United States Patent
`Bottcher et al.
`
`[19]
`
`I 1111111111111111
`11111 111111111111111
`IIIII IIIII IIIII IIIII IIIIII Ill lllll llll
`US005532241A
`Patent Number:
`Date of Patent:
`
`5,532,241
`Jul. 2, 1996
`
`[11]
`
`[45]
`
`[54] PIPERIDINES AND PIPERAZINES
`
`94/13659
`
`6/1994 WIPO .
`
`[75]
`
`Inventors: Henning Bottcher, Darmstadt;
`Christoph Seyfried,
`Seeheim-Jugenheim; Gerd Bartoszyk;
`Hartmut Greiner, both of Darmstadt,
`all of Germany
`
`[73] Assignee: Merck Patent Gesellschaft mit
`beschrankter Haftung, Darmstadt,
`Germany
`
`[21] Appl. No.: 314,734
`
`[22] Filed:
`
`Sep. 29, 1994
`
`[30]
`
`Foreign Application Priority Data
`
`Sep. 30, 1993
`
`[DE] Germany .......................... 43 33 254.4
`
`..................•...
`
`[51] Int. Cl.6
`
`A61K 31/495; A61K 31/445;
`C07D 405/10
`[52] U.S. Cl . .......................... 514/254; 544/373; 546/201;
`514/323
`[58] Field of Search .............................. 544/373; 514/254
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,002,948
`5,242,925
`5,418,237
`
`3/1991 Perregaard et al. .................... 544/373
`9/1993 Bottcher et al. ........................ 514/254
`5/1995 Bottcher et al. ........................ 514/253
`FOREIGN PATENT DOCUMENTS
`
`0490772
`4127849
`
`6/1992 European Pat. Off ..
`2/1993 Germany .
`
`Primary Examiner-Emily Bernhardt
`Attorney, Agent, or Firm-Millen, White, Zelano & Brani(cid:173)
`gan
`
`[57]
`
`ABSTRACT
`
`Piperidine and piperazine derivatives of the formula I
`
`I\
`
`lnd-Q-N
`
`Z-R1
`
`\__/
`
`wherein
`Ind is an indol-3-yl radical which is unsubstituted or
`mono- or polysubstituted by OH, OA, CN, Hal, COR2
`or CH2R2
`,
`R 1 is benzofuran-5-yl or 2,3-dihydrobenzofuran-5-yl,
`chroman-6-yl, chroman-4-on-6-yl, 3-chromen-6-yl or
`chromen-4-on-6-yl, which is unsubstituted or mono(cid:173)
`substituted by CN, CH20H, CH20A or COR2
`,
`Q is CmHzm•
`Nor CR3
`,
`A is alkyl having 1-6 C atoms,
`Hal is F, Cl, Br or I,
`R2 is OH, OA, NH2 , NHA or NA2 ,
`R3is H, OH or OA and
`mis 2, 3 or 4,
`and their physiologically acceptable salts, are active on the
`central nervous system.
`
`17 Claims, No Drawings
`
`Argentum EX1004
`
`Page 1
`
`

`

`2
`preferably methoxy and also ethoxy, n-propoxy, isopropoxy,
`n-butoxy, isobutoxy, sec-butoxy or tert-butoxy. NHA is
`preferably methylamino and also ethylamino,
`isopropy(cid:173)
`lamino, n-butylamino,
`isobutylamino, sec-butylamino or
`tert-butylamino. NA2 is preferably dimethylamino and also
`N-ethyl-N-methylamino, diethylamino, di-n-propylamino,
`diisopropylamino or di-n-butylamino.
`Analogously, CO-NHA
`is preferably N-methylcarbam(cid:173)
`oyl or N-ethylcarbamoyl; CO-NA 2 is preferably N,N-
`10 dimethylcarbamoyl or N,N-diethylcarbamoyl.
`The radical Ind is an indol-3-yl radical which is unsub(cid:173)
`stituted or mono- or, for example, disubstituted by the
`radicals indicated. Preferably, it is substituted in the 5-po(cid:173)
`sition. Substitution in the 4-, 6- or 7-position is also suitable.
`Furthermore, substitution in the 1- or 2-position is possible.
`Preferred substituents on the indol-3-yl radical are OH, OA,
`CN, CONH 2, CH2OH, but also CO2H, F, Cl, Br, I, CH2NH2,
`CONHA or CONA 2, where A preferably corresponds to
`methyl or ethyl.
`The radical RI is preferably benzofuran-5-yl, 2,3-dihy-
`drobenzofuran-5-yl, chroman-6-yl or chromen-4-on-6-yl,
`which is unsubstituted or monosubstituted by -CH 2OH,
`-CONH 2, -CO 2A or -CO 2NHA.
