ZA200406752B - Azetidine derivatives as CCR-3 receptor antagonists - Google Patents
Azetidine derivatives as CCR-3 receptor antagonists Download PDFInfo
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- ZA200406752B ZA200406752B ZA200406752A ZA200406752A ZA200406752B ZA 200406752 B ZA200406752 B ZA 200406752B ZA 200406752 A ZA200406752 A ZA 200406752A ZA 200406752 A ZA200406752 A ZA 200406752A ZA 200406752 B ZA200406752 B ZA 200406752B
- Authority
- ZA
- South Africa
- Prior art keywords
- alkyl
- substituted
- phenyl
- formula
- optionally substituted
- Prior art date
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- 102000004499 CCR3 Receptors Human genes 0.000 title description 2
- 108010017316 CCR3 Receptors Proteins 0.000 title description 2
- 239000002464 receptor antagonist Substances 0.000 title description 2
- 229940044551 receptor antagonist Drugs 0.000 title description 2
- 150000001539 azetidines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 113
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 113
- 229910052739 hydrogen Inorganic materials 0.000 claims description 85
- 239000001257 hydrogen Substances 0.000 claims description 85
- 125000001424 substituent group Chemical group 0.000 claims description 77
- 229910052757 nitrogen Inorganic materials 0.000 claims description 61
- 229910052736 halogen Inorganic materials 0.000 claims description 54
- 150000002367 halogens Chemical class 0.000 claims description 53
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 49
- 125000000623 heterocyclic group Chemical group 0.000 claims description 48
- 125000001624 naphthyl group Chemical group 0.000 claims description 48
- 229910052760 oxygen Inorganic materials 0.000 claims description 47
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 45
- 239000001301 oxygen Substances 0.000 claims description 44
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 43
- -1 Ci-Cs-alkoxy Chemical group 0.000 claims description 39
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 37
- 125000005842 heteroatom Chemical group 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 31
- 125000006413 ring segment Chemical group 0.000 claims description 31
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 30
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 28
- 229910052717 sulfur Chemical group 0.000 claims description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 150000003839 salts Chemical group 0.000 claims description 23
- 239000011593 sulfur Chemical group 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 21
- 125000006239 protecting group Chemical group 0.000 claims description 21
- 125000004423 acyloxy group Chemical group 0.000 claims description 19
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 19
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims description 18
- 125000000524 functional group Chemical group 0.000 claims description 18
- 150000002431 hydrogen Chemical group 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 239000000460 chlorine Substances 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 239000011737 fluorine Substances 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- 125000002252 acyl group Chemical group 0.000 claims description 15
- 125000004429 atom Chemical group 0.000 claims description 15
- 125000005605 benzo group Chemical group 0.000 claims description 14
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 13
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 13
- 125000004122 cyclic group Chemical group 0.000 claims description 13
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 10
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
- 239000005864 Sulphur Substances 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- 125000000962 organic group Chemical group 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000004442 acylamino group Chemical group 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 11
- 230000002757 inflammatory effect Effects 0.000 claims 2
- 206010027654 Allergic conditions Diseases 0.000 claims 1
- 101100515516 Arabidopsis thaliana XI-H gene Proteins 0.000 claims 1
- 102100024167 C-C chemokine receptor type 3 Human genes 0.000 claims 1
- 101710149862 C-C chemokine receptor type 3 Proteins 0.000 claims 1
- 208000027771 Obstructive airways disease Diseases 0.000 claims 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000008186 active pharmaceutical agent Substances 0.000 claims 1
- 230000001387 anti-histamine Effects 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 claims 1
- 239000000739 antihistaminic agent Substances 0.000 claims 1
- 229940124630 bronchodilator Drugs 0.000 claims 1
- 229940088679 drug related substance Drugs 0.000 claims 1
- 125000001188 haloalkyl group Chemical group 0.000 claims 1
- 208000027866 inflammatory disease Diseases 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000001404 mediated effect Effects 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 30
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 125000005843 halogen group Chemical group 0.000 description 10
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- 239000002585 base Substances 0.000 description 4
- 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 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
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- 150000005826 halohydrocarbons Chemical class 0.000 description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
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- 125000003341 7 membered heterocyclic group Chemical group 0.000 description 2
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- 125000003277 amino group Chemical group 0.000 description 2
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
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- BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical class NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
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- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
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- 229910052749 magnesium Inorganic materials 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
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 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
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 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
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000005400 pyridylcarbonyl group Chemical group N1=C(C=CC=C1)C(=O)* 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 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
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 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
- 125000001425 triazolyl group Chemical group 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
AZETIDINE DERIVATIVES AS CCR-3 RECEPTOR ANTAGONISTS
This invention relates to organic compounds, their preparation and their use as : pharmaceuticals.
In one aspect the invention provides compounds of formula I
H H Y R’ 0 a A
Ar—X N Cc C—N Cc N S R [
Tm 7 nT TU
H R" H 0) in free or salt form, where
Ar is phenyl optionally substituted by one or more substituents selected from halogen,
C;-Cs-alkyl, cyano or nitro;
R! is hydrogen or C;-Cs-alkyl optionally substituted by hydroxy, C1-Cs-alkoxy, acyloxy, halogen, carboxy, Ci-Cs-alkoxycarbonyl, -N(R#)R?, -CON(R€)R or by a monovalent cyclic organic group having 3 to 15 atoms in the ring system;
R2 is hydrogen, C1-Cg-alkyl or C3-Cio-cycloalkyl and R3 is Ci-Cs-alkyl substituted by phenyl, phenoxy, acyloxy or naphthyl, or R3 is C3-Cio-cycloalkyl optionally having a benzo group fused thereto, a heterocyclic group having 5 to 11 ring atoms of which 1 to 4 are hetero atoms, phenyl or naphthyl, said phenyl, phenoxy or naphthyl groups being optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, acyl, nitro, -SO2NH;, C;i-Cs- alkyl optionally substituted by Ci-Cs-alkoxy, C1-Cs-haloalkyl, C-Cs-alkoxy, Ci-Cs- haloalkoxy, Ci-Cs-alkylthio, -SO2-C1-Cs-alkyl, C1-Cs-alkoxycarbonyl, C1-Cs-acylamino optionally substituted on the nitrogen atom by C1-Cs-alkyl, C1-Cs-alkylamino, aminocarbonyl,
C1-Cs-alkylamino-carbonyl, di(Ci-Cs-alkyl)amino, di(Ci-Cs-alkyl)aminocarbonyl, di(Cs-Cs- alkyl)aminocarbonyl-methoxy, or R? and R3 together with the nitrogen atom to which they are attached denote a heterocyclic group having 5 to 10 ring atoms of which 1, 2 or 3 are hetero atoms; . R* and RS are each independently hydrogen or C;-Cs-alkyl, or R* is hydrogen and RS is hydroxy-Ci-Cs-alkyl, acyl, -SO2R® or ~CON(RS$)R7, or R* and RS together with the nitrogen * atom to which they are attached denote a 5-or 6-membered heterocyclic group;
RS and R7 are each independently hydrogen or Ci-Cs-alkyl, or Ré and R7 together with the nitrogen atom to which they are attached denote a S- or 6-membered heterocyclic group;
R# is C;-Cs-alkyl, Ci-Cs-haloalkyl, or phenyl optionally substituted by Ci-Cs-alkyl;
X is -C(=0)-, -O-, =CHa-, or CH(OH);
Y is oxygen or sulfur; mis1,2,3 or4; and n, p and q are each 0 or 1, n+p+q=1 or 2, n+q=1, p+q=1, and when nis 0, p is 0.
Terms used in the specification have the following meanings: “C1-Cs-alkyl” as used herein denotes straight chain or branched C;-Cs-alkyl, which may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight or branched pentyl, straight or branched hexyl, straight or branched heptyl, or straight or branched octyl. Preferably, Ci-Cs-alkyl is Ci-Ca-alkyl. “C3-Cio-cycloalkyl” as used herein may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl, cycloheptyl, bicycloheptyl, cyclooctyl, bicyclooctyl, bicyclononyl, tricyclononyl or tricyclodecyl. “C1-Cs-alkoxy” as used herein denotes straight chain or branched C1-Cs-alkoxy which may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, straight or branched pentoxy, straight or branched hexyloxy, straight or branched heptyloxy, or straight or branched octyloxy. Preferably, C;-Cs-alkoxy is C1-Cs-alkoxy. “C1-Cs-haloalkyl” as used herein denotes C;-Cs-alkyl as hereinbefore defined substituted by one or more halogen atoms, preferably one, two or three halogen atoms. “C1-Cs-haloalkoxy” as used herein denotes C;-Cs-alkoxy as hereinbefore defined substituted by one or more halogen atoms, preferably one, two or three halogen atoms. “Aminocarbonyl” as used herein denotes amino attached through the nitrogen atom to a carbonyl group. . "C;-Cs-alkylamino" and "di(C;-Cs-alkyl)amino"” as used herein denote amino substituted respectively by one or two Ci-Cs-alkyl groups as hereinbefore defined, which may be the same ~ or different. Preferably Ci-Cs-alkylamino and di(C;-Cs-alkyl)amino are respectively Ci-Cs- alkylamino and di(Cy-Cs-alkyl)amino.
