(12) United States Patent
`Rudolf et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,344,449 B1
`Feb. 5, 2002
`
`US006344449B1
`
`(54) MODIFIED AMINOACIDS,
`PHARMACEUTICALS CONTAINING THESE
`COMPOUNDS AND METHOD FOR THEIR
`PRODUCTION
`
`(75)
`
`Inventors: Klaus Rudolf; Wolfgang Eberlein;
`Wnlfhard 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)
`
`Onuoha et al Eur. J. Clin.
`(Medline abstract only)?“
`
`Invest. 31 (2001) 253-257
`
`Powell et al Br. J. Pharmacol. 131 (2000) 875-884 (Medline
`abstract only).*
`
`Hamilton ct al., A Quantitative Analysis of the Binding of
`N-Acyl Derivatives of alpha-Ammoamides 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
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`Primary Examirzer—John M. Ford
`(74) Attorney, Agent, or Firm—Robert P. Raymond; Alar1
`R. Stempel; Mary-Ellen M. Devlin
`
`(21) Appl. N0.:
`
`09/254,281
`
`(22) PCT Filed:
`
`Sep. 8, 1997
`
`(86) PCT No.:
`
`PCT/EP97/04862
`
`§ 371 Date:
`
`Oct. 12, 1999
`
`§ 102(e) Date: Oct. 12, 1999
`
`(87) PCT Pub. N0.: WO98/11128
`
`PCT Pub. Date: Mar. 19, 1998
`
`(30)
`
`Foreign Application Priority Data
`
`Sep. 10, 1996
`May 14, 1997
`
`(DE)
`(DE)
`
`....................................... .. 196 36 623
`....................................... .. 197 20 011
`
`(51)
`
`(52) U.S. Cl.
`
`Int. Cl.7 .................. .. C07D 243/10; C07D 239/80;
`A61K 31/55; A61K 31/517
`........................... .. 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
`
`W0
`
`WO93/25574
`
`* 12/1993
`
`OTHER PUBLICATIONS
`
`Fang et al Clin. Exp. Allergy 28 (1998) 228-232 (Medline
`abstract on1y).*
`Edvinsson Funct. Neurol. 15 Suppl. 3 (2000) 50-60 (Med-
`line abstract only).*
`
`(57)
`
`ABSTRACT
`
`The present invention relates to modified amino acids of
`general formula
`
`(1)
`
`2
`
`/R
`((|:H2)n
`o
`(c=o),,,
`X A
`R
`Z
`R11
`x
`
`R3
`
`\ /
`|
`R4
`
`wherein
`
`A, Z, X, n, m, R, R2, R3, R4 and R11 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
`
`   
`


`
`Lannett Holdings, Inc. LAN 1007
`
`

`
`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 (cid:9)
`
`(I)
`
`10 (cid:9)
`
`0
`
`R3
`'
`
`N
`
`la
`
`R11
`
`X
`
`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 C1_7-alkyl group which may be
`substituted in the w-position
`by a C4_„-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)-dioxoquinazolin-l-yl, 2,4(1H,3H)-
`dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-
`d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-
`d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-
`d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-
`d]pyrimidin-3-yl, 3,4-dihydro- 2(1H)-oxothieno[3,
`2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-
`oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-
`oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-
`oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-
`b en zo thiadi azin -2- yl, 1,3-dihydro-2H-2-
`oxoimidazopyridinyl, 1,3-dihydro-2(2H)-
`oxoimidazo[4,5-c]quinolin-3-yl, 1,3-dihydro-2H-2-
`o xo im id azol-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
`
`15 (cid:9)
`
`20 (cid:9)
`
`25 (cid:9)
`
`30 (cid:9)
`
`35 (cid:9)
`
`40 (cid:9)
`
`45 (cid:9)
`
`50 (cid:9)
`
`55 (cid:9)
`
`60 (cid:9)
`
`65 (cid:9)
`
`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 C1_6-alkylamino group optionally substi-
`tuted at the nitrogen atom by a C1_6alkyl group or by
`a phenylmethyl group, which may be substituted in the
`w-position
`by a C4_„-cycloalkyl group,
`by one or two phenyl groups, by a 1-naphthyl,
`2-naphthyl or biphenylyl group,
`by a 1H-indol-3-yl, 1,3-dihydro-2H-2-
`oxobenzimidazol-1-yl, (cid:9)
`2,4(1H,3H)-
`dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-
`3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl,
`3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl,
`3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl,
`3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl,
`3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl,
`3,4-dihydro-2(1H)-oxoquinazolin-l-yl, 3,4-dihydro-
`2(1H)-oxoquinazolin-3-yl, 2(1H)-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-
`thieny1)-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-c]quinolin-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-oxoimidazo[4,5-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 w-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, C3„-cycloalkyl
`groups, nitro, alkoxy, phenyl, phenylalkoxy,
`trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl,
`carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy,
`amino, acetylamino, propionylamino, benzoyl,
`benzoylamino, benzoylmethylamino, aminocarbonyl,
`alkylaminocarbonyl, dialkylaminocarbonyl,
`(1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl,
`(hexahydro-1H-azepin-l-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,
`
`(cid:9)
`

`
`US 6,344,449 B1
`
`3
`trifluoromethyl, amino or acetylamino group, or the
`group of formula
`
`R5 (cid:9)
`
`RN
`
`(T2).
