005864 Sulphur Substances 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
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- 125000001424 substituent group Chemical group 0.000 claims description 6
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- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
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- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005446 heptyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004708 n-butylthio group Chemical group C(CCC)S* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005071 nonynyl group Chemical group C(#CCCCCCCC)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N serine Chemical group OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
BENZOTHIAZOLE DERIVATIVES HAVING BETA-2-ADRENORECEPTOR AGONIST ACTIVITY
This invention relates to organic compounds, their preparation and use as pharmaceuticals.
In a tirst aspect the present invention provides compounds of formula I
HN—X -
HO
S, d=o0
OH in fres or salt or solvate form, wherein
X is -R1-Ar-R2 or -R*-Y;
Ar denotes a phenylene group optionally substituted by halo, hydroxy, Ci-Cio-alkyl, C;1-Cio- alkoxy, Ci-Cie-alkoxy-Ci-Cro-alkyl, phenyl, C1-Cro-alkyl substituted by phenyl, Ci-Cio-alkoxy substituted by phenyl, Ci-Cio-alkyl-substituted phenyl or by Ci-Cio-alkoxy-substituted phenyl;
R1 and R? are attached to adjacent carbon atoms in Ar, and either R! is C;-Cyo-alkylene and R2 is hydrogen, Ci-Cio-alkyl, C1-Cio-alkoxy or halogen or R! and RZ rogether with the carbon atoms in Ar to which they are attached denote a 5-, 6- or 7-membered cycloaliphatic ring;
Rs: is a bond or Ci-Cio-alkylene optionally substituted by hydroxy, Ci-Cio-alkoxy, Cs-Cro-aryl or C7-Cy-aralkyl; and
Yis C--Croalkyl, Ci-Cyo-alkoxy, C2-Cio-alkenyl or Cz-Cio-alkyny! optionally substituted by halo. cyano, hydroxy, Ci-Cie-alkyl, Ci-Cio-alkoxy or halo-C;-Cie-alkyl;
Cs-Cio-cycloalkyl optionally fused to one or more benzene rings and optionally substituted by C;-Cyo-alkyl, Ci-Cio-alkoxy, Ca-Cio-cycloalkyl, Cr-Cis-aralkyl, C7-Cis- aralky'oxy or Cs-Cio-aryl, where Cs-Cio-cycloalkyl, C7-Cis-aralkyl, C;-Cis-aralkyloxy or Cs-Cio-aryl are optionally substituted by halo, hydroxy, Ci-Cie-alkyl, Cs-Cio-alkoxy cr halo-C;-Cye-alkyl;
Cs-Cio-aryl optionally substituted by halo, hydroxy, Ci-Cie-alkyl, Ci-Cio-alkoxy, Ci-
Cio-haloalkyl, phenoxy, Ci-Cio-alkylthio, Cs-Cio-aryl, 4- to 10- membered heterocyclic ring having at least one ring nitrogen, oxygen or sulphur atom, or by NR*R¢ where Rb and Reare each independently Ci-Cio-alkyl optionally substituted by hydroxy, Ci-Cio- alkoxy or phenyl or R® may additionally be hydrogen; phenoxy optionally substituted by C;-Cyo-alkyl, C1-Cio-alkoxy or by phenyl optionally substituted by Cy-Cio-alkyl or Ci-Cio-alkoxy; a 4- to 10-membered heterocyclic ring having at least one ring nitrogen, oxygen or sulphur atom, said heterocyclic ring being optionally substituted by halo, Ci-Cio-alkyl,
C1 -Cie-alkoxy, halo-Ci-Cio-alkyl, Cé-Cio-aryl, C7-Cis-aralkyl, C7-Cis-aralkyloxy, C;-
Cio-alkoxycarbonyl or a 4- to 10-membered heterocyclyl-Cy-Cio-alkyl; -NRdR: where R¢ is hydrogen or C1-Cio-alkyl and Re is C;-Cyo-alkyl optionally substituted by hydroxy, or Re is C¢-Cyo-aryl optionally substituted by halo, or Re is a 4- to 10-membered heterocyclic ring having at least one ring nitrogen, oxygen or sulphur atom which ring is optionally substituted by phenyl or halo-substituted phenyl or Re is
Cs-Cio-arylsulfonyl optionally substituted by Ci-Cio-alkylamino or di(Ci-Cio- zlkyl)amino; -SRiwhere Rf is C¢-Cio-aryl or C7-Cia-aralkyl optionally substituted by halo, Ci-Cio- a’kyl, C:-Cyr-alkoxy or Ci-Cio-haloalkyl; or -CONHRe where Re is C1-Cyo-alkyl, C3-Cyo-cycloalkyl or Cs-Cio-aryl.
Terms used in the specification have the following meanings: “Halo” or "halogen" as used herein denotes a element belonging to group 17 (formerly group
VII) of thie Periodic Table of Elements, which may be, for example, fluorine, chlorine, bromine or iodine. Preferably halo or halogen is fluorine or chlorine.
“Ci-Cio-alkyl” as used herein denotes straight chain or branched alkyl that contains one to ten carbon atoms, which may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, scc-butyl, tert-butyl, straight or branched pentyl, straight or branched hexyl, straight or branched heptyl, straight or branched octyl, straight or branched nonyl, or straight or branched decyl. Preferably, Ci-Cio-alkyl is C1-Cs-alkyl. "Ci-Cho-alkylene” as used herein denotes a straight chain or branched alkylene that contains one to ten carbon ztoms, for example, methylene, ethylene, trimethylene, methylethylene, tetramethylene, -CH(CH3)CH,CHaz-, -CHCH(CH3)CHa-, straight or branched pentylene, straight or branched hexylene, straight or branched heptylene, straight or branched octylene, straight or branched nonylene, or straight or branched decylene. Preferably Ci-Cio-alkylene is
Ci-Cy alkylene, especially ethylene or methylethylene. “Ca-Cro-2lker vi” as used herein denotes straight chain or branched hydrocarbon chains that contain two to ten carbon atoms and one or more carbon-carbon double bonds, for example, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, tert-butenyl, straight or branched pentenyl, straight or branched hexenyl, straight or branched heptenyl, straight or brancaed ociznyl, straight or branched nonenyl, or straight or branched decenyl. Preferably “C-Crialkenvl” is “Cp-Ce-alkenyl”. “Cz-Cio-27kynyl” as used herein denotes straight chain or branched hydrocarbon chains that contain two to ten carbon atoms and one or more carbon-carbon triple bonds, for example, ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, straight or branched pentynyl, straight or branched hexynyl, straight or branched heptynyl, straight or branched octynyl, straight or branched nonynyl, or straight or branched decynyl. Preferably “Co-Cye-aky:ayl” is “Cy-Cy-alkynyl”. "C3-Cro~cveloalkyl” as used herein denotes cycloalkyl having 3 to 10 ring carbon atoms, for example a monocyclic group such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohepryl. ¢ yelooctyl, cyclononyl or cyclodecyl, any of which can be substituted by one or more, usually one or two, C;-Cs-alkyl groups, or a bicyclic group such as bicycloheptyl or bicyclooctyl. Preferably Cs-Cio-cycloalkyl is Cs-Ce-cycloalkyl, for example cyclopropyl, cyclobuty}. cvclopentyl, cyclohexyl or cycloheptyl. “Cs-Cao-haloalkyl” as used herein denotes C;-Cio-alkyl as hereinbefore defined substituted by one or m2 halogen atoms, preferably one, two or three halogen atoms.
