(12) United States Patent
`Rudolf et al.
`
`USOO6344449B1
`(10) Patent No.:
`US 6,344,449 B1
`(45) Date of Patent:
`Feb. 5, 2002
`
`(54) MODIFIEDAMINOACIDS,
`PHARMACEUTICALS CONTAINING THESE
`COMPOUNDS AND METHOD FOR THEIR
`PRODUCTION
`
`(*) Notice:
`
`(75) Inventors: Klaus Rudolf; Wolfgang Eberlein;
`Wolfhard Engel; Helmut Pieper, all of
`Biberach; Henri Doods, Warthausen;
`Gerhard Hallermayer,
`Maselheim/Sulmingen, all of (DE);
`Michael Entzeroth, Meudon (FR);
`Wolfgang Wienen, Biberach (DE)
`(73) Assignee: Dr. Karl Thomae GmbH, Biberach
`(DE)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`(21) Appl. No.:
`09/254,281
`(22) PCT Filed:
`Sep. 8, 1997
`(86) PCT No.:
`PCT/EP97/04862
`S371 Date:
`Oct. 12, 1999
`S 102(e) Date: Oct. 12, 1999
`(87) PCT Pub. No.: WO98/11128
`PCT Pub. Date: Mar. 19, 1998
`Foreign Application Priority Data
`(30)
`Sep. 10, 1996
`(DE) ......................................... 19636 623
`May 14, 1997
`(DE) ......................................... 197 20 O11
`(51) Int. Cl." .................... C07D 243/10; CO7D 239/80;
`A61K 31/55; A61K 31/517
`(52) U.S. Cl. ............................. 514/211.05; 514/252.17;
`544/284; 540/500
`(58) Field of Search ..................... 544/284; 514/252.17,
`514/211.05; 540/500
`
`(56)
`
`References Cited
`FOREIGN PATENT DOCUMENTS
`
`WO
`
`WO93/25574
`
`* 12/1993
`
`OTHER PUBLICATIONS
`Fang et all Clin. Exp. Allergy 28 (1998) 228-232 (Medline
`abstract only).*
`Edvinsson Funct. Neurol. 15 Suppl. 3 (2000) 50-60 (Med
`line abstract only).*
`
`Onuoha et al Eur. J. Clin. Invest. 31 (2001) 253–257
`(Medline abstract only).*
`Powell et al Br. J. Pharmacol. 131 (2000) 875–884 (Medline
`abstract only).*
`Hamilton et al., A Quantitative Analysis of the Binding of
`N-Acyl Derivatives of alpha-Aminoamides by alpha-Chy
`motrypsin, Proc. Nat. Acad. Sci. 55(3), pp. 664-669, 1966.*
`Bachem Bioscience Inc., Catalog US 6-1993. See entry
`Nos. E-1160 and E-1170 on p. 13, 1993.*
`
`* cited by examiner
`
`Primary Examiner John M. Ford
`(74) Attorney, Agent, or Firm-Robert P. Raymond; Alan
`R. Stempel; Mary-Ellen M. Devlin
`(57)
`ABSTRACT
`The present invention relates to modified amino acids of
`general formula
`
`(I)
`
`R2
`
`/ s".
`
`(CFO),
`A.
`
`R3,
`
`N 1
`
`O
`us
`
`Z.
`
`R
`
`R11
`
`X
`
`R4
`
`wherein
`A, Z, X, n, m, R, R, R, R and R'' are defined as in
`claims 1 to 5, their tautomers, their diastereomers, their
`enantiomers, the mixtures thereof and the Salts thereof,
`particularly the physiologically acceptable Salts thereof
`with inorganic or organic acids or bases, pharmaceuti
`cal compositions containing these compounds, the use
`thereof and processes for preparing them as well as
`their use for the production and purification of anti
`bodies and as labelled compounds in RIA- and ELISA
`assays and as diagnostic or analytical aids in neu
`rotransmitter research.
`
`3 Claims, No Drawings
`
`1
`
`EX2017
`Eli Lilly & Co. v. Teva Pharms. Int'l GMBH
`IPR2018-01426
`
`

`

`US 6,344,449 B1
`
`1
`MODIFIED AMINOACIDS,
`PHARMACEUTICALS CONTAINING THESE
`COMPOUNDS AND METHOD FOR THEIR
`PRODUCTION
`
`The present invention relates to modified amino acids of
`general formula
`
`5
`
`O
`ls
`R
`Z.
`
`R2
`
`/ s".
`
`(CFO),
`R3,
`A.
