U.S. patent application number 14/659800 was filed with the patent office on 2015-07-09 for 4-(azacycloalkyl)benzene-1,3-diol compounds as tyrosinase inhibitors, process for the preparation thereof and use thereof in human medicine and in cosmetics.
The applicant listed for this patent is GALDERMA RESEARCH & DEVELOPMENT. Invention is credited to Jean-Guy BOITEAU, Karine BOUQUET, Corinne MILLOIS BARBUIS, Sandrine TALANO.
Application Number | 20150191451 14/659800 |
Document ID | / |
Family ID | 40852143 |
Filed Date | 2015-07-09 |
United States Patent
Application |
20150191451 |
Kind Code |
A1 |
BOITEAU; Jean-Guy ; et
al. |
July 9, 2015 |
4-(AZACYCLOALKYL)BENZENE-1,3-DIOL COMPOUNDS AS TYROSINASE
INHIBITORS, PROCESS FOR THE PREPARATION THEREOF AND USE THEREOF IN
HUMAN MEDICINE AND IN COSMETICS
Abstract
4-(Azacycloalkyl)benzene-1,3-diol compounds are described
corresponding to general formula (I) below: ##STR00001## Also
described, are compositions including the same, processes for
preparation thereof and uses thereof in pharmaceutical or cosmetic
compositions to treat pigmentary disorders.
Inventors: |
BOITEAU; Jean-Guy;
(Valbonne, FR) ; BOUQUET; Karine; (St Laurent Du
Var, FR) ; TALANO; Sandrine; (Vence, FR) ;
MILLOIS BARBUIS; Corinne; (Saint Raphael, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GALDERMA RESEARCH & DEVELOPMENT |
BIOT |
|
FR |
|
|
Family ID: |
40852143 |
Appl. No.: |
14/659800 |
Filed: |
March 17, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14469199 |
Aug 29, 2014 |
8993596 |
|
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14659800 |
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14200954 |
Mar 7, 2014 |
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14469199 |
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13611546 |
Sep 12, 2012 |
8697726 |
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14200954 |
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13131363 |
Sep 12, 2011 |
8299259 |
|
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PCT/EP2009/066268 |
Dec 2, 2009 |
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13611546 |
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Current U.S.
Class: |
514/210.17 ;
514/318; 514/330; 514/423 |
Current CPC
Class: |
C07D 205/04 20130101;
A61P 43/00 20180101; A61P 17/00 20180101; C07D 207/08 20130101;
A61P 17/02 20180101; C07D 401/12 20130101; C07D 211/22 20130101;
A61K 9/06 20130101; C07D 207/16 20130101; C07D 211/60 20130101;
A61P 37/08 20180101; C07D 211/26 20130101 |
International
Class: |
C07D 401/12 20060101
C07D401/12; C07D 211/26 20060101 C07D211/26; C07D 211/60 20060101
C07D211/60; C07D 211/22 20060101 C07D211/22; C07D 205/04 20060101
C07D205/04; C07D 207/16 20060101 C07D207/16 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 2, 2008 |
FR |
0858207 |
Claims
1. A pharmaceutical or cosmetic composition comprising a compound
of formula (I) below: ##STR00021## in which: R1 represents: a
C.sub.1-C.sub.5 alkyl radical, a C.sub.3-C.sub.6 cycloalkyl
radical, an aryl radical, a substituted aryl radical, an aralkyl
radical, a C.sub.1-C.sub.5 alkoxy radical, an amino radical
corresponding to structure (a): ##STR00022## in which R2
represents: a hydrogen, a C.sub.1-C.sub.5 alkyl radical, a
C.sub.3-C.sub.6 cycloalkyl radical, an aryl radical, a substituted
aryl radical, a pyridyl radical, an aralkyl radical, a radical
corresponding to structure (b): ##STR00023## in which p can have
the value 1 or 2, a radical corresponding to structure (c):
##STR00024## in which R4 represents: a carboxymethyl --COOCH.sub.3