"C;-C;o-akylnmino” and di(Cy-Cro-alkyl)amino” as used herein denote amino substituted respective’: bv one cr two C:-Cyo-alkyl groups as hereinbefore defined, which may be the same ot different. Preferably Cy-Cao-alkylamino and di(Cy-Cio-alkyl)amino are respectively
Ci-Cs-alkylamino and di(Ci-Cs-alkyl)amino. «C1-Cro-alkvltnio” as used herein denotes straight chain or branched C;-Cro-alkylthio, which may be, for example, methylthio, ethylthio, n-propylthio, isopropyithio, n-butylthio, isobutylitia, sec-butylthio, tert-butylthio, straight or branched pentylthio, straight or branched hexvithio, straight or branched heptylthio, straight or branched octylthio, straight or branched ronivithic, or straight or branched decylthio. Preferably, Ci-Cio-alkylthio is C1-Cs- alkylthio. “Cy-Cro-alkoxv™ as used herein denotes straight chain or branched alkoxy that contains one to ten carbor atoms which may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxv. is :buzoxy, sec-butoxy, tert-butoxy, straight or branched pentoxy, straight or branched hexyloxy, straight or branched heptyloxy, straight or branched octyloxy, straight or branched rervloxy, or straight or branched decyloxy. Preferably, Ci-Cio-alkoxy is Ci-Cs- alkoxy. “Cy-Cao-2lkoxy-Ci-Cro-alkyl” as used herein denotes Cyi-Cio-alkyl as hereinbefore defined substituted by Ci-Cio-alkoxy. Preferably, Ci-Cio-alkoxy-Ci-Cio-alkyl is C1-Cs-alkoxy-Cy-Cs- alkvl. “«C;-{"ptlunnvearbonyl” as used herein denotes Ci-Cro-alkoxy as hereinbefore defined linked thrcuzh <i oxygen atom thereof to a carbonyl group. "Cs-Cro-arv]” as used herein denotes a monovalent carbocyclic aromatic group that contains 6 to 10 cath. atoms and which may be, for example, a monocyclic group such as phenyl or a bicy~lic ginap such as naphthyl. Preferably Cs-Cro-aryl is Co-Cy-aryl, especially phenyl. "Ce-Cram tsaifony:™ as used herein denotes Cs-Cio-aryl as hereinbefore defined linked throug 1 a zat 2ca atom thereof to a sulfonyl group. Preferably C¢-Cio-arylsulfonyl is Ce-Cs- ary!sulfonyl.
"Cy-C 1a-uralky]" as used herein denotes alkyl, for example C1-Cy-alkyl as hereinbefore defined, substituted by aryl, for example Ce-Cio-aryl as hereinbefore defined. Preferably, Cr- ~ Cus-aralkyl is C7-Cyo-aralkyl such as phenyl-C;-Cs-alkyl, particularly benzyl or 2-phenylethyl. "C:-Cis-cralkvloxy” as used herein denotes alkoxy, for example C3-Cq-alkoxy as hereinbefore defined, si.ost.tuted by aryl, for example Cs-Cyo-aryl. Preferably, Cr-Ciq-aralkyloxy is C»~Cio- aralk lox. such as phenyl-Ci-Cy-alkoxy, particularly benzyloxy or 2-phenylethoxy.
Ar as vsed herein may be, for example, phenylene which is unsubstituted or substituted by one or racre substituents selected from halogen, hydroxy, Ci-Cje-alkyl, Ci-Cio-alkoxy, C1-Cio- . alkoxy-C;-Cic-alkyl, phenyl, or Ci-Cie-alkyl substituted by phenyl, C;-Cio-alkoxy substituted by phenyl, (;-Cio-alkyl-substituted phenyl and Ci-Cjo-alkoxy-substituted phenyl. Preferably
Ar is pheriviere which is unsubstituted or substituted by one or two substituents selected from halogen, C:-Ce-alkyl, Ci-Cs-alkoxy, or Ci-Cy-alkoxy substituted by phenyl. Preferably one substituent in Ar is para to R! and optional second and third substituents in Ar are meta to Rl. "4. to 10-membered heterocyclic ring having at least one ring nitrogen, oxygen or sulphur atom” as used herein ay be, for example, pyrrole, pyrrolidine, pyrazole, imidazole, triazole, tetrazole, thiadiazole, oxazole, isoxazole, thiophene, thiazole, isothiazole, oxadiazole, pyridive. vy-ezine. pvridazine, pyrimidine, piperidine, piperazine, triazine, oxazine, morpholir:c,, quinoline, isoquinoline, naphthyridine, indane or indene. Preferred heterocyclic rings :ncluce -hiazole, pyrrolidine, piperidine, azacycloheptane and isoxazole. "4 to 10-mer:bered heterocyclyl-Ci-Cio-alkyl” denotes alkyl, for example C;-Cio-alkyl as hereinbefore defined, substituted by a 4- to 10-membered heterocyclic ring as hereinbefore defined. Preferably, 4- to 10-membered heterocyclyl-Ci-Cio-alkyl is Ci-Cs-alkyl substituted by a4 i § iueisbered heterocyclic ring having at least one ring nitrogen, oxygen or sulphur ator. "Optiona:tv substituted” as used herein means the group referred to can be substituted at one or more positions by any one or any combination of the radicals listed thereafter.
R1 and R2 tog:ther with the carbon atoms to which they are attached as a cycloaliphatic ring may be, { :t example, a cyclopentane ring, optionally substituted by one or two C;-Cy-alkyl groars, «roihexane ring, optionally substituted by one or two Cy-Cs-alkyl groups, or a cvciohepiare ing, preferably a cyclopentane ring.
WO his hich PCT/EP2003/008824
Throughout this specification and in the claims that follow, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understocd to imply the inclusion of a stated integer or step or group of integers or steps but not the exciusion of any other integer or step or group of integers or steps.