`N1
`
`R11
`
`X
`
`R4
`
`(I)
`
`1O
`
`15
`
`2
`each case via two adjacent carbon atoms, and the
`bicyclic heteroaromatic rings thus formed may
`also be bound via a carbon atom of the 1,4-
`butadienylene group,
`an unbranched C-alkylamino group optionally Substi
`tuted at the nitrogen atom by a C6-alkyl group or by
`a phenylmethyl group, which may be Substituted in the
`()-position
`by a Co-cycloalkyl group,
`by one or two phenyl groups, by a 1-naphthyl,
`2-naphthyl or biphenylyl group,
`by a 1H-ind ol-3-yl, 1,3-dihydro-2H-2-
`o Xob en Zimidazol-1-yl,
`2, 4 (1 H, 3 H)-
`dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin
`3-yl, 2,4(1H,3H)-dioxothieno3,4-dipyrimidin-3-yl,
`3,4-dihydro-2(1H)-oxothieno3,4-dipyrimidin-3-yl,
`3,4-dihydro-2(1H)-oxothieno3,4-dipyrimidin-1-yl,
`3,4-dihydro-2(1H)-oxothieno3,2-dipyrimidin-3-yl,
`3,4-dihydro-2(1H)-oxothieno3,2-dipyrimidin-1-yl,
`3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro
`2(1H)-oxoquinazolin-3-yl, 201H)-oxoquinolin-3-yl,
`2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo
`1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-
`thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-
`phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-
`phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-
`oxoimidazo[4,5-cquinolin-3-yl, 3,4-dihydro-5-
`phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-
`phenyl-2(1H)-oxopyrimidin-3-yl- or 1,3-dihydro
`2H-2-oxoimidazo4,5-b]pyridin-3-yl-group,
`by a 5-membered heteroaromatic ring linked via a
`carbon atom, which contains a nitrogen, oxygen or
`Sulphur atom or, in addition to a nitrogen atom,
`contains an oxygen, Sulphur or an additional nitrogen
`atom, whilst a nitrogen atom of an imino group may
`be Substituted by an alkyl group, or
`by a 6-membered heteroaromatic ring linked via a
`carbon atom, containing 1, 2 or 3 nitrogen atoms,
`whilst a 1,4-butadienylene group may be attached
`both to the 5-membered and to the 6-membered
`heteroaromatic monocyclic rings, in each case via
`two adjacent carbon atoms, and the bicyclic het
`eroaromatic rings thus formed may also be bound via
`a carbon atom of the 1,4-butadienylene group,
`whilst the phenyl, naphthyl and biphenylyl groups men
`tioned above for the substitution of the alkyl and
`alkylamino groups in the ()-position and optionally also
`partially hydrogenated mono- and bicyclic heteroaro
`matic rings in the carbon Skeleton may additionally be
`mono-, di- or trisubstituted by fluorine, chlorine or
`bromine atoms or by alkyl groups, Css-cycloalkyl
`groups, nitro, alkoxy, phenyl, phenylalkoxy,
`trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl,
`carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy,
`amino, acetylamino, propionylamino, benzoyl,
`benzoylamino, benzoylmethylamino, aminocarbonyl,
`alkylamino carbonyl, dialkylamino carbonyl,
`(1-pyrrollidinyl)carbonyl, (1-piperidinyl)carbonyl,
`(hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-
`piperazinyl)carbonyl, (4-morpholinyl)carbonyl,
`alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio,
`trifluoromethylsulphinyl or trifluoromethylsulphonyl
`groups, wherein the Substituents may be identical or
`different and the above-mentioned benzoyl, benzoy
`lamino and benzoylmethylamino groups may in turn
`additionally be substituted in the phenyl moiety by a
`fluorine, chlorine or bromine atom or by an alkyl,
`
`their tautomers, their diastereomers, their enantiomers,
`their mixtures and Salts thereof, particularly physiologi
`cally acceptable Salts thereof with inorganic or organic
`acids or bases, pharmaceutical compositions containing
`these compounds, the use thereof and processes for
`preparing them.
