(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization A, | I
`International Bureau
`
`p
`
`(43) International Publication Date
`29 June 2006 (29.06.2006)
`
`WO 2006/067165 A2
`
` (10) International Publication Number
`
`(51) International Patent Classification:
`
`Notclassified
`
`(21) International Application Number:
`PC1/EP2005/057002
`
`(22) International Filing Date:
`21 December 2005 (21.12.2005)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`04030770.4
`
`24 December 2004 (24.12.2004)
`
`EP
`
`(71) Applicant (for all designated States except DE, US):
`BOEHRINGER INGELHEIM INTERNATIONAL
`
`GMBH [DE/DE]; Binger Str. 173, 55216 Ingelheim Am
`Rhein (DE).
`
`(71) Applicant(for DE only): BOEHRINGER INGELHEIM
`PHARMA GMBH & CO. KG [DE/DE]; Binger Str. 173,
`55216 Ingelheim Am Rhein (DE).
`
`(72)
`(75)
`
`Inventors; and
`Inventors/Applicants (for US only): PARK, John, Ed-
`ward [US/DE]; Am Marktplatz 40, 88400 Biberach (DB).
`ROTH,Gerald, Jiirgen [DE/DE]; Akazienweg 47, 88400
`Biberach (DE). HECKEL, Armin [DE/DE]; Geschwis-
`ter-scholl-str. 71, 88400 Biberach (DE). CHAUDHARY,
`Nveed [GB/DE]; Kolping Strasse 27, 88400 Bibcrach
`(DE). BRANDL, Trixi [DE/DE]; Mailzerstrasse 8, 88447
`Warthausen (DE). DAHMANN, Georg [DE/DE]; Bahn-
`hofstrasse 14, 88448 Attenweiler
`(DE). GRAUERT,
`
`Matthias [DE/DE]; Osterbergstr.
`(DE).
`
`10, 88400 Biberach
`
`(74) Agent: HAMMANN,Heinz; Binger Str. 173, 55216 In-
`gelheim Am Rhein (DE).
`
`(81) Designated States (unless otherwise indicated, for every
`kind ofnational protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW,BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
`GB, GD, GE, GH, GM, HR, HU,ID, IL, IN, IS, JP, KE,
`KG, KM,KN,KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV,
`LY, MA, MD, MG, MK, MN, MW,MX, MZ, NA, NG,NI,
`NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG,
`SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US,
`UZ, VC, VN, YU, ZA, 7M, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind ofregional protection available): ARIPO (BW, GH,
`GM,KB, 1.S, MW, MZ, NA, SD, SL, SZ, TZ, UG, 7M,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU,IE, IS, IT, LT, LU, LV, MC, NL, PL, PT,
`RO,SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA,
`GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`without international search report and to be republished
`upon receipt of that report
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes and Abbreviations" appearing at the begin-
`ning of each regular issue of the PCT Gazette.
`
`(54) Title: MEDICAMENTS FOR THE TREATMENT OR PREVENTION OF FIBROTIC DISEASES
`
`R3
`
`(57) Abstract: The present inventionrelates to the use of
`indolinones of general formula (1) substituted in the 6 po-
`sition, wherein R, to Rs and X are defined as in claim 1,
`the isomers and the salts thereof, particularly the physiolog-
`ically acceptable salts thereof, as a medicamentfor the pre-
`vention or treatment of specific fibrotic diseases.
`
`
`
`
`
`
`
`WO2006/067165A2[IMMINININEIITINIINIETAAITMTTAATATT
`
`

`

`WO 2006/067165
`
`PCT/EP2005/057002
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`MEDICAMENTS FOR THE TREATMENT OR PREVENTION OF FIBROTIC
`
`
`
`
`
`
`DISEASES
`
`The present
`
`
`invention relates to a new use of indolinones
`
`
`
`of general formula
`
`R,
`
`N
`
`Ry
`
`Rp
`
`N
`
`=~
`
`NN
`
`Ry
`
`Rs
`
`x
`
`(I),
`
`substituted in the 6 position,
`
`
`
`diastereomers,
`
`
`
`the tautomers,
`
`the
`
`
`the mixtures thereof and
`
`
`
`the enantiomers,
`
`
`
`
`the salts thereof, particularly the physiologically
`
`acceptable salts thereof.
`
`
`
`BACKGROUND
`
`5
`
`10
`
`15
`
`20
`
`25
`
`

`

`WO 2006/067165
`
`PCT/EP2005/057002
`
`
`Compounds of
`
`the above
`
`
`
` formula I,
`general
`
`the tautomers,
`
`
`thereof
`
`the dias
`
`tereomers,
`
`the enantiomers,
`
`and the
`
`salts thereof,
`
`particu
`
`larly
`
`the mixtures
`
`
`the physiologically
`
` thereof,
`
`in particu lar an inhibiting ef
`
`
`acceptable salts
`
`
`
`have been described in WO
`
`01/27081 and WO 04/13099 as having valuable pharmacological
`
` Fect on various
`properti es,
`
`
`
`such as
`especially receptor tyrosine kinases
`kinases,
`
`
`P
`
`
`
`H
`
`GFLR and
`DGFRO, PDGFRB
`VEGFR2,
`EGFR,
`ER2,
`
`, FGFRI,
`
`FGFR3,
`
`
`CDK's
`
`(Cyclin
`
` Dependent
`
`as complexes of
`s uch as CDKi1,
`
`
`HGFR, as
`
`well
`
`10
`
`Kinases)
`
` D1, D2,
`
`
`with the
`CDK8 and CDK9
`
`
`
`93, E, F, Gl,
`
`CDK2,
`
`DK3,
`C
`
`
`ir speci
`fic cyclins
`
`CDK4,
`
`CDK5, CDK6,
`
`
`(A, Bl,
`
`
`B2,
`
`Cc,
`
`
`CDRK7,
`
`G2,
`
`and K)
`
`and
`
`to viral cyclin
`
` (cf. L.
`
`Mengtao in J. Virology
`
`71(3),
`
`1984-1991
`
`(1997)),
`
`in
`
`
` H,
`
` cells,
`
`
`
`he proliferati
`
`
`
`ar endothelial
`
`
`
`ion of
`the proliferat
`
`on of cultivated human cells,
`
`
`
`e.g.
`
`in
`
`angiogenesis, but
`
`other cells,
`
`in particular
`
`
`
`and on t
`
`15
`
`particul
`
`also on
`
`tumour c
`
` their us
`
`However,
`
`ells.
`
`none of
`
`e in the
`
`
` for
`
`these compounds have been described
`
`
` fibrotic
`the
`treatment or prevention of
`
`diseases
`
`
`referred to in the present
`
`invention.
`
`Remodeling is a normal response to tissue injury and
`
`in
`
`
`flammation that is observed in many tissues throughout
`
`
`
`the body. After resolution of
`
`
`of tissue damage,
`
`the tissue i
`
`original condition.
`
`
`
`
`Excessive uncontrol
`
`the infl
`ammation and repair
`
`ly returned to its
`Ss general
`
`
` led tissue repair or
`
`
`
`the failure to stop
`
` matrix componen
`
`remodeling when it is no longer
`
`fibrosis.
`
`Fibrosis is
`
`required leads
`
`characterized by excessive deposition
`
`
`
`ts and overgrowth of
`
`of extracellular
`
` roblasts. Fibrosis
`
`ib
`
`can occur in all tissues but is especi
`
`in
`
` ally prevalent
` to condition known as
`
`20
`
`25
`
`30
`
`