Pre zr covspounds of formula I in free or salt or solvate form include those wherein
Xis-po-y por -R2-Y;
Ar dezotes a ~henylene group optionally substituted by halo, Ci-Cio-alkyl, Ci-Cio-alkoxy or by C:-Cio-alkoxy substituted by phenyl;
R! and R2 are attached to adjacent carbon atoms in Ar, and either R: :5 C.-Cyo-alkylene and R2 is hydrogen, or R! and RZ rogether with the carbon atoms in Ar to which they are attached denote a 5-, 6- or 7-mz=mier:d cycloaliphatic ring;
Rae 5 Send or C1-Cro-alkylene optionally substituted by hydroxy, Cs-Cio-aryl or C7-Cie- aratkvi; and
Y is Cr-Cro-alkyl, Ci-Cro-alkoxy or Cz-Cig-alkynyl; Cs-Cio-cycloalkyl optionally fused to one or mere benzene rings and optionally substituted by C;-Cie-alkyl, Cs-Cio-cycloalkyl, CCis- aralkyl. C--Cj4-aralkyloxy optionally substituted by halo, or by C¢-Cie-aryl optionally substituted by Ci-Cio-alkyl or C;-Cio-alkoxy; Cs-Cio-aryl optionally substituted by halo, hydroxy. <5 -Cn-alkyl, phenoxy, Ci-Cye-alkylthio, C¢-Cio-aryl, a 4- to 10-membered het: =v uw: ng heving at 'east one ring nitrogen atom, or by NRPR¢ where Rb and Reare each ndvpinddendy Cr-Cre-alkyl optionally substituted by hydroxy or phenyl or Rb may addit.on ly be hydrogen; phenoxy optionally substituted by Ci-Cio-alkoxy; a 4- to 10- membered heterocyclic ring having at least one ring nitrogen or oxygen atom, said heterocyclic ring, being optionally substituted by Cy-Cio-alkyl, C¢-Cio-aryl, C7-Cis-aralkyl, C1-Cio- alkoxvcarhonyl or by a 4- to 10-membered heterocyclyl-Ci-Cio-alkyl; -NRYR¢ where Rd is hydrogen or 721-Cio-alkyl and Re is C1-Cio-alkyl, or Re is a 4- to 10-membered heterocyclic ring havi. a vio one ring nitrogen or oxygen atom which ring is optionally substituted by halo- subst-.ut ii vaienvl or Re is Cg-Cro-arylsulfony! optionally substituted by di(Cy-Cio-alkyl)amino;
SRE Rie Go-Crraryl or Cr-Cyg-aralkyl optionally substituted by halo or Ci-Cio- halozikyl: or -CONHRe where Re is C3-Cio-cycloalkyl or Cs-Cyg-aryl.
Especially rreferred compounds of formula I in free or salt or solvate form include those wher eiri
Xis--4 -¥lor-RaY;
Arde .te o. _henylene group optionally substituted by halo, Ci-Ce-alkyl, Ci-Cs-alkoxy or by
Ci-Cs-ulkony substituted by phenyl;
R? znd R* ace attached to adjacent carbon atoms in Ar, and either R! is C;-Cs-alkylene and R? is hydrogen, or R! and R? together with the carbon atoms in Ar to which they are attached denote a 5-, 6- or 7-menbered cycioaliphatic ring, especially a 5-membered cycloaliphatic ring;
Ra is 4 bead or Ci-Caalkylene optionally substituted by hydroxy, Cs-Cs-aryl or C7-Cro-aralkyl; and
YY is ©. 1c ollivl Ci-Cy-alkoxy or Ca-Ca-alkynyl; Cs-Cs~cycloalkyl optionally fused to one or more Serene rings and optionally substituted by Ci-Ce-alkyl, Cs-Ce-cycloalkyl, C7-Cio- aralky’, Cr-Cho-aralkyloxy optionally substituted by halo, or by Cs-Cs-aryl optionally substituted by Ci-Ca-alkyl or Ci-Cs-alkoxy; Ce-Cs-aryl optionally substituted by halo, hydroxy. Ci-Ca-alkyl, phenoxy, Cy-Cs-alkylthio, Cs-Cs-aryl, a 4- to 8-membered heterocyclic rinz having at least one ring nitrogen atom, or by NRER¢ where Rb and Reare each indep ndently Ci-Ca-alkyl optionally substituted by hydroxy or phenyl or R® may additionally be hviirczzi: phenoxy optionally substituted by C1-Cs-alkoxy; a 4- to 8-membered hetcrecyr lic ring having at least one ring nitrogen or oxygen atom, said heterocyclic ring being opt.onallv substituted Sv Ci-Cy-alkyl, Cs-Cs-aryl, C7-Cyo-aralkyl, Ci-Cs-alkoxycarbonyl or by a 4- to 8-membered heterocyclyl-Ci-Cy-alkyl; -NRéR¢ where R¢ is hydrogen or Cy-Cs-alkyl and
Re is Ci-Ca-altyl, or Reis a 4- to 8-membered heterocyclic ring having at least one ring nitrogen cr sulphur tom which ring is optionally substituted by halo-substituted phenyl or Re is Cs- Z3-amvisulfonyl optionally substituted by di(Ci-Cs-alkyl)amino; -SRf where Rf is C¢-Cs- arvl «+ CZ: ;c-aralkyl optionally substituted by halo or Ci-Cs-haloalkyl; or -CONHRS where
Reis J -ocioaleyl or Ce-Cs-aryl.
In a second aspect the present invention provides compounds of formula I in free or salt or solvare forin, wherein
X is -R1-Ar-K: or -Fo-Y;
Ar dernotes a phenylene group optionally substituted by halo, hydroxy, Ci-Cie-alkyl, Ci-Cio- alkn: ¢, 7. -Cyr-alkoxy-Ci-Cro-alkyl, phenyl, Ci-Cio-alkyl substituted by phenyl, Ci-Cio-alkoxy cubsaiot 4 by phenyl, Ci-Cro-alkyl-substituted phenyl or by Ci-Cio-alkoxy-substituted phenyl;
RY aa ki rv: attached to adjacent carbon atoms in Ar, and eitb er R? is Cs-Cio-vlkvlene and R® is hydrogen, Ci-Cio-alkyl, C1-Cio-alkoxy or halogen or R! ard KR? together with the carbon atoms in Ar to which they are attached denote a 5-, 6- or 7-membered cycloaliphatic ring;
Rais a head or Cp-Cho-alkylene optionally substituted by hydroxy, Ci-Cie-alkoxy, Cs-Cio-aryl or Cr-C.saratkyl; and
Yis {-Cioalkyl, Ci-Cio-alkoxy, Cz-Cio-alkenyl or Cz-Cio-alkynyl optionally substituted by k. +i», cvano, hydroxy, Ci-Cio-alkyl, Ci-Cio-alkoxy or halo-C;-Cjo-alkyl; «. -Cizcycloalkyl optionally fused to one or more benzene rings and optionally suvsititoted by Ci-Cao-alkyl, Ci-Cio-alkoxy, Cs-Cio-cycloalkyl, Cs-Cis-aralkyl, C;-Cia- aralkyloxy or Cs-Cio-aryl optionally substituted by halo, hydroxy, Ci-Cio-alkyl, C;-
Cro-alkoxy or halo-Ci-Cho-alkyl;
Cs-Cyz-aryl optionally substituted by halo, hydroxy, Ci-Cie-alkyl, Cy-Cio-alkoxy, Cs- '10-haloatkyl, phenoxy, Ci-Cio-alkylthio, Cs-Cio-aryl, 4- to 10- membered heterocyclic rie having at least one ring nitrogen, oxygen or sulphur atom, or by NRbR where Rb anc Reare each independently Ci-Cio-alkyl optionally substituted by hydroxy, Ci-Cio- zloty or phenyl or R® may additionally be hydrogen; phenoxy oprionally substituted by Cy-Cio-alkyl, Ci-Cio-alkoxy or by phenyl optionally substituted by Cy-Cro-alkyl or Ci-Co-alkoxy; 2 4- to 10-raembered heterocyclic ring having at least one ring nitrogen, oxygen or sulphur arom, said heterocyclic ring being optionally substituted by halo, Cy-Cio-alkyl, (i s-atkexy, halo-Ci-Cio-alkyl, Ce-Cio-aryl, C7-Crs-aralkyl, C+Cis-aralkyloxy, C;-
Cv alkoxycarbonyl or a 4- to 10-membered heterocyclyl-C;-Cyo-alkyl; + Leite where R¢ is hydrogen or Ci-Cio-alkyl and Re is C;-Cio-alkyl optionally sur t-tuted by hydroxy, or Re is C¢-Cio-aryl optionally substituted by halo, or Re is a 4- to 10-membered heterocyclic ring having at least one ring nitrogen, oxygen or sulphur ate vhich ring is optionally substituted by phenyl or halo-substituted phenyl or Re is
Cs Ci wrylsulionyl optionally substituted by Ci-Cro-alkylamino or di(Cy-Cio-
AU ETN
-£ 7 were &' is C-Cro-aryl or Cr-Cya-aralkyl optionally substituted by halo, C;-Cio- at :I 7-Cie-alkoxy or Ci-Cro-haloalkyl; or ~o-MHRe where Re is Cy-Cyo-alkyl, C3-Ciocycloalkyl or Cs-Cyo-aryl.