`In the above general formula I
`R denotes an unbranched C-7-alkyl group which may be
`Substituted in the co-position
`by a Co-cycloalkyl group,
`by one or two phenyl groups, by a 1-naphthyl,
`2-naphthyl or biphenylyl group,
`by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,
`3H)-dioxo quinazolin-1-yl, 2,4(1H,3H)-
`dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno 3,4-
`dpyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno 3,4-
`dpyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno 3,4-
`dpyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno3,2-
`dpyrimidin-3-yl, 3,4-dihydro- 2(1H)-oxothieno3,
`2-dpyrimidin-1-yl, 3,4-dihydro-2(1H)-
`oxo quinazolin-1-yl, 3,4-dihydro-2(1H)-
`oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 201H)-
`oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-
`benzothia diazin-2-yl, 1,3-dihydro-2H-2-
`oxoimidazopyridinyl, 1,3-dihydro-2(2H)-
`oxoimidazo 4.5-cquinolin-3-yl, 1,3-dihydro-2H-2-
`oxoimidazol-1-yl or 3,4-dihydro-2(1H)-
`OXopyrimidin-3-yl group, wherein the latter two
`groups may each be mono- or disubstituted in the 4
`and/or 5-position or in the 5- and/or 6-position by
`lower Straight chained or branched alkyl groups, by
`phenyl, biphenylyl, pyridinyl, diazinyl, furyl,
`thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl,
`isoxazolyl, pyrazolyl-1-methylpyrazolyl, imidazolyl
`or 1-methylimidazolyl groupS and the Substituents
`may be identical or different,
`by a 5-membered heteroaromatic ring linked via a
`carbon atom, which contains a nitrogen, oxygen or
`Sulphur atom or, in addition to a nitrogen atom,
`contains an oxygen, Sulphur or additional nitrogen
`atom, whilst a nitrogen atom of an imino group may
`be Substituted by an alkyl group,
`or by a 6-membered heteroaromatic ring linked via a
`carbon atom, which contains one, two or three nitro
`gen atoms,
`whilst a 1,4-butadienylene group may be attached
`both to the above-mentioned 5-membered het
`eroaromatic monocyclic rings and to the
`6-membered heteroaromatic monocyclic rings, in
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`
`

`

`3
`trifluoromethyl, amino or acetylamino group, or the
`group of formula
`
`US 6,344,449 B1
`
`(II)
`
`wherein
`p denotes the number 1 or 2,
`o denotes the number 2 or 3 or, if Y and Y are not
`Simultaneously nitrogen atoms, O may also denote 1.
`Y' denotes the nitrogen atom if R is a free pair of
`electrons, or the carbon atom,
`Y is the nitrogen atom or the group >CH-,
`R is a free pair of electrons if Y denotes the nitrogen
`atom or, if Y denotes the carbon atom, R denotes
`a hydrogen atom, a C-3-alkyl group, a hydroxy,
`cyano, aminocarbonyl, carboxy, alkoxycarbonyl,
`aminocarbonylamino, phenylmethyl or phenyl
`grOup,
`R denotes the hydrogen atom or, provided that Y is
`not a nitrogen atom, R together with R may denote
`an additional bond,
`R" denotes the hydrogen atom or, provided that Y is
`not a nitrogen atom and RandR together consti
`tute an additional bond, R together with R' may
`also denote a 1,4-butadienylene group,
`R" denotes a hydrogen atom or a C6-alkyl group
`which may be mono- or disubstituted in the
`()-position
`by a C-7-cycloalkyl group, by a 1-naphthyl,
`2-naphthyl, hydroxy, alkoxy, amino, alkylamino,
`dialkylamino, piperidinyl, morpholinyl, pyrrolidinyl,
`hexahydro-1H-1-aZepinyl, aminocarbonyl,
`alkylaminocarbonyl, acetylamino, cyano, aminocar
`bonylamino or alkylaminocarbonylamino group or
`by phenyl, pyridinyl or diazinyl groups, whilst these
`substituents may be identical or different,
`a CS-7-cycloalkyl group, a phenyl, pyridinyl, cyano,
`a mino, ben Zoylamino, a mino carbonyl,
`alkyla mino carbonyl, alko Xy carbonyl,
`phenylalkoxycarbonyl, aminocarbonylamino,
`alkyla mino carbonyl a mino,
`dialkylaminocarbonylamino, N-(aminocarbonyl)-N-
`alkylamino, N-(alkylaminocarbonyl)-N-alkylamino,
`N-(alkylamino carbonyl)-N-phenylamino,
`phenylaminocarbonylamino, phenyl(alkylamino)
`carbonylamino, N-(phenylaminocarbonyl)-N-
`alkylamino, N-(phenylaminocarbonyl)-N-
`phenylamino, benzoylamino carbonylamino,
`phenylalkyla mino carbonyl a mino,
`pyridinylaminocarbonylamino, N-(aminocarbonyl)-
`N-phenylamino, N-(alkylaminocarbonyl)-N-
`phenylamino, N-(aminocarbonylaminocarbonyl)-N-
`phenylamino, N-(pyridinyl)-N-(aminocarbonyl)
`amino, N-(pyridinyl)-N-(alkylaminocarbonyl)
`amino, phenylamino, pyridinylamino, 4-3,4-
`dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl or
`diazinylamino group,
`a Saturated, mono- or di-unsaturated 5- to 7-membered
`aza, diaza, triaza, oxaza, thiaza, thiadiaza- or S.S.-
`dioxido-thiadiaza-heterocycle.
