CA2054648A1 - 1-(2-arylethyl)-pyrrolidines - Google Patents

1-(2-arylethyl)-pyrrolidines

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Publication number
CA2054648A1
CA2054648A1 CA002054648A CA2054648A CA2054648A1 CA 2054648 A1 CA2054648 A1 CA 2054648A1 CA 002054648 A CA002054648 A CA 002054648A CA 2054648 A CA2054648 A CA 2054648A CA 2054648 A1 CA2054648 A1 CA 2054648A1
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Prior art keywords
methyl
amino
phenyl
ethyl
hydroxy
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CA002054648A
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French (fr)
Inventor
Rudolf Gottschlich
Karl-August Ackermann
Helmut Pruecher
Andrew Barber
Anton Haase
Hartmut Greiner
Gerd Bartoszyk
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Merck Patent GmbH
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Individual
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pain & Pain Management (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

Abstract Novel 1-(2-arylethyl)-pyrrolidines of the formula I
I

in which Ar, R1, R2 and R3 have the meaning stated in Claim 1, have analgesic properties.

Description

2 ~ 8 Merck Patent Gesellschaft mit beschr~nkter Haftung 61Q0 D a r m ~ t a d t 1-(2-Ar}~lethyl)-pyrrolidines The in~ention relates to novel 1-(2-arylethyl)-pyrrolidines of the formula I

Ar-CI{-NR~ -CO-CH2-R2 CH2-N ~

in which Ar is a phenyl group which is unsubstituted or mono-substitu~ed hy O~, -O-CO-NH2, -O-CO-NHA, -O-CO-NA2, NH2, -NH-CHO, -NH-CO-A, -NH-CO-NH2, -NH-CO-NHA or NEI-SO2-A, Rl is A, R2 i~ a phenyl, naphthyl, thienyl, benzothienyl or pyridyl group which is unsubstituted or mono- or disubstituted by A, Hal, CF3, OH, OA, -O-CO-NH2, -O-CO--NEI~, -O-CO-NA2, NO2, NH~, 8U-R~-CO-A, -~-~-~2~ -NH-CO-NHA, -NH-SO2A, -CO-A, -CONH2, -CONHA, -CONA2, -CHz-CONH2 and~or -O-CH2-CON~I2, R3 is OH or CH20H, A is alkyl with 1-4 C atom~ and Hal is F, Cl, Br or I, and the salts thereof.
DE-A1-3,935,371 describes compound~ of a formula ~ 2 --20~6~8 Rl ~__ ~ NR2-CO-CH2-R3 -(CH2)m CH2-N~
R~

in which Rl can also be H, R2 can also be A, R3 can also be a phenyl, thienyl, naphthyl or benzothienyl group which is unsubstitued or substituted in a particular manner, R4 can also be OH or CH~OH and m can also be 1.
However, neither compounds of ~he abovementioned formula I nor any individual compounds which are covered by this formula I are described therein. Thus, in Yiew of DE-Al-3,935,371, compounds of the formula I are novel and have, by comparison therewith, ~he nature of a selection in~ention.
~he ob~ect of th~ invention was to find novel compounds with valuable properties, especially those which can be used for the prepara~ion of drugs.
It ha been found that the compounds of formulaI
and their phy~iologically compatible ~alts possess valu-able pharmacolo~ical properties. They e~hibit an analge-sic action and antagonise inflammation-related hyper-algesia in particular. Thus the compounds are effective in the writhing test on mice or rats (for method see Siegmund et al., Proc. Soc. Exp. Biol. 95, (1957), 729-731). The analgesic action can also be demonstrated in the tail flick ~est on mice or rats (for nethodology see d'Amour and Smith, ~. Pharmacol. Exp. Ther. 72, tl94l), 74-79) and in the hot plate test (see Schmauss and YaXsh, J. Pharmacol. Exp. Ther. 228, (1984), 1-12 and the literature cited therein). Especially potent actions are to be ob~erved in rats in the model of carrageenin-inducedhyperalgesia (see Bar~oszyk and Wild, Neuroscience Letters lpl (1989) 95). In these tests, the compounds show little or no tendency to cause physical dependence.
Furthermore, antiinflammatory, antiasthmatic, diuretic, ~054fi4~
anticonvul~ant and/or antitu~sive actior~s are apparent which can al80 be demonstrated by methods commonly l~sed for this purpose. The compounds are moreover suitable for protecting again~t and treating cerebral oedemafi and states of supply deficiency of the central ner~ous system, especially hypoxia.
The compounds can therefore be used as pharma-cological active ingredients in human and veterinary medicine. They are also suitable as intermediates for the preparation of other compounds with valuable proper-ties.
The invention relates to compounds of formula I
and to their salts.
The group A is alkyl containing 1, 2, 3 or 4 C
atoms, especially methyl or ethyl, but al~o propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.
Accordingly the group OA is preferably methoxy or ethoxy or also propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy.
Accordingly, the group~ shown below have the preferred meaning~ specified as follows:
-O-CO-NHA: N-methyl-carbamoyl-oxy, N-ethyl-carbamoyl-oxy;
-O-CO-NA2: N,N-dimethyl-carbamoyl-oxy, N,N-diethyl-carbamoyl-oxy;
-NH-CO-A: Acetamido, propionamido;
-NH-CO-NHA: N'~methyl-ureido, N'-ethyl-ureido;
-N~-S02-A: Methylsulfonylamino, ethylsulfonylamino;
-CO-A: Acetyl, propionyl;
-CO-NHA: N-methyl-carbamoyl, N-ethyl-carbamoyl;
-CON~: N'N-dimethyl-carbamoyl, N,N-diethyl-carbamoyl.
Hal is preferably Cl, also preferably F, but also Br or I.
Ar is preferably unsub~tituted phenyl, also preferably o-, m- or p-aminophenyl, furthermore pre-ferably o-, m- or p-hydroxyphenyl, o-, m or p-formamido-phenyl, o-, m- or p-acetamidophenyl, o-, m or p-methyl-sulfonylaminophenyl, o-, m- or p-ureidophenyl, o-, m~ or _ 4 _ 20~ 8 p-N'-methylureidophenyl. Among the ~ubstituted phenyl radical~, those in the p position but also those in the m position are preferred.
R1 i~ preferably methyl.
Particularly preferred R2 radicals are 3,4-dichlorophenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p-formamidophenyl, o-, m- or p-acetamidophenyl, o-, m- or p-ureidophenyl, o-, m- or p-carbamoylmethylphenyl, l-naphthyl and 4-benzothienyl.
However, the R2 radical is preferably also phenyl, o-, m-or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-etho~ ~henyl, o-, m- or p-hydroxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, o-, m- or p-trifluoromethylphenyl, o-, m- or p-carbamoyloxy-phenyl, o-, m- or p-N-me~hylcarbamoyloxy-phenyl, -t m- or p-N,N-dimethylcarbamoyloxy-phenyl, o-, m- or p-N'-methylureido-phenyl, o-, m- or p-methylsulfonylamino-phenyl, o-, m-or p-acetyl-phenyl, o-, m- or p-car~amoylphenyl, o-, m-or p-N-methylcarbamoyl-phenyl, o-, m- or p-N,N-dLmethyl-carbamoyl-phenyl, o-, m- or p-carbamoylmethyl-phenyl, o-, m- or p-carbamoylmethoxy-phenyl, 2,3-, 2,4-, 2l5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-dLmethoxyphenyl, 2,3 , 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,~-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5 , 2,6-, 3,4- or 3,5-dibromophenyl, 2-amino-3-chlorophenyl, 2-Emino-4-~hlorophenyl,2-amino-5-chlorophenyl,2-amino-6-chloro-phenyl, 3-amino-2-chlorophenyl, 3-amino-4-chlorophenyl, 3Q 3-amino-5-chlorophenyl, 3-amino-6-chlorophenyl, 4-amino-2-chlorophenyl, 4-amino-3-chlorophenyl, 2-amino-3-, -4-, -5- or -6-bromophenyl, 3-amino-2-, -4-, -5- or -6-bromo-phenyl, 4-amino-2- or -3-bromophenyl, 2-chloro-4-hydroxy-phenyl, 3-chloro-4-hydroxyphenyl, 2-hydroxy-4-chloro-phenyl, 3-hydro~y-4-chlorophenyl, 3-chloro-4-carboxy-methoxyphenyl, 3-chloro-4-methoxycarbonylmethoxyphenyl, 3-chloro-4-ethoxycarbonylmethoxyphenyl, 2-naphthyl, 2-, 3-, 4-~ 5-, 6-, 7- or 8-chloro-1-naphthyl, 2- or 3-thienyl, 3-, 4- or 5-chloro-2-thienyl, 3-, 4- or 2 (3 ~ 4 6 ~ ~