`

`WO 2006/067165
`
`PCT/EP2005/057002
`
`organs with
`
`
`frequent exposure to chemical and biological
`
`insults including the lung,
`
`
`and liver (
`Eddy,
`
`
`
`1996,
`
`J Am Soc Nephrol,
`
`skin,
`
`digestive tract,
`
`kidney,
`
`7(12):2495-503;
`
`
`Biol, 298:
`
`S5-9;
`
`Dacic et al.,
`
`2003,
`
`Am J Respir Cell Mol
`
`
`Rev Immunol,
`
`4(8):583-94).
`
`
`Fibrosis often
`
`Wynn, 2004,
`
`
`
` Nat
`
`
`function(s)
`
`of the organ
`
`ain
`
`fact,
`
`life-threatening
`
`such as idiopathic pulmonary
`
`
`limited to organ transplantat
`
`liver cirrhosis,
`
`or renal
`
`cen
`
`for these diseases are of
`
`
`
`
` scleroderma,
`
`severely compromises the normal
`
`and many fibro
`tic diseases are,
`
`
`or severel y disfiguring,
`
`
`fibrosis (
`IPF),
`
`fibrosis.
`
`Treatment options
`
`procedure.
`
`tion,
`
`a risky and expensive
`
`
`
`CULre
`
`A large body of litera
`implicates the p
`
`
` factor
`growth factor
`(PDGF),
`vasc
`
`
`
`ial
`
`
`
`
`
` g
`
`
`
`
`fibroblast growth
`_~
`
`
`rowth facto
`(VEGF),
`
`latelet—derived
`
`
`
`(FGF),
`
`epidermal growth
`
`
`trans
`and
`forming grow
`factor
`(EGF),
`
`
`
`
`th factor
`families
`in the inducti
`
`th
`
`
`
`
`factor beta
`~
`
`
`
`pe
`
`on o
`
`
`
`
`rsistence of
`
`
`(TGFb)
`
`grow
`
`10
`
`15
`
` ular endothe]
`
`
`fibrosis
`
`(Levitzki,
`
`Cy
`
`15 (4) :229-35;
`
`Sstrutz et
`
`
` al.,
`
`tokine Growth
`
`Factor Rev,
`
`Kidney
`
`Intl,
`
`2000,
`
`Strutz et al.,
`
`2003,
`
`Springer Semin
`
`Immunopathol,
`
`24:459-
`
`76;
`
`Rice et al
`
`7
`
`1999,
`
`Amer J Pathol
`
`, 155(1) 3213-221;
`
`
`Broekelmann et
`
`al.,
`
`1991,
`
`Proc Nat Acad Sci,
`
`88:6642-6;
`
`
`
`
`
`2004,
`
`57:1521-38;
`
`
`
`Wynn,
`
`2004,
`
`Nat
`
`Rev Immunol,
`
`4(8):583-94).
`
`
`
`20
`
`295
`
`
`
`
`
`
`EGF and
`PDGF,
`
`Dmp
`H
`H
`
`
`family members are potent mitogens
`
`mesenchymal cells such as smooth muscle cel
`
` for
`
` ls,
`
` Basic Res Cardiol,
`
` myo
`fibroblasts
`
`
`and fibroblasts
`
`(
`
` Benit
`
`to et al., 1993, Growth
`
`Regul 3(3):172-
`
`9; Simm et al,
`
`1998,
`
`30
`
`93(S3):40-3;
`
`Klagsburn,
`
`Prog Growth Factor Res,
`
`1989,
`
`1(4):207-35; K
`
`9(8):1464-73),
`
`irkland et al.,
`
`the very cells which supplant normal tissue
`
`1998,
`
`J Am Soc Nephrol,
`
`

`

`WO 2006/067165
`
`PCT/EP2005/057002
`
`
`in fibrosis and are believed to play a role in tissue
`
`remodeling (Abboud, 1995, Annu Rev Physiol., 57:297-309;
`
`Jinnin et al., 2004, J Cell Physiol, online; Martinet et
`
`
`al., 1996, Arch Toxicol 18:127-39; Desmouliere, Cell
` Biology International, 1995, 19:471-6; Jelaska et al.,
`
`
`
`
`
`
`
`
`Springer Semin Immunopathol, 2000, 21:385-95).
`
`
`
`
`
`
`
`Inhibition of PDGF attenuates both liver fibrosis and lung
`
`
`fibrosis in experimental models, suggesting fibrosis in
`
`
`
`
`
`different organs may have a common origin (Borkham—
`
`
`
`Kamphorst et al., 2004, Biochem Biophys Res Commun; Rice et
`
`
`
`
`
`
`An EGF receptor
`al., 1999, Amer J Pathol, 155(1):213-221).
`
`kinase inhibitor was also active in this lung fibrosis
`
`
`
`
`model. Three-fold overexpression of an EGF family member,
`
`
`
`
`HB-EGF,
`in mouse pancreas islets was sufficient to cause
`
`development o
`Fibrosis in both the exocrine and endocrine
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`compartments
`
`(Means et al., 2003, Gastroenterology,
`
`124 (4) :1020-36).
`
`
`Similarly, FGF1/FGF2-deficient mice show dramatically
`
`
`decreased liver fibrosis after chronic carbon tetrachloride
`
`(CC14) exposure (Yu et al., 2003, Am J Pathol, 163(4):1653-
`
`62). FGF expression is increased in human renal
`
`
`interstitial
`fibrosis where it strongly correlates with
`
`
`
`
`
`
`
`
`
`
`interstitial scarring (Strutz et al., 2000, Kidney Intl,
`
`57:1521-38) as well as in a model of experimental
`
`
`
`
`fibrosis (Barrios et al., 1997, Am J Physiol, 273 (2 Pt
`
`1):L451-8), again lending credence to the idea that
`
`
`
`fibrosis in various tissues has a common basis.
`
`
`
`
`In addition, elevated levels of VEGF have been observed in
`
`several studies in persons with asthma (Hoshino et al.,
`
`
`lung
`
`
`

