United States Patent
`
`[191
`
`[11] Patent Number:
`
`5,786,361
`
`Miiller et al.
`
`[45] Date of Patent:
`
`Jul. 28, 1998
`
`US00578636lA
`
`[54] PYRIDAZINO-, PYRIMIDO-, PYRAZINC}
`AND TRIAZINOINDOLES,
`-PYRROLOCYCLOALKENES OR
`PYRROLOOXOCYCLDALKENES, OR
`PYRIDOPYRROLYLPYRIDO COMPOUNDS;
`COMPOSITIONS CONTAINING THEM. AND
`USE THEREOF T0 TREAT
`ATBEROSCLEROSIS
`
`[75]
`
`Inventors: Ulrich Miller. Wuppertal; Peter
`Eckenberg. Fxkrath; Rudi Grfitzmann.
`Solingcn; Hllmar Bischoff. Wuppenal;
`Dirk Denzer. Wupperta]; Ulrich
`Nielsch. Wuppe.rtaL all of Germany
`
`I73] Assignce: Bayer Aktiengesellschafl. Levcrkusen.
`Germany
`
`[2]] Appl. No; 337,076
`
`[22] Filed:
`
`Apr. 11, 1997
`
`[30]
`
`Foreign Application Priority Data
`
`Apr. 11, 199'?
`
`[DE]
`
`19615 265.8
`
`[51]
`
`Int. Cl.‘
`
`A61K 311505; A6lK 31:44;
`.4611: 31/495; A61K 31/53: C071) 4371404;
`C0713 471.-‘D4: COTD 487;‘ 14
`514267; 5144243: 514248-.
`[52] U.S. CL
`514x250; 514257; 5141292; 5141293: 544.~'l83;
`54!-H184; 544,033; 5444034; SMJZ46: 5443247:
`544/250; 5444251; 5444343; 544545; 546/82;
`54-ISI85
`[58] Field of Search ................................... .. 514243. 243.
`5141250. 257. 267. 292. 293: 54441 83.
`184. 233. 234. 246. 247. 250. 343. 345.
`251; 546182. 85
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`S,585,4fi)
`
`1231996 'I'hurk.au.f eta 1.
`
`5-I-4430
`
`FOREIGN PATENT DOCUMENTS
`
`0313430 121939
`6220059
`1311994
`
`Japan.
`Japan.
`
`01"HER PUBLICATIONS
`
`J. Clark und 1. W. Souton. J. Chem. Soc. Perkin Trans. I.
`1814 (1974).
`TD. Dulfy und D.G. Wibherley. J. Chem. Soc.. Perkin
`‘Trans. 1. 1921 (1974).
`Y. Kondo. R. Watanabe. T. Sakamoto and H. Yamanaka.
`Cheln. Pharm. Bull.. 37. 2.933 (1989).
`S. Scnda. K. Hiram und G.N. Yang. Chem. Phann. Bull. 20.
`399 (1982).
`S. Senda. K.Hirota und M."l‘a.kal1asl1i. J. Chem. Soc.. Perkin
`Trans. 1. 503 (1975).
`
`Primary Exam¢'ner—-Yogend.ra N. Gupta
`Arromey, Agent, or Firmfi§p1'ung Kramer Sd1aefe1' &
`Briscoe
`
`[57]
`
`ABSTRACT
`
`Compounds of the formula (I):
`
`R1
`
`R
`
`R3
`
`R‘
`
`D
`
`II
`
`N
`
`II
`A
`
`(I)
`
`R5
`
`C0-NI-l)\R°
`E L
`
`an: prepared by reaction of me phcnylaoetic acid derivatives
`substilmed by the appropriate heterocycles. optionally in an
`aclivated form. with phenylglycinuls. The compounds are
`suitable as active compounds in medicaments. in particular
`in medicaments having antiaflaerosclcrotic aaiviry.
`
`5233248
`5,306,320
`
`331993 Hubschweden et a1.
`411994 Decker et al.
`
`5444250
`546153
`
`7 Claims, No Drawings
`
`1 0”?
`
`PENN 1;x.22o7
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`1
`
`5,786.36]
`
`PYRIDAZINO-, PYRIMJDO-, PYRAZINO-
`AND TRIAZINOINDOLES,
`-PYRROLOCYCLOALKENES on
`PYRROLOOXOCYCLOALKENES, DR
`PYRIIJOFYRIIOLYLPYRIDO COMPOUNDS,
`com-osrriorts CONTAINING THEM, AND
`USE THEREOF TO TREAT
`ATHEROSCLERCBIS
`
`5
`
`0
`
`‘’
`
`3
`
`N/"
`I
`N‘ H
`R
`
`2
`
`-continued
`
`R”
`
`invention relates to new pyridazino-.
`The present
`pyrLtniI:l0—. pyTazi.no- and triazino-indoles. processes for
`their preparation and their use as rnedicarnents. In particular
`as antiatheroselerolie medicaments.
`It is known that raised blood levels of triglycerides
`(hypertriglyeeridaernia)
`and
`cholesterol
`(hypereholesterolaemia) are associated with the genesis of
`atherosclerotic vascular wall changes and coronary heart
`diseases.
`A distinctly increased risk of the development of coro-
`nary heart disorders moreover exists if these two risk factors
`occur in combination. which is in turn accompanied by an
`overproduction of apoliprotein B-100. There is thm-efore 15
`still a great need to make available effective medicaments
`for the conn'ol of atherosclerosis and of coronary heart
`
`I0
`
`15
`
`20
`
`The present invention relates to pyridazino-.