`wherein the above-mentioned heterocycles may be
`linked via a carbon or nitrogen atom and
`
`15
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`may contain one or two carbonyl groups adjacent to
`a nitrogen atom,
`may be Substituted at one of the nitrogen atoms by an
`alkyl, alkanoyl, aroyl, hydroxycarbonylalkyl,
`alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl,
`phenylmethyl or phenyl group,
`may be Substituted at one or two carbon atoms by a
`branched or unbranched alkyl group or by a
`phenyl, phenylmethyl, naphthyl, biphenylyl,
`pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-
`Oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl,
`1 - methyl pyra Zoly 1, imidazolyl or
`1-methylimidazolyl group, wherein the Substitu
`ents may be the same or different,
`and wherein a C-alkylene group may additionally
`be attached to the above-mentioned heterocycles
`via two adjacent carbon atoms or an olefinic
`double bond of one of the above-mentioned unsat
`urated heterocycles may be fused with a benzene,
`pyridine, diazine, 1,3-oxazole, thiophene, furan,
`thiazole, pyrrole, N-methyl-pyrrole, quinoline,
`imidazole or N-methylimidazole ring,
`or if Y is not a nitrogen atom and R and R together
`denote an additional bond, R' together with R" may
`also denote the 1,4-butadienylene group,
`or, if Y is a carbon atom, R^ together with R',
`including Y', also denotes a carbonyl group or a
`Saturated or mono-unsaturated 5- or 6-membered
`1,3-diaza-heterocycle which may optionally contain
`one or two carbonyl groups in the ring and, if it is
`unsaturated, may be benzofused at the double bond
`and may be Substituted at one of the nitrogen atoms
`by a methyl, aminocarbonyl, hydroxycarbonylalkyl,
`alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl,
`phenylmethyl or phenyl group,
`whilst the phenyl, pyridinyl, diazinyl, furyl, thienyl,
`pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl,
`pyrazolyl, 1-methylpyrazolyl, imidazolyl- or
`1-methylimidazolyl groups contained in the residues
`mentioned under R, R7 and R', as well as benzo,
`thieno, pyrido- and diazino-fused heterocycles in the
`carbon Skeleton may additionally be mono-, di- or
`trisubstituted by fluorine, chlorine or bromine atoms,
`by alkyl groups, Css-cycloalkyl groups, nitro,
`alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl,
`alkylsulphonylamino, phenyl, phenylalkoxy,
`trifluoro methyl,
`alko Xy carbonyl,
`alkoxycarbonylalkyl, carboxy, carboxyalkyl,
`dialkylaminoalkyl, hydroxy, amino, acetylamino,
`propionylamino, ben Zoyl, ben Zoylamino,
`be n Zoyl methyla mino, a mino carbonyl,
`alkylaminocarbonyl, dialkylamino carbonyl,
`hydroxyalkylaminocarbonyl, (4-morpholinyl)
`carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)
`carbonyl, (hexahydro-1-azepinyl)carbonyl,
`(4-methyl-1-piperazinyl)carbonyl, methylenedioxy,
`aminocarbonylamino, aminocarbonylaminoalkyl,
`alkylaminocarbonylamino, alkanoyl, cyano,
`trifluoro methoxy, triflu or methylthio,
`trifluoromethylsulphinyl- or trifluoromethylsulpho
`nyl groups, wherein the Substituents may be identical
`or different and the above-mentioned benzoyl,
`benzoylamino, benzoylaminocarbonylamino and
`benzoylmethylamino groups may in turn addition
`ally be substituted in the phenyl moiety by a fluorine,
`chlorine or bromine atom or by an alkyl,
`trifluoromethyl, amino- or acetylamino group
`
`3
`
`

`

`S
`and unless otherwise Specified the alkyl groups con
`tained in the above-mentioned radicals may contain
`1 to 5 carbon atoms,
`X denotes an oxygen atom or 2 hydrogen atoms,
`Z denotes a methylene group or the group —NR',
`wherein
`R" denotes a hydrogen atom or an alkyl or phenylalkyl
`grOup,
`R' denotes a hydrogen atom, a C-alkyl group, an
`alkoxycarbonyl group having a total of 2 to 4 carbon
`atoms or a phenylmethyl group,
`in denotes the number 1 or 2 or, if m is 1, n may also be
`0,
`m denotes the number 0 or 1,
`R° denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-
`tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H
`indol-3-yl, 1-formyl-1H-indol-3-yl, 1-(1,1-
`dimethylethoxycarbonyl)-1H-indol-3-yl, 4-imidazolyl,
`1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl,
`1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzob
`fur-3-yl, benzobthien-3-yl, pyridinyl, qui-nolinyl or
`isoquinolinyl group,