5-bromo-2-thienyl, 2-, 4- or 5-chloro-3-thienyl, 2-, 4-or 5-bromo-3~thienyl, 3,4-, 3,5- or 4,5-dichloro-2-thienyl, 5-amino-2-thienyl, 5-formamido-2-thienyl, 5-acetamido-2-thienyl, 5-methylsulfonylamino-2-thienyl, 5-ureido-2-thienyl, 5-N'-methylureido-2-thienyl, 2-, 3-, 5-, 6- or 7-benzothienyl, 2-, 3- or 4-pyridyl, 3-amino-4-pyridyl, 3-formamido-4-pyridyl, 3-acetamido-4-pyridyl, 3-methylsulfonylamino-4-pyridyl, 3-ureido-4-pyridyl, 3-N'-methylureido-4-pyridyl, 3-amino-4-methyl-2-pyridyl, 3-formamido-4-methyl-2-pyridyl, 3-acetamido-4-methyl-~-pyridyl, 4-methyl-3-methylsulfonylamino-2-pyridyl, 4-methyl-3-ureido-2-pyridyl, 4-methyl-3-N'-methylureido-2-pyridyl, 5-amino-4-methyl-3-pyridyl, 5-formamido-4-methyl-2-pyridyl, 5-acetamido-4-methyl-2-pyridyl, 4-me~hyl-5-methylsulfonylamino-2-pyridyl, 4-methyl-5-ureido-2-pyridyl, 4-methyl-5-N'-methylureido-2-pyridyl.
R3 is preferably OH, but also CH2OH.
The invention ~pecifically relates to compounds of the formulae Ia and Ib in which the radicals not defined in de~ail have the meanin~ indicated for formula I but in which R3 in Ia i5 OH and R3 in Ib is CHzOH.
The invention relates in particular to those compounds o formulae I, Ia and Ib in which at least one of said radical3 ha3 one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by partial formulae I' and Ia' and Ib', which have formulae I (and Ia and Ib) and wherein the radieal~ not described more precisely are as defined for formula I, but wherein R~ i~ phenyl, tolyl, methoxyphenyl, hydroxyphenyl, fluorophenyl, chlorophenyl, bromophenyl, dichlorophenyl, aminochlorophenyl, aminobromophenyl, chlorohydroxyphenyl, nitrophenyl, aminophenyl, ureido-phenyl, carbamoylmethylphenyl, carbamoylphenyl, car-bamoylme~hoxyphenyl, formamidophenyl, acetamidophenyl, methylsulfonamidophenyl,N~-methylureidophenyl,N-methyl-carbamoylphenyl, naphthyl, thienyl, benzothienyl or pyridyl.
Other preferred compound are those of formulae I'' and Ia~ and Ib'', which have formulae I and Ia and 2 0 .5 L~

Ib, but wherein R2 is dichlorophenyl, ~ninochlorophenyl, aminobromo-phenyl, nitrophenyl, aminophenyl, acetamidophenyl or ureidophenyl.
S Other preferred compounds are those of formulae ~''' and Ia''' and Ib''', which have formulae I and Ia and Ib, but wherein R2 is 3,4-dichlorophenyl, o- or p-nitrophenyl, o- or p-aminophenyl, o- or p-acetamidophenyl or o- or p-ureidophenyl.
Particularly preferred compounds of the formulae I, Ia, Ib, I~, Ia~, Ib', I~, Ia~ b'~, I''', Ia''' and Ib''' are those in which ~r is an unsubstitu~ed phenyl group.
Furthermore, preferred compounds amongst all those mentioned are those in which R1 is methyl.
The invention also relates to a process for pre-paring 1-(2-phenylethyl)-pyrrolidines of the formula I
according to Claim 1, and the salts thereof, charac-terised in that a compound of the formula II

Ar_CH_NRl -}~
C~2-N ~ II
~3 in which Ar, Rl and R3 have the meanings stated for formula I, is reacted with a compound of the formula III

in which R2 has the meaning stated for formula I, or with one of it functional derivatives, or in that a compound which otherwise correspond~ to the formula I but contains in place of one or more H atoms one or more groups which can be reduced or elLmi.nated by hydrogenolysis and~or C-C
and/or C-N bonds, is treated with a reducing agent, or in that, for the preparation of a compound of the _ 7 _ ~ ~
formula I which contains an amide group, a corresponding carboxylic acid or one of its esters is reac~ed with ammonia or with an amine of the formulae A NH2 or A2NH, and/or in that one or more of the radicals Ar and/or R2 in a compound of the formula I are converted into one or more other radicals Ar andJor R2, and/or in that a base of the formula I i~ converted by treatment with an acid into one of its salts.
The compounds of formula I are normally prepared by methods known per se, as described in the literature (e.g. in the standard works such as Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart), i.e. under reaction conditions which are known and suitable for said reactions. It is also possible to use variants which are known per se and are not mentioned in further detail here.
The starting materials are generally known or can be prepared analogously to known substances by processes ~0 known per se. If desired, they can also be formed in situ in a manner such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of formula I. On the other hand, the re-action can be carried out in steps, in which case it is pos ible to isolate other intermediates.
The individual proce~s variants are illustrated in further detail below.
The compounds of formula I can preferably be pre-pared by reacting the compounds of formula II with car-boxylic acids of formula III or their functional deriv-atives. Suitable functional derivatives of the compounds of formula III are especially the corre~ponding esters, in particular the methyl or ethyl esters, and the halides, anhydrides, azides or nitriles, the chlorides being preferred.
Compounds of the formula II can be obtained, for example, by reacting ~ alkanoylamino-phenylacetic acids (in which the alkanoyl group has 1-4 C atoms; e.g ~-formamido-phenylacetic acid) with 3-R3-pyrrolidines - 8 ~ 2 0 ~ g (3-hydroxypyrrolidine or 3-hydroxymethylpyrrolidine) to give the corresponding 3-R3-pyrrolidides and subsequent simultaneous reduction of the two amide groups with LiAlH4.
S Typical compounds of the formula II are, for example, 1-(2-methyl-/ 1-(2-ethyl~ (2-propyl-, 1-(2-isopropyl- or 1-(2-butylamino-2-phenyl-ethyl)-3-hydroxy-pyrrolidine, 1-(2-methyl-, 1-(2-ethyl-, 1-~2-propyl-, (1-(2-isopropyl- or (1-(2-butylamino-2-phenyl-ethyl)-3-hydroxymethyl-pyrrolidine.
Typical compounds of formula III are e.g. phenyl-acetyl chloride, bromide and azide, methyl and ethyl phenylacetate, phenylacetic anhydride, phenylacetonitrile and the corresponding derivatives of 3,4-dichlorophenyl-acetic acid (e.g. 3,~-dichlorophenylacetyl chloride3, of l-naphthylacetic acid (e.g. l-naphthylacetyl chloride), of 4-benzothienylacetic acid (e.g. 4-ben20thienylacetyl chloride) and o-, m- or p-nitrophenylacetic acid (e.g.
o-, m- or p-nitrophenylacetyl chloride).
Ths reaction of II with III or derivatives of III
is conveniently carried out in the presence or absence of an inert organic solvent, e.g. a halogenated hydrocarbon such as methylene chloride, chloroform or trichloro-ethene, an alcohol such as methanol, ethanol or butanol, an ether such as tetrahydrofuran (THF) or dioxane, an amide such a~ dimethylformamide (DMF~, or a sulfoxide such as dimethyl sulfoxidQ ~DMSO), and/or in the presence or absence of a condensation agent, e.g. a base, at temperatures in the range from -20 to 200, preferably from O to 100. Examples of suitable bases are alkali metal hydroxides such as NaOH or KOH, alkali metal car-bonateR such as Na2CO3 or K2CO3, and tertiary amines such as triethylamine or pyridine. Methylene chloride and triethylamine are especially preferred as the solvent and base respectively.
Suitable startLng materials for the preparation of compounds of formula I hy reducing corresponding com-pounds which instead of H atoms contain one or more additional reducible or hydrogenolytically cleavable 9 2~6~8 groups and/or C-C bonds and/or C-N bonds are, in particu-lar, compounds of formula IV