`pyraz:Ino- and triaztno-mdoles of the general formula (I)
`R]
`R3
`
`|
`
`I
`
`R
`
`N
`
`A R4
`
`D
`
`R,
`M-A
`
`R6
`
`Cg-
`
`3 L
`
`in which
`
`m
`
`30
`
`35
`
`40
`
`R1 and R2. including the double bond connecting them.
`together form a phenyl ring or a 5- to 8—n1ernbered 45
`cydoalkene 0, 0-mcydoalkenc ring
`.
`.
`.
`.
`.
`.
`wluch is optionally substituted up to 3 times 1|] an
`identical or dilferent manner by halogen.
`_
`_
`_
`_
`tl'lfllJ01‘0I[tCI2l'l)1. earboxyl. hydroxyl. by straight.-cha.|n 50
`°1' handled 311103)’ 01 a1k°XY°3l‘h°“Y1 0391'! h3“'1'1S “P
`‘D 5 WW" 310195 01' bl’ SW-iSm‘¢h31'-fl 01'
`'1f1|1€h°d
`alkrl hams up to 6 carbon atoms. which for its part
`can '36 Sl.IbS[itI.ltCd by
`Cl" by straight-chain Cl.’
`branched allroxy having up to 4 carbon atoms.
`R3 and R‘. including the double bond. together form a
`radical of the fomlula
`
`55
`
`I
`
`R1
`I
`-" Y0
`N\_
`
`R’
`
`0
`
`,
`
`l
`
`0
`
`N}
`,K
`
`0
`
`N
`Lin
`
`9
`
`.
`
`R“
`
`l
`
`N
`pl\ 12
`R
`
`.
`
`N
`
`60
`
`as
`
`I
`
`N %
`
`N
`K
`
`N
`
`D,
`
`l
`
`R”
`
`N
`
`N
`
`,
`
`in which
`R7. R9. R9_ R'°_ R“_ R12. R”, 11*4_p_15 and R15 are
`identical or or diiferent and denote hydrogen. carboxyl.
`straight-chain or branched alkoxy. alkylthio. acyl or
`alkoxycarbonyl each having up to L5 carbon atoms or
`“""5ht'°hf‘i“ P‘ b”;“d"°d “fl‘Y1?“""'-“E “P t° 6 9°“-"°“
`1at°ms‘;"'Em°h 1? opuonauy Substituted by hydfoxyl‘ or
`R ‘Win - lnclud-"18 the ‘1°'-"31": b°11d~ f°1'm3 P)T1dY1fin3-
`and
`4
`_
`_
`_
`_
`R fwd R ‘ h,l;°‘;’“_": mbcgummng _t:c]d?"bl° b‘_3“:;fi°3b°t¥’Er
`mm? P?“ 3’ nag‘
`. P y 1-.mgs?Pu°
`mg
`
`hydroxfl by maighwham of hmmmcd alkoxy or
`alkoxycarbony] each having up to 6 mrbon atoms 0!. by
`straight—chain or branched alkyl having up to 6 carbon
`atoms. _which for its part is substituted by hydroxyl or
`by straight-diam or branched alkoxy having up to 4
`carbon atoms.
`A and I) are identical or different and represent hydrogen.
`halogen. mfluoromethyl. hydroxyl or straight-chain or
`branched alkyl or allroxy each having up to 5 carbon
`3101115.
`E andL are identical or cliiferent and represent hydrogen.
`cycloalkyl having 3 to 8 carbon atoms or straight-chain
`or branched alkyl having up to 10 carbon atoms. which
`is optionally substituted by cyeloallryl having 3 to 6
`93330.“ 3‘°m-5- 01 1"3PI355m ?h€n3"1 which i5 °P‘i°D3l15"
`5'-'b5‘“'1t°d bl’ “"1033” W '11fl"°1‘3m'3fl1)'1- ‘Cl’
`E and L ggetbtier \v1'tll1 the carbon atom. form a 4-8-
`mt‘-‘mbfi
`‘-‘Y9 03”‘? 1'|11S~
`5
`R represents phenyl C‘ a 5- to-7-membcmd sammmd or
`unsaturated heterocycle having up to 3 heteroatoms
`[torn the Series S_ N andkx 0‘ ‘he cycles optionally
`being substituted up to 3 times in an identical or
`different mannerby nitrtncarboxyl. halogen. cyano or
`by straight-chain or branched alkenyl or a]koxycarbo-
`fly] cafj]
`up [0 6 ca[I)o]1 atgms 01'
`straight.
`chain or branched alkyl having up to -5 carbon atoms.
`which 15 <3P‘5°n331? Substituted by hY*1r°KY1- ‘$150131
`or by straight-L-ham or branched alkoxy or alkoxycar-
`bony! each having up to 6 carbon atoms. andlor the
`cycles opttonalljy being substituted by a group of the
`formula -011‘ or —NR‘3R‘°.
`in which
`R” denotes hydrogen or straight-chain or branched alkyl
`or allnenyl each having up to I5 carbon atoms.
`R” and R” are identical or difierent and denote
`phenyl. hydrogen or straight-chain or branched allryl
`having up to 6 carbon atoms or denote stra.ight—cha.in
`or branched acyl having up to 8 carbon atoms.