"C;-Cs-alkylaminocarbonyl” and "di(Ci-Cs-alkyl)aminocarbonyl" as used herein denote aminocarbonyl as hereinbefore defined substituted respectively on the nitrogen atom by one or . two C1-Cs-alkyl groups as hereinbefore defined, which may be the same or different.
Preferably C;-Cg-alkylaminocarbonyl and di(Ci-Cs-alkyl)aminocarbonyl are respectively Ci-Ca- alkylaminocarbonyl and di(C;-Cs-alkyl)aminocarbonyl. “C1-Cs-alkylthio” as used herein denotes C;-Cs-alkyl as hereinbefore defined linked to -S-. “Acyl” as used herein denotes alkylcarbonyl, for example Ci-Cs-alkylcarbonyl where Ci-Cs- alkyl may be one of the Ci-Cs-alkyl groups hereinbefore mentioned, optionally substituted by one or more halogen atoms; cycloalkylcarbonyl, for example Cs-Cs-cycloalkylcarbonyl where
Cs-Cs-cycloalkyl may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; 5- or 6- membered heterocyclylcarbonyl having one or two hetero atoms selected from nitrogen, oxygen and sulfur in the ring, such as furylcarbonyl or pyridylcarbonyl; arylcarbonyl, for example Cs-Cro-arylcarbonyl such as benzoyl; or aralkylcarbonyl, for example Cs to Cio-aryl-Cy-Cs-alkylcarbonyl such as benzylcarbonyl or phenylethylcarbonyl. Preferably acyl is Ci-Cs-alkylcarbonyl. “ Acyloxy” as used herein denotes alkylcarbonyloxy, for example C;-Cs-alkylcarbonyloxy where C;-Cs-alkyl may be one of the C;-Cs-alkyl groups hereinbefore mentioned, optionally substituted by one or more halogen atoms; cycloalkylcarbonyloxy, for example Cs-Cs- cycloalkylcarbonyloxy where Cs-Cs-cycloalkyl may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; 5- or 6- membered heterocyclylcarbonyloxy having one or two hetero atoms selected from nitrogen, oxygen and sulfur in the ring, such as furylcarbonyloxy or pyridylcarbonyloxy; arylcarbonyloxy, for example Ce-Cio- arylcarbonyloxy such as benzoyloxy; or aralkylcarbonyloxy, for example Cs to Cio-aryl-Ci-Cs- alkylcarbonyloxy such as benzylcarbonyloxy or phenylethylcarbonyloxy, or aryloxyalkylcarbonyloxy, for example, Cs-Cio-aryloxy-Ci-Cs-alkylcarbonyloxy, any of which is optionally substituted in the aryl moiety by at least one substituent selected from C;-Cs- ’ alkoxy, halogen, C;-Cs-alkylcarbonyl, aminosulfonyl, Ci-Cs-alkylaminosulfonyl and di(C;-Cs- alkyl)aminosulfonyl. Preferably acyloxy is C1-Cs-alkylcarbonyloxy, or benzoyloxy or ) phenoxy-Ci-Ca-alkylcarbonyloxy optionally substituted in the benzene ring thereof by at least one substituent selected from Ci-Cs-alkoxy, C1-Cs-alkylcarbony! or aminosulfonyl. « Acylamino” as used herein denotes amino substituted by acyl as hereinbefore defined.
“Halogen” as used herein may be fluorine, chlorine, bromine or iodine; preferably it is fluorine, chlorine or bromine. “Cy-Cs-alkoxycarbonyl” as used herein denotes Ci-Cs-alkoxy as hereinbefore defined attached . through the oxygen atom to a carbonyl group. “Di-(Ci-Cs-alkyl)aminocarbonylmethoxy” as used herein denotes aminocarbonylmethoxy disubstituted on the amino nitrogen atom by C;-Cs-alkyl as hereinbefore defined, the two
C1-Cs-alkyl groups being the same or different. "Optionally substituted" means the group referred to can be substituted at one or more positions by any one or any combination of the radicals listed thereafter.
In Ar, the phenyl group may be substituted, for example by one, two or three, preferably one or two halogen atoms, preferably selected from fluorine and chlorine atoms, or by one or two
C1-Cs-alkyl, cyano or nitro groups, or by Ci-Cs-alkyl and one or two halogen, preferably fluorine or chlorine, atoms. When there is one halogen substituent, it is preferably para to the indicated group X. When there are two or three halogen substituents, preferably one is para to the indicated group X and at least one of the others is ortho to the para-halogen substituent.
R3 as substituted phenyl may, for example, be substituted by one, two, three, four or five, preferably by one, two or three, of the abovementioned substituents. R3 may be, for example, phenyl substituted by one, two or three substituents selected from halogen, cyano, hydroxy, nitro, Cy-Ca-atkoxy, Ci-Cs-alkoxycarbonyl, Ci-Cs-haloalkoxy, -CO-NHz, di(Cy-Cs- alkyl)aminocarbonylmethoxy, Ci-Cs-alkyl optionally substituted by C;-Cs-alkoxy, Ci-Cs- haloalkyl, Ci-Cs-alkylcarbonyl, Ci-Cs-alkylthio, -SO2-NH,, -50,-C1-Cs-alkyl, di(Cy-Cs- alkyl)amino, C;-Cs-alkylaminocarbonyl or Ci-Cs-alkyl-carbonylamino. R3 as substituted phenyl is preferably phenyl substituted by one or more substituents selected from cyano, halogen, Ci-Ca-alkyl optionally substituted by Ci-Cs-alkoxy, Ci1-Cs-alkylcarbonyl, C;-Cs- ’ alkoxy, Ci-Cs-alkoxycarbonyl, -CO-NHoz, -5O2-NH,, -$02-C1-Cs-alkyl, Ci-Cs-alkyl- aminocarbonyl, di(C1-Cs-alkyl)aminocarbonyl-methoxy or Ci-Cs-alkyl-carbonylamino, especially cyanophenyl, particularly meta-cyanophenyl, and disubstituted phenyl where one substituent is C1-Cas-alkoxy or di(C1-Cs-alkyl)aminocarbonylmethoxy, preferably ortho to the bond linking R3 to the remainder of the molecule shown in formula I, and the other, preferably para to the Ci-Cs-alkoxy group, is C1-Cs-alkoxy, halogen, cyano or Ci-Cs-alkyl.
When R3 is Ci-Cs-alkyl substituted by optionally substituted phenoxy, the substituent(s) on phenoxy may be, for example, one, two or three substituents selected from halogen, cyano, . C1-Cs-alkyl, C1-Cs-alkoxy or Ci-Cs-alkylcarbonyl. : R3 as a heterocyclic group may be, for example, a group having § to 11 ring atoms of which one, two, three or four, preferably one or two, are hetero atoms selected from nitrogen, oxygen or sulfur, such as pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyranyl, pyrazinyl, or a S-, 6- or 7-membered heterocyclic, ring preferably having one or two oxygen or nitrogen ring atoms, fused to a benzene ring, said heterocyclic group being optionally substituted by substituents including halogen, Ci-Cs-alkyl optionally substituted by
C1-Cs-alkoxy, Ci-Cs-alkoxy, -SO,-Ci-Cs-alkyl, Cs-Cio-cycloalkyl, phenyl, phenyl-C;-Cs-alkyl and C-Cs-alkynyl.
R2 and R3 together with the nitrogen atom to which they are attached as a heterocyclic group may be, for example, a group having a 5- or 6-membered ring of which one, two or three are heteroatoms, optionally fused to a benzene ring, such as piperidyl, piperazinyl, morpholino, or benzopiperidyl, optionally substituted by one or more substituents including Cy-Cs-alkyl, Ci-
Cs-alkoxy, Cs-Cio-cycloalkyl and halogen.
R! as optionally substituted C1-Cs-alkyl is preferably optionally substituted Ci-Cs-alkyl, especially Ci-Ca-alkyl or substituted methyl or ethyl. When R! is substituted by a cyclic organic group, the latter may be a carbocyclic or heterocyclic group, for example a C3-Cys-carbocyclic group or a 5- to 7-membered heterocyclic group having one or more, preferably one, two or three, ring hetero atoms selected from nitrogen, oxygen and sulfur. The C3-Cis-carbocyclic group may be, for example, a cycloaliphatic group having 3 to 8 carbon atoms, preferably Cs - or Cs - cycloalkyl such as cyclopentyl, methylcyclopentyl or cyclohexyl. The Cs-Cis-carbocyclic group may alternatively be, for example, a C¢-Cis aromatic group, such as phenyl, which is unsubstituted or substituted by Ci-Cs-alkyl, Ci-Cs-alkoxy, halogen, cyano, -CON(R#)RS, -
SO:N(R*)RS or Cy-Cg-alkylsulfonylamino where R* and RS are as hereinbefore defined. The heterocyclic group may have one nitrogen, oxygen or sulfur atom in the ring or it may have two nitrogens, or one oxygen and one or two nitrogens, or one sulfur and one or two nitrogens in the ring. The heterocyclic group is preferably a heterocyclic aromatic group, especially a 5- or 6- membered heterocyclic group such as furyl, imidazolyl, thiazoly! or pyridyl. Preferred embodiments include those in which R! is hydrogen or C;-Cs-alkyl substituted by hydroxy or
C1-Cs-alkoxy.