Ar CH-NRI-CG-CH2-R~
¦ IV
Rs-R6 in which S Ar~ is (a~ Ar, (b) a radical which otherwise corxesponds to Ar but which contains in place of the H atom of an OH group or of an NH2 group a radical which can be eliminated by hydrogenolysis, or in place of an NH2 group an NO2 group, R is (a) R , (b) an oxo-alkyl group with 1-4 C
atom~, R4 is (a) R , (b) a radical which otherwise corresponds to R but which contains in place of the H atom of an OH group or of an NH2 group a radical which can be eliminated by hydrogenolysis, Rs is ta) -CHz-, (b) -CO- and R6 is (a) 3-R3-pyrrolidino, (b) 3-oxo-pyrrolidino, 3-formyl-pyrrolidino or 2-, 4- or 5-oxo-3-R3-pyrrolidino;
but where IV must be different from I, i.e. the radicals Ar', Rl', R4, R5 and R6 cannot at the same time each have the meanings indicated under ta).
The radical R4 can preferably be o-, m- or p-benzyloxyphenylacetyl.
A suitable reducing agent is preferably hydrogen in the presence of a catalyst, especially a noble metal, nickel or cobalt catalyst. Typical noble metals are, in particular, platinum and palladium, which can be present on supports (e.g. on charcoal, calcium carbonate or - lo - 2~3~
strontium carbonate), as oxides (e.g. platin~m oxide) or in finely divided form. Nickel and cobalt catalysts are conveniently used as Raney metals. Hydrogenation is conveniently carried out at pressures in the range from about 1 to about 200 bar and at temperatures in the range from about -80 to +150, preferably from 20 to 100, in the presence of an inert solvent, e.g. an alcohol such as methanol, ethanol or isopropanol, a carboxylic acid such as acetic acid, an ester such as ethyl acetate~ or an ether such a~ THF or dioxane.
To prepare a compound of the formula I which contains an amide group, that is to say one (or more~ of the groups -CONH2, -CONHA or -CONA2, it is possi~le to react a corresponding carboxylic acid or a corresponding ester, preferably a lowex alkyl ester, which contains the group COOA in place of the a~ide group, with ammonia or an amine of the formulae AN~2 or A2NH. Carboxylic acids are preferably reacted in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyl-diimida~ole in an inert solvent such a8 DMF at 15-40.
If de~ired, one or more of the radicals Ar and/or R2, in a compound of formula I, can be exchanged for one or more different radical~ Ar and/or R2.
Thus it i~ pos~ible to cleave ether groups (e.g.
OA groups) to form OH group~, e.g. by ~reatment wi~h di-methyl sulfide/boron tribromide complex/ e.g. in toluene, THF or DMSO, or by fusion with pyridine or aniline hydrohalide~, preferably pyridine hydrochloride, at about 150-250, or by treatment with diisobutylaluminium hydride in toluene at about 0-110.
It is also possible to etherify OH groups, e.g.
by first preparing the corresponding alkali metal (e.g.
Na or R~ alcoholates, phenolates or salts and then reacting these with appropria~e halogen compounds, e.g.
with alkyl halides such as methyl chloride, bromide or iodide, chloroacetamide or bromoacetamide, conveniently in the presence of one of the solvents indicated above, at temperatures in the range from 0 to 100.
Nitro groups can be reduced to amino groups, 11- 2~ 8 preferably by catalytic hydrogenation under the above-mentioned conditions, e.g. with Raney Ni in methanol or ethanol at 15-40 and under atmospheric pressure.
Pmino groups can be acylated, e.g. w~th acid chlorides such as acetyl or methanesulfonyl chloride, or the hemiester chlorides of oxalic acid or succinic acid, preferably in inert sol~ents such as dichloromethane at 15-40. Formylation of amino groups is also possible by reaction with excess formic acid at 80-100 for several hours. Reaction of primary amino compounds with cyanates, e.g. with KCNO in water at 15-40, gives the corres-ponding ureido compounds; with alkyl isocyanates, e.g.
in inert solvents such as THF at 15-40, it results in N'-alkyl~ureido compounds correspondingly.
A baae of formula I can be converted into the corresponding acid addition salt with an acid. Acids which can be used for this reaction are those producing physiologically compatible salts. Thu it is possible to use inorganic acids, e.g. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, and sulfamic acid, or organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono-basic or polybasic c~rboxylic, sulfonic or sulfuric acid~, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic ~cid, ~imelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, ~enzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethane-sulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemonosulfonic and naphthalenedisulfonic acids and lauryl sulfuric acid.
Salts with physiologically incompatible acids, e.g. pic-rates, can be used to purify the compounds of formula I.
If desired, the free bases of formula I can be liberated from their salts by treatment with strong bases such as sodium or potassium hydroxide or sodium or - 12 - 20~S~
potassium carbonate.
The compounds of formula I contain at least two chiral centres and can therefore exist in racemlc or optlcally active form. Racemates obtained can be mechanically or chemically resolved into the enantiomers by methods known per se. Preferably, diastereoisomers are formed from the racemic mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acid~ such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid or lactic aci~, or the variou~ optically active camphor-sulfonic acids such as ~-camphorsulfonic acid.
It is al~o a~vantageous to resolve enantiomers lS with the help of a column packed with an optically active resolving agent (e.g. dinitrobenzoylphenylglycine); a suitable eluent is e.g. a mixture of hexane/isopropa-nol/acetonitrile, e.g. in a volume ratio of 82:15:3.
Naturally it is also possible tc obtain optically active compounds of formula I by the methods described above using staxting materials (e.g. those of formula II) which are already optically active.
The invention further relates to the use of the compounds of formula I and their physiologically com-patible salts for making pharmaceu~ical preparations, especially by a non-chemical method. This can be done by conver~ing them into a suitable dosage form, together with at least one solid, liquid and/or semiliquid carrier or ad~unct and, if nece~sary, in combination with one or more additional active ingrediants.
The invention fllrther relates to compositions, especially pharmaceutical preparations, comprising at least one compound of formula I and/or one of its physio-logically compatible salts.
These preparations can be used as drugs in human or veterina~y medicine. Possible carriers are organic or inorganic substances which are suitable for enteral (e.g.
oral), parenteral or topical administration and which do not react with the novel compounds, for example water, - 13 - ~0~ 8 vegetable oils, benzyl a1cohols, alkylene glycols, poly-ethylene glycols, glycerol triacetate, gelatin, carbo-hydrates such as lactose or starch, magnesium stearate, t~lc and petroleum jelly. Forms used for oral adminis-tration are, in particular, tablets, pills, coatedtablets, capsules, powders, granule~, syrups, juices or drops, forms used for rectal administration are supposi-tories, forms used for parenteral administration are solutions, preferably oily or aqueous solutions, as well as suspPnsions, emulsions or implants, and forms used for topical administration are ointments, creams or powders.
The novel compounds can also be lyophilized and ~he resulting lyophilisates used e.g. to make in~ectable pre-parations. The preparations indicated can be sterilized and/or can contain adjunc~s such as lubricants, preser-vatives, stabilizers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer sub-stances, colorants, ta~te improvers and/or flavourings.
If desired, they can also contain one or more additional active ingredients, e.g. one or more vitamins.
The compounds of formula I and their physio-logically compatible salts can be used for combating diseases, especially conditions of pain.
Here the substances of the invention are normally administered analogously to known analgesics, preferably in dosages of between about l and 500 mg, especially of between 5 and l00 mg, per dosage unit. The daily dosag~
i~ preferably between about 0.02 and l0 mg/kg of body weight. However, the particular dose for each individual patient depends on a very wide variety of factors, for example efficacy of the particular compound used, age, body weight, general state of health, sex, diet, time and route of administration, rate of excretion, drug com-bination and severity of the particular disease for which the therapy is intended. Oral administration is pre-ferred.
All temperatures in the present specification are given in C. In the following Examples, I'conventional working-up~ means: Water or dilute sodium hydroxide - 14 - 2 0 j ~ ~ ~ 8 solution is added, if necessary, the mixture i~ extracted with methylene chloride, the phases are separatQd, the organic phase is dried with sodium sulfate and filtered, the filtrate i~ evaporated and the re~idue is purified by chromatography on silica gel and/or by crystallization.
HCl' = hydroehlQride. Rf = Rf on thin-layer silica gel 60 F254 (E. Merck, Art. No. 5715), CHzCl2/C~3OH 9:1 witn the addition of 0.5% triethylamine.
~ ~ ] = [ ~ ~ 20, c = 1 in methanol.