`
`2 0f32
`
`PENN Ex. 2207
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5.786.361
`
`3
`which is optionally substituted by a group of the
`formula —-—-N'R2°R“.
`in which
`tliiferent and denote
`R” and R“ are identical or
`hydrogen or stra.ight~cha.in or branched acyl having
`up to 8 carbon atoms.
`R‘ represents hydrogen. carboxyl or straight-chain or
`branched alkoxycarbonyl having up to 5 carbon atoms.
`orrepresents straight-chain or branched allcyl having up to
`6 carbon atoms. which is optionally substituted b_‘y
`hydroxyl or by a group of the formula —-0-CO—R2 .
`in which
`R“ denotes phenyl which is optionally substituted up
`to 3 times in an identical or different manner by
`halogen. hydroxyl or by straight-chain or branched
`allryl having up to 5 carbon atoms.
`or denotes straight-chain or branched allryl or allnenyl
`each having up to 22 carbon atoms. each of which is
`optionally substituted by a group of the formula
`-011”.
`in which
`
`triphenyimethyl or
`R” denotes hydrogen. benzyl.
`straight-chain or branched acyl having up to 6 carbon
`El.lIOl'EIS..
`
`if approtniate in an isomeric form. and their salts.
`The pyridazino-. pyrirnjdo-. pyrazino- and triazino-
`indoles according to the invention can also be present in the
`form of their salts. in general. salts with organic or inorganic
`bases or acids may be mentioned here.
`In the context of the present invention. physiologically
`acceptable salts are preferred. Physiologically acceptable
`salts of the compounds according to the invention can be
`salts of the substances according to the invention with
`mineral acids. carboxylic acids or sulphonic acids. Particu-
`larly preferred salts are. for example. those with hydrochlo-
`ric acid, hydrobtornic acid. sulphtuic acid. phosphoric acid.
`rnetltanesulphonic acid. cthanesulphonic acid. t.oluenesul-
`phonic acid. benzenesulphonlc acid. naphtha.lenedisul-
`phonic acid. acetic acid. propionic acid lactic acid. tartaric
`acid. citric acid. fumaric acid. maleic acid or benzoic acid.
`Physiologically acceptable salts can also be metal or
`ammoniurn salts of the compounds according to the inven-
`tion which have a free carboxyl group. Those particularly
`preferred are. for example. sodium. potassium. magnesium
`or calcium salts. and also ammonium salts which are derived
`from arnmonia. or organic amines. such as. for example.
`ethylamine. di- or triethylarnine. di- or tricthanolainine.
`dicyclohexylatnine. dimethylarninoethanol. arginine. lysine.
`ethylenediamine or 2-phenylelhylamine.
`The cycloalkene radical (R‘l'R’). including the double
`bond of the parent strucitue. in the context of the invention
`in general represents a 5- to 8-rnembercd. preferably 5- to
`7—membered. hydrocarbon radical such as. for example. a
`cyclobutene. cyclopentene. cyclohexene or cycloheptene
`radical. The cyclopentene. cyclohexene. cyclooctene and
`cycloheptene raditztls are preferred
`Heterocycle in the context of the invention in general
`represents a saturated or unsaturated 5- to 7-rnembered.
`preferably 5- to 6-membered. heterocycle which can contain
`up to 3 heteroatoms from the series S. N andlor 0. Examples
`which may be mentioned are: pyridyl.
`thienyl. ftnyl.
`pyrrolyl.
`thiaeolyl. oxazolyl.
`imidazolyl. morpholinyl or
`pipcridyl. Pyridyl and lhienyl are preferred
`The compounds according to the invention can exist in
`stereoisomeric forms which either behave as image and
`mirror image (enantiorners). or which do not behave as
`image and mirror image (diastereomers). The invention
`
`4
`relates both to the enantiorners and diastereorners or their
`respective rn.btt:ures. These rnixttues of the enantiomers and
`diastereomers can be separated into the stereoisomerically
`uniform constituents in a known manner.
`Preferred compounds of the general formula (I) are those
`in which
`
`R‘ and R2. including the double bond connecting them.
`together form a phenyl ring or a cyclopentene.
`cyclohexene. cycloheptene. cyclooctcne.
`oxocyclopentene. oxocyclohexene. oxocycloheptene or
`oxocyclooctene radical.
`which is optionally substituted up to 2 times in an
`identical or dilferent manner by fluorine. chlorine.
`bromine.
`trifiuorornethyl. carboxyl. hydroxyl. by
`straight-chain or branched allroxy or allroxycarbonyl
`each having up to 4 carbon atoms or by shaight-chain
`or branched allryl having up to 4 carbon atoms. which
`for its part can be substituted by hydmxyl or by
`straight-chain or branched alkoxy having up to 3 car-
`bon atoms.
`
`R” and R‘. including the double bond. together form a
`radical of the formula
`
`25
`
`35
`
`I
`
`I
`
`or
`
`I
`N
`
`0
`O
`
`0
`
`N
`
`0
`‘f’
`.\R_‘
`
`|
`
`0
`
`N/R9
`N ,no_
`,'...,
`
`R11
`
`N
`N ¢KR,1_
`
`I
`
`N/Ru
`»
`N'\R:i_
`
`t
`
`N‘\\*N
`N AR“
`
`Rls
`
`E ,N
`
`in which
`R1’. R8‘ R9. R10‘ RH. R12‘ R13‘ R14. R15 and R16 are
`identical or different and
`
`denote hydrogen- straight-chain or branched alkoxy.