or carboxyethyl --COOEt radical, a C.sub.1-C.sub.3 alkyl radical, a
hydrogen, and R5 represents: a substituted or unsubstituted aryl
radical, a C.sub.3-C.sub.6 cycloalkyl radical, a pyridyl, and R3
represents: a hydrogen, a C.sub.1-C.sub.5 alkyl radical; or R1 may
also represent a radical corresponding to formula (d): ##STR00025##
in which R6 represents: a hydrogen, a C.sub.1-C.sub.5 alkyl
radical, a C.sub.3-C.sub.6 cycloalkyl radical, an aryl radical, a
substituted aryl radical, a pyridyl radical, an aralkyl radical, R7
represents: a hydrogen, a C.sub.1-C.sub.5 alkyl radical, and R8
represents: a hydrogen, a hydroxyl, an amino radical, a
C.sub.1-C.sub.3 alkoxy radical; Y represents a hydrogen or a
fluorine, and m and n can have the value 0, 1 or 2, or a salt of a
compound of formula (I), or an enantiomer form thereof; and a
pharmaceutically acceptable or cosmetically acceptable carrier.
2.-23. (canceled)
Description
CROSS-REFERENCE TO EARLIER APPLICATIONS
[0001] This application is a continuation of copending U.S. patent
application Ser. No. 14/200,954, filed Mar. 7, 2014, which is a
continuation of U.S. patent application Ser. No. 13/611,546, filed
Sep. 12, 2012, now U.S. Pat. No. 8,697,726, which is a continuation
of U.S. patent application Ser. No. 13/131,363, filed Sep. 12,
2011, now U.S. Pat. No. 8,299,259, which is a National Stage of
PCT/EP2009/066268, filed Dec. 2, 2009, and designating the United
States (published in the English language on Jun. 10, 2010 as WO
2010/063774 A1; the title and abstract were also published in
English), which claims benefit of U.S. Provisional Patent
Application No. 61/193,460, filed Dec. 2, 2008 and also claims
priority under 35 U.S.C. .sctn.119 to French Patent Application No.
0858207, filed Dec. 2, 2008, each of the earlier applications being
hereby expressly incorporated by reference in their entirety and
each assigned to the assignee hereof.
[0002] The invention relates to novel
4-(azacycloalkyl)benzene-1,3-diol compounds as industrial and
useful products. It also relates to the process for the preparation
thereof and to the use thereof, as tyrosinase inhibitors, in
pharmaceutical or cosmetic compositions for use in the treatment or
prevention of pigmentary disorders.
[0003] Skin pigmentation, in particular human skin pigmentation, is
the result of melanin synthesis by dendritic cells, melanocytes.
Melanocytes contain organelles called melanosomes which transfer
melanin into the upper layers of keratinocytes which are then
transported to the surface of the skin through differentiation of
the epidermis (Gilchrest B A, Park H Y, Eller M S, Yaar M,
Mechanisms of ultraviolet light-induced pigmentation. Photochem
Photobiol 1996; 63: 1-10; Hearing V J, Tsukamoto K, Enzymatic
control of pigmentation in mammals. FASEB J 1991; 5:
2902-2909).
[0004] Among the enzymes of melanogenesis, tyrosinase is a key
enzyme which catalyses the first two steps of melanin synthesis.
Homozygous mutations of tyrosinase cause oculocutaneous albinism
type I characterized by a complete lack of melanin synthesis
(Toyofuku K, Wada I, Spritz R A, Hearing V J, The molecular basis
of oculocutaneous albinism type 1 (OCA1): sorting failure and
degradation of mutant tyrosinases results in a lack of
pigmentation. Biochem J 2001; 355: 259-269).
[0005] In order to treat pigmentation disorders resulting from an
increase in melanin production, for which there is no treatment
that meets all the expectations of patients and dermatologists, it
is important to develop new therapeutic approaches.