`whilst the above-mentioned aromatic and heteroaro
`matic groups in the carbon Skeleton may additionally
`be mono-, di- or trisubstituted by fluorine, chlorine
`or bromine atoms or by branched or unbranched
`alkyl groups, Cs-cycloalkyl groups, phenylalkyl
`groups, alkenyl, alkoxy, phenyl, phenylalkoxy,
`trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl,
`alkoxycarbonyl, carboxy, dialkylaminoalkyl,
`dialkylaminoalkoxy, hydroxy, nitro, amino,
`acetyla mino, propionylamino, ben Zoyl,
`be n Zoyla mino, ben Zoyl methyla mino,
`methyl Sulphony lo Xy, a mino carbonyl,
`alkylaminocarbonyl, dialkylaminocarbonyl,
`alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl,
`thiazoly 1,
`furyl,
`trifluoro methoxy,
`trifluoromethylthio, trifluoromethylsulphinyl- or tri
`fluoromethylsulphonyl groups, and the Substituents
`may be identical or different and the above
`mentioned benzoyl, benzoylamino- and benzoylm
`ethylamino groups may in turn additionally be Sub
`Stituted in the phenyl moiety by a fluorine, chlorine
`or bromine atom, or by an alkyl, trifluoromethyl,
`amino or acetylamino group,
`A denotes a bond or the divalent group of formula
`
`15
`
`25
`
`35
`
`40
`
`45
`
`R9
`
`(III)
`
`50
`
`US 6,344,449 B1
`
`6
`a mino carbonyl,
`hydro Xy carbonyl,
`aminoiminomethylamino, aminocarbonylamino,
`phenyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl,
`1-formyl-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-
`imidazolyl, 1-naphthyl, 2-naphthyl- or pyridinyl
`group, whilst the above-mentioned heterocycles,
`phenyl and naphthyl groupS may in turn be mono-,
`di- or trisubstituted in the carbon skeleton by
`fluorine, chlorine or bromine atoms or by methyl,
`alkoxy, trifluoromethyl, hydroxy, amino,
`acetylamino, a mino carbonyl, cyano,
`trifluoromethoxy, methylsulphonyl oxy,
`trifluoromethylthio, trifluoromethylsulphinyl or trif
`luoromethylsulphonyl groups, wherein the Substitu
`ents may be identical or different, and wherein the
`hydroxy, mercapto, amino, guanidino, indolyl and
`imidazolyl groups contained in the groups men
`tioned for R may be substituted with the protecting
`groups commonly used in peptide chemistry, pref
`erably with the acetyl, benzyloxycarbonyl or tert.bu
`tyloxycarbonyl group,
`R denotes a hydrogen atom,
`a C-7-alkyl group which may be Substituted in the
`()-position by a cyclohexyl, phenyl, pyridinyl, diazinyl,
`hydroxy, amino, alkylamino, dialkylamino, carboxy,
`aminocarbonyl, aminocarbonylamino, acetylamino,
`1-pyrrollidinyl, 1-piperidinyl, 4-(1-piperidinyl)-1-
`piperidinyl, 4-morpholinyl, hexahydro-1H-1-azepinyl,
`bis-(2-hydroxyethyl)amino, 4-alkyl-1-piperazinyl or
`4-(c)-hydroxyalkyl)-1-piperazinyl group,
`a phenyl or pyridinyl group,
`wherein the above-mentioned heterocyclic groups and
`phenyl groups may additionally be mono-, di- or
`trisubstituted in the carbon skeleton by fluorine,
`chlorine or bromine atoms or by methyl, alkoxy,
`trifluoromethyl, hydroxy, amino, acetylamino,
`aminocarbonyl, cyano, methylsulphonyloxy,
`trifluoromethoxy, trifluoromethylthio, trifluorometh
`ylsulphinyl or trifluoromethylsulphonyl groupS and
`the substituents may be identical or different,
`R" denotes a hydrogen atom or a C-alkyl group option
`ally Substituted by a phenyl or pyridinyl group or
`R and R together with the enclosed nitrogen atom
`denote a group of general formula
`
`R12
`
`(IV)
`
`Y3
`
`/, 7 YR 10,
`a 4-1 2 NCR 13R 14
`
`(CH2)
`
`AX s
`
`R8
`
`O
`
`hich is linked to the NR'R''
`ia the -CX
`Which Slinked to the
`group Via the - group
`wherein
`R and R together denote an n-propylene group or
`R denotes a hydrogen atom or an alkyl- or phenylalkyl
`group and
`R" denotes a hydrogen atom or a branched or
`unbranched Cis-alkyl group which, if it is
`unbranched, may be Substituted in the co-position by
`a hydroxy, mercapto, amino, alkylamino,
`dialkylamino, 1-aZe tidinyl, 1-pyrrollidinyl,
`1-piperidinyl, hexahydro-1-azepinyl, methylthio,
`
`55
`
`60
`
`65
`
`wherein
`Y denotes a carbon atom or, if R' denotes a free pair
`of electrons, Y may also be the nitrogen atom,
`r denotes the number 0, 1 or 2,
`q denotes the number 0, 1 or 2,
`R" denotes a hydrogen atom or an amino, alkylamino,
`dialkylamino, alkyl, cycloalkyl, aminoalkyl,
`alkyla mino alkyl, dialkyla mino alkyl,
`a minoimino methyl, amino carbonylamino,
`alkyla mino carbonyl a mino,
`cy cloalkyla mino carbonyl a mino,