`alkylthio. tray] or alkoxycarbonyl each having up to 4
`carbon atoms or straighuchain or branched alkyl hav-
`ing up to 4 carbon atoms. which is optionally substi-
`tuted by hydroxyl.
`
`or
`
`R‘ and R’. including the double bond. form a pyridyl ring.
`and
`
`R’ and R‘. likewise including the double bond. together
`form a pyridyl ring. both pyridyl rings optionally being
`substituted up to 2 times in an identical or different
`manner by fluorine. chlorine. bromine. t.ri.Eluoromet.hyl.
`carboxyl. hydroxyl. by straight-chain or branched
`alkoxy or allroxycarbonyl each having up to 4 carbon
`atoms or by straight-chain or branched allryl having up
`to 4 carbon atoms. which for its part is substituted by
`hydroxyl or by straight-chain or branched alkoxy hav-
`ing up to 3 carbon atoms.
`
`3of32
`
`PENN EX. 2207
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5.786.361
`
`5
`A and D are identical or different and
`
`represent hydrogen. fluorine. chlorine. bromine.
`nifluoromettiyl. liydroxyl or straight-chain or branched
`allryl or alkoxy each having up to 4 carbon atoms.
`E and L are identical or different and
`
`represent hydrogen. qrclopropyl. cyclobutyhcyclopentyl.
`cyclohexyl. cycloheptyl. cyclooctyl or straight-chain or
`branched allryl having up to 8 carbon atoms. which is
`optionally substituted by cyclopropyl. cyclopentyl or
`cyclohexyl. or represent phenyl which is optionally 10
`SlJbS1il'I.Itt':d by fluorine. chlorine or bromine. or
`E and L. together with the carbon atom. form a 4-?‘-
`membered cycloalkyl ring.
`R5 represents phenyl. pyridyl. fmyl. thienyl orirnidazolyl.
`cacti of which is optionally substituted up to 2 times in
`an identical or diiferent manner by nine. carboxyl.
`fluorine. chlorine. bromine. cyano. by s1:raight—cha.in or
`branched alkenyl or alltoxycarbonyl each having up to
`4 carbon atoms or by straight-cliai.n or branched allcyl 20
`
`having up to 5 carbon atoms. which is optionally
`substittlted by hydroxyl. carboxyl Cl’ by straiglit-chain
`or branched alkoxy or allroxycarbonyl each having up
`to 5 carbon atoms.
`
`15
`
`andlor the cycles are optionally substituted by a group of 25
`the formula —OR1 or —NR“3R‘9.
`in which
`
`6
`trifluoromethyl. carboxyl. hydroxyl. by
`bromine.
`straight-chain or branched alkoxy or alkoxycarbonyl
`each having up to 3 carbon atoms or by sI1‘aight—chain
`or branched alkyl having up to 3 carbon atoms. which
`for its part can be substituted by hydroxyl. methoxy or
`ethotty.
`R’ and R4. including the double bond. together form a
`radical of the formula
`
`0
`
`Y
`N
`
`‘iv,
`
`0
`
`R“
`
`R9
`N
`N’
`i A i A
`N
`0 .
`N
`‘,0
`R
`
`R”.
`
`R13
`
`N’
`
`l
`N-em.
`
`'
`
`N
`
`“N
`
`E /l\
`N ’ R1;
`
`i
`
`iv
`N
`
`0
`
`o
`
`0
`
`R“
`
`or
`
`E
`
`N
`
`N ’
`
`in which
`R". R‘. R9. R”. R“. R”. R”. R“. R" and R” are
`gigifim or dflfaem and denote ilydmgeni ‘straight-
`n or branched alkoxy or allrylthio each having up to
`3 carbon atoms or st:ra.ight-chain or branched alkyl
`having up to 3 carbon atoms. which is optionally
`substituted by hydroxyl.
`
`R‘ and it’. including the double bond. form a pyridyl ring.
`and
`R’ and R‘. likewise including the double bond. together
`.
`.
`.
`.
`.
`.
`§.'i.‘l‘..%.‘i.”‘.1“’.",§ ‘ESE *£’.L".};’".»’£.“’.’.’.'.’t‘.'§§.’§’..5’§l‘i°.§'."“£1-,‘iL".’i
`rnannerby nuoiine. chlorine. bromine. trifluoromethyl.
`carboxyl, hydroxyl. by straight-chain or branched
`anmxy M alkoxycarbonyl each having up to 3 carbon
`atoms orby straight-cha.in or branched alkyl having up
`to 3 carbon atoms. which for its part is substituted by
`hydmxy1_ met-noxy at ethoxy_
`A and D are identical or different and
`represent hydrogen.
`fluorine. chlorine. bromine or
`"“3“°'°m‘f'h¥1-_
`_
`E and L are identical or different and
`represent hydrogen. cyclopropyl. cyclobutyl. cyclopentyl.
`cyclohex1'1- eyelohe1=tyl- e>'cl00co'1 or sir-Iightaehain or
`branched allryl having up to 6 carbon atoms. which is
`°Pfi°fl3113’ Sllbsfiwled '33’ °Y°1CP"311‘)'1 Of °5"»'101'1€1Y1~ 01
`“P135031 Pheflyl which 55 0P1i0|1311Y Subslillllted bl’
`fl""1'in°- chl°Ti'1e '3‘ b1'°mi'1e~ 0'5
`E and I... together with the carbon atom. form a 5-7-
`membered cycloalkyl ring.