Preferred ¢ora>0unds of formula I in free or salt or solvate form include those wherein
Xis R14 Kor -Ra-Y,
Ar ienot: » y enylene group optionally substituted by halo, C1-Cyo-alkyl, Ci-Cio-alkoxy or by Cs key substituted by phenyl;
Rand Ri ¢ vrached to adjacent carbon atoms in Ar, and either R* © I Cig-atkylene and R? is hydrogen,
or K! anc 7 2 together with the carbon atoms in Ar to which they are attached denote a 5-, 6- or 7-membered cycloaliphatic ring;
Re is a bond 21 Ci-Cye-alkylene optionally substituted by hydroxy, Cs-Cie-aryl or C7-Cis- aralkyt: ed
Y is Cit oe 2eyl (C4-Cig-alkoiy or Ca-Cio-alkynyl; Ca-Cio-cycloalkyl optionally fused to one or nore ~:nx 52 rings and optionally substituted by C;-Cyo-alkyl, C3-Cio-cycloalkyl, C7-Cy4- aralky’, ('+-(:s-ara'kyloxy or Ce-Cio-aryl; Cs-Cro-aryl optionally substituted by halo, hydroxy,
Ci-Cio-al* +1, »henoxy, Ci-Cio-alkylthio, Cs-Cio-aryl, a 4- to 10-membered heterocyclic ring having at "cast one ring nitrogen atom, or by NRPR® where RP and Re are each independently
C1-Cic-alkv! oprionally substituted by hydroxy or phenyl or Rb may additionally be hydrogen; phenoiwy cetionally substituted by Ci-Cio-alkoxy; a 4- to 10-membered heterocyclic ring having a ies: one rin nitrogen or oxygen atom, said heterocyclic ring being optionally subst’ + ii Cj-Cieeaikyl, Ce-Cro-aryl, Cr-Cye-aralkyl, Ci-Cio-alkoxycarbonyl or by a 4- to 10-menier:< heterncyclyl-Ci-Cao-alkyl; -NRIR® where Rd is hydrogen or C;-Cio-alkyl and Re is C1-Coo-aikyl, or Re is a 4- to 10-membered heterocyclic ring having at least one ring nitrogen or oxyger atom which ring is optionally substituted by halo-substituted phenyl or Re is Cs-Cho- arylsultenvi optionally substituted by di(Ci-Cio-alkyl)amino; -SRf where Rf is C¢-Cio-aryl or
C7-Chs-avz- 1 optionally substituted by halo or Ci-Cio-haloalkyl; or -CONHRs where Rs is
Ci-lhercttos kvl or Ce-Ce-aryl.
Especial’ iv srrec compounds of formula I in free or salt or solvate form include those whe-ein
Xis -Floo Ror -Re-Y;
Ar duro; 2 phenylene group optionally substituted by halo, Ci-Cy-alkyl, Ci-Cs-alkoxy or by
Ci-Cii-allicy substituted by phenyl;
Rl ase Fo owre attached to adjacent carbon atoms in Ar, and either } 7+. Cy-atkyienc und R2 is hydrogen, of Ji ui . seetr er with the carbon atoms in Ar to which they are attached denote a 5-, 6- or “averted micloaliphatic ring, especially a S-membered cycloaliphatic ring;
Reis 2 bean rr Gy-Cy alkylene optionally substituted by hydroxy, Cs-Cs-aryl or C-Cyo-aralkyl; and
Y is Cy-Co-ulievl, Cr-Ca-alkoxy or Ca-Ce-alkynyl; Cs-Ce-cycloalkyl optionally fused to one or mers herr rings and optionally substituted by Ci-Cy-alkyl, Cs-Ce-cycloalkyl, C~Cio- ara” 007 eavalhybixy or Ce-Ce-aryl; Cs-Ca-aryl optionally substituted by halo, hydroxy,
Cave aencxy, Cr-Cs-alkylthio, Cs-Cs-aryl, a 4- to 8-membered heterocyclic ring haviar. :~:: ne -irg nitrogen atom, or by NRPR® where RP and Re are each independently
C1-Cs-alkyl optionally substituted by hydroxy or phenyl or Rb may additionally be hydrogen; phenoxy optionally substituted by Ci-Cs-alkoxy; a 4- to 8-membered heterocyclic ring having at least one ring nitrogen or oxygen atom, said heterocyclic ring being optionally substituted by C1-Cy-alkyl, Cs-Cs-aryl, Cr-Cyo-aralkyl, C1-Cs-alkoxycarbonyl or by a 4- to 8-membered heterocyclyl-Ci-Cy-alkyl; -NRER® where Rd is hydrogen or Ci-Cy-alkyl and Re is C1-Cy-alkyl, or
Re is a 4- to 8-membered heterocyclic ring having at least one ring nitrogen or sulphur atom which ring is optionally substituted by halo-substituted phenyl or Re is C¢-Cs-arylsulfonyl optionally substituted by di(C;-Cs-alkyl)amino; -SRf where Rf is Cs-Cs-aryl or C7-Cio-aralkyl optionally substituted by halo or Ci-Cs-haloalkyl; or -CONHRS where RS is Cs-Ce-cycloalkyl or Cs-Cy-aryl.