`Q is preferably -(CH 2)4-,
`but also -(CH 2)z-
`-(CH 2h-, while Z is preferably -N-,
`-C
`(OH)-
`-CH-.
`Accordingly, the invention relates particularly to those
`compounds of the formula I in which at least one of said
`radicals has one of the meanings indicated above, especially
`one of the preferred meanings indicated above. Some pre-
`ferred groups of compounds can be expressed by the fol-
`lowing partial formulae Ia to lg, which correspond
`to
`formula I and in which the radicals and parameters not
`described in greater detail are as defined for formula I, but
`in which:
`in Ia, Ind is an indol-3-yl radical substituted
`5-position by OH or OA;
`in lb, Ind is an indol-3-yl radical substituted
`5-position by CONH 2 or by CN;
`in le, Z is N and RI is substituted or unsubstituted
`benzofuran-5-yl;
`in Id, Z is -C(OH)-
`and RI is substituted or unsubsti(cid:173)
`tuted benzofuran-5-yl;
`in le, Z is N and RI is 2,3-dihydrobenzofuran-5-yl;
`in If, Z is N and RI is chroman-6-yl;
`in lg, Z is N and RI is chromen-4-on-6-yl.
`Especially preferred compounds are those of partial for(cid:173)
`mulae Ih and Iah to Igh, which correspond to partial for-
`50 mulae I and Ia to lg, but in which additionally: Q is
`-(CH2)4--
`The invention further relates to a process for the prepa(cid:173)
`ration of indole derivatives of the formula I and their salts,
`characterized in that a compound of the formula II
`
`5,532,241
`
`1
`PIPERIDINES AND PIPERAZINES
`
`SUMMARY OF THE INVENTION
`
`The invention relates to novel piperidine and piperazine
`derivatives of the formula I
`
`Ind-Q-N
`
`Z-R1
`
`\__/
`
`5
`
`15
`
`wherein
`Ind is an indol-3-yl radical which is unsubstituted or
`mono- or polysubstituted by OH, OA, CN, Hal, COR 2
`or CH 2R2
`,
`RI
`is benzofuran-5-yl or 2,3-dihydrobenzofuran-5-yl,
`chroman-6-yl, chroman-4-on-6-yl, 3-chromen-6-yl or
`chromen-4-on-6-yl, which is unsubstituted or mono(cid:173)
`substituted by CN, CH2OH, CH2OA or COR 2,
`Q is CmH2m,
`Z is Nor CR3
`,
`A is alkyl having 1-6 C atoms,
`Hal is F, Cl, Br or I,
`R2 is OH, OA, NH 2, NHA or NA 2,
`R3 is H, OH or OA and
`m 2, 3 or 4,
`and to their physiologically acceptable salts.
`An object of the invention is to provide novel compounds
`capable of being used for the preparation of drugs.
`Upon further study of the specification and appended
`claims, further objects and advantages of this invention will
`become apparent to those skilled in the art.
`It has been found that the compounds of the formula I and
`their physiologically acceptable acid addition salts possess
`valuable pharmacological properties. Thus, in particular,
`they are active on the central nervous system, especially in
`terms of 5-HTIA-agonist and 5-HT-reuptake inhibition. The
`compounds are furthermore active as serotonin agonists and 40
`antagonists. They inhibit the binding of tritiated serotonin
`ligands to hippocampal receptors (Cossery et al., European
`J. Pharmacol., 140:143-155 (1987)). They also modify the
`accumulation of DOPA in the corpus striatum and the
`accumulation of 5-HTP in the nuclei raphes (Seyfried et al., 45
`European J. Pharmacol., 160:31-41 (1989)). They also have
`analgesic and hypotensive effects; thus, in catheterized,
`conscious, spontaneously hypertensive rats (strain: SHR/
`Okamoto/NIH-MO-CHB-Kisslegg; method: q.v. Weeks and
`Jones, Proc. Soc. Exptl. Biol. Med., 104:646-648 (1960)),
`the directly measured blood pressure is lowered after oral
`administration of the compounds. They are also useful for
`prophylaxis and control of the sequelae of cerebral infarc(cid:173)
`tion
`(apoplexia cerebri) such as stroke and cerebral
`ischaemia.
`Compounds of the formula I and their physiologically
`acceptable acid addition salts can, therefore, be used as
`active ingredients for anxiolytics, antidepressants, antipsy(cid:173)
`chotics, neuroleptics, and/or antihypertensives, and also as
`intermediates for the preparation of other pharmaceutical 60
`active ingredients.
`The invention relates to the piperidine and piperazine
`derivatives of the formula I and to their physiologically
`acceptable acid addition salts.