`R’ represents phenyl. pyridyl or thienyl. each of which is
`optionally substituted up to 2 times in an identical or
`
`in
`
`R” denotes hydrogen or straight-chain or branched alkyl
`or nlkenyl each having up to 4 carbon atoms.
`R“ and R19 are identical or oiirereni and denote phenyL 3°
`hydrogen or straight-chain or branched alkyl having up
`to 5 Carbon atoms. or denote straight-chain CI branched
`acyl having up to 6 carbon atoms. which is
`'onaJly
`substitlltfid by a steep 0fthefenm1le—NR
`”.
`iilmwli-ildltill R“ are identical or ditferent and denote
`hyd-7°35“ 0‘ 5lI3*'3ht'¢hain ‘I branched ‘WY! having
`“P I0 5 0815011 3t°m3-
`R‘ represents hydrogen. carboxyl or straight-chain or
`branched alkoxyczirbonyl having up to 4 carbon atoms. 40 or
`or geprestgits straight-tifile or blenehatild alktél having :9
`to
`car
`it atoms. w ‘c
`is option
`y su stitu
`hydmxyl 0‘ by 3 gm“? °t the fmmh _'0_C0""R2a)l
`R” ooooooo wool which is optionally substituted up ‘*5
`to 3 times in en ider-ti-eel or different manner by
`fl”°1'l'3‘-’~ d1101'l11°~ bI°“15J1°-hYd1'°7‘-3'1 °1'b}’ Sfiaigh"
`chain or branched alltyl having up to 4 carbon atoms.
`°r denmcs §‘”'i3ht'cha'i“ ‘I hmdwd “KY1 "" 3”“ so
`enyl eeeh he-vies up to 20 eerben elem-'» each of
`which is optiogigally substituted by a group of the
`in :E.I;:la _0R ‘
`R23 denotes hydrogen‘ bcnzyl‘ mphenylmemyl or 55
`straight-chain or branched acyl having up to 5 carbon
`atoms.
`if appfopriatc in an isomeric farm, and their salts,
`Particularly preferred compounds of the general formula
`(I) are those in which
`R‘ and R2. including the double bond connecting them.
`together form a phenyl ring or a cyclopentene.
`cyclohexene. cycloheptene. cyclooctenc.
`oxocyclopenteneoxocyclohexene. oxocyclohepteneor
`oxocyclooctene radical.
`which is optionally substituted up to 2 times in an
`identical or different manner by fluorine. chlorine.
`
`35
`
`60
`
`(,5
`
`4 0f32
`
`PENN Ex. 2207
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5,786.36|
`
`7
`different manner by nitro. carboxyl. fluorine. chlorine.
`bromine. cyano. by straight-chain or branched alkenyl
`or alkoxycarbonyl each having up to 3 carbon atoms or
`by straight-chain or branched alkyl having up to 4
`carbon atoms. which is optionally substituted by 5
`hydroxyl. carboxyl or by straight-chain or branched
`alkoxy or alkoxycarbonyl each having up to 4 carbon
`atoms.
`
`I0
`
`andfor the cycles are o tionally substituted by a group of
`the formula —OR‘ or —N'R‘°R”'.
`in which
`R” denotes hydrogen or s1:ra.ight—chain or branched
`alltyl or aikenyl each having up to 3 carbon atoms.
`R“ and R” are identical or diiferent and denote
`phenyl. hydrogen or straight-chain or branched alkyl
`having up to 4 carbon atoms.
`or denote straight-chain or branched acyl having up to
`5 carbon atoms.
`which is optionally substituted by a group of the
`formula ——NR2°R2l.
`in which
`R” and R“ are identical or different and denote
`hydrogen or straight—chain or branched acyl having
`up to 5 carbon atoms.
`R‘ represents hydrogen. carbonyl or straight-chain or
`branched alkortycarbonyl having up to 3 carbon atoms.
`or represents straight-chain or branched alkyl having up to
`4 carbon atoms.
`
`which is optionally substituted by hydroxyl or by a group
`of the formula —0~—CO—R 2.
`in which
`R” denotes phenyl which is optionally substituted up
`to 3 times in an identical or different manner by
`sI:ra.ight—d1ain or branched alkyl having up to 3
`urban atoms. or denotes straight-chain or branched
`aikyl or alkenyl each having up to 19 carbon atoms.
`each of which is optionally substituted by a group of
`the formula —OR”.
`in which
`triphenylmethyl or
`R” denotes hydrogen. benzyl.
`sttaight—chain or branched acyl having up to 4 carbon
`atoms.
`
`8
`if appropriate in an isomeric form. and their salts.
`Very particularly preferred compounds of the general
`formula (I) are those
`in which
`
`A and D represent hydrogen.
`A process for the preparation of the compounds of the
`general formula (1) according to the invention has addition-
`ally been found. characterized in that racemic or alterna-
`tively already enantiomerically pure czrboxylie adds or
`their activated du'ivaI:ives of the general formula (II)
`
`(in
`
`R‘
`
`R2:
`
`R3
`
`:34
`
`: N i
`
`CH;
`
`A
`
`in which
`
`CD —R=‘
`
`is L
`
`D
`
`A. D. E. L. R‘. R”. R’ and R‘ have the meaning indicated
`above. and
`
`R3‘ represents hydroxyl or an activating radical. prefer-
`ably chloride. are amidated with compounds of the
`general formula (111)
`
`RS
`H,NJ\ no
`in which
`
`(“Tl
`
`R5 and R‘ have the meaning indicated above.