`phenylaminocarbonylamino, aminocarbonylalkyl,
`amino carbonylaminoalkyl, alkoxycarbonyl,
`alkoxycarbonylalkyl, carboxyalkyl or carboxy
`grOup,
`
`4
`
`

`

`7
`a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl,
`pyridinylcarbonyl- or phenylcarbonyl-group which
`may be mono-, di- or triSubstituted in the carbon
`skeleton by fluorine, chlorine or bromine atoms, or
`by alkyl, alkoxy, methyl Sulphonyl oxy,
`trifluoromethyl, hydroxy, amino, acetylamino,
`a mino carbonyl, a mino carbonyl amino,
`aminocarbonylaminomethyl, cyano, carboxy,
`carbalkoxy, carboxyalkyl, carbalkoxyalkyl,
`alkanoyl, co - (dialkyl a mino) alkanoyl,
`co-(dialkylamino) alkyl, co-(dialkylamino)
`hydroxyalkyl, co - (carb oxy) alkanoyl,
`trifluoromethoxy, trifluoromethylthio, trifluorometh
`ylsulphinyl or trifluoromethylsulphonyl groups,
`whilst the substituents may be identical or different,
`a 1,3-dihydro-2-oxo-2H-imidazolyl, 2,4(1H,3H)-
`dioxopyrimidinyl or 3,4-dihydro-2(1H)-
`OXopyrimidinyl group bound via a nitrogen atom,
`which may be Substituted by a phenyl group or fused
`at the double bond to a benzene, pyridine or diazine
`ring,
`a 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl
`grOup,
`a 4- to 10-membered azacycloalkyl group, a 5- to
`10-membered oxaza, thiaza- or diazacycloalkyl
`group or a 6- to 10-membered azabicycloalkyl
`grOup,
`wherein the above-mentioned mono- and bicyclic het
`erocycles may be bound via a nitrogen or carbon
`atom and
`may be Substituted by a C-7-alkyl group, by an
`alkanoyl, dialkylamino, phenylcarbonyl,
`pyridinylcarbonyl, carboxyalkanoyl, carboxyalkyl,
`alko Xy carbonylalkyl, alko Xy carbonyl,
`a mino carbonyl, alkylamino carbonyl,
`alkylsulphonyl, cycloalkyl- or cycloalkylalkyl
`group, by a
`cycloalkyl carbonyl,
`azacycloalkylcarbonyl, diazacycloalkylcarbonyl or
`Oxazacycloalkylcarbonyl group optionally Substi
`tuted in the ring,
`whilst the alicyclic parts contained in these Substitu
`ents may comprise 3 to 10 ring members and the
`heteroalicyclic parts may comprise 4 to 10 ring
`members and
`the above-mentioned phenyl and pyridinyl groups
`may in turn be mono-, di- or triSubstituted by
`fluorine, chlorine or bromine atoms, by alkyl,
`alkoxy, methylsulphonyloxy, trifluoromethyl,
`hydroxy, amino, acetylamino, aminocarbonyl,
`a mino carbonyl a mino,
`aminocarbonylaminomethyl, cyano, carboxy,
`carbalkoxy, carboxyalkyl, carbalkoxyalkyl,
`alkanoyl, co-(dialkylamino)alkanoyl, co-(carboxy)
`alkanoyl, trifluoromethoxy, trifluoromethylthio,
`trifluoromethylsulphinyl or trifluoromethylsul
`phonyl groups, whilst the Substituents may be
`identical or different, or
`R' together with R'' and Y denotes a 4- to
`7-membered cycloaliphatic ring in which a methyl
`ene group may be replaced by an -NH- or
`-N(alkyl)- group,
`whilst a hydrogen atom bound to a nitrogen atom
`within the group R' may be replaced by a pro
`tecting group,
`R"f denotes a hydrogen atom,
`a C-alkyl group, wherein an unbranched alkyl group
`may be Substituted in the co-position by a phenyl,
`
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`US 6,344,449 B1
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`8
`pyridinyl, diaZinyl, a mino, alkylamino,
`dialkylamino, 1-pyrrollidinyl, 1-piperidinyl,
`4-methyl-1-pipe raZinyl, 4-morpholinyl- or
`hexahydro-1H-1-azepinyl group,
`an alkoxycarbonyl, cyano or aminocarbonyl group or a
`free pair of electrons, if Y denotes a nitrogen atom,
`and
`R" and R' in each case denote a hydrogen atom or,
`if Y is a carbon atom, R' together with R'' also
`denotes another carbon-carbon bond, wherein R' is
`as hereinbefore defined and R' denotes a hydrogen
`atOm Or
`if Y is a carbon atom, R' together with R'' also
`denotes another carbon-carbon bond and R'
`together with R" and the enclosed double bond
`denotes a partially hydrogenated or aromatic 5- to
`7-membered mono- or bicyclic carbocycle or
`heterocycle,
`whilst all the above-mentioned alkyl and alkoxy groups
`and the alkyl groups present within the other groups
`mentioned may contain 1 to 7 carbon atoms, unless
`otherwise Specified,
`all the above-mentioned cycloalkyl groups and the
`cycloalkyl groups present within the other groups
`named may contain 5 to 10 carbon atoms, unless
`otherwise Specified, and
`the term “aroyl group' used above denotes, for example,
`the benzoyl or naphthoyl group.