`The radical A is alkyl having 1, 2, 3, 4, 5 or 6 C atoms, 65
`especially 1 or 2 C atoms, preferably methyl and also ethyl,
`n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl. OA is
`
`20
`
`25
`
`30
`
`35
`
`or
`or
`
`in the
`
`in the
`
`55
`
`Ind-Q-X
`
`1
`
`II
`
`wherein
`X1 is X or NH2 ,
`X is Cl, Br, I, OH or an OH group functionally modified
`to form a reactive group, and
`Ind and Q are as defined, is reacted with a compound of
`the formula III
`
`X2-(CH 2),-ZR 1-(CH 2),-X 3
`
`III
`
`wherein
`
`Page 2
`
`

`

`5,532,241
`
`3
`X 2 and X3 can be identical or different and are each X if
`X 1=NH 2 or are together NH in other cases, and
`Z and R 1 are as defined, or in that to prepare a compound
`of the formula I in which Z is N, a compound of the
`formula IV
`
`Ind-Q-N(CH
`
`2-CH 2-X),
`
`IV
`
`wherein
`X, Q and Ind are as defined, is reacted with a compound 10
`. of the formula V
`
`R 1-NH 2
`
`V
`
`wherein
`R 1 is as defined, or in that a compound which has formula
`I except that one or more hydrogen atoms have been
`replaced by one or more reducible groups and/or one or
`more additional C-C and/or C-N bonds are treated
`with a reducing agent,
`or in that a compound which has formula I except that one
`or more hydrogen atoms have been replaced by one or more
`solvolyzable groups is treated with a solvolyzing agent,
`and/or in that an OA group is optionally cleaved to form an
`OH group, and/or an Ind group and/or an Ar group is
`converted into another Ind and/or Ar group, and/or in that a
`resulting base or acid of the formula I is converted into one
`of its salts by treatment with an acid or base.
`The compounds of the formula I are otherwise prepared
`by methods known per se, such as those described in the
`literature (e.g. in the standard works such as Houben-Wey!,
`Methoden der Organischen Chemie (Methods of Organic
`Chemistry), Georg-Thieme-Verlag, Stuttgart; Organic Reac(cid:173)
`tions, John Wiley & Sons, Inc., New York; German Offen(cid:173)
`legungsschrift 41 01 686), namely under reaction conditions
`such as those which are known and suitable for said reac(cid:173)
`tions. It is also possible to make use of variants known per
`se, which are not mentioned in greater detail here.
`If desired, the starting materials for the claimed process
`can also be formed in situ in such a way that they are not
`isolated from the reaction mixture but are immediately
`reacted further to give the compounds of the formula I.
`In the compounds of the formula II, X 1 is preferably X;
`accordingly, in the compounds of the formula III, X2 and X3
`are together preferably NH. The radical X is preferably Cl or
`Br, but it can also be I, OH or an OH group functionally
`modified to form a reactive group, especially alkylsulfony(cid:173)
`loxy having 1-6 C atoms (e.g., methanesulfonyloxy) or
`arylsulfonyloxy having 6-10 C atoms (e.g., benzenesulfo(cid:173)
`nyloxy, p-toluenesulfonyloxy, naphthalene-I- or -2-sulfony(cid:173)
`loxy).
`Accordingly, the indole derivatives of the formula I can be
`obtained especially by reacting compounds of the formula
`Ind-Q-Cl
`or Ind-Q-Br
`with piperidine/piperazine
`derivatives of the formula III in which X2 and X3 together
`are an NH group (designated as Illa hereafter).
`Some of the compounds of the formulae II and, in
`particular, III are known; the unknown compounds of the
`formulae II and III can easily be prepared analogously to the
`known compounds.
`Primary alcohols of the formula Ind-Q-OH
`can be
`obtained, e.g., by reducing the appropriate carboxylic acids
`or their esters. Treatment with thionyl chloride, hydrogen
`bromide, phosphorus tribromide or similar halogen com(cid:173)
`pounds yields the corresponding halides of the formula
`Ind-Q-Hal.
`The corresponding sulfonyloxy compounds
`can be obtained from the alcohols Ind-Q-OH
`by reaction
`with the appropriate sulfonyl chlorides.
`
`4
`The iodine compounds of .the formula Ind-Q-I
`can be
`obtained, e.g., by reacting potassium iodide with the appro(cid:173)
`priate p-toluenesulfonic acid esters. The amines of the
`formula Ind-Q-N
`2 can be prepared, e.g., from the halides
`5 with potassium phthalimide or by reducing the appropriate
`nitriles.