[0006] Most of the skin-lightening compounds that are already known
are phenols or hydroquinone derivatives. These compounds inhibit
tyrosinase, but the majority of them are cytotoxic to melanocytes
owing to the formation of quinones. There is a risk of this toxic
effect causing a permanent depigmentation of the skin. The
obtaining of compounds that can inhibit melanogenesis while at the
same time being very weakly cytotoxic or devoid of toxicity to
melanocytes is most particularly sought.
[0007] Among the compounds already described in the literature,
patent application WO 99/15148 discloses the use of 4-cycloalkyl
resorcinols as depigmenting agents.
[0008] Patent FR2704428 discloses the use of 4-haloresorcinols as
depigmenting agents.
[0009] Patent applications WO 2006/097224 and WO 2006/097223
disclose the use of 4-cycloalkylmethyl resorcinols as depigmenting
agents.
[0010] Patent application WO 2005/085169 discloses the use of alkyl
3-(2,4-dihydroxyphenyl)propionate as a depigmenting agent.
[0011] Patent application WO 2004/017936 discloses the use of
3-(2,4-dihydroxyphenyl)acrylamide as a depigmenting agent.
[0012] Patent application WO 2004/052330 discloses the use of
4-[1,3]dithian-2-ylresorcinols as depigmenting agents.
[0013] More particularly, patent EP0341664 discloses the use of
4-alkyl resorcinols as depigmenting agents, among which 4-n-butyl
resorcinol, also known as rucinol, is part of the composition of a
depigmenting cream sold under the name Iklen.RTM..
[0014] The applicant has now discovered, unexpectedly and
surprisingly, that novel compounds of
4-(azacycloalkyl)benzene-1,3-diol structure have a very good
tyrosinase enzyme-inhibiting activity and a very low cytotoxicity.
Furthermore, these compounds have a tyrosinase enzyme-inhibiting
activity that is greater than that of rucinol while at the same
time being less cytotoxic with respect to melanocytes than
rucinol.
[0015] These compounds find uses in human medicine, in particular
in dermatology, and in the cosmetics field.
[0016] Thus, the present invention relates to the compounds of
general formula (I) below:
##STR00002##
in which: R1 represents:
[0017] a C.sub.1-C.sub.5 alkyl radical,
[0018] a C.sub.3-C.sub.6 cycloalkyl radical,
[0019] an aryl radical,
[0020] a substituted aryl radical,
[0021] an aralkyl radical,
[0022] a C.sub.1-C.sub.5 alkoxy radical,
[0023] an amino radical corresponding to structure (a):
##STR00003##
[0024] in which R2 represents: [0025] a hydrogen, [0026] a
C.sub.1-C.sub.5 alkyl radical, [0027] a C.sub.3-C.sub.6 cycloalkyl
radical, [0028] an aryl radical, [0029] a substituted aryl radical,
[0030] a pyridyl radical. [0031] an aralkyl radical, [0032] a
radical corresponding to structure (b):
##STR00004##
[0033] in which p can have the value 1 or 2, [0034] a radical
corresponding to structure (c):
##STR00005##
[0035] in which R4 represents: [0036] a carboxymethyl --COOCH.sub.3
or carboxyethyl --COOEt radical, [0037] a C.sub.1-C.sub.3 alkyl
radical, [0038] a hydrogen,
[0039] and R5 represents: [0040] a substituted or unsubstituted
aryl radical, [0041] a C.sub.3-C.sub.6 cycloalkyl radical, [0042] a
pyridyl,
[0043] and R3 represents: [0044] a hydrogen, [0045] a
C.sub.1-C.sub.5 alkyl radical;
[0046] R1 may also represent a radical corresponding to formula
(d):
##STR00006##
[0047] in which R6 represents: [0048] a hydrogen, [0049] a
C.sub.1-C.sub.5 alkyl radical, [0050] a C.sub.3-C.sub.6 cycloalkyl
radical, [0051] an aryl radical, [0052] a substituted aryl radical.