`

`WO 2006/067165
`
`PCT/EP2005/057002
`
`—~
`
`5 -
`
`
`2001, J Allergy Clin Immunol 107:1034-39; Hoshino et al.
`
`2001, J Allergy Clin Immunol 107:295-301; Kanazawa et al.
`
`
`
`
`
`
`
`
`,
`
`,
`
`
`
`
`
`2002, Thorax 57:885-8; Asai et al.,
`
`
`J Allergy Clin Immunol
`
`110:571-5, 2002; Kanazawa et al., 2004, Am J Respir Crit
`
`
`
`
`Care Med, 169:1125-30). Inducible expression of VEGF ina
`
`transgenic mouse model
`
`induces an asthma-like phenotype,
`
`edema, angiogenesis and smooth muscle hyperplasia (Lee et
`
`al., 2004, Nature Med 10:1095-1103).
`
`
`
`
`Finally, TIGFb stimulates production of extracellular matrix
`
`proteins including
`
`believed to play an
`
`tissues
`
`(Leask et al
`
`fibronectin and collagens and is
`
`
`important role in fibrosis in many
`
`
`
`
`l., 2004, FASEB J 18(7):816-27; Bartram
`
`
`
`
`et al.,
`
`2004,
`
`Chest
`
`125(2):754-65; Strutz et al., 2003,
`
`
`
`
`Immunopathol, 24:459-76; Wynn, 2004, Nat Rev
`
`
`
`Inhibitors of
`
`Springer Semin
` Immunol,
`
`4(8):583-94).
`
`
`
`TGFb production and
`
` fibrosis
`signaling pathways are active in a number of
`
`
`
`animal
`
`models
`
`(Wang
`
`
`et al., 2002, Exp
`
`Lung Res,
`
`28:405-17;
`
`Laping,
`
`2003,
`
`Curr Opin Pharmacol,
`
`3 (2) 2204-8).
`
`in
`
`As summarized above,
`
`
`factors are upregulated
`several growth
`
`
`
` factor seems to
`inhibition of a single
`fibrosis and the
`
`
`
`
`in the fibrosis models.
`Fibrosis
`reduce the severity of
`
`
`
` NVI
`
` ON
`SUMMARY OF THE
`
` we
`found that the compounds of above general
`
`Surprisingly,
`
`
`
`
` formula I
`
`
`are ef
`Fective in the treatment or prevention of
`
`
`Fibrotic diseases.
`specific
`
`
`
`10
`
`15
`
`20
`
`295
`
`30
`
`

`

`WO 2006/067165
`
`PCT/EP2005/057002
`
`The present inven
`
`
`tion thus relates to the use of the
`
`
`
`
`
`
`for the preparation of
`formula
`compounds of above general
`
`
`
`
`a medicament £
`or the treatment or prevention of specific
`
`
`
`
`fibrotic diseases.
`
`The present
`
`invention also
`
`
`relates to a method for the
`
`
`treatment or prevention of specific
`
`administration
`
`to a pati ent
`
`
`composition comprising a compound of above
`
`
`
`a I,
`formu]
`general
`
`together with a pharmaceutically
`
`in need
`
`
`thereof of a
`
`fibrotic diseases, by
`
`
`
`
`pharmaceutical
`
`
`10
`
`15
`
`20
`
`suitable carri
`
`er. The expression
`
`"patient" is meant to
` preferably the human
`
`comprise the mammalian animal body,
`
`body.
`
`
`vention further relates to a pharmaceutical
`in
`The present
`
`composition for the treatment or prevention of specific
`
`
`
`a IT alone or in combination with one or more
`general
`formu]
`
`
`
`
`
`
` fibrotic diseases which comprises a compound of above
`
`further therapeutic agents.
`
`
`T
`
`
`
`
`
`
`
`
`
`
`TH
` NVENT
`
`DETAILLED DESCRIPTION OF
`
`ON
`
`
`In accordance with the present invention,
`
`
`
`Formula
`above general
`are the compounds
`
`295
`
`
`the compounds of
`
`

`

`WO 2006/067165
`
`PCT,
`
`/EP2003/057002
`
`in which
`
`X denotes an oxygen or sulphur atom,
`
`Ri, denotes a hydrogen atom or a prodrug group such as a
`
`Cy-a-alkoxycarbonyl or Cy-4a-alkanoyl group,
`
`
`
`Ro denotes a carboxy group,
`
`Ci-e-alkoxy-—carbonyl group,
`
`a straight-chain or branched
`
`a C47-cycloalkoxy—carbonyl or an
`
`aryloxycarbonyl group,
`
`10
`
`15
`
`t-chain or branched C;-¢-al
`
`which is
`
`terminally substituted in
`
`
`a straigh
`
` aminocarbonyl,
`
`phenyl, heteroaryl, carboxy, Ci-3;-al
`
`Ci-3-alkylamino-carbonyl or
`
`
`
`Lkoxy-carbonyl group,
`
`the alkyl moiety by a
`
`Lkoxy—carbonyl,
`
`
`
`20
`
`di-(Ci-3-alkyl)-aminocarbonyl group,
`
`a straigh
`
`which is
`
`
`
`t-chain or branched C2-~.-alkoxy-—carbonyl group,
`
`terminally substituted in the alkyl moiety by a
`
`chlorine atom or a hydroxy,
`
`Ci-3-alkoxy, amino,
`
`25
`
`Cy-3-alkylamino or di-(C,-3-alkyl)—-amino group,
`
`