`Most of the piperazine derivatives Illa are known and can
`be obtained, e.g., by reacting bis(2-chloroethyl)amine or
`bis(2-chloroethyl)ammonium chloride with 5-aminobenzo(cid:173)
`furan, 2,3-dihydro-5-aminobenzofuran, 6-aminochroman or
`6-aminochromen-4-one or an appropriately substituted
`derivative of the compounds mentioned. Compounds of the
`formula III (X2 and X 3=X
`in each case) can be prepared.,
`e.g., by reducing diesters of the formula alky I 00C-CH 2-
`ZR1-CH2-COO-alkyl
`to give compounds of the for-
`HO-CH 2-CH 2-ZR 1-CHrCH 2OH
`15 mula
`(III,
`X 2=X 3=0H),
`this being followed, if desired, by reaction
`with SOCl2 or PBr 3•
`The reaction of the compounds of formulae II and III
`proceeds according to methods such as those known from
`the literature for the alkylation of amines. The components
`can be melted together in the absence of a solvent, in a
`sealed tube or an autoclave if necessary. It is also possible,
`however, to react the compounds in the presence of an inert
`solvent. Examples of suitable solvents are hydrocarbons
`25 such as benzene, toluene or xylene; ketones such as acetone
`or butanone; alcohols such as methanol, ethanol, isopro(cid:173)
`panol or n-butanol; ethers such as tetrahydrofuran (THF) or
`dioxane; amides such as dimethylformamide (DMF) or
`N-methylpyrrolidone; or nitriles such as acetonitrile, or else,
`if desired, mixtures of these solvents with one another or
`mixtures with water. It can be favorable to add an acid(cid:173)
`binding agent, for example an alkali metal or alkaline earth
`metal hydroxide, carbonate or bicarbonate or another alkali
`metal or alkaline earth metal salt of a weak acid, preferably
`35 a potassium, sodium or calcium salt, or to add an organic
`base such as triethylamine, dimethylaniline, pyridine or
`quinoline, or an excess of the amine component Ind-Q(cid:173)
`NH2 or of the piperidine or piperazine derivative of the
`formula Illa. The reaction time is between about a few
`40 minutes and 14 days, depending on the conditions used, and
`the reaction temperature is preferably about 0°-150°, nor(cid:173)
`mally 20°-130°.
`It is also possible to obtain a compound of the formula I
`by reacting a compound of the formula Ind-Q-N(CH
`2-
`45 CH2-X) 2 (IV) with a compound of the formula R 1-NH 2
`(V).
`Most of the compounds of the formula V are known; the
`unknown compounds can easily be prepared analogously to
`the known compounds. For example, starting from the
`50 appropriately substituted nitro compounds, they can be
`converted into the amines of the formula V by reduction.
`The compounds of the formula IV can be prepared by
`reaction of Ind-Q-Cl,
`Ind-Q-Br
`or Ind-Q-I
`with
`secondary amines of the formula HN(CH 2-CH 2-X)z.
`The reaction of compounds IV and V proceeds according
`to methods which are known from the literature and were
`given above for the alkylation of amines.
`A compound of the formula I can also be obtained by
`treating a precursor, in which hydrogen atoms have been
`60 replaced by one or more reducible groups and/or one or
`more additional C-C and/or C-N bonds, with a reducing
`agent, preferably at temperatures of about-80 to 250°, in the
`presence of at least one inert sol vent.
`Reducible groups (groups replaceable by hydrogen) are,
`in particular, oxygen in a carbonyl group, hydroxyl, aryl(cid:173)
`sulfonyloxy (e.g. p-toluenesulfonyloxy), N-benzenesulfo(cid:173)
`nyl, N-benzyl or O-benzyl.
`
`20
`
`30
`
`55
`
`65
`
`Page 3
`
`

`

`5,532,241
`
`5
`In principle, compounds containing only one of the
`above-mentioned groups or additional bonds, or compounds
`containing two or more of the above-mentioned groups or
`additional bonds adjacent to one another, can be converted
`into a compound of the formula I by reduction, it being 5
`possible simultaneously to reduce substituents in the Ind
`group which are present in the starting compound. This is
`preferably carried out using nascent hydrogen or complex
`metal hydrides or by means of a Wolff-Kishner reduction or
`the reductions with hydrogen gas under transition metal 10
`catalysis.
`Preferred starting materials for the reduction have formula
`VI
`
`6
`are suitable for this purpose are, in particular, ethers such as
`diethyl ether, di-n-butyl ether, THF, dioxane, diglyme or
`1,2-dimethoxyethane, and hydrocarbons such as benzene.