[0053] a pyridyl radical. [0054] an aralkyl radical,
[0055] R7 represents: [0056] a hydrogen, [0057] a C.sub.1-C.sub.5
alkyl radical,
[0058] and R8 represents: [0059] a hydrogen, [0060] a hydroxyl,
[0061] an amino radical, [0062] a C.sub.1-C.sub.3 alkoxy radical: Y
represents a hydrogen or a fluorine, and m and n can have the value
0, 1 or 2, and also the salts of the compounds of formula (I), and
the isomer and enantiomer forms thereof.
[0063] Among the salts of the compounds of general formula (I) with
a pharmaceutically acceptable base, mention may preferably be made
of the salts with an organic base or with an inorganic base.
[0064] The suitable inorganic bases are, for example, potassium
hydroxide, sodium hydroxide or calcium hydroxide.
[0065] The suitable organic bases are, for example, morpholine,
piperazine or lysine.
[0066] The compounds of general formula (I) may also exist in the
form of hydrates or of solvates.
[0067] The solvents that are suitable for forming solvates are, for
example, alcohols such as ethanol or isopropanol.
[0068] According to the present invention, the term
"C.sub.1-C.sub.5 alkyl" denotes a linear or branched, saturated
hydrocarbon-based chain containing from 1 to 5 carbon atoms.
[0069] According to the present invention, the term
"C.sub.1-C.sub.3 alkyl" denotes a linear or branched, saturated
hydrocarbon-based chain containing from 1 to 3 carbon atoms.
[0070] According to the present invention, the term
"C.sub.3-C.sub.6 cycloalkyl" denotes a cyclic, saturated
hydrocarbon-based chain containing from 3 to 6 carbon atoms.
[0071] According to the present invention, the term "aryl" denotes
a phenyl or a naphthyl.
[0072] According to the present invention, the term "substituted
aryl" denotes a phenyl or a naphthyl substituted with one or more
groups of atoms chosen from an alkyl, an alkoxy, a fluorine and a
trifluoromethyl.
[0073] According to the present invention, the term "aralkyl"
denotes a C.sub.1-C.sub.5 alkyl radical as defined above and
substituted with a substituted or unsubstituted aryl radical.
[0074] According to the present invention, the term
"C.sub.1-C.sub.5 alkoxy" denotes an oxygen atom substituted with a
linear or branched, saturated hydrocarbon-based chain containing
from 1 to 5 carbon atoms.
[0075] According to the present invention, the term
"C.sub.1-C.sub.3 alkoxy" denotes an oxygen atom substituted with a
linear or branched, saturated hydrocarbon-based chain containing
from 1 to 3 carbon atoms.
[0076] According to the present invention, the compounds of general
formula (I) that are particularly preferred are those for
which:
[0077] R1 represents an aralkyl radical or an amino radical
corresponding to structure (a):
##STR00007##
[0078] in which R2 represents: [0079] a C.sub.1-C.sub.5 alkyl
radical, [0080] an aralkyl radical or [0081] a radical
corresponding to structure (d):
##STR00008##
[0082] in which R4 represents: [0083] a carboxymethyl --COOCH.sub.3
or carboxyethyl --COOEt radical, [0084] a C.sub.1-C.sub.3 alkyl
radical,
[0085] and R5 represents: [0086] a substituted or unsubstituted
aryl radical,
[0087] and R3 represents a hydrogen,
[0088] Y represents a hydrogen atom or a fluorine,
[0089] m=1 and n=1,
and also the salts of these compounds of general formula (I), and
the isomer and enantiomer forms thereof.