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 ) understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
Preferred compounds include those of formula I in free or salt form, where
Ar is phenyl substituted by one or two substituents selected from halogen and C;-Cs-alkyl;
R! is hydrogen, C;-Cs-alkyl optionally substituted by hydroxy or Cy-Cs-alkoxy, acyloxy, Ci-
Cs-alkyl substituted by benzoyloxy or phenoxy-C;-Cs-alkylcarbonyloxy which are optionally substituted in the benzene ring by at least one substituent selected from C;-Cg-alkoxy, C;-Cs- alkylcarbonyl and aminosulfonyl, or Ci-Cs-alkyl substituted by naphthyl;
R2 is hydrogen or C;-Cs-alkyl, and R3 is C;-Cs-alkyl substituted by phenyl or phenoxy, or C;-
Cs-alkyl substituted by benzoyloxy or phenoxy-C;-Cs-alkylcarbonyloxy which are optionally substituted in the benzene ring by at least one substituent selected from C;-Cs-alkoxy, Ci-Cs- alkylcarbonyl and aminosulfonyl, or C;-Cs-alkyl substituted by naphthyl, or R3 is C3-Cs- cycloalkyl optionally having a benzo group fused thereto, a heterocyclic group having 5 to 11 ring atoms of which one or two are hetero atoms, selected from nitrogen, oxygen or sulfur, or phenyl, benzyl or naphthyl, said phenyl, phenoxy and naphthyl groups being optionally substituted by one, two or three substituents selected from halogen, cyano, nitro, hydroxy, Ci-
Cs-alkoxy, C1-Cs-haloalkoxy, Ci-Cs-alkyl, Ci1-Cs-alkylcarbonyl, C;-Cs-alkylthio, di(C;-Cs- alkyl)amino or Ci-Cs-alkylcarbonylamino, or R? and R3, together with the nitrogen atom to which they are attached, denote a heterocyclic group having a N-heterocyclic ring optionally fused to a benzene ring;
X is =O-, -C(=0)- or -CHy~;
Y is oxygen or sulfur; and mis1,2,3or4.
Especially preferred compounds include those of formula Iin free or salt form, where
Ar is phenyl substituted by one or two substituents selected from halogen and C;-Cs-alkyl; ‘ R! is hydrogen, C;-Cs-alkyl optionally substituted by hydroxy or Ci-Cs-alkoxy, acyloxy, Ci-
Cs-alkyl substituted by benzoyloxy or phenoxy-Ci-Cs-alkylcarbonyloxy which are optionally } substituted in the benzene ring by at least one substituent selected from Ci-Cs-alkoxy, C1-Cq- alkylcarbonyl and aminosulfonyl, or Ci-Cs-alkyl substituted by naphthyl;
R2 is hydrogen or C;-Cs-alkyl, and R3 is C1-Cs-alkyl substituted by phenyl or phenoxy, or C;-
Cs-alkyl substituted by benzoyloxy or phenoxy-Ci-Cs-alkylcarbonyloxy which are optionally substituted in the benzene ring by at least one substituent selected from Ci-Cs-alkoxy, C1-Cs- alkylcarbonyl and aminosulfonyl, or Ci-Cs-alkyl substituted by naphthyl, or R3 is Cs-Cs- . cycloalkyl optionally having a benzo group fused thereto, a heterocyclic group having Sto 11 ring atoms of which one or two are hetero atoms, selected from nitrogen, oxygen or sulfur, or : phenyl, benzyl or naphthyl, said phenyl, phenoxy and naphthyl groups being optionally substituted by one, two or three substituents selected from halogen, cyano, nitro, hydroxy, Ci1-
Cs-alkoxy, Ci-Cs-haloalkoxy, C1-Cs-alkyl, Ci-Cs-alkylcarbonyl, Ci-Cs-alkylthio, di(Ci-Cs- alkyl)amino or Ci-Cs-alkylcarbonylamino, or R2 and R3, together with the nitrogen atom to which they are attached, denote a heterocyclic group having a N-heterocyclic ring optionally fused to a benzene ring;
X is —O-, -C(=0)- or -CHaz~;
Y is oxygen or sulfur; and mis1,2,3 or 4.
In a second aspect the present invention provides compounds of formula I in free or salt form, where
Ar is phenyl optionally substituted by one or more substituents selected from halogen,
C;1-Cs-alkyl, cyano or nitro;
R! is hydrogen or Ci-Cs-alkyl optionally substituted by hydroxy, Ci-Cs-alkoxy, acyloxy, halogen, carboxy, C1-Cs-alkoxycarbonyl, -N(R4)RS, -CON(RS)R’ or by a monovalent cyclic organic group having 3 to 15 atoms in the ring system;
R2 is hydrogen or Ci-Cs-alkyl and R? is C;-Cs-alkyl substituted by phenyl, phenoxy, acyloxy or naphthyl, or R3 is Cs-Cao-cycloalkyl optionally having a benzo group fused thereto, a heterocyclic group having § to 11 ring atoms of which 1 to 4 are hetero atoms, phenyl or naphthyl, said phenyl, phenoxy or naphthyl groups being optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, acyl, nitro, -SO.NH, Ci-Cs-alkyl optionally substituted by Ci1-Cs-alkoxy, C1-Cg-haloalkyl, C1-Cs-alkoxy, Ci-Cs-haloalkoxy, Cs-
Cs-alkylthio, -502-C1-Cs-alkyl, Ci-Cs-alkoxycarbonyl, Ci-Cs-acylamino optionally substituted on the nitrogen atom by Ci-Cs-alkyl, Ci-Cs-alkylamino, aminocarbonyl, C;-Cs-alkylamino- carbonyl, di(C;-Cs-alkyl)amino, di(C1-Cs-alkyl)aminocarbonyl, di(C1-Cs-alkyl)aminocarbonyl- methoxy, or R2 and R? together with the nitrogen atom to which they are attached denote a heterocyclic group having to 10 ring atoms of which 1, 2 or 3 are hetero atoms;
R# and RS are each independently hydrogen or Cy-Cs-alkyl, or R* is hydrogen and RS is hydroxy-C;-Cs-alkyl, acyl, -SO:R? or ~CON(R¢)R?, or R# and RStogether with the nitrogen . atom to which they are attached denote a 5-or 6-membered heterocyclic group;
RS and R7 are each independently hydrogen or C1-Cs-alkyl, : or Ré and R7 together with the nitrogen atom to which they are attached denote a 5- or 6- membered heterocyclic group;
R?# is Ci-Cs-alkyl, C1-Cs-haloalkyl, or phenyl optionally substituted by Ci-Cs-alkyl;
X is -C(=0)-, -O-, -CH:-, or CH(OH);
Y is oxygen or sulfur; mis 1,2, 3 or 4, and n, p and q are each 0 or 1, n+p+q=1 or 2, n+q=1, p+q=1, and when nis 0, p is 0.
Preferred compounds of formula I in free or salt form include those in which
Ar is phenyl substituted by one or two substituents selected from fluorine and chlorine;
R! is hydrogen, Ci-Cs-alkyl substituted by hydroxy or Ci-Cs-alkoxy, acyloxy, C1-Cs-alkyl substituted by benzoyloxy or phenoxy-Ci-Cs-alkylcarbonyloxy which are optionally substituted in the benzene ring by at least one substituent selected from Ci-Cs-alkoxy, C1-Cs- alkylcarbonyl and aminosulfonyl, or C;-Cs-alkyl substituted by naphthyl;
R2 is hydrogen or Ci-Cs-alkyl, and R? is Ci-Cs-alkyl substituted by phenyl or phenoxy, or Ci-
Ca-alky! substituted by benzoyloxy or phenoxy-Ci-Ca-alkylcarbonyloxy which are optionally substituted in the benzene ring by at least one substituent selected from Ci-Cs-alkoxy, Ci-Cs- alkylcarbonyl and aminosulfonyl, or Ci-Cs-alkyl substituted by naphthyl, or R3 is Cs-Cs- cycloalkyl optionally having a benzo group fused thereto, a heterocyclic group having 5 to 11 ring atoms of which one or two are hetero atoms, selected from nitrogen, oxygen or sulfur, or phenyl, benzyl or naphthyl, said phenyl, phenoxy and naphthyl groups being optionally substituted by one, two or three substituents selected from halogen, cyano, nitro, hydroxy, C;-
Cs-alkoxy, C1-Cs-haloalkoxy, Ci-Cs-alkyl, C;-Cg-alkylcarbonyl, Ci-Cs-alkylthio, di(Ci-Cs- alkyl)amino or Ci1-Cs-alkylcarbonylamino, or R2 and R3, together with the nitrogen atom to which they are attached, denote a heterocyclic group having a N-heterocyclic ring optionally fused to a benzene ring;
X is —=O-, -C(=0)- or -CHz-;
Y is oxygen; and mis 2,3 or4.