`
`Yi (cid:9)
`
`(CIFIY22)p
`
`R7
`
`wherein
`p denotes the number 1 or 2,
`o denotes the number 2 or 3 or, if Y1 and Y2 are not
`simultaneously nitrogen atoms, o may also denote 1.
`Y1 denotes the nitrogen atom if R5 is a free pair of
`electrons, or the carbon atom,
`Y2 is the nitrogen atom or the group >CH—,
`R5 is a free pair of electrons if Y1 denotes the nitrogen
`atom or, if Y1 denotes the carbon atom, R5 denotes
`a hydrogen atom, a C1_3-alkyl group, a hydroxy,
`cyano, aminocarbonyl, carboxy, alkoxycarbonyl,
`aminocarbonylamino, phenylmethyl or phenyl
`group,
`R6 denotes the hydrogen atom or, provided that Y1 is
`not a nitrogen atom, R6 together with R5 may denote
`an additional bond,
`R7 denotes the hydrogen atom or, provided that Y1 is
`not a nitrogen atom and R5 and R6 together consti-
`tute an additional bond, R7 together with RN may
`also denote a 1,4-butadienylene group,
`RN denotes a hydrogen atom or a C1_6-alkyl group
`which may be mono- or disubstituted in the
`w-position
`by a C5_ 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 C5_7-cycloalkyl group, a phenyl, pyridinyl, cyano,
`amino, benzoylamino, aminocarbonyl,
`alkylaminocarbonyl, alkoxycarbonyl,
`phenylalkoxycarbonyl, aminocarbonylamino,
`alkylaminocarbonylamino,
`dialkylaminocarbonylamino, N-(aminocarbonyl)-N-
`alkylamino, N-(alkylaminocarbonyl)-N-alkylamino,
`N-(alkylaminocarbonyl)-N-phenylamino,
`phenylaminocarbonylamino, [phenyl(alkylamino)]
`carbonylamino, N-(phenylaminocarbonyl)-N-
`alkylamino, N-(phenylaminocarbonyl)-N-
`phenylamino, benzoylaminocarbonylamino,
`phenylalkylaminocarbonylamino,
`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,
`dihydro-2(1H)-oxoquinazolin-3-y1]-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
`
`5 (cid:9)
`
`10 (cid:9)
`
`15 (cid:9)
`
`20 (cid:9)
`
`25 (cid:9)
`
`30 (cid:9)
`
`35 (cid:9)
`
`40 (cid:9)
`
`45 (cid:9)
`
`50 (cid:9)
`
`55 (cid:9)
`
`60 (cid:9)
`
`65 (cid:9)
`
`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-methylpyrazolyl, imidazolyl or
`1-methylimidazolyl group, wherein the substitu-
`ents may be the same or different,
`and wherein a C3_6-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 Y1 is not a nitrogen atom and R5 and R6 together
`denote an additional bond, RN together with R7 may
`also denote the 1,4-butadienylene group,
`or, if Y1 is a carbon atom, RN together with R5,
`including Y1, 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 R5, R7 and RN, 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, C3_8-cycloalkyl groups, nitro,
`alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl,
`alkylsulphonylamino, phenyl, phenylalkoxy,
`trifluoromethyl, (cid:9)
`alkoxycarbonyl,
`alkoxycarbonylalkyl, carboxy, carboxyalkyl,
`dialkylaminoalkyl, hydroxy, amino, acetylamino,
`propionylamino, benzoyl, benzoylamino,
`benzoylmethylamino, aminocarbonyl,
`alkylaminocarbonyl, dialkylaminocarbonyl,
`hydroxyalkylaminocarbonyl, (4-morpholinyl)
`carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)
`carbonyl, (hexahydro-l-azepinyl)carbonyl,
`(4-methyl-l-piperazinyl)carbonyl, methylenedioxy,
`aminocarbonylamino, aminocarbonylaminoalkyl,
`alkylaminocarbonylamino, alkanoyl, cyano,
`trifluoromethoxy, (cid:9)
`trifluormethylthio,
`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
`
`

`
`US 6,344,449 B1
`