`The protecting groups mentioned in the foregoing defi
`nitions and hereinafter are the protecting groups which are
`commonly known from peptide chemistry, particularly
`a phenylalkoxycarbonyl group having 1 to 3 carbon atoms
`in the alkoxy moiety, optionally Substituted in the
`phenyl nucleus by a halogen atom, by a nitro or phenyl
`group or by one or two methoxy groups,
`for example the benzyloxycarbonyl, 2-nitro
`benzyloxycarbonyl, 4-nitro-benzyloxycarbonyl,
`4-methoxy-ben Zyloxycarbonyl, 2-chloro
`benzyloxycarbonyl, 3-chloro-benzyloxycarbonyl,
`4-chloro-benzyloxycarbonyl, 4-Biphenylyl-O.C.-
`dimethyl-benzyloxycarbonyl or 3,5-dimethoxy-O.C.-
`dimethyl-benzyloxycarbonyl group,
`an alkoxycarbonyl group having a total of 1 to 5 carbon
`atoms in the alkyl moiety,
`for example the methoxycarbonyl, ethoxycarbonyl,
`n-propoxy carbonyl, iSopropoxy carbonyl,
`n-butoxycarbonyl, 1-methylpropoxycarbonyl,
`2-methylpropoxycarbonyl or tert.butyloxycarbonyl
`grOup,
`the allyloxycarbonyl, 2,2,2-trichloro - (1,1-
`dimethylethoxy) carbonyl
`O
`9-fluorenylmethoxycarbonyl group or
`the formyl, acetyl or trifluoroacetyl group.
`The present invention relates to racemates, where the
`compounds of general formula I have only one chiral
`element. However, the application also covers the individual
`diastereomeric pairs of antipodes or mixtures thereof which
`occur when there is more than one chiral element in the
`compounds of general formula (I).
`Particularly preferred are compounds of general formula
`I wherein Z denotes NR' and m assumes the value 0 and
`which are in the D- or (R)-configuration with regard to the
`partial amino acid structure of the formula
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`US 6,344,449 B1
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`(V)
`
`-R
`(CH2)
`
`A, \
`
`R1
`
`X
`
`and which are in the L- or (S)-configuration with regard
`to the partial amino acid structure of formula
`
`1O
`
`R9
`
`R8
`
`O
`
`(III)
`
`15
`
`which may be present in the group A. AS for the other
`compounds covered by general formula I, the preferred
`isomers are those which are spatially constructed analo
`gously to the (R)-configured partial structure of for
`mula V with regard to the partial structure of formula
`VI
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`(VI)
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`phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-
`oxoimidazo[4,5-cquinolin-3-yl, 3,4-dihydro-5-
`phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-
`phenyl-2(1H)-oxopyrimidin-3 -yl- or 1,3-dihydro
`2H-2-oxoimidazo4,5-b]pyridin-3-yl-group,
`by a 5-membered heteroaromatic ring linked via a
`carbon atom, which contains a nitrogen, oxygen or
`Sulphur atom or, in addition to a nitrogen atom,
`contains an oxygen, Sulphur or an additional nitrogen
`atom, whilst a nitrogen atom of an imino group may
`be Substituted by an alkyl group, or
`by a 6-membered heteroaromatic ring linked via a
`carbon atom and containing 1, 2 or 3 nitrogen atoms,
`whilst a 1,4-butadienylene group may be attached
`both to the 5-membered and to the 6-membered
`heteroaromatic monocyclic rings via two adjacent
`carbon atoms in each case and the bicyclic heteroaro
`matic rings thus formed may also be bound via a
`carbon atom of the 1,4-butadienylene group,
`whilst the phenyl, naphthyl and biphenylyl groups men
`tioned above for the substitution of the alkylamino
`groups in the co-position and optionally partially hydro
`genated mono- and bicyclic heteroaromatic rings in the
`carbon skeleton may additionally be mono-, di- or
`trisubstituted by fluorine, chlorine or bromine atoms,
`by alkyl groups, Cs-cycloalkyl groups, nitro, alkoxy,
`phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl,
`alkoxycarbonylalkyl, carboxy, carboxyalkyl,
`dialkylaminoalkyl, hydroxy, amino, acetylamino,
`propionylamino, benzoyl, ben Zoylamino,
`benzoyl methyla mino,
`a mino carbonyl,
`alkylamino carbonyl, dialkylamino carbonyl,
`(1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl,
`(hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-
`piperazinyl)carbonyl, (4-morpholinyl)carbonyl,
`alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio,
`trifluoromethylsulphinyl- or trifluoromethylsulphonyl
`groups, whilst the Substituents may be identical or
`different and the above-mentioned benzoyl,
`benzoylamino- and benzoylmethylamino groups in turn
`may additionally be substituted in the phenyl moiety by
`a fluorine, chlorine or bromine atom or by an alkyl,
`trifluoromethyl, amino or acetylamino group,
`whilst all the above-mentioned alkyl and alkoxy groups
`and the alkyl groups present within the other groups
`mentioned may contain 1 to 4 carbon atoms, unless
`otherwise Stated,
`their tautomers, their diastereomers, their enantiomers,
`mixtures thereof and the salts thereof.