In a third aspect the present invention provides compounds of formula I in free or salt form, where
Ar is phenyl optionally substituted by one or more substituents selected from halogen,
Ci-Cs-alkyl, cyano or nitro;
R! is hydrogen or Ci-Cs-alkyl optionally substituted by hydroxy, Ci-Cs-alkoxy, acyloxy, halogen, carboxy, C:-Cs-alkoxycarbonyl, -N(R*)RS, -CON(RS$)R’ or by a monovalent cyclic organic group having 3 to 15 atoms in the ring system;
R2 is hydrogen or C1-Cs-alkyl and R? is C1-Cs-alkyl substituted by phenyl, phenoxy, acyloxy or naphthyl, or R3 is C3-Cio-cycloalkyl optionally having a benzo group fused thereto, a heterocyclic group having S to 11 ring atoms of which 1 to 4 are hetero atoms, phenyl or naphthyl, said phenyl, phenoxy or naphthyl groups being optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, acyl, nitro, C;-Cs-alkyl, Ci-Cs- haloalkyl, C1-Cs-alkoxy, C1-Cs-haloalkoxy, Ci-Cs-alkylthio, C;-Cs-alkoxycarbonyl, acylamino,
C1-Cs-alkylamino, di(Ci-Cs-alkyl)amino or di(C1-Cs-alkyl)aminocarbonylmethoxy, or R2 and R3 together with the nitrogen atom to which they are attached denote a heterocyclic group having 5 to 10 ring atoms of which 1, 2 or 3 are hetero atoms;
R* and RS are each independently hydrogen or Ci-Cs-alkyl, or R# is hydrogen and R? is hydroxy-Ci-Cs-alkyl, acyl, -SO2R8 or -CON(Ré)R7, or R* and RS together with the nitrogen atom to which they are attached denote a 5-or 6-membered heterocyclic group;
R¢ and R7 are each independently hydrogen or C1-Cs-alkyl, or R6 and R7 together with the nitrogen atom to which they are attached denote a S- or 6-membered heterocyclic group;
RS is C;-Cs-alkyl, C1-Cs-haloalkyl, or phenyl optionally substituted by C1-Cs-alkyl;
X is =C(=O)-, -O-, -CHz-, or CH(OH);
Y is oxygen or sulfur; mis 1,2, 3 or 4; and n, p and q are each 0 or 1, n+p+q=1 or 2, n+g=1, p+q=1, and when n is 0, p is 0.
Preferred compounds of formula I'in free or salt form include those in which
Ar is phenyl substituted by one or two substituents selected from fluorine and chlorine;
R! is hydrogen, C1-Ca-alkyl substituted by hydroxy or Ci-Cs-alkoxy, C1-Cy-alkyl substituted by benzoyloxy or phenoxy-Ci-Ca-alkylcarbonyloxy which are optionally substituted in the benzene ring by at least one substituent selected from C;-Cs-alkoxy, Ci-Cs-alkylcarbonyl and aminosulfonyl, or Ci-Ca-alkyl substituted by naphthyl;
R2 is hydrogen or Ci-Cs-alkyl, and R3 is C1-Cs-alkyl substituted by phenyl or phenoxy, or C;-
Cs-alkyl substituted by benzoyloxy or phenoxy-Ci-Cs-alkylcarbonyloxy which are optionally substituted in the benzene ring by at least one substituent selected from C;-Cs-alkoxy, Ci-Cs- alkylcarbony! and aminosulfonyl, or C;-Cs-alkyl substituted by naphthyl, or R? is Cs-Cs- cycloalkyl optionally having a benzo group fused thereto, a heterocyclic group having 5 to 11 ring atoms of which one or two are hetero atoms, selected from nitrogen, oxygen or sulfur, or : phenyl, benzyl or naphthyl, said phenyl, phenoxy and naphthyl groups being optionally substituted by one, two or three substituents selected from halogen, cyano, nitro, hydroxy, Ci-
Cy-alkoxy, Ci-Ca-haloalkoxy, Ci-Cs-alkyl, Ci-Cs-alkylcarbonyl, Ci1-Cs-alkylthio, di(C1-Cs- alkyl)amino or Cs-Cs-alkylcarbonylamino, or R2 and R3, together with the nitrogen atom to which they are attached, denote a heterocyclic group having a N-heterocyclic ring optionally fused to a benzene ring;
X is -O-, -C(=0)- or -CHaz-;
Y is oxygen; and mis2,3or4.
Especially preferred compounds of formula I in free or salt form include: (1) Compounds of formula II
H H Oo ae—x— ngs —n—o—r
H RH where
Ar is phenyl substituted by one or two substituents selected from fluorine and chlorine, one of said substituents being para to the indicated group X;
R! is hydrogen, Ci-Cs-alkyl substituted by hydroxy or Ci-Cs-alkoxy, Ci-Cs-alkyl substituted by benzoyloxy or phenoxy-Ci-Cs-alkylcarbonyloxy which are optionally substituted in the benzene ring by at least one substituent selected from C;-Cs-alkoxy, Ci-Cs-alkylcarbonyl and aminosulfonyl, or C1-Cs-alkyl substituted by naphthyl;
R3 is phenyl substituted by one, two or three substituents selected from halogen, cyano, di(C;-
Cs-alkyl)amino, Ci-Cs-alkylcarbonylamino or C;-Cs-alkoxy, or R3 is naphthyl optionally substituted by fluorine, or R3 is Ci-Cs-alkyl substituted by phenoxy which is optionally substituted by one or two substituents selected from halogen, cyano, C1-Cs-alkyl, Ci-Cs-alkoxy or Ci-Cs-alkylcarbonyl, or R? is Ci-Cy-alkyl substituted by benzoyloxy or phenoxy-C;-Cs- alkylcarbonyloxy which are optionally substituted in the benzene ring by at least one substituent selected from Ci-Cs-alkoxy, Ci-Cs-alkylcarbonyl and aminosulfonyl, or R3 is a heterocyclic group having a 5- or 6-membered heterocyclic ring in which one or two ring atoms are hetero atoms selected from nitrogen, oxygen and sulfur optionally fused to a benzene ring which is optionally substituted by one or two substituents selected from halogen, C1-Cs-alkoxy and C;-Cs-alkylcarbonyl;
X is =O-; and mis 2 or 3. (2) Compounds of formula Ill
H H oO R
EE ar—x— nA-o-e—n—c—n— i
H RH where
Ar is phenyl substituted by one or two substituents selected from fluorine and chlorine, one of said substituents being para to the indicated group X;
R! is hydrogen, Ci-Cs-alkyl substituted by hydroxy or Ci-Cs-alkoxy;
R? is hydrogen or Ci-Cs-alkyl and R3 is Cs-Co-cycloalkyl, a heterocyclic group having Sto 11 ring atoms of which one or two are nitrogen or oxygen atoms, phenyl optionally substituted by one, two or three substituents selected from fluorine, chlorine, hydroxy, nitro, Ci1-Cs-alkyl, Ci-
Cs-alkylcarbonyl or Ci-Cs-alkoxy, phenyl-Ci-Cs-alkyl substituted in the phenyl group by one or two substituents selected from halogen and C;-Cs-alkyl, Ci-Cs-alkyl substituted by naphthyl, or Cs-Ce-cycloalkyl having a benzo group fused thereto, or R? and R? together with the nitrogen atom to which they are attached denote a heterocyclic group having a 6-membered
N-heterocyclic ring fused to a benzene ring which is optionally substituted by up to 2 C;-Cs- alkoxy groups;
X is -O- or -C(=0)-; and mis 2 or 3. (3) Compounds of formula Ill where
Ar is phenyl substituted by chlorine para to the indicated group X and optionally also : substituted by chlorine meta to the indicated group X;
R! is hydrogen or Ci-Cs-alkyl substituted by hydroxy, Ci-Cs-alkoxy or C;-Cs-acyloxy; : R? is hydrogen;
R3 is a heterocyclic group having § to 11 ring atoms of which 1 to 4 are hetero atoms selected from nitrogen, oxygen and sulphur or atoms, preferably a heterocyclic ring having S atoms of which 1 to 4 are heteroatoms selected from nitrogen, oxygen and sulphur substituted by one or two substituents selected from Ci-Cs-alkyl, Cs3-Ce-cycloalkyl and -5O2-Ci-Cas-alkyl, or R¥ is phenyl optionally substituted by one, two or three substituents selected from halogen, cyano,
C1-Cs-alkyl optionally substituted by C;-Cs-alkoxy, C3-Cs-cycloalkyl, Ci-Cs-alkoxy, Ci-Cs- alkoxycarbonyl, (C1-Cs-alkyl)aminocarbonyl, di(C;-Ca-alkyl)aminocarbonyl, aminocarbonyl, -
SO;NH;, -SO3-C1-Cs-alkyl and Cy-Cy-acylamino optionally substituted on the nitrogen atom
X by Ci-Cs-alkyl;
X is -O-, -CH_- or -C(=0)-; and mis 2. (4) Compounds of formula Illa
H H y R? ax — Org fg—n—S re lia
H RH where
Ar is phenyl optionally substituted by fluoro or chloro para to the indicated group X and/or optionally substituted by fluoro, chloro or C;-Cs-alkyl meta to the indicated group X;
R1is hydrogen or C;-Cs-alkyl optionally substituted by hydroxy;
R2 is hydrogen or C;-Cs-alkyl;
R3 is C3-Cs-cycloalkyl, or R3 is a heterocyclic group having 5 to 11 ring atoms of which 1 to 4 are hetero atoms selected from nitrogen, oxygen and sulphur or atoms, preferably a heterocyclic ring having 5 atoms of which 1 to 4 are heteroatoms selected from nitrogen, oxygen and sulphur substituted by one or two substituents selected from C;-Cs-alkyl and Cs-
Cs-cycloalkyl, or R? is phenyl substituted by C;-Cs-alkoxy;
X is -O-, -CH;- or -C(=0)-;
Y is O or S; and mis 1 or 2. (5) Compounds of formula IV
H H Oo ar—x— NAG n—s—s Iv
Im TT]
H RHO where
Ar is phenyl substituted by one or two substituents selected from fluorine and chlorine, one of said substituents being para to the indicated group X;
R! is hydrogen or Ci-Cs-alkyl substituted by hydroxy or Ci-Cs-alkoxy;
R3 is phenyl optionally substituted by halogen, Ci-Cs-alkyl or cyano, or R3 is an aromatic N- or S-heterocyclic group having S to 10 ring atoms, or R3 is phenyl-Ci-Cs-alkyl;
X is =O-; and mis 2 or 3.