Example 1 30 ml of triethylamine are added to a solution of 22 g of 1-(2-methylamino-2-phenyl-ethyl)-3-hydroxy-pyrrolidine [di-HCl', m.p.201; obtainable by reaction of ~-formamido-phenylacetic acid with 3-hydroxypyrrolidine to ~ive ~-formamido-phenylacetic acid 3-hydroxypyr-rolidide (oil) and reduction with LiAlH4] in 250 ml of dichloromethane. Subsequently a solution of 22.4 g of 3,4-dichlorophenylacetyl chloride in 200 ml of dichloro-methane is added dropwise while stirring, the mixture is then stirred at 20 for 2 h and conventional working-up results in 1-[2-(N-3 J 4-dichlorophenylacetyl-N-methyl-amino)-2 phenylethyl]-3-hydroxy-pyrrolidine.
Rf 0.37. HCl', m.p. 201.

Example 2 In analogy to Example 1, 1-(2-methylamino-2-phenylethyl~-3-hydroxymethyl-pyrrolidine[obtainableby reduction of ~-formamido-phenylacetic acid 3-hydroxy-methyl-pyrrolidide with LiAl~4~ and 3,4-dichlorophenyl-acetyl chloride result in 1-[2-~N-3,4-dichlorophenyl-acetyl-N-methyl-amino) 2-phenylethyl]-3-hydroxymethyl-pyrrolidine, Rf 0.36. HCl', m.p. 225.

Example 3 In analogy to Example 1, 1-[2-~N-methyl-N-p-nitrophenylacetyl-amino)-2-phenylethyl]-3-hydroxypyr-rolidine, Rf 0.34, is obtained with p-nitrophenylacetyl 2 ~

chloride.
~ --Formamido-phenylacetic acid 3-hydroxy-pyrro-lidide res~lts analogously ~via 1-(2-methy]amino-2-phenyl-e~hyl)-3R-hydroxy-pyrrolidine7 in 1-/2-N-methyl-N-p-nitro-phenylacetylamino)-2-phenyl-ethyl]-3R-hydroxy-pyrroli-dine, Rf 0.34; [~] -2.2. HCl', m.p. 235.
~ S-Formamido-phenylaceticacid3-hydroxy-pyrroli-dide results analogously/via 1-(2S-methylamino-2- phenyl-ethyl)-3-hydroxy-pyrrolidine/ in 1-[2S-(N-methyl-N-p-nitro-phenylacetylamino)-2-phenyl-ethyl~-3-hydroxy-pyrrolidine, Rf Q.34.
~ S-Formamido-phenylacetic acid 3S-hydroxy-pyrrolidide results analogously /via 1-(2S-methyl~ o-2-phenyl-ethyl)-3S-hydroxy-pyrrolidine/ in 1-/2S-(N-methyl-N-p-nitrophenylacetyl-amino)-2-phenyl-ethyl/-3S-hydroxy-pyrrolidine, Rf. 0.34.
The following are obtained analogou~ly with o- or m-nitrophenylacetyl chloride:
1-[2-(N methyl-N-o-nitrophenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-o-nitrophenylacetyl-amino)-2-phenyl-ethyl]-3R-hydroxy-pyrrolidine 1-[2-(N-methyl-N-o-nitrophenylacetyl-amino)-2-phenyl-ethyl]-3S-hydroxy-pyrrolidine 1-[2S-(N-methyl-N-o-nitrophenylacetyl-amino)-2-phenyl-ethyl~-3-hydroxy-pyrrolidine, Rf 0.64 1-[2-(N-methyl-N-m-nitrophenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-m-nitrophenylacetyl-amino)-2-phenyl-ethyl]-3R-hydroxy-pyrrolidine 1-[2-(N-methyl-N-m-nitrophenylacetyl-amino)-2-phenyl-ethyl]-3S-hydroxy-pyrrolidine 1-[2S-(N-methyl-N-m-nitrophenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine.