[0090] Among the compounds of formula (I) which are part of the
context of the present invention, mention may in particular be made
of the following: [0091] 1:
3-(2,4-dihydroxyphenyl)azetidine-1-carboxylic acid tert-butyl ester
[0092] 2: [3-(2,4-dihydroxyphenyl)azetidin-1-yl]phenylmethanone
[0093] 3: 3-(2,4-dihydroxyphenyl)azetidine-1-carboxylic acid
pentylamide [0094] 4:
3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl
ester [0095] 5: 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic
acid isobutyl ester [0096] 6:
3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid
cyclohexylamide [0097] 7:
3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid phenylamide
[0098] 8: 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid
(4-fluorophenyl)amide [0099] 9:
3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid
(4-trifluoromethylphenyl)amide [0100] 10:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid ethyl ester
[0101] 11: [4-(2,4-dihydroxyphenyl)piperidin-1-yl]phenylmethanone
[0102] 12: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
butylamide [0103] 13:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid propylamide
[0104] 14: 1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]butan-1-one
[0105] 15:
1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-methylpropan-1-one
[0106] 16: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
phenylamide [0107] 17:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(4-fluorophenyl)amide [0108] 18:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid p-tolylamide
[0109] 19: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
phenethylamide [0110] 20:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(3-fluorophenyl)amide [0111] 21:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
((R)-1-phenylethyl)amide [0112] 22:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
methylphenylamide [0113] 23:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
pyridin-2-ylamide [0114] 24:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-phenylethyl)amide [0115] 25:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-phenylpropyl)amide [0116] 26:
(R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-on-
e [0117] 27:
1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-one
[0118] 28: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
2-fluorobenzylamide [0119] 29:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
3-fluorobenzylamide [0120] 30:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
4-fluorobenzylamide [0121] 31:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid benzylamide
[0122] 32: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
2-methylbenzylamide [0123] 33:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
3-methylbenzylamide [0124] 34:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
4-methylbenzylamide [0125] 35:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
2-methoxybenzylamide [0126] 36:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
3-methoxybenzylamide [0127] 37:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
4-methoxybenzylamide [0128] 38:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-p-tolylethyl)amide [0129] 39:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
[(S)-1-(4-fluorophenyl)ethyl]amide [0130] 40:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(S)-indan-1-ylamide [0131] 41:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-naphthalen-1-ylethyl)amide [0132] 42:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-naphthalen-2-ylethyl)amide [0133] 43:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
[(S)-1-(4-methoxyphenyl)ethyl]amide [0134] 44:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
[(S)-1-(3-methoxyphenyl)ethyl]amide [0135] 45:
(S)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-on-
e [0136] 46:
4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-phenylethyl)amide [0137] 47:
(R)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylethanone
[0138] 48:
(S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylethanone
[0139] 49:
(R)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-3-phenylpropan-1--
one [0140] 50:
(S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-3-phenylpropan-1--
one [0141] 51:
(R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-(4-fluorophenyl)e-
thanone [0142] 52:
(R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-phenylethanone
[0143] 53:
(S)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-phenylethanone
[0144] 54:
(R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-(4-trifluoromethy-
lphenyl)ethanone [0145] 55:
2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-phenylbutan-1-one
[0146] 56:
(S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-methoxy-2-phenylethanone
[0147] 57: 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-cyclohexylethyl)amide [0148] 58:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(1,2,3,4-tetrahydronaphthalen-1-yl)amide [0149] 59:
(R)-{[4-(2,4-dihydroxyphenyl)piperidine-1-carbonyl]amino}phenylacetic