The compounds represented by formula I are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable acid addition salts of the compound 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-carboxylic acid or 3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such as methanesulfonic acid or benzenesulfonic acid. These salts may be prepared from compounds of formula I by known salt-forming procedures.
Compounds of formula I which contain acidic, e.g. carboxyl, groups, are also capable of forming salts with bases, in particular pharmaceutically acceptable bases such as those well known in the art; suitable such salts include metal salts, particularly alkali metal or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, or salts with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolamines, benzylamines or pyridine. These salts may be prepared from compounds of formula I by known salt-forming procedures.
When R1 is other than hydrogen, the carbon atom to which R! is attached in formula I is asymmetric, in which case 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 the invention are those described hereinafter in the
The invention also provides a process for the preparation of compounds of formula I which comprises (i) (A) for the preparation of compounds of formula I where nis 1, pis 1, q is 0 and R? is : hydrogen, reacting a compound of formula V iN ar—x— noe, v
H R' where Ar, X, m and R! are as hereinbefore defined, with a compound of formula VI
Yy=Cc=N—R’ vi where Y and R3 are as hereinbefore defined, with the proviso that when R! contains a reactive functional group it may be in protected form, and, where R! in the product contains a protected functional group, replacing the protecting group by hydrogen; (B) for the preparation of compounds of formula I where nis 1, pis 1, g is 0 and R? is hydrogen or Ci-Cs-alkyl, reacting a compound of formula VII
TT pei ito) vi
H R 0 where Ar, X, m and R! are as hereinbefore defined, with a compound of formula VIII
R=—N—R’ vill where R2 and R3 are as hereinbefore defined, or and, where R in the product contains a protected functional group, replacing the protecting group by hydrogen; (C) for the preparation of compounds of formula I where nis 1, pis 1, q is 0 and R? and R3 together with the nitrogen atom to which they are attached denote a heterocyclic group, reacting a compound of formula IX ar—x— nm IX where Ar and X are as hereinbefore defined, with a compound of formula X
H H Y R
Lb n—t—— X
ERAN
H RH where m, R1 and Y are as hereinbefore defined, R? and R3 together with the nitrogen atom to which they are attached denote a heterocyclic group having § to 10 ring atoms of which one, two or three are hetero atoms, and L is halogen, preferably bromine; (D) for the preparation of compounds of formula Iwhen nis 1, pis 0,qis O and Y is oxygen, reacting a compound of formula IX where Ar and X are as hereinbefore defined, with a compound of formula XI
H H 0)
SE
L—-c——c—N—C—r XI (Tm V0
H RH where L, m, R? and R3 are as hereinbefore defined; (E) for the preparation of compounds of formula I where nis 1, pis 0,q is 0 and Y is oxygen, reacting a compound of formula V where Ar, X, m and R! are as hereinbefore defined, with a compound of formula XII
Cl—Cc—R’ Xi i where R3 is as hereinbefore defined, and, where R! in the product contains a protected functional group, replacing the protecting group by hydrogen; (F) for the preparation of compounds of formula I where nis 1, pis 0, q is 0, R? is hydrogen and Y is oxygen, reacting a compound of formula V where Ar, X, m and R! are as hereinbefore defined, with a compound of formula XIII
HO—C—R® Xi where R3 is as hereinbefore defined, and, where R! in the product contains a protected functional group, replacing the protecting group by hydrogen; (G) for the preparation of compounds of formula I where nis 0, pis 0, and qis 1, reacting a compound of formula IX where Ar and X are as hereinbefore defined in the form of a hydrohalide salt with a compound of formula XIV
H H 0) nh,
L—-c——C—N—S—R Xv
EEA
H RH O where L, m, R! and R? are as hereinbefore defined; (H) for the preparation of compounds of formula Iwhere nis 1, pis1,qis0 and Y is oxygen, reacting a compound of formula V where Ar, X, m and R1 are as hereinbefore defined, with a compound of formula XV 0 R { Hots XV where R2 and R3 are as hereinbefore defined; or (I) for the preparation of compounds of formula I where nis 1, pis 0,qis 0, Y is oxygen and R? is C;-Cs-alkyl or Cs3-Cio-cycloalkyl, reacting a compound of formula V where Ar, X, m and R! are as hereinbefore defined, with a compound of formula XVI 0 R
LR Xvi where R2 is Ci-Cs-alkyl or C3-Cyo-cycloalkyl, R3 is as hereinbefore defined and Z is a halogen, with the proviso that when R? contains a reactive functional group it may be in protected form, and, where R? in the product contains a protected functional group, replacing the protecting group by hydrogen; and (ii) recovering the product in free or salt form.
Process variant (A) may be effected using known procedures for reaction of amines with isocyanates or analogously e.g. as hereinafter described in the Examples. The reaction is conveniently carried out in an organic solvent, for example a halohydrocarbon such as dichloromethane (DCM) or an ether such as dioxane. The reaction temperature may be e.g. from 0 °C to 100 °C, conveniently ambient temperature.
Process variant (B) may be effected using known procedures for reaction of carbamic acid phenyl esters with amines or analogously e.g. as hereinafter described in the Examples. The reaction is conveniently carried out in an organic solvent such as dimethyl sulfoxide (DMSO).
The reaction temperature may be e.g. from 0 to 100 °C, conveniently ambient temperature.
Process variant (C) may be effected using known procedures for reaction of heterocyclic secondary amines with haloalkylureas or analogously e.g. as hereinafter described in the
Examples. The reaction is usually effected between the hydrochloride salt of the compound of formula IX and the compound of formula X in the presence of a tertiary amine. The reaction . is conveniently effected in an organic solvent, e.g. a halohydrocarbon such as DCM. The reaction temperature may be e.g. from 0 to 100 °C, conveniently ambient temperature.
Process variant (D) may be effected using known procedures for reaction of heterocyclic secondary amines with N-(haloalkyl) amides or analogously e.g. as hereinafter described in the
Examples. It is usually effected between the hydrochloride salt of the compound of formula
IX and the compound of formula XI in the presence of a tertiary amine. Reaction is conveniently effected in an organic solvent such as acetonitrile. The reaction temperature may be e.g. from 0 to 100 °C, conveniently ambient temperature.
Process variant (E) may be effected using known procedures for amide-forming reaction of amines with acid halides or analogously.
Process variant (F) may be effected using known procedures for amide formation, for example by reaction in the presence of a tertiary amine and a peptide coupling agent, conveniently in an organic solvent, e.g. a halohydrocarbon such as DCM. The reaction temperature may be e.g. from 0 to 40°C, conveniently ambient temperature.
Process variant (G) may be effected using known procedures for reaction of heterocyclic secondary amines with N-(haloalkyl) sulfonamides or analogously e.g. as hereinafter described in the Examples. It is usually effected in the presence of a tertiary amine, conveniently in an organic solvent such as acetonitrile. The reaction temperature may be e.g. from 0 to 100 °C, conveniently ambient temperature.