2~5~ ~8 - 15a -Example 4 Thefollowing are ohtained in analogy to E~ample 1 with o~, m- or p-methylphenylacetyl chloride:
1-[2-(N-o-methylphenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-m-methylphenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine l-[2-(N-p-methylphenylacetyl-N-methyl-aminoj-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
with o-, m- or p-fluorophenylacetyl chloride:
l-[2-(N-o-fluorophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy pyrrolidine 1-[2-(N-m-fluorophenylacetyl N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-p-fluorophenylacetyl~N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
with o-, m- or p-chlorophenylacetyl chloride:
l-~2-(N-o-chlorophenylacetyl-N~methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-m-chlorophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-p-chlorophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
with o-, m- or p-bromophenylacetyl chloride:
l-[2-(N-o-bromophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-m-bromophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-p-bromophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
with o-, m- or p trifluoromethyl-phenylacetyl chloride:

- 16 - 2~

1-[2-(N-methyl-N o-trifluorophenylacetyl-amino)-2-ph~nyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-m-trifluorophenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine l-[2-(N-methyl-N-p-trifluorophenylacetyl-amin~) 2-phenyl-ethyl~-3-hydroxy-pyrrolidine;
with o-, m- or p-methoxyphenylacetyl chloride:
1-[2-(N-o-methoxyphenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-m-methoxyphenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-~2-(N-p~methoxyphenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
with o-, m- or p-acetylphenylacetyl chloride:
l-[2-(N-o-acetylphenylacetyl N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-m-acetylphenylacetyl-~-methyl-amino~-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-t2-(N-p-acetylphanylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
with o-, m- or p-carbamoylphenylacetyl chloride:
1-[2-(N-o-carbamoylphenylacetyl-N-methyl~amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-m-carbamoylphenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-L2S-(N-m-carbamoylphenylacetyl-N-methyl-amino)-2-phenyl-ethyl7-3S-hydroxy-pyrrolidine, Rf 0.15 1-[2-(N-p-carbamoylphenylacetyl-N-methyl-~mino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-/2S-(N-p-carbamoylphenylacetyl-N-methyl-amino)-2-phenyl-ethyl7-3S-hydroxy-pyrrolidine, Rf 0.12;

2(~5~ll8 with o-, m- or p-(N-methylcarbamoyl)-phenylacetyl chloride:
l-[2-(N-methyl-N-o-(N~methylcarbamoyl)-phenylacetyl-amino)-2-phenyl-ethyl~-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-m-(N-methylcarbamoyl)-phenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy~pyrrolidine 1-~2-(N-methyl-N-p-(N-methylcarbamoyl)-phenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
with o-, m- or p-(N,N-dimethylcarbamoyl)-phenyl-acetyl chloride:
1-[2-(N-o-(N,N-dLmethylcarbamoyl)-phenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine l-[2-(N-p-~N,N-dimethylcarbamoyl)-phenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-m-(N,N-dimethylcarbamoyl)~phenylac~tyl-N-methyl-amino)-2-phenyl-ethyl~-3-hydroxy-pyrrolidine;
with o-, m- or p-carbamoylmethyl phenylacetyl chloride:
l-[2-(N-o-carbamoylmethyl-phenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-m-carbamoylmethyl-phenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-p-carbamoylmethyl-phenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-/ZS-(N-p-carbamoylmethyl-phenylacetyl-N-methyl-amino)-2-phenyl-ethyl7-3S-hydroxy-py~rolidine, Rf 0~18;
with o-, m- or p-carbamoylmethoxy-phenylacetyl chloride:
1-[2-(N-o-carbamoylmethoxy-phenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine l-[2-(N-m-carbamoylmethoxy-phenylacetyl-N-methyl-amino)-2-phenyl-ethyl3-3-hydroxy-pyrrolidine 1-[2-(N-p-carbamoylmethoxy-phenylacetyl-N-methyl-amino)-2 0 ~j 4 ~ ~ 8 2-phenyl-ethyl~-3-hydroxy-pyrrolid.ine;
with phenylacetyl chloride:
1-[2-(N~methyl-N-phenylacetyl-~mino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
with 1- or 2-naphthylacetyl chloride:
1-[2-(N-methyl-N~ naphthylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-C2-(N-methyl-N-(2-naphthylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
with 2- or 3-thienylacatyl chlorides 1-[2-(N-methyl-N-(2-thienylacetyl-amino)-2-phenyl-ethyl~-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-(3-thienylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
with 4-benzothienyl-acetyl chloride:
1-[2-(N-(4-benzothienylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
with 2-, 3- or 4-pyridylacetyl chloride:
1-[2-(N methyl-N-(2-pyridyl)-acetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine l-t2-(N~methyl-N-(3-pyridyl)-acetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-(4-pyridyl)-acetyl amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
with 5-nitro-2-thienyl-acetyl chloride:
1-[2-(N-methyl-N-(5-nitro-2-thienyl-acstyl)-amino~-2-phenyl-athyl3-3-hydroxy-pyrrolidine;
with 3-, 4-, 5- or 6-chloro-2-nitrophenylacetyl chloride:
1-[2-(N-3-chloro-2 nitrophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-t2-(N-4-chloro-2-nitrophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydro~y-pyrrolidine l-t2-(N-5-chloro-2-nitrophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-6-chloro-2-nitrophenylacetyl-N-methyl-amino)-2-phenyl-ethyl~-3-hydroxy-pyrrolidine;
with 2-, 4-, 5- or 6-chloro-3-nitrophenylacetyl chloride:

19 2~5~ t~
1-[2-(N-2-chloro-3-nitrophenylacetyl-N-methyl-amino)-2-phenyl-ethyl~-3-hydroxy~pyrrolidine 1 [2-(N-4-chloro-3-nitrophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]~3-hydroxy-pyrrolidine S 1-[2-(N-5-chloro-3-nitrophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidins 1-[2-(N-6-chloro-3-nitrophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydro~y-pyrrolidine;
with 2- or 3-chloro-4-nitrophenylacetyl chloride:
1-~2-(N-2-chloro-4 nitrophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-3-chloro-4-nitrophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
with 3-, 4-, 5- or 6-bromo-2-nitrophenylacetyl lS chloride:
1-[2-(N-3-bromo-2-nitrophenylacetyl-N-methyl-amino)~2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-4-bromo-2-nitrophenylacetyl-N~methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-5-bromo-2-nitrophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2 (N-6-bromo-2-nitrophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
with 2-, 4-, 5- sr 6-bromo-3-nitrophenylacetyl chloride:
1 [2-(N-2-bromo-3-nitrophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-4-bromo-3-nitrophenylacetyl-~-methyl-amino)-2-phenyl-ethyl~-3-hydroxy-pyrrolidine 1-[2-(N-5-bromo-3-nitrophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-6-bromo-3-nitrophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydro~y-pyrrolidine;
with 2- or 3-bromo-4-nitrophenylacetyl chloride:
1-[2-(N-2-bromo-4-nitrophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-3-bromo-4-nitrophenylacetyl-N methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine.