`

`WO 2006/067165
`
`PCT/EP2005/057002
`
`
`an aminocarbonyl or methylaminocarbonyl group, an
`
`ethylaminocarbonyl group optionally substituted in the 2
`
`
`position of the ethyl group by a hydroxy or C,-3-alkoxy
`
`group or a di-(Ci-»-alkyl)-aminocarbonyl group,
`
`R3 denotes a hydrogen atom,
`
`a Ci-s-alkyl, C37-cycloalkyl,
`
`
`trifluoromethyl or heteroaryl group,
`
`a phenyl or naphthyl group, a phenyl or naphthyl group
`
`mono-— or disubstituted by a fluorine, chlorine, bromine or
`
`
`
`
`
`iodine atom, by a trifluoromethyl, C,-3-alkyl or C,-3-alkoxy
`
`group, whilst
`in the event of disubstitution the
`
`
`
`substituents may be identical or different and wherein the
`
`
`
`
`
`
`
`
`
`10
`
`15
`
`20
`
`
`
`
`
`
`
`abovementioned unsubstituted as well as the mono- and
`
`disubstituted phenyl and naphthyl groups may additionally
`
`be substituted
`
`
`
`by a hydroxy, hydroxy—Cyi-3-alkyl or C,-3-alkoxy—C,_3-alkyl
`
`group,
`
`by a cyano, carboxy, carboxy—Ci-:-alkyl, Ci-s-alkoxycarbonyl,
`
`aminocarbonyl, Ci-3s-alkylamino-carbonyl or di- (Ci-3-alkyl)-
`
`
`
`aminocarbonyl group,
`
`295
`
`by a nitro group,
`
`
`by an amino, Ci-3-alkylamino, di- (Ci-3-alkyl)-amino or amino-
`
`Cy-3-alkyl group,
`
`30
`
`by a Ci-3-alkylcarbonylamino, N-(C,-3-alkyl) —-Ci-3-alkyl-
`
`carbonylamino, C)-3-alkylcarbonylamino—C,-3:-alkyl,
`
`N- (Ci-3-alkyl)—-Ci-3-alkylcarbonylamino—-C,-3-alkyl, Ci-3-alkyl-
`
`

`

`WO 2006/067165
`
`PCT/EP2005/057002
`
`sulphonylamino, Ci-3-alkylsulphonylamino-Ci-3-alkyl,
`
`N- (Ci-3-alkyl)—-C.i-3:-alkylsulphonylamino—Ci_-3-alkyl or
`
`aryl-C,_-3,;-alkylsulphonylamino group,
`
`
`
`by a cycloalkylamino, cycloalkyleneimino, cyclo-
`
`alkyleneiminocarbonyl, cycloalkyleneimino—Ci-:-alkyl,
`
`
`
`
`
`
`
`cycloalkyleneiminocarbonyl-C, 3-alkyl or
`
`cycloalkyleneiminosulphonyl—-C,-3-alkyl group having 4 to 7
`
`ring members in each case, whilst in each case the
`
`10
`
`
`methylene group in position 4 of a 6- or 7-membered
`
`cycloalkyleneimino group may be replaced by an oxygen or
`
`sulphur atom, by a sulphinyl, sulphonyl,
`
`-—-NH
`
`or -N(Ci-3-alkyl) group,
`
`15
`
`
`or by a heteroaryl or heteroaryl—C;-3-alkyl group,
`
`Rz denotes a C3-7-cycloalkyl group,
`
`
`whilst the methylene group in the 4 position of a 6- or 7-
`
`20
`
`membered cycloalkyl group may be substituted by an amino,
`
`Cy-3-alkylamino or di-(Ci-3-alkyl)-amino group or replaced by
`
`an —-NH or -N(Ci-2-alkyl) group,
`
`295
`
`30
`
`or a phenyl group substituted by the group Rs, which may
`
`
`additionally be mono- or disubstituted by fluorine,
`
`
`
`
`
`
`
`chlorine, bromine or iodine atoms, by Ci-5-alkyl,
`
`
`trifluoromethyl, hydroxy, Ci-3-alkoxy, carboxy,
`
`
`
`Cy-3-alkoxycarbonyl, amino, acetylamino,
`
`Cy-3-alkyl—-sulphonylamino, aminocarbonyl,
`
`Cy-3-alkyl—-aminocarbonyl, di-(Ci-3:-alkyl)-aminocarbonyl,
`
`aminosulphonyl, Ci-3-alkyl-aminosulphonyl,
`
`di-(Cy-3-alkyl)-aminosulphonyl, nitro or cyano groups,
`
`

`

`WO 2006/067165
`
`PCT/EP2005/057002
`
`
`
`
`wherein the substituents may be identical or different and
`
`wherein
`
`
`Re denotes a hydrogen, fluorine, chlorine, bromine or
`
`iodine atom,
`
`a cyano, nitro, amino, ( 5s-alkyl, C3 7-cycloalkyl,
`
`
`trifluoromethyl, phenyl,
`
`tetrazolyl or heteroaryl group,
`
`
`
`
`
`
`
`the group of
`formula
`
`oH
`
`0
`
`N
`
`NH
`
`O f
`
`wherein the hydrogen atoms bound to a nitrogen atom may in
`
`
`each case be replaced independently of one another by a
`
`Cyi-3-alkyl group,
`
`a C, 3-alkoxy group,
`
`Cy-3-alkoxy, amino-Czo-3-alkoxy, Ci-3-alkylamino-—Cz-3-alkoxy,
`
`di-(Cy-3-alkyl)—-amino-—C2z_-3-alkoxy, phenyl—C;-3-alkylamino—
`
`a C, 3-alkoxy—C, 3;3-alkoxy, phenyl-—
`
`
`
`
`
`
`Co-3-alkoxy, N-(Ci-3-alkyl) -pheny1-—C,_3-alkylamino-—Cyz_-3—-alkoxy,
`
`Cs-7-cycloalkyleneimino—Co_3-alkoxy or C,-3-alkylmercapto
`
`group,
`
`a carboxy, Ci4a-alkoxycarbonyl, aminocarbonyl, Ci-3-alkyl-
`
`amino-carbonyl, N-(Ci-s-alkyl1)—-Ci_-3-alkylaminocarbonyl,
`
`phenyl-Ci-3-alkylamino-carbonyl,
`
`N- (Cy_-3-alkyl)—-phenyl—C;_2z-alkylamino-carbonyl,
`
`piperazinocarbonyl or N-(C,-3-alkyl) -piperazinocarbony]
`
`group,
`
`10
`
`15
`
`20
`
`25
`
`