`Solvents which are suitable for a reduction with NaBH4 are
`primarily alcohols such as methanol or ethanol, as well as
`water and aqueous alcohols. Reduction by these methods is
`preferably carried out at temperatures of about-80 to +150°,
`especially about 0°-100°.
`The reduction of -CO-
`groups in acid amides (e.g.,
`those of the formula VI in which Lis a -(CH 2)n_1-CO(cid:173)
`group) to CH2 groups can be carried out to particular
`advantage with LiAIH4 in THF at temperatures of preferably
`about 0°-66°. Arylsulfonyl protecting groups located in the
`I-position of the indole ring can be simultaneously elimi-
`VI 15 nated by reduction. N-Benzyl groups can be eliminated by
`reduction with sodium in liquid ammonia.
`It is also possible to reduce one or more carbonyl groups
`to CH2 groups according to the Wolff-Kishner method, e.g.,
`by treatment with anhydrous hydrazine in absolute ethanol,
`20 under pressure, at
`temperatures of preferably about
`150°-250°. A sodium alcoholate is advantageously used as
`the catalyst. The reduction can also be varied according to
`the Huang-Minlon method by carrying out the reaction with
`hydrazine hydrate in a high-boilirig water-miscible solvent
`25 such as diethylene glycol or triethylene glycol, in the pres(cid:173)
`ence of an alkali such as sodium hydroxide. The reaction
`mixture is normally boiled for about 3-4 hours. The water is
`then distilled off and the hydrazone formed is decomposed
`at temperatures of up to about 200°. The Wolff-Kishner
`30 reduction can also be carried out with hydrazine in dimethyl
`sulfoxide at room temperature.
`Moreover, it is possible to carry out certain reductions by
`using H2 gas under the catalytic action of transition metals,
`such as, e.g., Raney Ni or Pd. In this way, e.g., Cl, Br, I, SH
`35 or, in certain cases, even OH groups can be replaced by
`hydrogen. Nitro groups can also be converted into NH2
`groups by catalytic hydrogenation with Pd/H2 in methanol.
`Compounds which have formula I except that one or more
`H atoms have been replaced by one or more solvolyzable
`40 groups can be solvolyzed, especially hydrolyzed, to give the
`compounds of the formula I.
`The starting materials for the solvolysis can be obtained
`for example by reacting Illa with compounds which have
`formula II (X 1=X) except that one or more H atoms have
`45 been replaced by one or more solvolyzable groups. Thus, in
`particular, 1-acylindole derivatives (which have formula I
`except that, in the I-position of the Ind radical, they contain
`an acyl group, preferably an alkoxycarbonyl, alkanoyl,
`alkylsulfonyl or arylsulfonyl group having up to 10 C atoms
`in each case, such as methanesulfonyl, benzenesulfonyl or
`p-toluenesulfonyl) can be hydrolyzed to give the corre(cid:173)
`sponding indole derivatives unsubstituted in the I-position
`of the indole ring, e.g. in an acidic or, preferably, neutral or
`alkaline medium at temperatures of preferably about
`55 0°-200°. Sodium, potassium or calcium hydroxide, sodium
`or potassium carbonate, or ammonia, is conveniently used as
`the base. The chosen solvents are preferably water; lower
`alcohols such as methanol or ethanol; ethers such as THF or
`dioxane; sulfones such as tetramethylene sulfone; or mix-
`tures
`thereof, especially mixtures containing water.
`Hydrolysis can also be carried out simply by treatment with
`water alone, especially at the boiling point.
`A compound of the formula I can furthermore be con(cid:173)
`verted to another compound of the formula I by methods
`65 known per se.
`Compounds of the formula I in which Ind is an indol- 3-yl
`radical substituted by CO-R 1 can be obtained by derivatizing
`
`50
`
`lnd'-L-N
`
`Z-R 1
`
`wherein
`Ind' is an Ind radical which can additionally be substituted
`in the I-position by an arylsulfonyl group or an alky(cid:173)
`loxycarbonyl group,
`L is Q or a chain which corresponds to the radical Q
`except that one or more -CH 2-
`groups have been
`replaced by -CO-
`and/or one or more hydrogen
`atoms have been replaced by one or more OH groups
`or a double bond, and
`R 1 has the meaning given,
`but wherein the following meanings cannot apply simulta(cid:173)
`neously: Ind'=Ind and L--Q.
`In the compounds of the formula VI, L is preferably
`-CO-(CH 2)n_2-CO-, wherein n is 2, 3 or 4[specifically
`-COCO-,
`-COCH 2CO-,
`-CO-(CH 2h-CO-,
`-CO-(CH 2h-CO-],
`-(CH 2)n-i -CO-, wherein n is
`2, 3 or 4 [specifically -CH 2-CO-,
`-CH 2CH2-CO-,
`-(CH 2)3-CO
`-or
`-(CH 2)4-CO-],
`further examples
`-CO-(CH 2h-,
`being -CO-CH 2CH2-,
`-CH 2-
`CO-CH2CH2-
`or -CH 2CH2-CO-CH 2-.