2 ~ ~7 f~

Example 5 6 g of 3-chloro-4-hydroxy-phenylacetohydrazide (obtainable from ethyl 3-chloro-4-hydrQxy-phenylacetate with hydrazine~ are dis~olved in 200 ml of water and 40 ml of 1 N hydrochloric acid and, while stirring at 0-3, a solution of 2.4 g of NaNO2 in 40 ml of water is added dropwise, and the mixture is then stirred for 30 min and the azide which has formed is extracted wi~h dichloromethane. ~fter the solution has been dried over MgSO4 and concentrated to 50 ml it is added dropwise with stirring to a ~olution of 6.6 g of 1~(2-methylamino-2-phenyl-ethyl)-3-hydroxy-pyrrolidine and 4.4 ml of tri-ethylamine in 100 ml of dichloromethane. The mixture i~
then stirred at 20 for 2 h and subjected to conventional working-up, resulting .in 1-[2-(N-3-chloro-4-hydroxy-phenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine.
~xample 6 A solution of 1 g of 1-[2-(N-p benzyloxyphenyl-acetyl-N-methyl-amino)-2~phenyl-ethyl]-3-hydroxy-pyr-rolidine [obtainable from 1-(2-methylamino-2-phenyl-ethyl)-3-hydroxypyrrolidine and p-benzyloxyphenylacetyl chloride] in 25 ml of ethyl acetate is hydrogenated on 0.5 g of 5% Pd-C at 20 and under 1 bar until the hydro-gen uptake ceases, ~hen the mixture is filtered and evaporated to result in 1-[2-(N-p-hydroxyphenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine.
The following are obtained analogously by hydro-genolysis of the corresponding o- or m-benzyloxyphenyl-acetyl derivatives:
1 - r 2-(N-o-hydroxyphenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-m-hydroxyphenylacetyl-N-methyl-amino~-2-phenyl-ethyl]-3-hydroxy-pyrrolidine.
The following are obtained analogously by hydro-genolysi~ of 1- r 2-(N-methyl-N-m-trifluoromethyl-phenyl-acetyl-amino) 2-o-~ -m- or -p-benzyloxyphenyl-ethyl]-3-hydroxy-pyrrolidine:
1-[2-(N-methyl-N-m-trifluoromethyl-phenylacetyl-amino)-- 21 - 20~648 2-o-hydroxyphenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl~N-m-trifluoromethyl-phenylacetyl-amino)-2-m-hyd~oxyphenyl-ethyl]-3-hydroxy-pyrrolidin~
1-[2-(N-methyl-N-m-trifluoromethyl-phenylacetyl-amino)-2-p-hydroxyphenyl-ethyl]-3-hydroxy-pyrrolidine.
Example 7 A ~olution of 10 g of 1-[2-(N-3-(benzyloxy-car-bonyl-amino)-4-pyridyl~acetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine [obtainable from 1-(2-methylamino-2-phenyl-ethyl)-3-hydroxy-pyrrolidine and 3-benzyloxycarbonylamino-4-pyridyl-acetyl chloride]
in 250 ml of methanol is hydrogenated on 0.5 g of 5% Pd-C
at 20 and under 1 bar until the hydrogen uptake ceases, and the mixture is filtered and evaporated to result in 1-[2-(N-(3-amino-4-pyridyl-acetyl~-N-methyl-amino)-2-phenylethyl]-3 hydroxy-pyrrolidine.
The following are obtained analogoucly by hydro-genolysis of the corresponding benzyloxycarbonyl deriva-tives:
1-[2-~N-(3-amino-4-methyl-2-pyridyl-acetyl~-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-(5-amino-4-methyl-2-pyridyl-acetyl)-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-m-trifluoromethylphenylacetyl-amino~-2-o-aminophenyl-ethyl]-3-~ydro~y-pyrrolidine 1-[2-(N-methyl-N-m-trifluoromethylphenylacetyl-amino)-2-m-aminophenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-m-trifluoromethylphenylacetyl-amino)-2-p-aminophenyl-ethyl~-3-hydroxy-pyrrolidine.
Example 8 A mixture of 3.82 g of 1-[2-(N-p-carboxyphenyl-acetyl-N-methyl-amino)-2-phenyl-ethyl~-3-hydroxy-pyrrolidine [obtainable by reaction of 1-(2-methylamino-2-phenylethyl)-3-hydroxy-pyrrolidine with 4-methoxy-carbonyl-phenylacetyl chloride to give 1-t2-(N-p-methoxy-carbonyl-phenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine and subsequent hydrolysis], 1.62 g of carbonyldiimidazole and 140 ml of DMF is stirred at 20 for 1 h. 15 ml of aqueous NH3 solution are added, and -- 22 ~ 4 8 the mi~ture i~ stirred Eor a further 12 h, evaporated and taken up in 1 N aqueous hydrochloric acid. It is wa~hed with ethyl ~cetate, sub~ected to conventional working-up with sodium hydroxide solution/ethyl acetate to result in 1-~2-(N-p-carbamoyl-phenylacetyl-N-methylamino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine; R~ O .12 .
Example 3 A solution of 10 g of 1-[2-(N-methyl-N-p-nitro-phenylacetylamino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine (Example 3) in 200 ml of methanol is hydrogenated at 20 and under atmospheric pressure on 5 g of Raney Ni until the calculated amount has been taken up. The mixture is filtered, and the filtrate is evaporated to result in 1-[2-(N-p-aminophenylacetyl-N-methyl-amino3-2-phenyl-ethyl]-3-hydroxy-pyrrolidine ("A"), Rf 0.31.
The following compounds are obtained analogou~ly by reduction of the corresponding nitro compound~:
1-[2-(N-p-aminophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3R-hydroxy-pyrrolidine, Rf 0.31; [~] -2.9;
di-HCl' monohydrate, m.p. 61 1-[2-(N-p-aminophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3S-hydroxy-pyrrolid.ine, Rf 0.31; [~] -2.9;
1-[2S-(N-p-aminophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3S-hydroxy-pyrrolidine, Rf 0.31; r ~ ] f 121.5;
di-HCl' dihydrate, m.p. 232 1-[2-(N-o-aminophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-o-aminophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3R-hydroxy-pyrrolidine 1-[2-(N-o-aminophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3S-hydroxy-pyrrolidine 1-[2S-(N-o-aminophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3S-hydroxy-pyrrolidine, Rf 0.36; [~] ~136.1;
di-HCl' dihydrate, m.p. 20S
1-[2-(N-m-aminophenylaoetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-m-aminophenylacetyl~N-methyl-amino)-2-phenyl-ethyl]-3R-hydroxy-pyrrolidine 1-[2-(N-m-aminophenylacetyl-N-methyl-amino)-2-phenyl-2 ~ 8 ~thyl]-3S-hydroxy-pyrrolidine 1-[2S-(N-m-aminophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrxolidine 1-[2-(N-5-amino-2-thienyl-acetyl-N-methyl-amino)-2-phenyl-ethyl]~3-hydroxy-pyrrolidine 1-[2-(N-2-amino-3-chlorophenylace~yl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine l-[2-(N-2-amino-4-chlorophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-2-amino-5-chlorophenylacetyl-N-methyl~amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-2-amino-6-chlorophenylacetyl-N-methyl-amino~-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-3-amino-2-chlorophenylacetyl-N-methyl-amino~-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-~N-3-amino-4-chlorophenylacetyl-N-methyl-amino)-2-phenyl-ethyl] 3-hydroxy-pyrrolidine 1-[2-(N-3-amino-5-chlorophenylacetyl-N-methyl-amino)~
2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-3-amino-6-chlorophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-~N-4-amino-2-chlorophenylacetyl-N-methyl-amino)-2-phenyl-ethyl~-3-hydroxy-pyrrolidine 1 ~2-(N-4-amino-3-chlorophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydxoxy-pyrrolidine 1-[2-(N-2-amino-3-bromophenylacetyl--N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-2-amino-4-bromophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy~pyrrolidine 1-[2-(N-2-amino-5-bromophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-2-amino-6-bromophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-3-amino-2-bromophenylacetyl-N methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-3-amino-4-bromophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1 [2-(N-3-amino-5-bromophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine - 24 - 20~4~
1-[2-(N~3-amino-6-bromophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-4-amino-2-bromophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-tN-4 amino-3-brcmophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydxoxy-pyrrolidine.
Example 10 3.53 g of "A' are dissolved in 175 ml of di-chloromethane and, while ~tirring, a solution of 0.8 g of acetyl chlorid~ in 10 ml of dichloromethane is added dropwise. The solution is stirred for 10 minutes and then concentrated,andtheresultingl-~2-(N-p-acetamidophenyl-acetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyr-rolidine i~ filtered off. Rf 0.19.
The following are obtained analogously by acyla-tion of the corre~ponding primary amino compound~:
1-[2 ~N-p-acetamidophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3R-hydroxy-pyrrolidine, Rf 0.19; [~] -2.4 HCl' dihydrate, m.p. 125 1-~2-(N-p-acetamidophenylacetyl-N-methyl-amino)-2~phenyl~
ethyl]-3S-hydroxy-pyrrolidine, Rf 0.19; [~] +2.4 1-[2S-~N-p-acetamidophenylacetyl-N-methyl-amino)~2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-/2S-(N-p-acetamidophenylacetyl-N-methyl-amino)-2-phenyl-ethyl/-3S-hydroxy-pyrrolidine, Rf 0,19 1-~2-~N-o-acetamidophenylaretyl-N-methyl-amino)-2-phenyl-ethyl~-3-hydroxy-pyrrolidine 1-[2-(N-o-acetamidophenylacetyl-N-methyl-amino)-2 phenyl-ethyl]-3R-hydroxy-pyrrolidine 1-[2-(N-o-acetamidophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3S-hydroxy-pyrrolidina 1-[2S-(N-o~acetamidophenylacetyl-N-methyl-amino~-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-/2S-(N-o-acetamidophenylacetyl-N-methyl-amino)-2-phenyl-ethyl/-3S-hydroxy- pyrrolidine, Rf 034 2~4~'~8 1-[2-(N-m-acetamidophenylacetyl-N~methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-~2-(N-m-acetamidophenylacetyl-N-methyl-amino)-2-phenyl-ethyl3-3R-hydroxy-pyrrolidine 1-[2-(N-m-acetamidophenylacetyl-N-methyl-amino)-2-phenyl~
ethyl]-3S-hydroxy-pyrrolidine 1-[2S-(N-m-acetamidophenylacetyl-N-methyl-amino)-2-phenyl-ethyl~-3-hydroxy-pyrrolidine l-[2-(N~5 acetamido-2-thienyl-acetyl-N-me~hyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-(3-acetamido-4-pyridylacetyl)-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-(3-acetamido-4-methyl-2-pyridylacetyl)-N-methyl-~mino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-(5-acetamido-4-methyl-2 pyridylacetyl~-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-m-trifluoromethylphenylacetyl-amino)-2-o-acetamidophenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-m-trifluoromethylphenylacetyl-amino)-2-m-acetamidophenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N m-trifluoromethylphenylacetyl-amino)-2-p-acetamidophenyl-ethyl]-3-hydroxy-pyrrolidine l-[2-(N-methyl-N-o-methyl~ulfonylamino-phenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-/2S-(N methyl-N-o-methylsulfonylamino-phenylacetyl-amino)-2-pherlyl-ethyl/-3S-hydroxy-pyrrolidine, Rf 0.51 l-[2-(N-methyl-N-m-methylsulfonylamino-phenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine l-[2-(N-methyl-N-p-methylsulfonylamino-phenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1~[2-(N-methyl-N-5-methylsulfonylamino-2-thienylacetyl-amino)-2-phenyl-ethyl]-3-hydro~y-pyrrolidine 1-[2-(N-methyl-N-~3-methylsulfGnylamino-4-pyridylacetyl)-amino)-2-phenyl-ethyl~-3-hydroxy-pyrrolidine 2~5~ ~8 1-[2-(N-methyl-N-(3-methylsulfonylaminv-4-methyl 2-pyri-dylacetyl)-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N~(5~me~hylsulfonylamino-~-methyl-2-pyri-dylacetyl)-amino)-2-phenyl-ethyl~-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N~m-trifluoromethylphenylacetyl-amino)-2-o-methylsulfonylaminophenyl-ethyl]-3~hydroxy-pyrrolidine 1-[2-(N-methyl-N-m-trifluoromethylphenylacetyl-amino)-2-m-methylsulfonylaminophenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-~N-methyl-N-m-trifluoromethylphenylacetyl-amino)-2-p-methylsulfonylaminophenyl-ethyl]-3-hydroxy-pyrrolidine.
Example 11 A mixture of 1 g of "A" and 10 ml of ~COOH is boiled for 2 h and then evaporated. Conventional ~orking-up results in 1-[2-(N-p-formamidophenylacetyl-N-methyl-amino)-2-phenylethyl~-3-hydroxy-pyrrolidine.
The following are obtained analogously by for-mylation of the corresponding primary amino compounds:
1-[2-(N-p formamidophenylacetyl~N-methyl-amino)-2-phenyl-thyl]-3R-hydroxy-pyrrolidine 1-[2-(N-p-formamidophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1w[2S-(N-p-formamidophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine l-t2-(N-o-formamidophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-~2-~N-o-formamidophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3R-hydroxy-pyrrolidine 1-[2-(N-o-fo.rmamidophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3S-hydroxy-pyrrolidine 1-[2S-(N-o-formamidophenylacetyl-N~methyl-amino)-2-phenyl-ethyl]-3S-hydroxy-pyrrolidine 1-[2-(N-m-formamidophenylacetyl-N-methyl-amino)-2-phenyl-ethyl~-3-hydroxy-pyrrolidine 1-[2-(N-m-formamidophenylacetyl-N-methyl-amino~-2-phenyl-ethyl]-3R-hydroxy-pyrrolidine 1-[2-(N-m-formamidophenylacetyl-N-methyl-amino~-2-phenyl-ethyl]-35-hydroxy-pyrrolidine 1-[2S-(N-m-formamidophenylacetyl-N-me~hyl-amino)-2-phenyl-ethyl]-3S-hydroxy-pyrrolidine -- 27 - 20~