`

`WO 2006/06
`
`7165
`
`PCT/EP2005/057002
`
`a Ci-3-alkylaminocarbonyl
`
`or N- (Ci-s-alkyl)-
`
`Ci-3-alkylaminocarbony]
`
`group wherein an alkyl moiety is
`
`substituted by a carboxy or C.-3;-alkoxycarbonyl group or in
`
`the 2 or 3 position by a di-(Ci-s-alkyl)-amino, piperazino,
`
`N- (Ci-3-alkyl)-piperazino or a 4-
`
`to 7-membered
`
`cycloalkyl eneimino group,
`
`
`a C3-7-cycloalkyl-carbonyl group,
`
`
`
`10
`
`
`wherein the methylene group in the 4 position of the 6- or
`
`moiety may be substituted by an
`7-membered cycloalkyl
`
`Ci-3-alkylamino
`or di-(Ci-3s-alkyl)-amino group or
`
`amino,
`
`replaced by an —-NH or —-N ( Cy-3-alkyl)
`
`group,
`
`15
`
`a 4- to 7-membered cycloalkyleneimino group wherein
`
`a methylene group linked to the imino
`
`by a carbonyl or sulphonyl group or
`
`group may be replaced
`
`20
`
`the cycloalkylene moiety may be
`
`
`fused to a phenyl ring or
`
`one or two hydrogen atoms may each be
`
`replaced by a Ci-3-
`
`alkyl group and/or
`
`295
`
`
`in each case the methylene group in the 4 position of a 6-
`
`or 7-membered cycloalkyleneimino group may be substituted
`
`by a carboxy, C,-3-alkoxycarbonyl, aminocarbonyl,
`
`)-aminocarbonyl,
`ky]
`Cy-37-al
`
`ky]
`kylaminocarbonyl, di-(Ci_3-al
`
` l-—C,-3-al] ky] amino group or
`
`amino or N-(C)-3-al
`phenyl]1—Cy1-3-a] ky]
`
`
`phenyl]
`
`)-
`
`30
`
`

`

`WO 2006/067165
`
`PCT/EP2005/057002
`
`may be replaced by an oxygen or sulphur atom, by a
`
`sulphinyl,
`
`
`
`
`
`sulphonyl, —-NH,
`
`-—-N(Cyi-3-alkyl),
`
`-N(phenyl),
`
`-N(C,_;-alkyl-car
`
`bonyl) or -N(benzoyl) group,
`
`a Ci-4-alkyl group substituted by the group R;7, wherein
`
`R7 denotes a C3-7-cycloalkyl group,
`
`
`
`10
`
`
`whilst the methylene group in the 4 position of a 6- or 7-
`
`membered cycloalkyl group may be substituted by an amino,
`
`Cy-3-alkylamino or di-(Ci-3-alkyl)-amino group or replaced by
`
`
`
`
`
`an -NH or -N(Ci-3-alkyl) group or
`
`15
`
`in a 5- to 7-membered cycloalkyl group a —(CH2)2z group may
`
`be replaced by a -CO-NH group,
`
`a —(CH2)3 group may be
`
`replaced by a —NH-CO-NH or —CO-NH-CO group or a —(CHb»)a4
`
`group may be replaced by a —-NH-CO-NH-CO group, whilst
`
`in
`
`each case a hydrogen atom bound to a nitrogen atom may be
`
`
`
`20
`
`replaced by a Ci-3-alkyl group,
`
`an aryl or heteroaryl group,
`
`295
`
`30
`
`a hydroxy or C,-z-alkoxy group,
`
`
`
`
`
`an amino, Ci-7-alkylamino, di-(Ci-7-alkyl) -amino,
`
`phenylamino, N-phenyl-C,-3-alkyl-amino, phenyl—C;-3-alkyl—-
`
`amino, N-(Ci_-3-alkyl) —phenyl1-—-C)_3-alkylamino or di-
`
`(ephenyl—Ci-3-alkyl)-amino group,
`
`an @-hydroxy-—Cs-3,-alkyl-amino, N-(C,-3-alkyl) -@-hydroxy—
`
`Co-3-alkyl—-amino, di- (@-hydroxy—Cz-3-alkyl) -amino,
`
`

`

`WO 2006/067165
`
`PCT/EP2005/057002
`
`di-(@- (C1-3s-alkoxy) -—Co-3-alkyl)-amino or N-(dioxolan—
`
`2-y1l)—-Ci-3-alkyl-amino group,
`
`a C,;-,;-alkylcarbonylamino-Cp_3-alkyl-amino or
`
`Cy-3-alkylcarbonylamino-—Co-3-alky1—N- (Ci-3-alkyl)-amino group,
`
`a C,-3;-alkylsulphonylamino, N—-(Cy_3-alkyl) —Cy,_3-alkyl—-
`
`sulphonylamino, Ci-3-alkylsulphonylamino-—Cz2-3-alkyl-amino or
`
`
`
`Cy, 3-alkylsulphonylamino-—C, 3:-alky1—-N-(C; 3-alkyl) -—amino
`
`10
`
`group,
`
`a hydroxycarbonyl-C,_-3-alkylamino or N-(Ci-3-alkyl)-
`
`hydroxycarbonyl—Ci_3-alkyl-amino group,
`
`15
`
`a guanidino group wherein one or two hydrogen atoms may
`
`each be replaced by a Ci-3-alkyl group,
`
`
`
`
`
`a group of
`formula
`
`20
`
`—N (Rg) -CO- (CH2) n-R9
`
`
`
`
`
`(It),
`
`wherein
`
`Rg denotes a hydrogen atom or a Ci-3-alkyl group,
`
`25
`
`30
`
`
`n denotes one of the numbers 0, 1,
`
`2 or 3 and
`
`
`
`Rg denotes an amino, C,4-alkylamino, di-(Ci-4-alkyl)-amino,
`
`phenylamino, N-(Ci-a-alkyl)-phenylamino, benzylamino,
`
`N- (Ci-,-alkyl)-benzylamino or Cis.-alkoxy group,
`
`a 4- to 7-
`
`membered cycloalkyleneimino group, whilst in each case the
`
`methylene group in the 4 position of a 6- or 7-membered
`
`
`
`