acid methyl ester [0150] 60:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(pyridin-3-ylmethyl)amide [0151] 61:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(pyridin-4-ylmethyl)amide [0152] 62:
4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
benzylamide [0153] 63:
4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
butylamide [0154] 64:
4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(3-fluorophenyl)amide [0155] 65:
4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
phenethylamide [0156] 66:
(R)-{[4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carbonyl]amino}phenyla-
cetic acid methyl ester [0157] 67:
4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(S)-indan-1-ylamide [0158] 68:
4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
[(S)-1-(4-methoxyphenyl)ethyl]amide [0159] 69:
4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-cyclohexylethyl)amide [0160] 70:
(R)-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenyl-
ethanone [0161] 71:
(S)-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenyl-
ethanone [0162] 72:
(R)-2-amino-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidin-1-yl]-2-phenylet-
hanone [0163] 73:
(S)-2-amino-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidin-1-yl]-2-phenylet-
hanone [0164] 74:
(R)-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenyl-
propan-1-one [0165] 75:
(S)-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenyl-
propan-1-one [0166] 76:
(R)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylpropan-1--
one [0167] 77:
(S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylpropan-1--
one [0168] 78:
(R)-{[4-(2,4-dihydroxyphenyl)piperidine-1-carbonyl]amino}-(4-fluorophenyl-
)acetic acid methyl ester [0169] 79:
(S)-{[4-(2,4-dihydroxyphenyl)piperidine-1-carbonyl]amino}-(4-fluorophenyl-
)acetic acid methyl ester [0170] 80:
(R)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-methyl-3-phenyl-
propan-1-one [0171] 81:
(S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-methyl-3-phenyl-
propan-1-one [0172] 82:
4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(pyridin-3-ylmethyl)amide [0173] 83:
4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(pyridin-4-ylmethyl)amide [0174] 84:
(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
((R)-1-phenylethyl)amide [0175] 85:
(R)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylbutan-1-o-
ne [0176] 86:
(S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylbutan-1-o-
ne [0177] 87:
(S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-(4-fluorophenyl)-2-hydrox-
yethanone [0178] 88:
(R)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-(4-fluorophenyl)-2-hydrox-
yethanone [0179] 89:
(S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-(3-methoxypheny-
l)ethanone [0180] 90:
(R)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-(3-methoxypheny-
l)ethanone. [0181] 91:
4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
cyclohexylmethylamide [0182] 92:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
cyclohexylmethylamide [0183] 93:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(2-ethylbutyl)amide [0184] 94:
4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(2-ethylbutyl)amide [0185] 95:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
cyclopentylmethylamide [0186] 96:
4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
cyclopentylmethylamide [0187] 97:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(6-methylpyridin-3-ylmethyl)amide [0188] 98:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(4-methylpyridin-3-ylmethyl)amide [0189] 99:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(5-methylpyridin-3-ylmethyl)amide [0190] 100:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(2-methylpyridin-3-ylmethyl)amide [0191] 101:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(2,6-dimethylpyridin-4-ylmethyl)amide [0192] 102:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(2-pyridin-2-ylethyl)amide [0193] 103:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(2-pyridin-3-ylethyl)amide [0194] 104:
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(2-pyridin-4-ylethyl)amide
[0195] The compounds of general formula (I) are prepared according
to the general reaction scheme shown in FIG. 1.
[0196] The compounds 2,4-bis(benzyloxy)bromobenzene (X=Br; Y=H) or
1,5-bis(benzyloxy)-2-fluoro-4-iodobenzene (X=I; Y=F) (1), which are
commercially available or prepared according to conventional
synthesis methods (W. D. Langley, Org. Synth. I, 122 (1932)) (in
the case of the fluoro compounds, Mottram, L. F.;
Boonyarattanakalin, S.; Kovel, R. E.; Peterson, B. R. Organic
Letters 2006, 8(4), 581-584) react in the presence of butyllithium,
for example, with azacycloalkanones (2) which are commercially
available or prepared according to conventional synthesis methods
(W. D. Langley, Org. Synth. I, 122 (1932)) so as to give the
corresponding benzyl alcohols of general formula (3) in which Y=H
or F and Z=ethyl or tert-butyl (Annoura, H.; Nakanishi, K.; Uesugi,
M.; Fukunaga, A.; Imajo, S.; Miyajima, A.; Tamura-Horikawa, Y.;
Tamura, S.; Bioorg Med Chem 2002. 10 (2), 371-383).