1-[2-(N-5-formamido-2-phenylacetyl-N-methyl-amino)-2-phenyl-ethyl3-3-hydroxy-pyrrolidine 1-[2-(N-3--formamido-4-pyridylacetyl-N-methyl-amino)-2-phenyl-ethyl~-3-hydroxy-pyrrolidine 1-[2-(N-3-formamido-4-methyl-2-pyridylacetyl-N-amino)-2-phenyl-ethyl~-3-hydroxy-pyrrolidine 1-[2-(N-5-formamido~4-methyl-2-pyridylacetyl-N-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-~2-~N-methyl-N-m-trifluoromethylphenylacetyl-amino)-7.-o-formamidophenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-m-trifluoromethylphenylacetyl-amino)-2-m-formamidophenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-m-trifluoromethylphl3nylacetyl-amino)-2-p-formamidophenyl-ethyl]-3-hydroxy-pyrrolidinQ.
ExEmple 12 4.26 g of "A" dihydrochloride are dissolved in 50 ml of water, and 0.81 g of KCN0 is added. After the mixture has been stirred at 20 for 3 h it is concentra-ted to result in l-[2-(N-methyl-N-p-ureidophenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine, Rf 0.09.
The following are obtained analogously fxom the corresponding primary aminess 1-[2-(N-methyl-N-p-ureidophenylacetyl-amino)-2~phenyl-ethyl]-3R-hydroxy-pyrrolidine, Rf 0.09; ~] -2.7 HCl' trihydrate, m.p. 94 1-[2-(N-methyl-N-p-ureidophenylacetyl-amino)-2 phenyl-ethyl]-3S-hydroxy-pyrrolidine, Rf 0.09; [~] +2.7 1-[2S-(N-methyl-N-p-ureidophenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine, Rf 0. 09; [ r] +114.O~
1-[2-(N-methyl-N-o-ureidophenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-o-ureidophenylacetyl-amino)-2-phenyl-ethyl]-3R-hydroxy-pyrrolidine 1-[2-(N-methyl N-o-ureidophenylacetyl-amino)-2-phenyl-ethyl]-3S-hydroxy-pyrrolidine 1-[2S-(N-methyl-N-o-ureidophenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine, Rf 0.20; [~ +107.9 HCl' trihydrate, m.p. 151 20~64~
- 2~ -1-/2S-(N--methyl-N-o-ureidophenyl~ce-tyl-amino)-2-phenyl-ethylJ-3s-hydroxy-pyrrolidine, Rf 0.20 1-[2-(N-methyl-N-m-ureidophenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-m-ureidophenylacetyl-amino)-2-phenyl-ethyl]-3R-hydroxy pyrrolidine 1-[2-(N-methyl-N-m-ureidophenylacetyl-amino)-2-phenyl-ethyl]-3S-hydroxy-pyrrolidine 1-[2S-(N-methyl-N-p-ureidophenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-5-ureido-2-thienylacetyl-amino)-2-phenyl-ethyl3-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-3-ureido-4-pyridylace~yl-amino~-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-~2-(N-methyl-N-3-ureido-4-methyl-pyridylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-5-ureido-4-methyl-pyridylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-m-trifluoromethylphenylacetyl-amino)-2-o-ureidophenyl-ethyl~-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-m-trifluoromethylphenylacetyl amino)-2-m-ureidophenyl-ethyl]-3-hydroxy-pyrrolidine l-[2-(N-methyl-N-m-trifluoromethylphenylacetyl-amino)-2-p-ureidophenyl ethyl]-3-hydroxy-pyrrolidine.
Example 13 A mixture of 5.53 g of "A", 0.57 g of methyl isocyanate and 50 ml of THF is stirred at 20 for 30 min.
The mixture is evaporated and subjected to conventional working-up to result in 1-[2-(N-methy].-N-p-(N'-methyl-ureido)-phenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine.