`

`WO 2006/067165
`
`PCT/EP2005/057002
`
`14
`
`cycloalkyleneimino group may
`
`be replaced by an oxygen or
`
`sulphur atom, by a sulphinyl,
`
`
`
`sulphonyl, —-NH, —-N(C._-3;-alkyl),
`
`bonyl) or -N(benzoyl) group,
`
`
`or, if
`
`n denotes one of the
`
`—-N(phenyl),
`
`-N(Ci,_;-alkyl-car
`
`
`
`
`
`numbers 1,
`
`2 or 3,
`
`it may also denote a hydrogen atom,
`
`
`
`
`
`a group of
`formula
`
`—N (R19) — (CH2) m7 (CO) g9-R11
`
`
`
`
`
`
`
`(
`
`dy
`
`wherein
`
`arylcarbonyl,
`
`a Cyi_3-alkyl
`
`group,
`
`a
`
`phenyl-Ci-3-alkyl-carbonyl,
`
`arylsulphonyl or phenyl—-Ci-3-al-
`
`
`
`Rio de notes a hydrogen atom,
`
`Cy-3-alkylcarbonyl,
`
`
`
`Cyi-2-alkylsulphonyl,
`
`
`
`
`
`
`
`kylsulphonyl group,
`
`
`m denotes one of the numbers
`
`1, 2,
`
`3 or 4,
`
`o denotes the number 1 or,
`
`
`£m denotes one of the numbers
`
`i
`
`2,
`
`3 or 4,
`
`o may also denote
`
`the number
`
`0 and
`
`Ri, denotes an amino, Ci-4-alk
`
`ylamino, di-(Ci-4-alkyl)-amino,
`
`phenylamino,
`
`N- (Ci-4-alkyl)-benzylamino,
`
`N- (Cy-a-alkyl)—-phenylamino,
`
`benzylamino,
`
`
`
`Ci-4-alkoxy or
`
`Cyi-3-alkoxy—Ci-3-alkoxy group,
`
`a di-(Ci-4-alkyl) -amino-Ci_-3-
`
`
`
`alkylamino group optionally substituted in the
`
`
`
`
`
`to 7-membered
`
`by a Ci-3-alkyl group or a 4-
`
`cycloalkyleneimino group, wherein the cycloalkylene moiety
`
`
`may be fused to a phenyl ring or in each case the methylene
`
`group in the 4 position of a 6—- or 7-membered
`
`cycloalkyleneimino group may be replaced by an oxygen or
`
`
`
`1 position
`
`
`
`
`
`10
`
`15
`
`20
`
`25
`
`30
`
`

`

`WO 2006/067165
`
`PCT/EP2005/057002
`
`sulphur atom, by a sulphinyl,
`
` sulphonyl, —-NH, —-N(Ci-3-alkyl), -N(phenyl), —-N(Ci-3:-alkyl-car
`
`bonyl) or -N(benzoyl) group,
`
`a Cya-j7-cycloalkylamino, Cy-7-cycloalky1l—C;-3-alkylamino or
`
`
`Ca-y-cycloalkenylamino group wherein position 1 of the ring
`
`
`
`is not
`
`involved in the double bond and wherein the
`
`abovementioned groups may each additionally be substituted
`
`at the amino-nitrogen atom by a Cs-7-cycloalkyl, Ce-4-alkenyl
`
`10
`
`Or Cyi-4-alkyl group,
`
`a 4- to 7-membered cycloalkyleneimino group, wherein
`
`
`
`
`
`
`
`
`
`the cycloalkylene moiety may be fused to a phenyl group or
`
`imidazolo,
`
`thiazolo, pyridino, pyrazino or
`
`
`
`to an oxazolo,
`
`
`pyrimidino group optionally substituted by a fluorine,
`
`chlorine, bromine or iodine atom, by a nitro, C;-3-alkyl,
`
`Ci-3-alkoxy or amino group, and/or
`
`15
`
`295
`
`30
`
`20
`
`one or two hydrogen atoms may each be replaced by a
`
`Cy-3-alkyl, Cy-;-cycloalkyl or phenyl group and/or
`
`the methylene group in the 3 position of a 5-membered
`
`cycloalkyleneimino group may be substituted by a hydroxy,
`
`
`
`hydroxy—Ci-3-alkyl, C1-3-alkoxy or C,-3-alkoxy-—Ci-3-alkyl
`
`group,
`
`
`
`
`the methylene group in the 3 or 4 position of a 6- or 7-
`
`membered cycloalkyleneimino group may in each case be
`
`substituted by a hydroxy, hydroxy—-C;3-alkyl, C,-3-alkoxy,
`
`Cy-3-alkoxy—Ci-s-alkyl, carboxy, Ci-4-alkoxycarbonyl,
`
`carbonyl, Ci-3-alkylaminocarbonyl, di-(Ci-3-alkyl)-
`
`amino—
`
`

`

`WO 2006/067165
`
`PCT/EP2005/057002
`
`aminocarbonyl, phenyl-C,-3-alkylamino or N-(Ci-3-alkyl)-—
`
`phenyl—-Ci-3-alkyl-amino group or
`
`may be replaced by an oxygen or sulphur atom, by a
`
`sulphinyl, sulphonyl, —-NH, —N(C,-3-alkyl-
`
`),
`
`),
`
`-N(phenyl), —-N(phenyl-Ci-3z-alkyl-
`
`-N(Cy1 3-alkyl-carbonyl-), —-N(C,1 a-alkyl-—
`
`
`
`
`
`hydroxy-carbonyl—-),
`
`-N(Cy-4-alkoxy-—carbonyl-—-), —-N(benzoyl-)
`
`or —-N(phenyl—Ci-3-alkyl—-carbonyl-) group,
`
`wherein a methylene group linked to an imino-nitrogen atom
` of the cycloalkyleneimino group may be replaced by a
`
`carbonyl or sulphonyl group or in a 5- to 7-membered
`
`monocyclic cycloalkyleneimino group or a cycloalkyleneimino
`
`
`group fused to a phenyl group the two methylene groups
`
`linked to the imino-nitrogen atom may each be replaced by a
`
`
`
`10
`
`15
`
`carbonyl group,
`
`20
`
`or Re denotes a Ci-4-alkyl group which is substituted by a
`
`carboxy, Ci-3-alkoxycarbonyl, aminocarbonyl,
`
`Ci-3-alkylaminocarbonyl or di-(Ci-3-alkyl) -aminocarbony]
`
`group or by a 4- to 7-membered cycloalkyleneiminocarbonyl
`
`group,
`
`295
`
`an N- (Cyi-3-alkyl)—-C2-4-alkanoylamino group which is
`
`additionally substituted in the alkyl moiety by a carboxy
`
`or Cy-3-alkoxycarbonyl group,
`
`30
`
`
`
`
`
`a group of
`formula
`
`—N (R12) —CO-(CH2) p-R1 3
`
`
`(LV),
`
`