`Another Subgroup of compounds of general formula I
`deserving Special mention comprises those wherein
`R, R, R", R', X, Z and m and n are defined as for the
`first Subgroup hereinbefore,
`R denotes an unbranched C-7-alkyl group which may be
`Substituted in the co-position
`by a Co-cycloalkyl group,
`by one or two phenyl groups, by a 1-naphthyl,
`2-naphthyl- or biphenylyl-group,
`by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,
`3H)-dioxo quinazolin-1-y 1, 2,4(1H,3H)-
`dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno3,4-
`dpyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno 3,4-
`dpyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno 3,4-
`dpyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno3,2-
`dpyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno3,2-
`dpyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin
`
`45
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`
`The compounds of general formula I have valuable phar
`macological properties based on their selective CGRP
`antagonistic properties. The invention further relates to
`40
`medicaments containing these compounds, their use and the
`preparation thereof.
`A Subgroup of compounds of general formula I which
`deserves Special mention comprises those wherein
`A, R, R, R", R', X, Z and m and n are as hereinbefore
`defined and
`R denotes an unbranched C-alkylamino group option
`ally Substituted at the nitrogen atom by a C-alkyl
`group or by a phenylmethyl group, which may be
`Substituted in the co-position
`by a Co-cycloalkyl group,
`by one or two phenyl groups, by a 1-naphthyl,
`2-naphthyl or biphenylyl group,
`by a 1H-in dol-3-yl, 1,3-dihydro-2H-2-
`o Xob en Zimidazol-1-yl,
`2, 4(1H,3H)-
`dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin
`3-yl, 2,4(1H,3H)-dioxothieno3,4-dpyrimidin-3-yl,
`3,4-dihydro-2(1H)-oxothieno3,4-dipyrimidin-3-yl,
`3,4-dihydro-2(1H)-oxothieno3,4-dipyrimidin-1-yl,
`3,4-dihydro-2(1H)-oxothieno3,2-dipyrimidin-3-yl,
`3,4-dihydro-2(1H)-oxothieno3,2-dipyrimidin-1-yl,
`3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro
`2(1H)-oxoquinazolin-3-yl, 201H)-oxoquinolin-3-yl,
`2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo
`1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-
`thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-
`phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-
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`US 6,344,449 B1
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`1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-
`oxoquinolin-3-yl, 201H)-oxoquinoxalin-3-yl, 1,1-
`dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-
`dihydro-2H-2-oxoimidazopyridinyl, 1,3-dihydro-2
`(2H)-oxoimidazo[4,5-cquinolin-3-yl, 1,3-dihydro
`2H-2-oxoimidazol-1-yl- or 3,4-dihydro-2(1H)-
`oXopyrimidin-3-yl-groups, whilst the latter two
`groups may each be mono- or disubstituted in the 4
`and/or 5-position or in the 5- and/or 6-position by
`lower Straight-chained or branched alkyl groups, by
`phenyl, biphenylyl, pyridinyl, diazinyl, furyl,
`thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl,
`isoxazolyl, pyrazolyl-1-methylpyrazolyl, imidazolyl
`or 1-methylimidazolyl groups, and the Substituents
`may be identical or different,
`by a 5-membered heteroaromatic ring linked via a
`carbon atom, which contains a nitrogen, oxygen or
`Sulphur atom or in addition to a nitrogen atom
`contains an oxygen, Sulphur or an additional nitrogen
`atom, whilst a nitrogen atom of an imino group may
`be Substituted by an alkyl group,
`or by a 6-membered heteroaromatic ring linked via a
`carbon atom, which contains one, two or three nitro
`gen atoms,
`whilst a 1,4-butadienylene group may be attached
`both to the above-mentioned 5-membered and to
`the 6-membered heteroaromatic monocyclic rings,
`in each case via two adjacent carbon atoms, and
`the bicyclic heteroaromatic rings thus formed may
`also be bound via a carbon atom of the 1,4-
`butadienylene group,
`whilst the phenyl, naphthyl- and biphenylyl-groups men
`tioned hereinbefore for the substitution of the alkyl
`groups in the co-position and optionally partially hydro
`genated mono- and bicyclic heteroaromatic rings in the
`carbon skeleton may additionally be mono-, di- or
`trisubstituted by fluorine, chlorine or bromine atoms,