`Compounds of the formula VI can be prepared, e.g., by
`reacting 4-R 1-piperazine or 4-R 1-piperidine with a com(cid:173)
`pound of the formula VII
`
`lnd'-L--X
`
`1
`
`VII
`
`wherein
`R1 Ind', L and X 1 are as defined above, under the
`conditions indicated above for the reaction of II with
`III.
`If nascent hydrogen is used as the reducing agent, this can
`be produced, e.g., by treating metals with weak acids or with
`bases. Thus, it is possible, e.g., to use a mixture of zinc with
`an alkali metal hydroxide solution or a mixture of iron with
`acetic acid. It is also appropriate to use sodium or another
`alkali metal dissolved in an alcohol such as ethanol, isopro(cid:173)
`panol, butanol, amyl or isoamyl alcohol or phenol. It is also
`possible to use an aluminum-nickel alloy in aqueous-alka(cid:173)
`line solution, ethanol being added if necessary. Sodium
`amalgam or aluminum amalgam in aqueous-alcoholic or
`aqueous solution is also suitable for producing the nascent
`hydrogen. The reaction can also be carried out in the
`heterogeneous phase, in which case it is convenient to use an
`aqueous phase and a benzene or toluene phase.
`Other reducing agents which can be used to particular
`advantage are complex metal hydrides such as LiAlH4 ,
`NaBH4 ,
`diisobutylaluminum
`hydride
`or
`NaAl(OCH2CH2OCH3hH 2, and diborane, catalysts such as
`BF3, A1Cl3 or LiBr being added if desired. Solvents which
`
`60
`
`Page 4
`
`

`

`5,532,241
`
`10
`
`35
`
`7
`appropriate carboxyindol-3-yl compounds. It is possible,
`e.g., to esterify the acids with appropriate alcohols or
`alcoholates, using methods known per se. It is also possible
`to amidate acids or esters with primary or secondary amines.
`It is preferred to react the free carboxylic acid with the amine
`under the conditions of a peptide synthesis. This reaction is
`preferably carried out in the presence of a dehydrating agent,
`e.g., a carbodiimide such as dicyclohexylcarbodiimide or
`else N-(3-dimethylarninopropyl)-N-ethylcarbodiimide, or
`propanephosphonic anhydride (q.v. Angew. Chem. 92, 129
`(1980)), diphenylphosphoryl azide or 2-ethoxy-N-ethoxy(cid:173)
`carbonyl-1,2-dihydroquinoline, in an inert solvent, e.g., a
`halogenated hydrocarbon such as methylene chloride, an
`ether such as THF or dioxane, an amide such as DMF or
`dimethylacetamide, or a nitrile such as acetonitrile, at tem(cid:173)
`peratures of preferably about -10 to 40, preferably about
`0°-30°. Instead of the acid or amide, it is also possible to use
`reactive derivatives of these substances in the reaction, e.g.,
`those in which reactive groups are blocked by protecting
`groups in an intermediate step. The acids can also be used in
`the form of their activated esters, which are conveniently
`formed in situ, e.g., by the addition of 1-hydroxybenztria(cid:173)
`zole or N-hydroxysuccinimide.
`Furthermore, cyano-substituted indol-3-yl radicals can be
`hydrolyzed to give carboxy-indol-3-yl or carbamido-indol-
`3-yl radicals.
`Conversely, however, it is particularly convenient to pre(cid:173)
`pare the nitriles by elimination of water, starting from the
`amides, e.g., by means of trichloroacetyl chloride/Et 3N
`[Synthesis (2), 184, (1985)] or with POC13 (J. Org. Chem.
`26, 1003 (1961)).
`A base of the formula I can be converted with an acid into
`the corresponding acid addition salt. Acids which produce
`physiologically acceptable salts are suitable for this reaction.