`

`WO 2006/067165
`
`PCT/EP2005/057002
`
`17 -
`
`wherein
`
`group or a Ci-3-alkyl group terminally substituted by a
`
`phenyl, heteroaryl,
`trif]l
`ucoromethyl,
`
`a Ci-e-alkyl or C3-7-cycloalkyl
`
`hydroxy, Ci-3-alkoxy,
`
`Riz denotes a hydrogen atom,
`
`
`
`
`
`
`
`a—-alkylamino-carbonyl,
`aminocarbonyl, Ci
`
`amino-carbonyl, Ci_-3-alkyl]
`-carbonyl, Ci
`
`di- (Cz, 4-alkyl)-
`
`-3-alkyl-sulphonyl-
`
`
`
`
`
`amino,
`
`10
`
`N- (Ci-3-alkyl) -Ci-3-alkyl-sulphonylamino,
`
`Ci-3-alkyl-aminosulphonyl or di-(Ci-3-alkyl) -aminosulphonyl
`
`group and
`
`
`p denotes one of the numbers
`
`0, 1,
`
`2 or 3 and
`
`15
`
`Ri3
`
`or,
`
`
`assumes the meanings of the abovementioned group Rj),
`
`
`
`if p denotes one of
`
`the numbers 1,
`
`2 or 3, it may also
`
`denote a hydrogen atom,
`
`
`
`
`
`Formula
`a group of
`
`—N (R14) —(CH2) g (CO) r-R15
`
`(V),
`
`wherein
`
`Rig denotes a hydrogen atom,
`
`Cyi-3-al kyJ
`carbonyl,
`
`arylcarbonyl,
`
`a Ci-.-alkyl group, a
`
`phenyl-Ci-3-alkylcarbonyl,
`
`heteroarylcarbonyl,
`
`
`
`Cy-a-alkylsulphonyl, aryl]
`
`sulphonyl,
`
`heteroaryl—Cy-3-alkylcarbonyl,
`
`
`
`
`
`
`
`
`phenyl-C;-3-alkylsulphonyl,
`
`heteroarylsulphonyl or
`
`heteroaryl-C, :-alkyl-sulphonyl group,
`
` 1, 2,
`
`3 or 4,
`
`
`q denotes one of
`
`the numbers
`
`20
`
`25
`
`30
`
`

`

`WO 2006/067165
`
`PCT/EP2005/057002
`
`
`
`r denotes the number 1 or, if gq is one of the numbers 2,
`
`3
`
`or 4, it may al so denote the number
`
`0O and
`
`Ris
`
`assumes the meanings of the abovementioned group R;,
`
`
`
`
`
`
`
`a group of
`formula
`
`10
`
`—N (R16) —SO2-R17
`
`
`(VI),
`
`wherein
`
`
`
`Rig denotes a hydrogen atom or a Cyi-4,-alkyl group optionally
`
`terminally substituted by a cyano,
`
`
`trifluoromethyl]
`
`N- (Ci-3-alkyl ) -t
`
`—carbonylamino or
` rifluoromethyl-carbonyl-amino group and
`
`
`
`15
`
`20
`
`25
`
`30
`
`Riz denotes a Ci-3-alkyl group,
`
`substituted by a di- (Ci-3-alkyl)-
`an amino group
`
`amino—Ci-3-alkyl]
`-—carbonyl or di-(C,-3-alkyl)—-
`
`
`
`
`
`amino—C;-3-—alky] -sulphonyl group and a di-(Ci-3-alkyl)-
`
`aminocarbonyl—-C;-3-alkyl group,
`
`or an N-(C,-3-alkyl)—-Ci-s-alkylsulphonylamino or
`
`
`
`
`
`N- (Ci-3-alkyl)-phenylsulphonylamino group wherein the alkyl
`
`moiety is addit
`
`group,
`
`ionally substituted by a cyano or carboxy
`
`wherein all the
`
`
`single-bonded or fused phenyl groups
`
`contained in the groups mentioned under Re may be mono- or
`
`
`disubstituted by fluorine, chlorine, bromine or iodine
`
`
`
`
`
`

`

`WO 2006/067165
`
`PCT/EP2005/057002
`
`
`
`atoms, by Ci-s-alkyl,
`trifluoromethyl, hydroxy, Ci-3-alkoxy,
`
`carboxy, Ci-3-alkoxycarbonyl, aminocarbonyl,
`
`Cy-4-alkylamino-carbonyl, di-(Cy4-alkyl)-amino-carbonyl,
`
`aminosulphonyl, Ci-3-alkyl-aminosulphonyl,
`
`di-(Cy-3-alkyl)—-aminosulphonyl, Ci-3-alkyl—-sulphonylamino,
`
`
`
`nitro or cyano groups, wherein the substituents may be
`
`
`
`
`
`identical or different, or two adjacent hydrogen atoms of
`
`the phenyl groups may be replaced by a methylenedioxy
`
`
`
`10
`
`15
`
`20
`
`295
`
`group,
`
`and
`
`Rs denotes a hydrogen atom or a C;-3-alkyl group,
`
`wherein by an aryl group is meant a phenyl or naphthyl
`
`
`group optionally mono- or disubstituted by a fluorine,
`
`
`
`chlorine, bromine or iodine atom, by a cyano,
`
`
`trifluoromethyl, nitro, carboxy, aminocarbonyl, Cj,-3-alkyl
`
`
`
`or Cyi-3-alkoxy group and
`
`by a heteroaryl group is meant a monocyclic 5- or 6-
`
`membered heteroaryl group optionally substituted by a Ci-3-
`
`alkyl group in the carbon skeleton, wherein
`
`the 6-membered heteroaryl group contains one,
`
`two or three
`
`nitrogen atoms and
`
`
`the 5-membered heteroaryl group contains an imino group
`
`optionally substituted by a C,-3-alkyl or phenyl-—-C;,-3-alkyl
`
`
`
`30
`
`group, an oxygen or sulphur atom or
`
`