In a third aspect the present invention provides compounds of formula H
HN—R-Ar-R*
HO
S
=o [|]
N
OH in free or salt or solvate form, where
Ar denotes a phenylene group optionally substituted by one or more substituents selected from halogen, Ci-Cs-alkyl, Ci-Cs-alkoxy, C;-Cs-alkoxy-Ci-Cs-alkyl, or Ci-Cs-alkoxy substituted by phenyl, C;-Cs-alkyl-substituted phenyl or by C;-Cs-alkoxy-substituted phenyl,
R! and R? are attached to adjacent carbon atoms in Ar, and either R! is C;-Cs-alkylene and R? is hydrogen, C;-Cs-alkyl, Ci-Cs-alkoxy or halogen or R! and R2 together with the carbon atoms in Ar to which they are attached denote a 5-, 6- or 7- membered cycloaliphatic ring.
Further preferred compounds of formula I in free or salt or solvate form include those of formula III
RR . _y®
HO
R* yg
S
Ya . in free or salt or solvate form, where R! is C2-Cs-alkylene and R? is hydrogen, or R! and R2 together with the carbon atoms to which they are attached on the indicated benzene ring "denote a S-membered cycloaliphatic ring, R? and RS are each hydrogen, R* is hydrogen, C1-Ce- alkyl, C1-Cy-alkoxy or Ci-Cs-alkoxy substituted by phenyl and RS is hydrogen or Ci-Cs-alkyl.
Especially preferred compounds of formula I in free or salt or solvate form include those of formula II where R! is C;-Cj-alkylene, R2, R3, RS and R¢ are each hydrogen, and R* is C1-Cs- alkyl, C;-Cs-alkoxy or C;-Cs-alkoxy substituted by phenyl, and those where R! and R? together with the carbon atoms to which they are attached on the indicated benzene ring denote a cyclopentyl group fused to the benzene ring, R3 and RS are each hydrogen and R* and
RS are each independently hydrogen or C;-Cy-alkyl.
The compounds represented by formulae I, II or III are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable acid addition salts of the compounds of formula I include those of inorganic acids, for example, hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example aliphatic monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid and butyric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, aromatic carboxylic acids such as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids such as o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxynaphthalene- 2-carboxvlic acid or 3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such as methanesultonic acid or benzenesulfonic acid. These salts may be prepared from compounds of formula I by known salt-forming procedures.
In formulae I, IT and III, the carbon atom alpha to the phenolic ring carries a hydroxy group and so is asymmetric, so the compounds exist in individual optically active isomeric forms or as mixtures thereof, e.g. as racemic or diastereomeric mixtures. The invention embraces both individual optically active R and S isomers as well as mixtures, e.g. racemic or diastereomeric mixtures, thereof,
Specific especially preferred compounds of formulae I, II or IIl are those described hereinafter in the Examples.
The present invention alse provides a process for the preparation of compounds of formula I in free or salt or solvate form which comprises: (i) either {A) reacting a compound of formula IV
R—N—X
HO
S ow
OH where XY. is as hereinbefore defined and R7 denotes a protecting group, to replace R7 by hydrogen, or (B) reacting a compound of formula V
R—N—X
HO nS. —R’ v po rt ° vnere X and R7 are as hereinbefore defined and R? and R? each independently denote a protecting group, to convert groups R’, R8 and R? to hydrogen; and (ii) recovering the compound of formula I in free or salt or solvate form.
Where reference is made herein to protected functional groups or to protecting groups, the protecting groups may be chosen in accordance with the nature of the functional group, for example as described in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M.
Wats, John Wiley & Sons Inc, Second Edition, 1991, which reference also describes procedures suitable for replacement of the protecting groups by hydrogen.
The protecting group R” may be, for example, a group chosen from known amine-protecting groups. Preferred protecting groups R7 include araliphatic groups such as benzyl. Protecting groups R® and R® may be chosen from known phenolic hydroxy - and alcoholic hydroxy-
protecting groups respectively. Preferred groups R® and R? include Ci-Cs-alkyl groups, particularly branched groups such as isopropyl and tert-butyl.
Process variaat (A) may be effected, for example, using known procedures for conversion of arnine-prozecting groups to hydrogen or analogous procedures. For example, where R7 is a benzyl group .t may be converted to hydrogen by hydrogenolysis of the compound of formula
II, e.g. with a carboxylic acid such as formic acid, preferably in the presence of a palladium catalyst. This de-protection reaction may be carried out using procedures as described hereinafter in the Examples or analogous procedures.
Process variant (B) may be effected using known procedures for conversion of hydroxy- protecting groups to hydrogen or analogous procedures. For example, where, R? and R? are alkyl grouns, R® and R? may be converted to hydrogen by hydrogenolysis of the compounds of formula 1V, e.g. with a carboxylic acid such as formic acid preferably in the presence of a palladium catalyst, for example as hereinbefore described for conversion of R? to hydrogen, or by treatment with an acid alone such as formic acid, hydrochloric acid or trifluoroacetic acid, in either case the resulting 2-hydroxybenzothiazole compound being in tautomeric equilibrium with the benzothiazol-2-one form.