`Thus, it is possible to use inorganic acids, e.g., sulfuric acid,
`hydrohalic acids such as hydrochloric acid or hydrobromic
`acid, phosphoric acids such as orthophosphoric acid, nitric
`acid and sulfamic acid, as well as organic acids, i.e., spe(cid:173)
`cifically aliphatic, alicyclic, araliphatic, aromatic or hetero(cid:173)
`cyclic monobasic or polybasic carboxylic, sulfonic or sul(cid:173)
`furic acids, such as formic acid, acetic acid, propionic acid, 40
`pivalic acid, diethylacetic acid, malonic acid, succinic acid,
`pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric
`acid, malic acid, benzoic acid, salicylic acid, 2-phenylpro(cid:173)
`pionic acid, citric acid, gluconic acid, ascorbic acid, nico(cid:173)
`tinic acid, isonicotinic acid, methanesulfonic or ethane- 45
`sulfonic
`acid,
`ethanedisulfonic
`acid,
`2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-tolu(cid:173)
`enesulfonic acid, naphthalenemonosulfonic and naphtha(cid:173)
`lenedisulfonic acids and laurylsulfuric acid.
`If desired, the free bases of the formula I can be liberated 50
`from their salts by treatment with strong bases such as
`sodium or potassium hydroxide or sodium or potassium
`carbonate provided there are no other acid groups in the
`molecule. In those cases where the compounds of the
`formula I have free acid groups, salt formation can also be 55
`achieved by treatment with bases. Suitable bases are alkali
`metal hydroxides, alkaline earth metal hydroxides or organic
`bases in the form of primary, secondary or tertiary amines.
`The invention further relates to the use of the compounds
`of the formula I and their physiologically acceptable salts for 60
`the manufacture of pharmaceutical preparations, especially
`by a non-chemical route. For this purpose, they can be
`converted into a suitable dosage form together with at least
`one excipient or adjunct and, if appropriate, in combination
`with one or more additional active ingredients.
`The invention further relates to compositions, especially
`pharmaceutical preparations, containing at least one com-
`
`8
`pound of the formula I and/or one of their physiologically
`acceptable salts. These preparations can be used as drugs in
`human or veterinary medicine. Possible excipients are
`organic or inorganic substances which are suitable for
`5 enteral (e.g.,oral), parenteral or topical administration and
`which do not react with the novel compounds, examples of
`such excipients being water, vegetable oils, benzyl alcohols,
`polyethylene glycols, gelatin, carbohydrates such as lactose
`or starch, magnesium stearate, talc and petroleum jelly.
`Tablets, coated tablets, capsules, syrups, juices, drops or
`suppositories are used in particular for enteral administra(cid:173)
`tion, solutions, preferably oily or aqueous solutions, as well
`as suspensions, emulsions or
`implants are used for
`parenteral administration, and ointments, creams or powders
`are used for topical administration. The novel compounds
`15 can also be lyophilized and the resulting lyophilizates used,
`e.g., to manufacture injectable preparations.
`The preparations indicated can be sterilized and/or can
`contain adjuncts such as lubricants, preservatives, stabilizers
`and/or wetting agents, emulsifiers, salts for influencing the
`20 osmotic pressure, buffer substances, colorants, taste correc(cid:173)
`tors and/or flavorings. If desired, they can also contain one
`or more additional active ingredients, e.g. one or more
`vitamins.
`The compounds of the formula I and their physiologically
`25 acceptable salts can be used for the therapeutic treatment of
`the human or animal body and for controlling diseases. They
`can be used for treating disorders of the central nervous
`system, such as tension, depressions and/or psychoses, and
`side-effects in the treatment of hypertension (e.g., with
`30 a-methyldopa). The compounds can also be used in endo(cid:173)
`crinology and gynecology, e.g., for the therapeutic treatment
`of acromegaly, hypogonadism, secondary amenorrhea, pre(cid:173)
`menstrual syndrome and undesired puerperal lactation, and
`also for the prophylaxis and therapy of cerebral disorders
`(e.g., migraine), especially in geriatrics in a manner similar
`to certain ergot alkaloids and for controlling the sequelae of
`cerebral infarction (apoplexia cerebri), such as stroke and
`cerebral ischemia.
`In these treatments, the. substances of the invention are
`normally administered analogously to known, commercially
`available preparations (e.g., bromocriptine, dihydroergocor(cid:173)
`nine), preferably in dosages of about 0.2-500 mg, especially
`0.2-50 mg per dosage unit. The daily dosage is preferably
`about 0.001-10 mg/kg of body weight. The low dosages
`(about 0.2-1 mg per dosage unit; about 0.001-0.005 mg/kg
`of body weight) are particularly suitable for use as anti-
`migraine preparations; dosages of about 10-50 mg per
`dosage unit are preferred for the other indications. However,
`the particular dose for each individual patient depends on a
`very wide variety of factors, for example, the activity of the
`particular compound used, age, body weight, general state of
`health, sex, diet, time and method of administration, rate of
`excretion, drug combination and severity of the particular
`disease to which the therapy is applied. Oral administration
`is preferred.