##STR00009##
[0197] The compounds of general formula (4) are obtained by
hydrogenation of the benzyl alcohols of general formula (3) in the
presence of hydrogen and of a palladium-based catalyst such as
palladium-on-charcoal, for example, in a solvent such as methanol
(Merschaert, A.; Delhaye, L.; Kestemont, J.-P.; Brione, W.;
Delbeke, P.; Mancuso, V.; Napora, F.; Diker, K.; Giraud, D.;
Vanmarsenille, M.; Tetrahedron Lett 2003, 44 (24). 4531-4534).
##STR00010##
[0198] The compounds of general formula (4) may be benzylated using
benzyl bromide and a base such as potassium carbonate, for example,
in a solvent such as methyl ethyl ketone, for example, in order to
give the compounds of general formula (5) (Bolek, D.; Guetschow,
M.; J Heterocycl Chem 2005, 42 (7), 1399-1403).
##STR00011##
[0199] The compounds of general formula (5) are converted to amines
of general formula (6) through the action of trifluoroacetic acid,
for example, if Z=tert-butyl (Kasyan, A.; Wagner, C.; Maier, M. E.;
Tetrahedron 1998, 54 (28), 8047-8054) or else through the action of
an aqueous solution of potassium hydroxide, for example, if Z=ethyl
(Morice, C.; Domostoj, M.; Briner, K.; Mann, A.; Suffert, J.;
Wermuth, C.-G.; Tetrahedron Lett 2001, 42 (37), 6499-6502).
##STR00012##
[0200] The compounds of general formula (6) are subsequently
converted to compounds of general formula (7).
##STR00013##
[0201] The compounds of general formula (7) may: [0202] either be
ureas: they are obtained by reacting the compounds of general
formula (6) with isocyanates, for example (Ranise, A.; Schenone,
S.; Bruno, O.; Bondavalli, F.; Filippelli, W.; Falcone, G.;
Rivaldi, B.; Farmaco 2001, 56 (9), 647-657); [0203] or be amides;
they are obtained by reacting the compounds of general formula (6)
with acyl chlorides, for example (Katritzky, A. R.; Singh, S. K.;
Cai, C.; Bobrov, S.; J Org Chem 2006, 71 (9), 3364-3374) or with
acids (De Laszlo, S. E.; Allen. E. E.; Li, B.; Ondeyka. D.; Rivero,
R.; Malkowitz, L.; Molineaux, C.; Siciliano, S. J.; Springer, M.
S.; Greenlee, W. J.; Mantlo, N.; Bioorg Med Chem Lett 1997, 7 (2),
213-218); [0204] or be carbamates: they are obtained by reacting
the compounds of general formula (6) with chloroformates, for
example (Brackeen, M. F.; Cowan, D. J.; Stafford, J. A.; Schoenen,
F. J.; Veal, J. M.; Domanico, P. L.; Rose, D.; Strickland, A. B.;
Verghese, M.; Feldman, P. L.; J Med Chem 1995, 38 (24),
4848-4854).
[0205] The compounds of general formula (I) are, finally, obtained
by hydrogenation of the compounds of general formula (7) in the
presence of hydrogen and of a palladium-based catalyst such as
palladium-on-charcoal, for example, in a solvent such as methanol,
for example.
##STR00014##
[0206] The invention is therefore directed towards the use of at
least one compound of general formula (I) as defined above, as a
medicament.
[0207] The invention is also directed towards the use, as a
medicament, of at least one compound of general formula (I) as
defined above, in which said compound has a tyrosinase-inhibiting
activity.
[0208] The invention is also directed towards the use of at least
one compound of general formula (I) as defined above, for the
preparation of a pharmaceutical or cosmetic composition in which
said compound has a tyrosinase-inhibiting activity.
[0209] Advantageously, the compounds of the present invention have
an IC.sub.50 value (dose which inhibits 50% of the enzymatic
activity) with respect to tyrosinase of less than or equal to 10
.mu.M, and more particularly less than or equal to 1 .mu.M.