Compounds of formula IV may be prepared by reduction of a compound of formula VI
R—N—X
Op [ »=o vi
OH g where ¥ and E are as hereinbefore defined. The reduction may be effected using known methods far reduction of ketones to alcohols, or analogous methods, including asymmetric reductions. For example, the compounds of formula VI may be reacted with NaBH, in an inert solvent such as an aliphatic alcohol. Suitable reaction temperatures are from -80° C to 100° C, conveniently from -5° C to 5° C. The reduction may be effected using known procedures or analogously as described hereinafter in the Examples. :
Compeunds of formula V may be prepared by reacting a compound of formula VII
Claims (2)
1. uc owtof formuial HN—X ra aS, I { =O Se PR N H CH int. co oweelate [oon wherein Xig to oop -RaY; Ar (enote - 2 phenylene grou opticnally shbstituted by halo, hydroxy, Ci-Cje-alkyl, C1-Cio- alkcxy, 7 -C-p-alkoxy-C:-Cho-alkyl, phenyl, Ci-Cio-alkyl substituted by phenyl, Ci-Cio-alkoxy subctizie. 1. phenyl, C3-Cyo-alkyl-suborituted phenyl or by Ci-Cio-alkoxy-substituted phenyl; Rt nd are attacked to adiazert carbon atoms in Ar, and eitk + V7 Cyg-alkylene and Ri is hydrogen, Ci-Cio-alkyl, C1-Cio-alkoxy or halogen or F?rvd 0 onether with th2 carbo stoms in Ar to which they are attached denote a S-, 6- or 7-mem ered cycloaliphatic ring; } Re... +c ¢ 0p-Cro-alklenz optior. iy substituted by hydroxy, Ci-Cio-alkoxy, Ce-Cio-aryl ori wu xvliend Yis r oalkyl, G-Cop alkoxy, Ca-Clin-alkenyl or C2-Cio-alkynyl optionally substituted by in cvane. hydeegy. Co-Cie-a'keil. Cyi-Cyg-alkoxy or halo-Ci-Cio-alkyl;
C.-L .o-cycloalkyt optionally fuscd to one or more benzene rings and optionally stizured by C;-C aralkyl. C3-Cro-alkoxy, Cs-Cio-cycloalkyl, C7-Ci4-aralkyl, C7-Cis- wr exy 9 Ce-Cro-aryl, where Ci-Cio-cycloalkyl, Cr-Cis-aralkyl, C7-Cys-aralkyloxy roar, 1 are op.oonally subetituted by halo, hydroxy, Ci-Cio-alkyl, Ci-Cio-alkoxy ce =CreCye-aliev]s {is “..u-arvl optionally substituted by halo, hydroxy, Ci-Cie-alkyl, Ci-Cio-alkoxy, Ci- lizloalkyl, phencyv. C;-Tip-alkvithio, C¢-Cio-aryl, 4- to 10- membered heterocyclic
WO Thi PCT/EP2003/008824 rit © Raving at least one ring nitrogen, oxygen or sulphur atom, or by NRYR¢ where Rb an-l K:are each indepzndently Cy Cio-alkyl optionally substituted by hydroxy, Ci-Cio-
all. ony or phenyl or 2° may additionally be hydrogen; pli .xv optionally substituted by Ci-Cie-alkyl, C;-Cio-alkoxy or by phenyl optionally = + red 37 C-Caralkyl or C--Coo-2lkoxy; a 2+ 10-memberzd heterocyel's ring having at least one ring nitrogen, oxygen or sul hui atom, said heterocyclic ring being optionally substituted by halo, C1-Cio-alkyl, C+ C c-alkoxy, bali:-C:-Cio-alky!, Cs-Cro-aryl, C7~Cis-aralkyl, C;-Cis-aralkyloxy, C;- (1 -a:koxycarbonvl or a 4- to 10-memberad heterocyclyl-Cs-Cio-alkyl; “Lmwhere Rd is badrogen or (C1-Cio-alkyl and Re is C;-Cio-alkyl optionally sibs tuted oy hydrox, or Re is Cg-Cho-aryl optionally substituted by halo, or Re is a 4- tw 10 pemkered heerocyclic ring having at least one ring nitrogen, oxygen or sulphur avs.» which ring is optionally su bstituted by phenyl or halo-substituted phenyl or Re is i Cro-arylsulfonyl optionally substituted by Cy-Co-alkylamino or di{Ci-Cio- aikyl> imino; - here RE Co-Crp-eryl or Gy-Cys-aralkyl optionally substituted by halo, Ci-Cio- a bo $r-Ca-alkoxv or Ci-Cae-hz\oalkyl; or Dt Re where (03 5s Ci-Caa. vl, Ca-Che-cycloalkyl or C¢-Cio-aryl.
2. A cciinenad according to Hlzim 1, wm which Xis Rew bor -Ra-Y; Ar dena: . henv'ene group optionally substituted by halo, Ci-Cie-alkyl, Ci-Cyo-alkoxy or by O;-0 Lay iubsdosied cy oneny!; Rland tt i strached ro adjacent carbon atoms in Ar, and either R' 7 + - “o-ukvien: and R2is hy “rogen, or R! and wogetiier with the carbon zroms in Ar to which they are attached denote a 5-, 6- or 7-me 1! 2rd cycloaliphatic ring; Rais a bi dr C-Crgmalkvione opticnaily substituted by hydroxy, Cs-Cio-aryl or C7-Cia- aral'sal, Yi Co “erly CoCr dke wv or Ca-Umealkynyl; C3-Cro-cycloalkyl optionally fused to one or more «1: 2 rings arc otionaly substituted by Cy-Cio-alkyl, Cs-Cro-cycloalkyl, C7-Cia-
aralv 1. Co Cs-aralkyloxy opdonally sabstivzted by halo, or by Ce-Cio-aryl optionally subetvoo 0 Up igalked or CC emalkoxy; Cs-Che-aryl optionally substituted by halo, nyo lean] ob ancy, C-Coollylthio, Cs-Cio-aryl, a 4- to 10-membered heteroc:i'z © rg having ar least one ring nitrogen atom, or by NRPR¢ where R? and Reare each indepcaently Ci-Cis-alkyl optisnalty substituted by hydroxy or phenyl or Rb may additionally te hydrogen; phenoxy optionally substituted by Ci-Cie-alkoxy; a 4- to 10- membere: i reserocyclic ring having at least one ring nitrogen or oxygen atom, said heterocyclic ring: bene aniionally substituted bv Cy-Cho-alkyl, Cs-Cho-aryl, Cr-Cis-aralkyl, Ci-Cio- alkoxv + bor by a 4 so [0-membered heterocyclyl-Ci-Cio-alkyl; -NRIR¢ where RY is hve raze cg 0-Creeatky] 2ac Re je Ci-Crealkvl, or Re is a 4- to 10-membered heterocyclic ring having «it Va ir one ring nitrogen or (xveer atom which ring is optionally substituted by halo- substitu eu cavl or Reis C -Che-aryisaifonyvl] optionally substituted by di(Ci-Cio-alkyl)amino; -SRfwhire Rf js Cs-Crg-arvl or Cr7-Cig-aralkyl optionally substituted by halo or C;-Cio- haloalky.: or -CONHRS where R# is C3-Cio-cycloalkyl or Cs-Cyo-aryl.