`5 (cid:9)
`
`5
`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 -NR1,
`wherein
`R1 denotes a hydrogen atom or an alkyl or phenylalkyl
`group,
`R11 denotes a hydrogen atom, a C1_3-alkyl group, an
`alkoxycarbonyl group having a total of 2 to 4 carbon
`atoms or a phenylmethyl group,
`n denotes the number 1 or 2 or, if m is 1, n may also be
`0,
`m denotes the number 0 or 1,
`R2 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 -formy1-1H-indo1-3-yl, 1 -(1,1 -
`dimethylethoxycarbony1)-1H-indo1-3-yl, 4-imidazolyl,
`1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl,
`1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzo[b]
`fur-3-yl, benzo[b]thien-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, C3_8-cycloalkyl groups, phenylalkyl
`groups, alkenyl, alkoxy, phenyl, phenylalkoxy,
`trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl,
`alkoxycarbonyl, carboxy, dialkylaminoalkyl,
`dialkylaminoalkoxy, hydroxy, nitro, amino,
`acetylamino, propionylamino, benzoyl,
`benzoylamino, benzoylmethylamino,
`methylsulphonyloxy, aminocarbonyl,
`alkylaminocarbonyl, dialkylaminocarbonyl,
`alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl,
`thiazolyl, (cid:9)
`furyl, (cid:9)
`trifluoromethoxy,
`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, 45
`amino or acetylamino group,
`A denotes a bond or the divalent group of formula
`
`6
`aminocarbonyl,
`hydroxycarbonyl, (cid:9)
`aminoiminomethylamino, aminocarbonylamino,
`phenyl, 1H-indol-3-yl, 1 -methy1-1H-indo1-3-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, aminocarbonyl, cyano,
`trifluoromethoxy, methylsulphonyloxy,
`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 R9 may be substituted with the protecting
`groups commonly used in peptide chemistry, pref-
`erably with the acetyl, benzyloxycarbonyl or tert.bu-
`tyloxycarbonyl group,
`R3 denotes a hydrogen atom,
`a C1_7-alkyl group which may be substituted in the
`w-position by a cyclohexyl, phenyl, pyridinyl, diazinyl,
`hydroxy, amino, alkylamino, dialkylamino, carboxy,
`aminocarbonyl, aminocarbonylamino, acetylamino,
`1 -pyrrolidinyl, 1 -piperidinyl, 4-(1-piperidiny1)-1-
`piperidinyl, 4-morpholinyl, hexahydro-1H-1-azepinyl,
`[bis-(2-hydroxyethyl)]amino, 4-alkyl-l-piperazinyl or
`4-(w-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,
`R4 denotes a hydrogen atom or a C1_3-alkyl group option-
`ally substituted by a phenyl or pyridinyl group or
`R3 and R4 together with the enclosed nitrogen atom
`denote a group of general formula
`
`(IV)
`
`10
`
`15 (cid:9)
`
`20 (cid:9)
`
`25 (cid:9)
`
`30 (cid:9)
`
`35 (cid:9)
`
`40 (cid:9)
`
`R9
`
`R- (cid:9)
`
`0
`
`(which is linked to the NR3R4 group via the -CX group)
`wherein
`R8 and R9 together denote an n-propylene group or
`R8 denotes a hydrogen atom or an alkyl- or phenylalkyl
`group and
`R9 denotes a hydrogen atom or a branched or
`unbranched C1_5-alkyl group which, if it is
`unbranched, may be substituted in the w-position by
`a hydroxy, mercapto, amino, alkylamino,
`dialkylamino, 1-azetidinyl, 1 -pyrrolidinyl,
`1 -piperidinyl, hexahydro-l-azepinyl, methylthio,
`
`50 (cid:9)
`
`55 (cid:9)
`
`60 (cid:9)
`
`65 (cid:9)
`
`....................- (CI-12),
`N (cid:9)
`----CR13R14
`
`wherein
`Y3 denotes a carbon atom or, if R12 denotes a free pair
`of electrons, Y3 may also be the nitrogen atom,