`in inert solvents. if appropriate in the presence of bases
`andicir auxiliaries.
`
`The process according to the invention can be illustrated
`by way of example by the following equation:
`
`COD!-I
`
`HOBT
`
`H;N/\\/ 0”
`
`5of32
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`
`

`
`10
`
`Me
`
`N/
`
`lN
`
`‘Me
`
`0
`
`0
`
`N
`
`5.786.361
`
`—oontinued
`
`0
`
`0
`
`Me
`
`N2
`IN
`
`‘Lie
`
`|
`
`N
`
`C0—N}l/\/ 0“ +
`
`Co-
`
`OH
`
`Suitable solvents here for the amidation are inert organic
`solvents whidil do not change under the reaction conditions.
`These include others. such as diethyl ether or
`tetrahydrofuran. halogenohydrocarbons such as
`dichloromethane.
`trichloromethane.
`tetrachloromethane.
`1.2-dichlcroethane. nichloroethane. telrachloroethane. 1.2-
`dichloroethylene or Irichloroethylene. hydrocarbons such as
`benzene. xylene. toluene. hexane. cyclol1e;xa.ne_ or petro-
`leum fractions. nitromethane. dimethylformamide. acetone.
`acetonitrile or hexarnethylphosphcramide. It is also possible
`to employ mixtures of the solvents. Dichlioromethane.
`tetrahydrofuran. acetone and dimethylformamide are par-
`ticularly preferred.
`Bases which can be employed for the process according
`to the invention are in general inorganic or organic bases.
`These preferably include alkali metal hydroxides such as. for
`example. sodium hydroxide or potassium hydroxide. alka-
`line eanh metal hydroxides such as. for example. barium
`hydroxide. alkali metal carbonates such as sodium carbonate
`or potassium carbonate. alkaline earth metal carbonates such
`as calcium carbonate. or alkali metal or alkaline earth metal
`alkoxides such as sodium or potassium rnethoxide. sodium
`or potassium ethoxide or potassium tert—butoxide. or organic
`amines (Irialky1(C1—C5)arnines) such as Iridhylamine. or
`heterocycles such as 1.4-diazabicyclo[2.2.2]octane
`(DABCO).
`l.S-diazabicyclo[5.-4.0]undec—7-ene (DBU).
`pyridine. diarninopyrldine. methylpiperidine or morpholine.
`It is also possible to employ as bases alkali metals such as
`sodium and their hydrides such as sodium hydride. Sodium
`and potassium carbonate and triethylamine are preferred.
`The base is employed in an amount from 1 tool to 5 mol.
`preferably from 1 mol to 3 mol. relative to 1 mol of the
`compound of the general formula (]I).
`The reaction is in general carried out in a temperature
`range from 0° C. to 150° C.. preferably from +20° C. to
`+1 10° C.
`The reaction can be carried out at norrnal. elevated or
`reduced pressure (e.g. 0.5 to 5 bar). In general. the reaction
`is carried. out at normal pressure.
`The reaction can optionally also proceed via the activated
`stage of the acid halides. which can be prepared from the
`corresponding acids by reaction with lhionyl chloride. phos-
`phorus lrichloride. phosphorus penlachloride. phosphorus
`Iribromide or oxaiyl chloride.
`The abovementioned bases can also be employed as
`acid-binding auxiliaries for the amidalion.
`Suitable auxiliaries are also dehydrating reagents. These
`include. for example. carhodiirnides such as diisopropylcar—
`bodiimide. dicyclohcxylcarbodiimide or N—(3-
`dirnethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
`
`or carbonyl compounds such as carbonyldiirnidazole or
`1.2-oxaaolium compounds such as 2-ethyl-5-phenyl-1}
`oxazc-lium—3—sulphonate or propancphosphonic anhydride
`or isobutyl chloroformate or benzotriazolyloxy-tris—
`(dimethylan:I.iI:|o)phosphonium hexa—fluorophosphate or
`diphenyl phosphoramidate or methane-sulphonyl chloride.
`if appropriate in the presence of bases such as triethylamine
`or N-etliylmorpholine or N—melhylpiperidine or d.icyclo—
`hexylcarbodiimide and N-hydroxysuccinimide.
`The auxiliaries are in general employed in an amount
`from 0.5 to 3 mol. preferably from 1 to 1.5 mol. relative to
`l mol of the appropriate carboxylic acids.
`The carboxylic acids of the general formula (II) can be
`prepared by first preparing. by reaction of compounds of the
`general formula (IV)
`
`A
`
`'l'—CH;
`
`C0215”
`
`in which
`
`A. D. E and L have the meaning indicated above.
`
`T represents a typical leaving group such as. for example.
`chlorine. bromine. iodine. tosylate or mesylate. prefer-
`ably bromine. and
`
`30
`
`35
`
`45
`
`50
`
`55
`
`R15 represents (C1-C4)-alkyL
`
`with compounds of the general formula (V)
`
`65
`
`in which
`
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`
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`
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`lPR20l5-01836
`
`

`
`11
`R‘. R“. R’ and R‘ have the meaning indicated above.