3. covert cerording to claim 2, in which Xii-b ENGLERT Ar tec 0 280 oheny.ene ger eptioraly substituted by halo, Ci-Cs-alkyl, C1-Cs-alkoxy or by Ci-Ce-a:b wy abstoated sv shen: Rlard “1 = ¢ attached to advicent carbon atoms in Ar, and either R? j< © -Cy-ulkvlene and R? is hydrogen, - or Ra: 1? -ogethier with the carbon atoms in Ar to which they are attached denote a 5-, 6- or’ or Le cyooalithatis ring especially a S-riembered cycloaliphatic ring; ESN Tne 7a oadonally subscituted by hydroxy, Ce-Cs-aryl or C~Cyo-aralkyl; aald Yiv Go esto CCrelbox, or Co Coalkynvly Cs-Ce-cycloalkyl optionally fused to one or morz hei i sings and ootivaally substituted by Ci-Ce-alkyl, C3-Ce-cycloalkyl, C7-Cio- aralkyt, ©. -Cip erathyioxy op renally substituted by halo, or by Cs-Cs-aryl optionally substitu: J iy C-Cyelky! or Ci-Crealke <y; Ce-Cs-aryl optionally substituted by halo,
hyd. 7 Coalaly ol nes v, C-Ca-alkrtthio, Ce-Cs-aryl, a 4- to 8-membered heterocyclic ring cote me tol reteset a ue. <r by NRPRe where RP and Reare each ingen oo -Upe dy eoationaily subetitutzd by hydroxy or phenyl or RP may additionally be hiv ivo hanes ovicenally suber tated by Ci-Co-alkoxy; a 4- to 8-membered hetzrozv 1 © ir having at ie st ope iro nitrogen or oxygen atom, said heterocyclic ring being opt'onaliv itsivured by Ci-t-a’kyl, Ce -Ci-aryl, Cr7-Cro-aralkyl, C;-Cy-alkoxycarbonyl or by a 4- to E-pwarbered heter:cyivi-Cy-Cy-alkyl; -NRIRe where R? is hydrogen or Ci-Cs-alkyl and wo ' PCT/EP2003/008824 Reis Cove 0 Lor Reis = 4 to §-mertwered heterocyclic ring having at least one ring nitreges or vicar atoms which ring is ootionally substituted by halo-substituted phenyl or Re is Coors = 1 onl optically substitviad by di(Cs-Ce-alkyl)amino; -SRf where Rf is Cs-Cs-
ary. © 3. 0 vrdod apis dy enlstitieed by halo or Cy-Cy-haloalkyl; or -CONHRS where ke. aoaevlor aU gar i, 4, sc. accerding 0 ain Dir tree or sale or solvate form, wherein : x ie ber or ITH Ye Ar donee so onvlens grown, optionally sebstitated by halo, hydroxy, Ci-Cie-alkyl, Ci-Cio- allene 0 alkony-Co alkyl, cher vl, Ci-Cog-alkyl substituted by phenyl, Ci-Cio-alkoxy suber ro hy chev Cy Chperlkyl-cubstiroted phenyl or by Ci-Cyo-alkoxy-substituted phenyl; Fi: oo peebeg to udiccenr zarbon atoms in Ar, and eith © 7 Ui akylere and RY is hydrogen, Ci-Cio-alkyl, Ci-Cio-alkoxy or halogen or Bc 0 ocetwewitt whe carbon cooms in Ar to which they are attached denote a 5-, 6- or 7 re: tr boycloa¥olare ting; Raina i wt rm Ce yealkrlens opticarlly substituted by hydroxy, Ci-Cio-alkoxy, Ce-Cio-aryl or (~". 1 “bend Yie 0. eel, Goerlieaikox, Coe Tro-alkenyl or Co-Cro-alkynyl optionally substituted by ne hangs Op-ealkyt, Gr-Cho-alkoxy or halo-Ci-Cio-alkyl; + cwziznikyl cio onal’ fused -o one or more benzene rings and optionally Cored By CTL alked Ohara tkoxy, Ca-Cro-cycloalkyl, Cr7-Cis-aralkyl, C7-Cia- ww ony ol Clegg rel option atly substituted by halo, hydroxy, Ci-Cie-alkyl, Cs- Ca ay er satu Death, velo vb endorse rubsiiouces by halo, hydroxy, Ci-Cie-alkyl, Ci-Cio-alkoxy, Cs- Cae GL ob se DC tonite, Ce-Cao-aryl,y 4- to 10- membered heterocyclic el ba fam hab acy oxygen or sulphur atom, or by NRPRe where Rb Co ce ark dese dese $-Cho-alkyl optionally substituted by hydroxy, Ci-Cio- cox oop sngnyl or 2 ray addiienelly be hydrogen Coton ofnata suinttate 3 he U-Che alkyl, Ci-Cro-alkoxy or by phenyl optionally on ood vale alkd or Cs-atkoxy; i 1leweaboe emerocyai ving having at least one ring nitrogen, oxygen or sone sev creeyvelic ac being optionally substituted by halo, Ci-Cho-alkyl,
Co. Swetz Cg oa ky s-Cagearyl, Cr-Cue-aralkyl, C7-Cis-aralkyloxy, Cs- : senkas oo ad on i owemt ered heterocyelyl-Cy-Cyo-alkyls whe #591 drogen or Uy-Croealkyl and Re is Ci-Cio-alkyl optionally hoo ad bby eon or Reds (Co he-ary] optionally substituted by halo, or Re is a 4-
WO eg apr PCT/EP2003/008824
1.2" ahmed hee coclic river having at least one ring nitrogen, oxygen or sulphur © «ch “ng opronally sot utiruted by phenyl or halo-substituted phenyl or Re is ty arytsvlfon 1 onticnally substituted by Ci-Cio-alkylamino or di(Ci-Cho-alkyl)- SRS I2 Ere Ris Gg Caryl ar C-Cha-aralkyl optionally substituted by halo, Ci-Cio- Leeson or Co-UC gha alkyl; or coe ae mere ves CoC econ. Co-Cra cycloalkyl or Cs-Cho-aryl.