2 ~ 8 - ~9 -The following are obtained analogously from the corresponding primary amines:
1-[2-(N-methyl-N-o-(N'-methyl-ureido)-phenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N m-(N'-methyl-ureido)-phenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-3-(N'-methylureido)-4-pyridylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine ! 1-[2-(N-methyl-N-3-(N'-methylureido~-4-methyl-2-pyridyl-acetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine 1-[2-(N-methyl-N-5-(N'-methylureido)-4 methyl-2-pyridyl-acetyl-amino)-2-phenyl ethyl]-3-hydroxy-pyrrolidine.
E~ample 14 a) Analogously to Exampl~ L~S-~N-(4-methoxy-3-nitro-phenylacetyl)-N-methyl-amino)-2-phenyl-ethyl/-3S-hydroxy-pyrrolidine (Rf 0.44) i~ obtained from 1-(2S-methylamino-2_ phenyl-ethyl)-3S-hydroxy-pyrro-lidine and 4-methoxy-3-nitro-phenylacetyl chloride.
b) By hydrogenation in analogy to Example 9, 1- ~S-(N
(3-a~ino-4-methoxy-phenylacetyl)-N-methyl-amino)-2-phenyl-ethyl/-3S-hydroxy-pyrrolidine ~R~ 0.31) is obtained from the compound prepared according to a).
The following Ex~mple~ relate to pharmaceutical preparations containing amines of formula I or their acid addition ~alt~:
Example A: Tablets A mixture of 0.]. kg o 1-[2S-~N-o~aminophenyl-acetyl-N-methylamino)-2-phenyl-ethyl~-3-hydroxy-pyr-rolidine dihydrochloride dihydrate, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of mag-nesium stearate is compressed to tablets in conventional manner such that each tablet contains 10 mg of active ingredient.

_ 30 - 20~48 Example B: Coated tablets Tablets are produced by compression analogously to Ex~mple A and are then covered in conventional manner with a coating of sucrose, potato starch, talc, traga-canth and colorant.
Example C: Capsule~
2 kg of 1-2S-(N-methyl-N-o-ureidophenylacetyl-amino)-2-phenylethyl]-3-hydroxy-pyrrolidine hydrochloride dihydrate are filled into hard gelatin capsules in conventional manner such that each capsule contains 20 mg of active ingredient.
Example D: ~mpoules A solution of 1-[2S-(N-p-aminophenylacetyl-N-methylamino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine dihydrochloxide dihydrate in 15 l of propane-1,2-diol and 15 l of double-distilled water is filtered under sterile conditions and filled into ampoules, and the ampoules are sealed under sterile conditions. Each ampoule contains 2 mg of active ingredient.
Tablets, coated tablets, capsules and ~mpoule~
which contain one or more of the other acti~e ingredients of formula I and/or their physiologically compatible salt~ can be obtained in analogous manner.

Claims (8)

1. 1-(2-Arylethyl)-pyrrolidines of the formula I

I

in which Ar is a phenyl group which is unsubstituted or mono-substituted by OH, -O-CO-NH2, -O-CO-NHA, -O-CO-NA2, NH2, -NH-CHO, -NH-CO-A, -NH-CO-NH2, -NH-CO-NHA or NH-SO2-A, R1 is A, R2 is a phenyl, naphthyl, thienyl, benzothienyl or pyridyl group which is unsubstituted or mono- or disubstituted by A, Hal, CF3, OH, OA, -O-CO-NH2, -O-CO-NHA, -O-CO-NAk, NO2, NH2, -NH-CHO, -NH-CO-A, -NH-CO-NH2, -NH-CO-NHA, -NH-SO2A, -CO-A, -CONH2, -CONHA, -CONA2, -CH2-CONH2 and/or -O-CH2-CONH2, R3 is OH or CH2OH, A is alkyl with 1-4 C atoms and Hal is F, Cl, Br or I, and the salts thereof.
2. a) 1-[2-(N-3,4-dichlorophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
b) 1-[2-(N-3,4-dichlorophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxymethyl-pyrrolidine;
c) 1-[2-(N-methyl-N-p-nitrophenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
d) 1-[2-(N-p-aminophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
e) 1-[2-(N-p-acetamidophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;

f) 1-[2-(N-methyl-N-p-ureidophenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
g) 1-[2-(N-o-aminophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
h) 1-[2-(N-methyl-N-o-ureidophenylacetyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine;
i) 1-[2-(N-m-aminophenylacetyl-N-methyl-amino)-2-phenyl-ethyl]-3-hydroxy-pyrrolidine and the salts thereof.
3. A proces for preparing 1-(2-phenylethyl)-pyr-rolidines of the formula I according to Claim 1, and the salts thereof, characterised in that a compound of the formula II

II

in which Ar, R1 and R3 have the meanings stated for formula I, is reacted with a compound of the formula III

in which R2 has the meaning stated for formula I, or with one of its functional derivatives, or in that a compound which otherwise corresponds to the formula I but contains in place of one or more H atoms one or more groups which can be reduced or eliminated by hydrogenolysis and/or C-C and/or C-N bonds, is treated with a reducing agent, or in that, for the preparation of a compound of the formula I which contain an amide group, a corresponding carboxylic acid or one of its esters is reacted with ammonia or with an amine of the formulae A-NH2 or A2NH, and/or in that one or more of the radicals Ar and/or R2 in a compound of the formula I are converted into one or more other radicals Ar and/or R2, and/or in that a base of the formula I is converted by treatment with an acid into one of its salts.
4. A process for making a pharmaceutical prepara-tion, characterised in that a compound of formula I
and/or one of its physiologically compatible salts is converted into a pharmaceutical dosage form, together with at least one solid, liquid or semiliquid carrier or adjunct.
5. A pharmaceutical preparation, characterised in that it contains at least one compound of formula I
and/or one of its physiologically compatible salts.
6. A compound of formula I and/or its physiologi-cally compatible salts for combating diseases.
7. Use of a compound of formula I and/or one of its physiologically compatible salts for the preparation of a drug.
8. Use of a compound of formula I and/or one of its physiologically compatible salts for combating diseases.
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US7960429B2 (en) 2007-03-30 2011-06-14 Tioga Pharmaceuticals, Inc Kappa-opiate agonists for the treatment of diarrhea-predominant irritable bowel syndrome
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