`the compounds of the general forrnnla (VI)
`
`5 .7 86,361
`
`{V1}
`
`R‘
`
`R3
`
`R3
`
`R‘
`
`N
`
`C]-I;
`
`A
`
`in which
`
`CO—R”
`
`e
`
`L
`
`D
`
`12
`
`A
`
`D
`
`T—CH2
`
`A
`
`D
`
`T-CH1
`
`(EH—CO-1—R2”
`E
`
`IEH—C0:— R”
`L
`
`(xa)
`
`Oil‘-“J
`
`A. D. E. L. R‘. R2. R3. R‘ and R25 have the meaning 15 in which
`indicated above.
`
`in inert solvents. if appropriate in the presence of a base.
`and then hydrolysing the esters according to customary
`methods.
`The enantiornerimlly pure acids. i.e. compounds of the 20
`formula (II)
`in which E and L must be different. are
`moreover obtained by. starting from the D- or 1.-menthyl
`esters of the general formula (VII)
`
`A
`
`D
`
`H30
`
`Cl{2—CO;—R3°
`
`fV1I)2s
`
`A. D. E. L. T and R25 have the meaning indicated.
`then by reaction with the compounds of the general formula
`(V) preparing the enmtiomerically pure compon nds of the
`general formulae ()C[a) and (Xlb)
`
`R2
`
`R3
`
`Ofla)
`
`in which
`
`A and D have the meaning indicated above and
`R2‘ represents D- or I.—mentl1yl.
`by reaction with compounds of the general forrnnlae
`(VIE[a] and (Vllib)
`
`11
`
`R:
`
`R3
`
`R-I
`
`D
`
`ll
`
`N
`
`ll
`A
`
`{KW}
`
`E—Z (VI|In)
`L—z fVIIIb)
`
`in which
`E and L are diiferent and otherwise have the meaning
`indicated. and
`
`2 represents halogen. preferably bromine.
`preparing the enantiomerically pure rnthyl esters of the
`general formulae (Dial) and (Die)
`
`A
`
`0
`
`H:C
`
`t;:rI;—co;—R”
`E
`n
`
`A
`
`HJC
`
`(Din)
`
`mm 55
`
`(|3H—CO1R"
`L
`
`in which
`
`A. D, E L. R’. R2. R3. R‘ and R 2‘ have the meaning
`indicated.
`
`and then converting these by hydrolysis into the enantio—
`rnerically pure acids of the general forrnula (I1) and option-
`ally by reaction with activating reagents intothe correspond-
`ing activated carboxylic acid derivatives of the general
`formula (11).
`Additionally. the enantiomerically pure acids of the for-
`mula (II) can be prepared by first converting racemic car-
`boxylic acids of the general formula (XII)
`
`5
`
`70
`
`Om)
`
`f|ZH2—C0;—R*
`L
`
`in which
`A. D. E. L and R2‘ have the meaning indicated.
`convening these in a next step by a halogenation into the
`compounds of the general formulae (Xa) and (Xb)
`
`in which
`
`A. D. E and L have the meaning indicated above.
`
`by reaction with (R)— or (S)-phenylethylarnine in inert
`solvents and subsequent crystallization of the phene1l1ylarn-
`monium salts and subsequent hydrolysis of the salts into the
`enantiomerically pure compounds of the general formula
`(X]I1a.b)
`
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`
`

`
`(xvta)
`
`(XVIb)
`
`14
`
`D
`
`N
`
`A
`
`R3
`
`R‘
`
`R3
`
`is!
`
`R‘
`
`A
`
`D
`
`3 (
`
`IIH—CChtfiu
`E
`
`I (
`
`III!-—CCl-;tB|.l
`L
`
`R7
`
`R‘
`
`R2
`
`R‘
`
`13
`
`5.736.361
`
`A
`
`D
`
`(KIIIE)
`
`('X]IIb)
`
`I f
`
`ill! —C02H
`E
`
`t 1
`
`'33—C01H
`L
`
`H3C
`
`H3C
`
`A
`
`D
`
`in which
`
`A. D. E and L have the meaning indicated above.
`
`in a further step with isobutene. in inert solvents and in the 3”
`[resence of acids. preparing the enantiomerically pure esters
`of the general fomiula (I-{IVa.b)
`
`in which
`
`(XIVa}
`
`(xrvb)
`
`I (
`
`|3H—C0;l.Bu
`E
`
`I‘
`
`('31-I—C();tBI.1
`L
`
`A
`
`D
`
`A
`
`D
`
`H3C
`
`I-I3C
`
`A. D. E. L. R‘. R’. R3 and R‘ have the meaning indicated
`above.
`and in the last steps. as described at the beginning.preparing
`the corresponding enantiomerically pure acids and activated
`derivatives.
`Suitable solvents for the processes are customary organic
`solvents which do not change under the reaction conditions.
`These preferably include ethers such as diethyl ether.
`dioxane. tetrahydrofuran. glycol dimethyl ether. or hydro-
`carbons such as benzene. toluene. xylene. hexane. cyclo-
`hexane or petroleum fractions. or halogenohydrocarbons
`such as dichloromethane.
`trichlorornethane.
`tetrachloromethane. dichloroethylene. trichloroethylene or
`chlonobenzene. or ethyl acetate.