`r denotes the number 0, 1 or 2,
`q denotes the number 0, 1 or 2,
`R1° denotes a hydrogen atom or an amino, alkylamino,
`dialkylamino, alkyl, cycloalkyl, aminoalkyl,
`alkylaminoalkyl, dialkylaminoalkyl,
`aminoiminomethyl, aminocarbonylamino,
`alkylaminocarbonylamino,
`cycloalkylaminocarbonylamino,
`phenylaminocarbonylamino, aminocarbonylalkyl,
`aminocarbonylaminoalkyl, alkoxycarbonyl,
`alkoxycarbonylalkyl, carboxyalkyl or carboxy
`group,
`
`

`
`US 6,344,449 B1
`
`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, methylsulphonyloxy,
`trifluoromethyl, hydroxy, amino, acetylamino,
`aminocarbonyl, aminocarbonylamino,
`aminocarbonylaminomethyl, cyano, carboxy,
`carbalkoxy, carboxyalkyl, carbalkoxyalkyl,
`alkanoyl, w-(dialkylamino)alkanoyl,
`w-(dialkylamino)alkyl, w-(dialkylamino)
`hydroxyalkyl, (cid:9) w-(carboxy)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-y1
`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 C1_7-alkyl group, by an
`alkanoyl, dialkylamino, phenylcarbonyl,
`pyridinylcarbonyl, carboxyalkanoyl, carboxyalkyl,
`alkoxycarbonylalkyl, alkoxycarbonyl,
`aminocarbonyl, alkylaminocarbonyl,
`alkylsulphonyl, cycloalkyl- or cycloalkylalkyl
`group, by a cycloalkylcarbonyl,
`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,
`aminocarbonylamino,
`aminocarbonylaminomethyl, cyano, carboxy,
`carbalkoxy, carboxyalkyl, carbalkoxyalkyl,
`alkanoyl, w-(dialkylamino)alkanoyl, w-(carboxy)
`alkanoyl, trifluoromethoxy, trifluoromethylthio,
`trifluoromethylsulphinyl or trifluoromethylsul-
`phonyl groups, whilst the substituents may be
`identical or different, or
`Rlo together with R12 and Y3 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 R1° may be replaced by a pro-
`tecting group,
`R12 denotes a hydrogen atom,
`a C1_4-alkyl group, wherein an unbranched alkyl group
`may be substituted in the co-position by a phenyl,
`
`10
`
`1 5
`
`5 (cid:9)
`
`8
`pyridinyl, diazinyl, amino, alkylamino,
`dialkylamino, 1 -pyrrolidinyl, 1-piperidinyl,
`4-methyl-l-piperazinyl, 4-morpholinyl- or
`hexahydro-1H-1-azepinyl group,
`an alkoxycarbonyl, cyano or aminocarbonyl group or a
`free pair of electrons, if Y3 denotes a nitrogen atom,
`and
`R13 and R14 in each case denote a hydrogen atom or,
`if Y3 is a carbon atom, R12 together with R14 also
`denotes another carbon-carbon bond, wherein R1° is
`as hereinbefore defined and R13 denotes a hydrogen
`atom or
`if Y3 is a carbon atom, R12 together with R14 also
`denotes another carbon-carbon bond and R1°
`together with R13 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-benzyloxycarbonyl, 2-chloro-
`benzyloxycarbonyl, 3-chloro-benzyloxycarbonyl,
`4-chloro-benzyloxycarbonyl, 4-Biphenylyl-a,a-
`dimethyl-benzyloxycarbonyl or 3,5-dimethoxy-a,a-
`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-propoxycarbonyl, isopropoxycarbonyl,
`n-butoxycarbonyl, 1-methylpropoxycarbonyl,
`2-methylpropoxycarbonyl or tert.butyloxycarbonyl
`group,
`the allyloxycarbonyl, 2,2,2-trichloro-(1,1 -
`dimethylethoxy)carbonyl (cid:9)
`or
`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
`60 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
`65 I wherein Z denotes NR1 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
`
`20 (cid:9)
`
`2 5
`
`30 (cid:9)
`
`35
`
`40 (cid:9)
`
`45 (cid:9)
`
`50 (cid:9)
`
`55 (cid:9)
`
`

`