Process variant (H) may be effected using known procedures for reaction of amines with carbamic acid phenyl esters or analogously e.g. as hereinafter described in the Examples. The reaction is conveniently carried out in an organic solvent such as dimethyl sulfoxide (DMSO).
The reaction temperature may be e.g. from 20 to 100 °C, conveniently ambient temperature.
Process variant (I) may be effected using known procedures for amide-forming reaction of amines with halo-formamides or analogously e.g. as hereinafter described in the Examples.
The reaction temperature may be e.g. from 0 to 40°C, conveniently ambient temperature. : Compounds of formula V may be prepared by reacting a compound of formula IX with a compound of formula XVII
H H
Lg gn—r? XVil
Tn 7
H R H where RY, L and m are as hereinbefore defined, with the proviso that when R! contains a reactive functional group such as a hydroxy group, the reactive group may be in protected form, for example a hydroxy group protected as a tert-butoxy group, and R? is hydrogen or an amine-protective group, for example a tert-butoxycarbonyl group, and, where R is a protective group, replacing R? in the product by hydrogen, and, where R! in the product contains a protected functional group, replacing the protecting group by hydrogen. When R? is hydrogen, reaction between a compound of formula XVII and a salt of a compound of formula
IX may be effected by the procedures described in US 4559349. When R? is a protective group, reaction between compounds of formulae XVII and IX may be effected using known methods, for example in the presence of a tertiary organic base such as triethylamine or 1,8-diaza- bicyclo[5.4.0Jundec-7-ene (DBU), conveniently in an inert organic solvent, for example a polar solvent such as dimethylformamide, the reaction temperature suitably being from 0 to 40°C, preferably ambient temperature. Replacement of a protective group R? by hydrogen may be effected using known procedures; for example, where R? is tert-butoxycarbonyl, by treatment with a carboxylic acid such as trifluoroacetic acid. Replacement of a protecting group in R! may be affected using known procedures, for example, when R! contains a hydroxy group protected as an ether group, such as tert-butoxy, by treatment with HBr in a carboxylic acid such as acetic acid; when RY is a protective group, this treatment also replaces R? by hydrogen.
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.
Compounds of formulae VI are commercially available or may be prepared by known methods.
Compounds of formula VII may be prepared by reacting a compound of formula V with . phenyl chloroformate in the presence of a base such as a tertiary amine, for example as hereinafter described in the Examples.
Compounds of formulae VIII are commercially available or may be prepared by known methods.
Compounds of formula IX where X is —O- may be prepared by reacting a compound of formula XVII 0
II “©
HC—8—0 N—R Xvi 0) with a compound of formula Ar-OH in the presence of sodium hydride, where Ar is as hereinbefore defined and R1° is a protecting group, and replacing R1° in the product by hydrogen. The reaction may be carried out in an inert organic solvent such as DMF. Suitable reaction temperatures may be from 20°C to 150°C, conveniently from 50 to 70°C. The replacement of R10 by hydrogen may be affected using known procedures, for example where
R10 is benzhydryl by reacting the product of the reaction of the compound of formula XVII and
Ar1-OH with 1-chloroethyl chloroformate, a suitable reaction temperature being 10-30°C, conveniently at room temperature.
Compounds of formula IX where X is ~C(=O)- may be prepared by reacting a compound of formula XIXa or formula XIXb 0)
I} ”
CH;—O—N—C N—R XiXa
CH, : n=o— n—r® XIXb with a compound of formula XX
Ar—MgBr XX
Claims (21)
1. A compound of formulal : H H Y Rr’ 0 wrx ngo—nfe Hw EA ANNAN RE H RH 0) in free or salt form, where Ar is phenyl optionally substituted by one or more substituents selected from halogen, Ci-Cs-alkyl, cyano or nitro; Ris hydrogen or Ci1-Cs-alkyl optionally substituted by hydroxy, Ci-Cs-alkoxy, acyloxy, halogen, carboxy, Ci-Cs-alkoxycarbonyl, -N(R*)RS, -CON(R¢)R” or by a monovalent cyclic organic group having 3 to 15 atoms in the ring system; R2 is hydrogen, Ci-Cs-alkyl or C3-Cio-cycloalkyl and R3 is Ci-Cs-alkyl substituted by phenyl, phenoxy, acyloxy or naphthyl, or R3 is C3-Cio-cycloalkyl optionally having a benzo group fused thereto, a heterocyclic group having 5 to 11 ring atoms of which 1 to 4 are hetero atoms, phenyl or naphthyl, said phenyl, phenoxy or naphthyl groups being optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, acyl, nitro, -SO2NHz, C1-Cs- alkyl optionally substituted by C;-Cs-alkoxy, Ci-Cs-haloalkyl, C;-Cs-alkoxy, C;-Cs- haloalkoxy, Ci-Cs-alkylthio, -502-Ci-Cs-alkyl, Ci-Cg-alkoxycarbonyl, C1-Cs-acylamino optionally substituted on the nitrogen atom by C;-Cs-alkyl, C1-Cs-alkylamino, aminocarbonyl, C;-Cs-alkylamino-carbonyl, di(C;-Cs-alkyl)amino, di(Cs-Cs-alkyl)aminocarbonyl, di(C;-Cs- alkyl)aminocarbonyl-methoxy, or R? and R? together with the nitrogen atom to which they are attached denote a heterocyclic group having 5 to 10 ring atoms of which 1, 2 or 3 are hetero atoms; R# and RS are each independently hydrogen or C;-Cs-alkyl, or R* is hydrogen and RS is hydroxy-Ci-Cs-alkyl, acyl, -SO:R® or -CON(R$)R?, or R* and RS together with the nitrogen atom to which they are attached denote a S-or 6-membered heterocyclic group; RS and R7 are each independently hydrogen or C;-Cs-alkyl, or Ré and R7 together with the nitrogen atom to which they are attached denote a 5- or 6-membered heterocyclic group; RS is Cy-Cg-alkyl, Ci-Cs-haloalkyl, or phenyl optionally substituted by C1-Cs-alkyl; X is -C(=0)-, -O-, -CHz-, or CH(OH); Y is oxygen or sulfur; mis 1,2, 3 or 4; and n, p and q are each 0 or 1, n+p+g=1 or 2, n+g=1, p+q=1, and when nis 0, pis 0.
2. A compound according to claim 1, in which Ar is phenyl substituted by one or two substituents selected from halogen and C;-Cs-alkyl; : R! is hydrogen, Ci-Cs-alkyl optionally substituted by hydroxy or C1-Cs-alkoxy, acyloxy, Ci- Cs-alkyl substituted by benzoyloxy or phenoxy-Ci-Cs-alkylcarbonyloxy which are optionally : substituted in the benzene ring by at least one substituent selected from C1-Cs-alkoxy, Ci-Cs- alkylcarbonyl and aminosulfonyl, or Ci-Cs-alkyl substituted by naphthyl; R? is hydrogen or C;-Cs-alkyl, and R3 is C1-Cs-alkyl substituted by phenyl! or phenoxy, or Ci- Cs-alkyl substituted by benzoyloxy or phenoxy-Ci-Cs-alkylcarbonyloxy which are optionally substituted in the benzene ring by at least one substituent selected from C;-Cs-alkoxy, Ci-Cs- alkylcarbonyl and aminosulfonyl, or C1-Cs-alkyl substituted by naphthyl, or R3 is C3-Cs- cycloalkyl optionally having a benzo group fused thereto, a heterocyclic group having 5 to 11 ring atoms of which one or two are hetero atoms, selected from nitrogen, oxygen or sulfur, or phenyl, benzyl or naphthyl, said phenyl, phenoxy and naphthyl groups being optionally substituted by one, two or three substituents selected from halogen, cyano, nitro, hydroxy, Ci- Cs-alkoxy, Ci-Cs-haloalkoxy, Ci-Cs-alkyl, C1-Cs-alkylcarbonyl, C1-Cs-alkylthio, di(Ci-Cs- alkyl)amino or C;-Cs-alkylcarbonylamino, or R? and R3, together with the nitrogen atom to which they are attached, denote a heterocyclic group having a N-heterocyclic ring optionally fused to a benzene ring; X is =O-, -C(=0)- or -CHz-; Y is oxygen or sulfur; and mis 1,2,3 or 4.