`Without further elaboration, it is believed that one skilled
`in the art can, using the preceding description, utilize the
`present invention to its fullest extent. The following pre(cid:173)
`ferred specific embodiments are, therefore, to be construed
`as merely illustrative, and not !imitative of the remainder of
`the disclosure in any way whatsoever.
`In the foregoing and in the following examples, all
`temperatures are set forth uncorrected in degrees Celsius and
`unless otherwise indicated, all parts and percentages are by
`65 weight.
`The entire disclosure of all applications, patents and
`publications, cited above and below, and of corresponding
`
`Page 5
`
`

`

`5,532,241
`
`9
`German application P 43 33 254.4, filed Sep. 30, 1993, are
`hereby incorporated by reference.
`In the following Examples, "working-up in conventional
`manner" means: Water is added if necessary, extraction is
`carried out with methylene chloride, the organic phase is 5
`separated off, dried over sodium sulfate and filtered, the
`filtrate is evaporated and the residue is purified by chroma(cid:173)
`tography on silica gel and/or by crystallization. Tempera(cid:173)
`tures are given in ° C. Rf values were obtained by thin layer
`chromatography on silica gel.
`
`EXAMPLES
`
`Example 1
`
`10
`of 3-(4-chlorobutyl)-5-methoxycarbonylindole with 1-(2,3-
`dihydrobenzofuran-5-yl)piperazine:
`1-[ 4-(5-methoxycarbony lindol-3-y l)buty l]-4-(2,3-dihy(cid:173)
`drobenzofuran- 5-yl)piperazine;
`of 3-(4-chlorobutyl)-5-methoxycarbonylindole with 4-(2,3-
`dihydrobenzofuran-5-yl)piperidine:
`1-[ 4-(5-methoxycarbony lindol-3-y I )buty l]-4-(2,3-dihy(cid:173)
`drobenzofuran- 5-yl)piperidine;
`of 3-(4-chlorobutyl)-5-methoxycarbonylindole with 4-(2,3-
`lO dihydrobenzofuran-5-yl)-4-hydroxypiperidine:
`1-[ 4-(5-methoxycarbony lindol-3-yl)buty l]-4-(2,3-dihy(cid:173)
`drobenzofuran- 5-yl)-4-hydroxypiperidine;
`of 3-( 4-chlorobutyl)-5,6-dimethoxyindole with 1-(chroman-
`15 6-yl)piperazine:
`1-[ 4-(5,6-dimethoxyindol-3-yl)butyl ]-4-( chroman-6-
`yl)piperazine;
`of 3-( 4-chlorobutyl)-5-cyanoindole with 1-(2-carboxyben(cid:173)
`zofuran- 5-yl)piperazine:
`1-[ 4-(5-cyanoindol-3-y l)buty l]-4-(2-carboxybenzofuran-
`5-yl)piperazine;
`of 3-(4-chlorobutyl)-6-fluoroindole with 1-(2,3-dihydroben(cid:173)
`zofuran- 5-yl)piperazine:
`1-[ 4-( 6-fluoroindol-3-y l)buty l]-4-(2,3-dihydrobenzofu(cid:173)
`ran- 5-yl)piperazine.
`
`1.8 g of 3-(4-chlorobutyl)-5-methoxyindole [obtainable
`by diazotization of p-methoxyaniline, reaction with ethyl
`cyclohexanone-2-carboxy late according
`to Japp-Klinge(cid:173)
`mann to give 4-(2-carbethoxyindol-3-yl)butyric acid, alka(cid:173)
`line hydrolysis, decarboxylation, reduction with LiAIH4 and 20
`reaction with SOCl2 ] and 1.9 g of 1-(2-hydroxymethylben(cid:173)
`zofuran-5-yl)piperazine [obtainable by reaction of N,N(cid:173)
`bis(2-chloroethyl)arnine with
`2-hydroxymethyl-5-arni(cid:173)
`nobenzofuran] are dissolved in 200 ml of acetonitrile and the
`mixture is stirred at room temperature for 10 hours. Cus- 25
`tomary working up gives l-[4-(5-methoxyindol-3-yl)butyl]
`-4-(2-hydroxymethylbenzofuran-
`5-yl)piperazine, m.p.
`159°.
`The following are obtained analogously by reaction of
`3-(4-chlorobutyl)-5-methoxyindole with 1-(2,3-dihydroben- 30
`zofuran- 5-yl)piperazine:
`1-[ 4-(5-methoxyindol-3-yl)butyl]-4-(2,3-dihydrobenzo(cid:173)
`furan- 5-yl)piperazine, m.p. 111 °-112°;
`of 3-(4-chlorobutyl)-5-hydroxyindole with 1-(chroman-6-
`yl)piperazine:
`1-[ 4-(5-h