`triethylamine. pyridine.
`dimethyl
`sulphoxide. dimethylformamide.
`hexamethylphosphoramide. acetonitrile. acetone or
`nitrornethane. It is also possible to use mixtures of the
`solvents mentioned. Dirnethylformamide. toluene and tet-
`rahydrofuran are preferred.
`Bases which can be employed for the processes according
`to the invention are in general inorganic or organic bases.
`These preferably include alkali metal hydroxides such as. for
`example. sodium hydroxide or potassium hydroxide. alka-
`line earth metal hydroxides such as. for example. barium
`hydroxide. alkali metal carbonates and hydrogen carbonates
`such as sodium carbonate. sodium hydrogen carbonate or
`potassium carbonate. alkaline earth metal carbonates such as
`calcium carbonate. or alkali metal or alkaline earth metal
`allroxides such as sodium or potassium methoxide. sodium
`or potassium ethoxide or potassium Inert-butoxide. or organic
`amines (tria1kyl(C,—C5)ar.nines) such as triethylamine. or
`heterocycles such as
`l.4--diazabicyclo[2.2.2loctane
`(DABCO). 1.8-diazabicyclol5.4.0]undec-7-ene (DBU.
`pyridine. diaminopyridine. methylpiperidine or rnorpholine.
`It is also possible to employ as bases alkali metals such as
`sodium or their hydrides such as sodium hydride. Sodium
`hydrogen carbonate. potassium carbonate and potassium
`tat-butoxide. DBU or DABCO are preferred.
`Suitable solvents for the hydrolysis are water or the
`organic solvents customary for hydrolysis. These preferably
`include alcohols such as methanol. ethanol. propanol. iso-
`propanol or butanol. or ethers such as tenahydrofuran or
`dioxane. or dintethylformamide. or dimethyl sulphoxide.
`and byreaction with the compounds of the general formula 65 Particularly preferably. alcohols such as methanol. ethanol.
`(V) converting into the enantiomerically pure esters of the
`propanol or isopropanol are used.
`It
`is also possible to
`general formula (XVIa.b)
`employ rnixtines of the solvents mentioned.
`
`in which
`
`A. D. E and L have the meaning indicated above.
`
`as described above converting by a halogenation into the
`enantiomerically pure compounds of the general formula
`(XVa.h)
`
`{X'Va)
`
`am»)
`
`C|.‘H—C0;t.‘Bu
`E
`
`C (
`
`I31-I—C0;tBu
`L
`
`A
`
`D
`
`r—mc
`
`A
`
`1)
`
`'1‘ —H;C
`
`in which
`
`A. D. T’. E and L have the meaning indicated above.
`
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`
`

`
`5.786.361
`
`15
`
`The hydrolysis can optionally also be carried out using
`acids such as. for exarnple. trifluoroacetic acid. acetic acid.
`hydrochloric acid. hydrobromic acid. rnethanesulphonic
`acid. sulphuric acid or perchloric acid. preferably using
`trilluoroacetic acid.
`The hydrolysis is in general carried out in a temperature
`range from 0°C. to +l00°C.. preferably from +2D° C. to
`+80° C.
`In general. the hydrolysis is carried out at normal pres-
`sure. However. it is also possible to work at reduced pressure
`or at elevated pressure (e.g. from 0.5 to 5 bar).
`When carrying out the hydrolysis. the base is in general
`employed in an amount from 1 to 3 mol. preferably from 1
`to 1.5 mol. relative to 1 mol of the ester. Molar amounts of
`the reactants are particularly preferably used.
`The hydrolysis of ttrt-butyl esters is in general carried out
`using acids. such as. for example. hydrochloric acid or
`triliuoroaoetic acid. in the presence of one of the solvents
`indicated above andlor water or mixtures thereof. preferably
`with dioxane or tetrahydrofuran.
`The general process according to the invention is in
`general carried out in a temperature range from -30" C. to
`+200” C.. preferably from 80° C. to 150° C.
`Suitable conditions for the individual steps of the prepa-
`ration of enantiomerically pure acids are preferably the
`following:
`The preparation of the compounds of the general formulae
`(Dirt) and (ixb) is preferably carried out in dimethy]forma-
`rnide and potassitun tert—butoxid.e in a temperature range
`from —l0° C. to +10” C.
`The ltalogenation of the compounds of the general for-
`mulae (Xa) and (Xb) is carried out in chlorobenzene using
`l.3—dibromo-5.5-dimethylhydantoin in the presence of am-
`bisisobutyronitrile in a temperature range from 0° C. to 110°
`C.
`
`The reaction to give the compounds of the general for-
`mulae (X1a) and (K113) is carried out under a protective gas
`atmosphere in dirnethylformarnide and potassium tert-
`butoxide in a temperature range from 0° C. to 30° C.
`The hydrolysis of the compounds of the general fonnulae
`(X13) and (XII3) can be carried out as described above. the
`system Billrfforrnic acid being particularly preferred. The
`hydrolysis is carried out in a temperature range from 20° C.
`to 100° C.
`The reaction of the compounds of the general formula
`(XII) is carried out using methylene chloride under reflux.
`Suitable activating reagents are preferably t;rifluo-
`romethanesulphonyl chloride. rnesyl chloride. oxalyl chlc»
`ride and thionyl chloride. Thionyl chloride is particularly
`preferred.
`The reaction to give the compounds of the gene