`US 6,344,449 B1
`
`9
`
`and which are in the L- or (S)-configuration with regard
`to the partial amino acid structure of formula
`
`R9
`
`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
`
`(VI)
`
`The compounds of general formula I have valuable phar-
`macological properties based on their selective CGRP-
`antagonistic properties. The invention further relates to
`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, R2, R3, R4, R11, X, Z and m and n are as hereinbefore
`defined and
`R denotes an unbranched C1_6-alkylamino group option-
`ally substituted at the nitrogen atom by a C1_6-alkyl
`group or by a phenylmethyl group, which may be
`substituted in the w-position
`by a C4_10-cycloalkyl group,
`by one or two phenyl groups, by a 1-naphthyl,
`2-naphthyl or biphenylyl group,
`by (cid:9) a 1 H-indo1-3-yl, 1 ,3-dihydro-2H-2-
`oxobenzimidazol- 1 -yl, (cid:9)
`2,4(1 H,3H)-
`dioxoquinazolin-l-yl, 2,4(1H,3H)-dioxoquinazolin-
`3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl,
`3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl,
`3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl,
`3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl,
`3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl,
`3,4-dihydro-2(1H)-oxoquinazolin-l-yl, 3,4-dihydro-
`2(1H)-oxoquinazolin-3-yl, 2(1H)-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-
`pheny1-2H-2-oxoimidazol-1 -yl, 1,3-dihydro-5-
`
`10
`phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-
`oxoimidazo[4,5-c]quinolin-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-oxoimidazo[4,5-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 w-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, C3„-cycloalkyl groups, nitro, alkoxy,
`phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl,
`alkoxycarbonylalkyl, carboxy, carboxyalkyl,
`dialkylaminoalkyl, hydroxy, amino, acetylamino,
`propionylamino, benzoyl, benzoylamino,
`benzoylmethylamino, (cid:9)
`aminocarbonyl,
`alkylaminocarbonyl, dialkylaminocarbonyl,
`(1 -pyrrolidinyl)carbonyl, (1 -piperidinyl)carbonyl,
`(hexahydro-1H-azepin-l-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
`R2, R3, R4
`, R11, X, Z and m and n are defined as for the
`first subgroup hereinbefore,
`R denotes an unbranched C1_7-alkyl group which may be
`substituted in the w-position
`by a C4_10-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)-dioxoquinazolin-l-yl, 2,4(1 H,3H)-
`dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-
`d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-
`d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-
`d]pyrimidin-l-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-
`d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-
`d]pyrimidin-l-yl, 3,4-dihydro-2(1H)-oxoquinazolin-
`
`5 (cid:9)
`
`10
`
`15 (cid:9)
`
`20 (cid:9)
`
`25 (cid:9)
`
`30 (cid:9)
`
`35 (cid:9)
`
`40 (cid:9)
`
`45
`
`5
`
`55 (cid:9)
`
`60 (cid:9)
`
`65 (cid:9)
`
`

`
`US 6,344,449 B1
`
`10
`
`15
`
`11
`1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-
`oxoquinolin-3-yl, 2(1H)-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-c]quinolin-3-yl, 1,3-dihydro- 5
`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, (cid:9)
`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 20
`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 hete