3. A compound according to claim 1, in which Ar is phenyl substituted by one or two substituents selected from halogen and Ci-Ca-alkyl; R! is hydrogen, C;-Cs-alkyl optionally substituted by hydroxy or Cy-Cs-alkoxy, acyloxy, Ci- Cs-alkyl substituted by benzoyloxy or phenoxy-Ci-Cs-alkylcarbonyloxy which are optionally substituted in the benzene ring by at least one substituent selected from C1-Cs-alkoxy, Ci-Cs- alkylcarbonyl and aminosulfonyl, or Ci-Cs-alkyl substituted by naphthyl; R2 is hydrogen or Ci-Cs-alkyl, and R? is C1-Cs-alkyl substituted by phenyl or phenoxy, or Ci- } Cs-alkyl substituted by benzoyloxy or phenoxy-Ci-Cs-alkylcarbonyloxy which are optionally substituted in the benzene ring by at least one substituent selected from Ci-Cs-alkoxy, Ci-Cq- alkylcarbonyl and aminosulfonyl, or C1-Cs-alkyl substituted by naphthyl, or R? is Cs-Cs- cycloalkyl optionally having a benzo group fused thereto, a heterocyclic group having 5 to 11 ring atoms of which one or two are hetero atoms, selected from nitrogen, oxygen or sulfur, or phenyl, benzyl or naphthyl, said phenyl, phenoxy and naphthyl groups being optionally substituted by one, two or three substituents selected from halogen, cyano, nitro, hydroxy, Ci- Cs-alkoxy, C1-Cs-haloalkoxy, Ci-Cs-alkyl, C1-Cs-alkylcarbonyl, C1-Cs-alkylthio, di(Cy-Cs- alkyl)amino or C;-Cs-alkylcarbonylamino, or R2 and RS, together with the nitrogen atom to which they are attached, denote a heterocyclic - group having a N-heterocyclic ring optionally fused to a benzene ring; X is —O-, -C(=0)- or -CHa-; Y is oxygen or sulfur; and mis1,2,3or4.
4. A compound according to claim 1, which is of formula II H H (0) de I Tm 7 H R" H where Ar is phenyl substituted by one or two substituents selected from fluorine and chlorine, one of said substituents being para to the indicated group X, R! is hydrogen, Ci-Cs-alkyl substituted by hydroxy or C;-Cs-alkoxy, C1-Cs-alky! substituted by benzoyloxy or phenoxy-Cy-Cs-atkylcarbonyloxy which are optionally substituted in the benzene ring by at least one substituent selected from C1-Cs-alkoxy, Ci1-Cs-alkylcarbonyl and aminosulfonyl, or Ci-Cs-alkyl substituted by naphthyl, R3 is phenyl substituted by one, two or three substituents selected from halogen, cyano, di(Ci- Ca-alkyl)amino, Ci-Cs-alkylcarbonylamino, Ci-Cs-alkoxy, or R3 is naphthyl optionally substituted by fluorine, or R3 is C1-Cs-alkyl substituted by phenoxy which is optionally substituted by one or two substituents selected from halogen, cyano, C1-Cs-alkyl, Ci-Cs-alkoxy or Ci-Ca-alkylcarbonyl, or R? is C1-Cs-alkyl substituted by benzoyloxy or phenoxy-Ci-Cs- alkylcarbonyloxy which are optionally substituted in the benzene ring by at least one substituent selected from C;-Cs-alkoxy, Ci-Cs-alkylcarbonyl and aminosulfonyl, or R3is a : heterocyclic group having a S- or 6-membered heterocyclic ring in which one or two ring atoms } are hetero atoms selected from nitrogen, oxygen and sulfur optionally fused to a benzene ring which is optionally substituted by one or two substituents selected from halogen, C;-Cs-alkoxy : and Ci1-Cs-alkylcarbonyl, X is -O-, and mis 2 or 3.
5. A compound according to claim 1, which is of formula II H i 0 Rr : ar—x— ftp n-ne m H RH where Ar is phenyl substituted by one or two substituents selected from fluorine and chlorine, one of said substituents being para to the indicated group X, R! is hydrogen, Ci-Cs-alky! substituted by hydroxy or C1-Cs-alkoxy, R2 is hydrogen or Ci-Cs-alkyl and R3 is Cs-Cs-cycloalkyl, a heterocyclic group having S to 11 ring atoms of which one or two are nitrogen or oxygen atoms, phenyl optionally substituted by one, two or three substituents selected from fluorine, chlorine, hydroxy, nitro, C1-Cs-alkyl, Ci- Cs-alkylcarbonyl or Ci-Cs-alkoxy, phenyl-Ci-Cs-alkyl substituted in the phenyl group by one or two substituents selected from halogen and Ci-Cs-alkyl, Ci-Cas-alkyl substituted by naphthyl, or Cs-Cs-cycloalkyl having a benzo group fused thereto, or R2 and R3 together with the nitrogen atom to which they are attached denote a heterocyclic group having a 6-membered N-heterocyclic ring fused to a benzene ring which is optionally substituted by up to 2 C+-Cs- alkoxy groups, X is =O- or =C(=0)-, and m is 2 or 3.
6. A compound according to claim 1, which is also of formula III, where Ar is phenyl substituted by chlorine para to the indicated group X and optionally also substituted by chlorine meta to the indicated group X, R1 is hydrogen or Ci-Cs-alkyl substituted by hydroxy, Ci-Cs-alkoxy or Ci-Cs-acyloxy, R2? is hydrogen, R3 is a heterocyclic group having S to 11 ring atoms of which 1 to 4 are hetero atoms selected from nitrogen, oxygen and sulphur or atoms, or R3 is phenyl optionally substituted by one, two or three substituents selected from halogen, cyano, Ci-Ca-alkyl optionally substituted by . Ci-Ca-alkoxy, Cs-Cs-cycloalkyl, Ci-Cs-alkoxy, C1-Cs-alkoxycarbonyl, (C;-Cy-alkyl)amino- carbonyl, di(Ci-Cs-alkyl)aminocarbonyl, aminocarbonyl, -502NH,, -50,-C;-Cs-alkyl and Ci- : Cs-acylamino optionally substituted on the nitrogen atom by Ci-Cs-alkyl, X is -O- , -CH;- or -C{=O)-, and m is 2.
7. A compound according to claim 1, which is also of formula Illa H H Y R : ar—x— Arey lla H RH where Ar is phenyl optionally substituted by fluoro or chloro para to the indicated group X and/or optionally substituted by fluoro, chloro or C;-Cs-alkyl meta to the indicated group X; Ris hydrogen or Ci-Cs-alkyl optionally substituted by hydroxy; R? is hydrogen or C;-Cs-alkyl; R3 is C3-Ce-cycloalkyl, or R3 is a heterocyclic group having 5 to 11 ring atoms of which 1 to 4 are hetero atoms selected from nitrogen, oxygen and sulphur or atoms, preferably a heterocyclic ring having 5 atoms of which 1 to 4 are heteroatoms selected from nitrogen, oxygen and sulphur substituted by one or two substituents selected from Ci-Cs-alkyl and Cs- Cs-cycloalkyl, or R3 is phenyl substituted by C;-Cs-alkoxy; X is -O-, -CH:- or -C(=O)-; Y is O or S; and mis 1 or 2.
8. A compound according to claim 1, which is of formula IV H H Oo ar—x— ONE g—n—3—w Iv BER H RH O where Ar is phenyl substituted by one or two substituents selected from fluorine and chlorine, one of said substituents being para to the indicated group X, R1 is hydrogen or C;-Cs-alkyl substituted by hydroxy or Ci-Cs-alkoxy, R? is phenyl optionally substituted by halogen, C1-Cs-alkyl or cyano, or R? is an aromatic N- or S-heterocyclic group having 5 to 10 ring atoms, or R3 is phenyl-C1-Cs-alkyl, X is -O- and mis2or 3.
9. A compound according to claim 1, where Ar is phenyl optionally substituted by one or more substituents selected from halogen, Ci-Cs-alkyl, cyano or nitro, R! is hydrogen or Ci-Cg-alkyl optionally substituted by hydroxy, Ci-Cs-alkoxy, acyloxy, . halogen, carboxy, Ci-Cs-alkoxycarbonyl, -N(R#)RS, -CON(Ré)R7 or by a monovalent cyclic organic group having 3 to 15 atoms in the ring system, R? is hydrogen or Ci-Cs-alkyl and R3 is C;-Cs-alkyl substituted by phenyl, phenoxy, acyloxy or naphthyl, or R3 is Cs-Cio-cycloalkyl optionally having a benzo group fused thereto, a heterocyclic group having $ to 11 ring atoms of which 1 to 4 are hetero atoms, phenyl or naphthyl, said phenyl, phenoxy or naphthyl groups being optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, acyl, nitro, -SO2NH,, C;-Cs-alkyl optionally substituted by Ci1-Cs-alkoxy, Ci-Cs-haloalkyl, C-Cs-alkoxy, C1-Cs-haloalkoxy, Ci- Cs-alkylthio, -502-C;-Cs-alkyl, C1-Cs-alkoxycarbonyl, Ci-Cs-acylamino optionally substituted on the nitrogen atom by C;-Cs-alkyl, Ci-Cs-alkylamino, aminocarbonyl, C;-Cs-alkylamino- carbonyl, di(C;-Cs-alkyl)amino, di(Ci-Cs-alkyl)aminocarbonyl, di(C1-Cs-alkyl)aminocarbonyl- methoxy, or R? and R3 together with the nitrogen atom to which they are attached denote a heterocyclic group having S to 10 ring atoms of which 1, 2 or 3 are hetero atoms, R* and RS are each independently hydrogen or Ci-Cs-alkyl, or R* is hydrogen and RS is hydroxy-C;-Cs-alkyl, acyl, -SOzR® or -CON(R€)R’, or R* and Ritogether with the nitrogen atom to which they are attached denote a 5-or 6-membered heterocyclic group, RS and R7 are each independently hydrogen or Ci-Cs-alkyl, or R¢ and R7 together with the nitrogen atom to which they are attached denote a 5- or 6-membered heterocyclic group, RS is C1-Cs-alkyl, C1-Cs-haloalkyl, or phenyl optionally substituted by C1-Cs-alkyl, X is -C(=0)-, -O-, -CHz-, or CH(OH), Y is oxygen or sulfur, mis1,2, 3 or4,and n, p and q are each 0 or 1, n+p+q=1 or 2, n+g=1, p+q=1, and when nis 0, pis 0.