S. Accor oo amnordim, oo lzim £0 which Xis-RV-ar | = REY Ar denc: i: ienylene group ontionally substituted by halo, Ci-Cio-alkyl, Ci-Cyo-alkoxy or by Ci- C+. “1 nv enbstirat:-d by pheavl; Rland i’ oached to advent carbo z*oms in Ar, and eithee 1 + 4 oaalioder sa BZ in be open, or R? ov othr» 1b carbon» crms in Ar to which they are attached denote a §-, 6- or 7-me itor yclealiphonc ing: Raisa to Cp€alkeiene opricnaliy substituted by hydroxy, Cs-Cie-aryl or C-Cis- aralkvly Yis Con UL C5-Chamalbovy or Co-Cho-alkynyl; Cs-Cro-cycloalkyl optionally fused to one or more Lorzz tnngs and codonally sutstituted by Ci-Cro-alkyl, C3-Cio-cycloalkyl, C7-Cis- aralky © 0 cormiovles, or De-ia2ny Ci-Cra-aryl optionally substituted by halo, hydroxy, CrCl fiwaw, C0 lkydthon, 1.2 Crveeryl, a 4- to 10-membered heterocyclic ring haviry: | adn roo varem, or v7 2 IRPRC where RP and Reare each independently City Dy ens raed 9v hy teovy or phenyl or RP may additionally be hydrogen; phency +, Ache urst by €5-Che alkoxy; a 4- to 10-membered heterocyclic ring having <1 .. =" ne ring nitrogen or oxygen atom, said heterocyclic ring being optionally substitu, i, 1 Coralkot, €L-Curarvl, Cr-Cig-aralkyl, Ci-Cho-alkoxycarbonyl or by a 4- to 10-vse 0 cima yetl Seeadeve T3900 where RY is hydrogen or Ci-Cho-alkyl and Re is C0 v Eras 0 oem co hererocyclic ring having at least one ring nitrogen oroxviy . whine is. otienally evtstirated by halo-substituted phenyl or Re is Ce-Cio- aryl 1.0 rae su fad ny 0) CC -alkyl)amino; -SRf where Rf is Cs-Cyo-aryl or Co-Urertins wrcnally subocrated by fiala or C1-Cro-haloalkyl; or -CONHRE where Ré is C3-Cio-¢o vl aryl or Celio,
6. Acs ecient in ich Xie BF SSE
WoO PCT/EP2003/008824 Arne rao chenylene grou oprionally substituted by halo, C;-Cy-alkyl, Ci-Cy-alkoxy or by Ci-t2+ oc uhsututed by vhenyl; RUSS Leben aie fedi Zod atoms in Ar, and either EN I RERUN (It Ser 2 or “loi cletier ob eescbor wrms in Ar to which they are attached denote a S-, 6-
or’. SRE “nz. wstacia'ly 4 S-membered cycloaliphatic ring; Raise - Ded eats ven oprionsile substituted by hydroxy, Ce-Cs-aryl or C7-Cro-aralkyl; anu Yis Civ gan iy Cr-Cye2 Nios or Ga-Ca-alkynyly Cs-Ce-cycloalkyl optionally fused to one or ma frend cro wdly snbatineed by Ci-Ce-alkyl, Ca-Ce-cycloalkyl, Cr-Cio- arab cor wines pe e-Ceerve (s-Ca-aryl optionally substituted by halo, hydroxy, C12 corsa 0 Ualienliking Us-Ceeuryl, a 4- to 8-membered heterocyclic ring Fev sacrrr woenevory of by NRPRe where RP and Reare each independently CoCo vinmely oro, ted by hydroxy or phenyl or RP may additionally be hydrogen; pheno cpt. wally cubstimd by C1-Cs-alkoxy; a 4- to 8-membered heterocyclic ring having aticast «wv 5 piteogen or sxygen atom, said heterocyclic ring being optionally substituted by Cs 7 cyt Ce-Cs-aryl. 1. ~Cyc-ara'kyl, Ci-Cs-alkoxycarbonyl or by a 4- to 8-membered hetero rb Cle ley -DIFPIR svhere RE is hydrogen or Ci-Cy-alkyl and Re is Cy-Cy-alkyl, or Rei oz ep herea te racy TC virg saving at least one ring nitrogen or sulphur atom whit deadly il area by hele-sebstituted phenyl or Re is Cg-Cy-arylsulfonyl optic, aed by co =a siky Suminos -SRfwaere Rf is Cg-Cs-aryl or C7-Cho-aralkyl optisinii v1. -ameed by sa or C:-Ce-taloalkyl; or -CONHRE where Rs is C3-Ce-cycloalkyl or C0, a To + ueeeord'ne t+ <lsiie Locher ris also a compound of formula II ow —lopr-R po. i el TI J==0 0 NTN , H oH inf Sse aEe {U0 Whore PESUNENT wong encsalls cubs seted by one or more substituents selected from bales i ere tney ealkoxy-Cr-Coealkyl, or Ci-Cs-alkoxy substituted by phe: reste 3 phen er vs Ch-Ce-alkoxy-substituted phenyl,
WO Toa PCT/EP2003/008824 LES cxited to ac ene carb atoms in Ar, and ¢icher boo Crakylens sed Res ocen, Cy-Cealkyl, Ci-Cs-alkoxy or halogen or R! and Routt or with the carton atoms in Ar to which they are attached denote a 5-, 6- or 7- member: oo lealiphatic ring.
£. wo otac.ording to claim 7 thc is also a compound of formula II “\ R® a 4 t= RA R HO Tr a RA Ad —~S, J =o 7 N [|] H CH inte: » 1 rsolvate forr,, where RY ia C2-Ce-alkylene and R? is hydrogen, or R1 and R2 togstiv. © cevarbom cirms to which the, are attached on the indicated benzene ring derote oo mberea eye cal phane rey, 13 and RS are each hydrogen, R* is hydrogen, Ci-Ci- alkyl, C = alkoxy or Ci-Ce alkoxy substituted by phenyl and RS is hydrogen or Ci-Cs-alkyl.
S. A cor vo =l of forraula 1 as dedined in (Jaim 1, substantially as described in any one of the loreveaz ples wn. CA ezewrdin ov ans oeading claim for use as a pharmaceutical.
11. Ayo .occeorcal compusirion comprising as active ingredient a compound according to any oie of ©. Lio 9, oywionally togziher with a pharmaceutically acceptable diluent or carriet ©. © 2
12. ke. mpound acerrding to any one of claims 1 to 9 for the manufacture of a mero © wrhr treaties - of 5 cendizon which is prevented or alleviated by activation of che 1p ero
33. Use = 4 «unpound according to any one of claims 1 to 9 for the manufacture of a medic:r: + “wr rhe treatment of an obstructive or inflammatory airways disease.
Wer PCT/EP2003/008824
14. A mec. for the preparation of a cemnonnd of formula I as claimed in claim 1 which Comin is. =. (i ¢ © A) reacting 1 compound of formula IV RE—N-—X I
HO. - A PN --S TT Np Iv Ny Loh / ~~ N rH OH «iis as defined in Claim « and R7 denotes a protecting group, to replace R7 by ER roeen, or (J reacting a2 compound of formula V HEREIES ¢ 1 HO—~_ ; As TH I v ol 7 “N RC were X ard R7 ave as hereinbetore defined and R® and R? each independently denote
2.ting, group, to convert ous R7, RY and R? to hydrogen; and (ii) >. rng che cor prund of formula in free or salt or solvate form.
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| GB0218629A GB0218629D0 (en) | 2002-08-09 | 2002-08-09 | Organic compounds |
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ID=9942087
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200500371A ZA200500371B (en) | 2002-08-09 | 2005-01-14 | Benzothiazole derivatives having Beta-2-adrenoreceptor agonist activity |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN1301980C (en) |
| GB (1) | GB0218629D0 (en) |
| ZA (1) | ZA200500371B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB201107985D0 (en) * | 2011-05-13 | 2011-06-29 | Astrazeneca Ab | Process |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9211172D0 (en) * | 1992-05-27 | 1992-07-08 | Fisons Plc | Compounds |
| TW356468B (en) * | 1995-09-15 | 1999-04-21 | Astra Pharma Prod | Benzothiazolone compounds useful as beta2-adrenoreceptor and dopamine DA2 receptor agonists process for preparing same and pharmaceutical compositions containing same |
| GB9526511D0 (en) * | 1995-12-23 | 1996-02-28 | Astra Pharma Prod | Pharmaceutically active compounds |
-
2002
- 2002-08-09 GB GB0218629A patent/GB0218629D0/en not_active Ceased
-
2003
- 2003-08-08 CN CNB038182939A patent/CN1301980C/en not_active Expired - Fee Related
-
2005
- 2005-01-14 ZA ZA200500371A patent/ZA200500371B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GB0218629D0 (en) | 2002-09-18 |
| CN1701064A (en) | 2005-11-23 |
| CN1301980C (en) | 2007-02-28 |
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