`

`WO 2006/067165
`
`PCT/EP2005/057002
`
`
`
`an imino group optionally substituted by a Ci-3-alkyl or
`
`phenyl1-Ci-3-alkyl group or an oxygen or sulphur atom and
`
`additionally a nitrogen atom or
`
`an imino group optionally substituted by a Cy-3-alkyl or
`
`phenyl-Ci-z-alkyl group and two nitrogen atoms,
`
`and moreover a phenyl ring may be fused to the
`
`abovementioned monocyclic heterocyclic groups via two
`
`adjacent carbon atoms and the bonding takes place via a
`
`
`nitrogen atom or via a carbon atom of
`
`the heterocyclic
`
`
`moiety or a fused phenyl ring,
`
`
`some or all of the hydrogen atoms in the abovementioned
`
`alkyl and alkoxy groups or in the alkyl moieties contained
`
`
`
` optionally being
`in the above-defined groups of Formula
`
`
`
`
`replaced by fluorine atoms,
`
`the saturated alkyl and alkoxy moieties with more than 2
`
`carbon atoms which are present in the groups defined
`
`
`
`hereinbefore also include the branched isomers thereof,
`
`
`
`
`
`
`
`such as for example the isopropyl,
`
`tert.butyl,
`
`isobutyl
`
`group, unless otherwise stated,
`
`and
`
`
`
`Saturated N-heterocycle such as trogen atom, e.g. a
`
`
`additionally the hydrogen atom of any carboxy group present
`
`or a hydrogen atom bound to a nit
`
`hydrogen atom of an amino, alkylamino or
`
`imino group ora
`
`the piperidinyl group, may
`
`each be replaced by a group which can be cleaved in vivo.
`
`
`
` By a group which can be cleaved in vivo from an imino or
`
`amino group is meant,
`
`
`for example,
`
`a hydroxy group, an acyl
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`group such as the benzoyl or pyridinoyl group or a
`
`
`Ci-ig-alkanoyl group such as the formyl, acetyl, propionyl,
`
`butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl
`
`group,
`
`a Ci-41,-alkoxycarbonyl group such as the methoxy—
`
`carbonyl, ethoxycarbonyl, propoxycarbonyl,
`
`isopropoxycar-—
`
`
`
`bonyl, butoxycarbonyl,
`
`tert.butoxycarbonyl, pentoxycarbo-—
`
`nyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl,
`
`
`
`
`
`decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or
`
`hexadecyloxycarbonyl group, a phenyl—-Ci-«-alkoxycarbonyl
`
`group such as the benzyloxycarbonyl, phenylethoxycarbonyl
`
`or phenylpropoxycarbonyl group, a C;,-3-alkylsulphonyl-—
`
`
`
`
`
`
`
`
`
`
`Co-a-alkoxycarbonyl, Ci-3s-alkoxy-—C2-4a-alkoxy-
`
`Coa-alkoxycarbonyl or R.CO-O- (ReCR,) -O-CO group wherein
`
`
`
`R. denotes a Ci-s-alkyl, Cs-j-cycloalkyl, phenyl or phenyl-
`
`Ci-3-alkyl group,
`
`Re denotes a hydrogen atom,
`
`a Cy_-3-alkyl, Csj7-cycloalkyl or
`
`phenyl group and
`
`
`
`
`
`Rg denotes a hydrogen atom,
`
`a Ci-z,-alkyl or ReCO—-O- (R¢CRg)—-O
`
`
`group wherein R, to R, are as hereinbefore defined,
`
`wherein additionally the amino group may be a phthalimido
`
`group, whilst the abovementioned ester groups may also be
`
`used as a group which can be converted in vivo into a
`
`carboxy group.
`
`
`
`
`
`formula I which
`One sub-group of compounds of general
`
`deserves special mention comprises those wherein
`
`
`
`
`
`
`X, R1, and R3 to Rs are as hereinbefore defined and
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`R. denotes a straight-chain or branched C)-,.-alkoxy—carbonyl
`
`group,
`
`a Cy_,;-cycloalkoxycarbonyl or a aryloxycarbonyl
`
`group,
`
`a straight-chain or branched Ci-¢-alkoxy—carbonyl group,
`
`which is terminally substituted in the alkyl moiety by a
`
`phenyl, heteroaryl, carboxy, C,:-alkoxycarbonyl,
`
`aminocarbonyl, Ci-3-alkylaminocarbonyl or
`
`10
`
`di-(Ci-3-alkyl)-aminocarbonyl group,
`
`a straight-chain or branched C2z.6-alkoxy—carbonyl group,
`
`which is terminally substituted in the alkyl moiety by a
`
`
`
`chlorine atom or a hydroxy, Ci 3-alkoxy, amino,
`
`15
`
`Cy-3-alkylamino or di-(C,-3-alkyl)-amino group,
`
`the tautomers,
`
`the diastereomers,
`
`the enantiomers,
`
`the
`
`
`
`mixtures thereof and the salts thereof.
`
`20
`
`
`
`
`
`formula I which
`A second sub-group of compounds of general
`
`deserves special mention comprises those wherein
`
`
`
`X, Ri and Rz to R, are as hereinbefore defined and
`
`
`
`295
`
`Rz2 denotes an aminocarbonyl or methylaminocarbonyl group,
`
`
`
`an ethylaminocarbonyl group optionally substituted in the 2
`
`
`position of the ethyl group by a hydroxy or Ci-3-alkoxy
`
`group or a di-(Ci-2,-alkyl)-aminocarbonyl group,
`
`30
`
`the tautomers,
`
`the diastereomers,
`
`the enantiomers,
`
`the
`
`
`
`mixtures thereof and the salts thereof.
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`WO 2006/067165
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`
`
`
`
`
`formula I which
`A third