10. A compound according to claim 1, where Ar is phenyl optionally substituted by one or more substituents selected from halogen, C1-Cs-alkyl, cyano or nitro, R! is hydrogen or C;-Cs-alkyl optionally substituted by hydroxy, C;-Cs-alkoxy, acyloxy, halogen, carboxy, C-Cs-alkoxycarbonyl, -N(R*)R?, -CON(R#)R7 or by a monovalent cyclic organic group having 3 to 15 atoms in the ring system, R? is hydrogen or Ci-Cs-alkyl and R3 is C;-Cs-alkyl substituted by phenyl, phenoxy, acyloxy or naphthyl, or R3 is C3-Cyo-cycloalkyl optionally having a benzo group fused thereto, a heterocyclic group having S to 11 ring atoms of which 1 to 4 are hetero atoms, phenyl or naphthyl, said phenyl, phenoxy or naphthyl groups being optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, acyl, nitro, Ci-Cs-alkyl, Ci-Cs- . haloalkyl, C;-Cs-alkoxy, Ci-Cs-haloalkoxy, Ci-Cs-alkylthio, Ci-Cs-alkoxycarbonyl, acylamino, Ci-Cs-alkylamino, di(Ci-Cs-alkyl)amino or di(Ci-Cs-alkyl)aminocarbonylmethoxy, or R? and R3 together with the nitrogen atom to which they are attached denote a heterocyclic group having $ to 10 ring atoms of which 1, 2 or 3 are hetero atoms, R* and RS are each independently hydrogen or Ci-Cs-alkyl, or R* is hydrogen and R® is hydroxy-Ci-Cs-alkyl, acyl, -SO2R8 or -CON(R#)R’, or R* and RStogether with the nitrogen atom to which they are attached denote a S-or 6-membered heterocyclic group, RS and R7 are each independently hydrogen or C;-Cs-alkyl, or R¢ and R7 together with the nitrogen atom to which they are attached denote a 5- or 6-membered heterocyclic group, RS is C1-Cs-alkyl, C1-Cs-haloalkyl, or phenyl optionally substituted by Ci-Cs-alkyl, X is -C(=0)-, -O-, -CHa-, or CH(OH), Y is oxygen or sulfur, mis 1,2, 3 or 4, and n, p and q are each 0 or 1, n+p+g=1 or 2, n+q=1, p+q=1, and when nis 0, pis 0.
11. A compound according to claim 1 substantially as described in any one of the Examples.
12. A compound according to any one of the preceding claims in combination with another drug substance which is an anti-inflammatory, a bronchodilator or an antihistamine.
13. A compound according to any one of the preceding claims for use as a pharmaceutical.
14. A pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1 to 12.
15. The use of a compound according to any one of claims 1 to 12 for the manufacture of a medicament for the treatment of a condition mediated by CCR-3.
16. Use according to claim 15, in which the condition is an inflammatory or allergic condition, particularly an inflammatory or obstructive airways disease.
17. A process for the preparation of a compound of formula I as claimed in claim 1 which comprises (i) (A) for the preparation of compounds of formula I where nis 1, pis 1, q is 0 and R? is . hydrogen, reacting a compound of formula V 1 Ar—X N—{C——c—nH Vv lm] ? H R where Ar, X, m and R! are as hereinbefore defined, with a compound of formula VI Y=C=N—R® vi where Y and R3 are as hereinbefore defined, with the proviso that when R? contains a reactive functional group it may be in protected form, and, where R1 in the product contains a protected functional group, replacing the protecting group by hydrogen; (B) for the preparation of compounds of formula I where nis 1, pis 1,q is 0 and R? is hydrogen or C;-Cs-alkyl, reacting a compound of formula VII NE rex nfo) vil H R 0 where Ar, X, m and R! are as hereinbefore defined, with a compound of formula VIII R>=—N—R? Vili where R2 and R32 are as hereinbefore defined, or and, where R! in the product contains a protected functional group, replacing the protecting group by hydrogen; (C) for the preparation of compounds of formula I where nis 1, pis 1, q is 0 and R? and R3 together with the nitrogen atom to which they are attached denote a heterocyclic group, reacting a compound of formula IX w—x— NH IX where Ar and X are as hereinbefore defined, with a compound of formula X
H H M Rr? Ao grote X : H RH where m, R! and Y are as hereinbefore defined, R2 and R3 together with the nitrogen atom to which they are attached denote a heterocyclic group having 5 to 10 ring atoms of which one, two or three are hetero atoms, and L is halogen, preferably bromine; (D) for the preparation of compounds of formula I when nis 1, pis 0,qis 0 and Y is oxygen, reacting a compound of formula IX where Ar and X are as hereinbefore defined, with a compound of formula XI H H 0 Ln L—{-ct—c—N—c—r Xl SERA H RH where L, m, R! and R3 are as hereinbefore defined; (E) for the preparation of compounds of formula I where nis 1, pis 0, qis 0 and Y is oxygen, reacting a compound of formula V where Ar, X, m and R! are as hereinbefore defined, with a compound of formula XII ci—C—R’ Xi where R3 is as hereinbefore defined, and, where R! in the product contains a protected functional group, replacing the protecting group by hydrogen; (F) for the preparation of compounds of formula I where nis 1, pis 0, qis 0, R2 is hydrogen and Y is oxygen, reacting a compound of formula V where Ar, X, m and R! are as hereinbefore defined, with a compound of formula XIII HO—C—R® Xi 5 where R? is as hereinbefore defined, and, where R1 in the product contains a protected functional group, replacing the protecting group by hydrogen; (G) for the preparation of compounds of formula I where nis 0, p is 0, and q is 1, reacting a compound of formula IX where Ar and X are as hereinbefore defined in the form of a hydrohalide salt with a compound of formula XIV
“ “ab - ! Case 4-32412A HO 56 Ty L—-c——G—N—s— R? Xv Te 11 H RH O where L, m, R! and R3 are as hereinbefore defined; (H) for the preparation of compounds of formula I wherenis 1, pis 1,qis0 and Y is oxygen, reacting a compound of formula V where Ar, X, m and R! are as hereinbefore defined, with a compound of formula XV 0 R O—C—N—R XV where R2? and R3 are as hereinbefore defined; or (I) for the preparation of compounds of formula I where nis 1, pis 0, qis 0, Y is oxygen and R2 is C;-Cs-alkyl or C3-Cie-cycloalkyl, reacting a compound of formula V where Ar, X, m and R! are as hereinbefore defined, with a compound of formula XVI 0 R nr Z—C—N—R Xvi where R2 is C;1-Cs-alkyl or Cs3-Cio-cycloalkyl, R? is as hereinbefore defined and Z is a halogen, with the proviso that when R! contains a reactive functional group it may be in protected form, and, where R! in the product contains a protected functional group, replacing the protecting group by hydrogen; and (ii) recovering the product in free or salt form.
18. A compound according to claim 1, substantially as herein described and exemplified and/or described with reference to the examples AMENDED SHEET
, \ [AEE [I 84/A
19. A composition according to claim 14, substantially as herein described and exemplified and/or described with reference to the examples.
20. Use according to claim 15, substantially as herein described and exemplified and/or described with reference to the examples.
21. A process according to claim 17, substantially as herein described and exemplified and/or described with reference to the examples. AMENDED SHEET
Applications Claiming Priority (1)
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GB0206218A GB0206218D0 (en) | 2002-03-15 | 2002-03-15 | Organic compounds |
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ZA200406752A ZA200406752B (en) | 2002-03-15 | 2004-08-25 | Azetidine derivatives as CCR-3 receptor antagonists |
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EC (1) | ECSP045288A (en) |
GB (1) | GB0206218D0 (en) |
ZA (1) | ZA200406752B (en) |
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2002
- 2002-03-15 GB GB0206218A patent/GB0206218D0/en not_active Ceased
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GB0206218D0 (en) | 2002-05-01 |
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