[0210] The invention also relates to a compound of general formula
(I) for use thereof in the treatment and/or prevention of
pigmentary disorders.
[0211] In fact, the compounds of general formula (I) according to
the invention are particularly suitable for use related to the
treatment or prevention of pigmentary disorders such as melasma,
chloasma, lentigines, senile lentigo, irregular hyperpigmentations
related to photoageing, freckles, post-inflammatory
hyperpigmentations due to an abrasion, a burn, a scar, dermatosis,
a contact allergy; naevi, genetically determined
hyperpigmentations, hyperpigmentations of metabolic or drug-related
origin, melanomas or any other hyperpigmentary lesion.
[0212] A subject of the present invention is also a pharmaceutical
composition for use in particular in the treatment of the
abovementioned conditions, and which is characterized in that it
comprises, in a pharmaceutically acceptable carrier that is
compatible with the method of administration selected for said
composition, a compound of general formula (I) in one of its isomer
and enantiomer forms, or a salt thereof with a pharmaceutically
acceptable base.
[0213] The term "pharmaceutically acceptable carrier" is intended
to mean a medium that is compatible with the skin, the mucous
membranes and the skin appendages.
[0214] The composition according to the invention can be
administered topically. Preferably, the pharmaceutical composition
is packaged in a form suitable for topical application.
[0215] When used topically, the pharmaceutical composition
according to the invention is more particularly for use in the
treatment of the skin and the mucous membranes and may be in
liquid, pasty or solid form, and more particularly in the form of
ointments, creams, solutions or gels.
[0216] The compositions used for topical application have a
concentration of compound according to the invention of generally
between 0.001% and 10% by weight, preferably between 0.01% and 5%
by weight, relative to the total weight of the composition.
[0217] The compounds of general formula (I) according to the
invention also find a use in the cosmetics field, in particular in
protecting against the harmful aspects of the sun, for preventing
and/or combating photoinduced or chronological ageing of the skin
and skin appendages.
[0218] A subject of the invention is therefore also a composition
comprising, in a cosmetically acceptable carrier, at least one of
the compounds of general formula (I). The term "cosmetically
acceptable medium" is intended to mean a medium that is compatible
with the skin, the mucous membranes and the skin appendages.
[0219] A subject of the invention is also the cosmetic use of a
composition comprising at least one compound of general formula
(I), for preventing and/or treating the signs of ageing and/or the
skin.
[0220] A subject of the invention is also the cosmetic use of a
composition comprising at least one compound of general formula
(I), for body or hair hygiene.
[0221] The cosmetic composition according to the invention
containing, in a cosmetically acceptable carrier, a compound of
general formula (I), or one of its isomer and enantiomer forms or a
salt thereof with a cosmetically acceptable base, may be in
particular in the form of a cream, a milk, a gel, suspensions of
microspheres or nanospheres or lipid or polymeric vesicles,
impregnated pads, solutions, sprays, foams, sticks, soaps, washing
bases or shampoos.
[0222] The concentration of compound of general formula (I) in the
cosmetic composition is preferably between 0.001% and 10% by
weight, relative to the total weight of the composition.
[0223] The pharmaceutical and cosmetic compositions as described
above may also contain inert additives, or even pharmacodynamically
active additives as regards the pharmaceutical compositions, or
combinations of these additives, and in particular:
[0224] wetting agents;
[0225] flavour enhancers;
[0226] preservatives, such as para-hydroxybenzoic acid esters;
[0227] stabilizers;
[0228] moisture regulators;
[0229] pH regulators;
[0230] osmotic pressure modifiers;
[0231] emulsifiers;
[0232] UV-A and UV-B screening agents;
[0233] antioxidants, such as .alpha.-tocopherol, butylated
hydroxyanisole or butylated hydroxytoluene, superoxide dismutase,
ubiquinol; sodium metabisulphite;
[0234] emollients;
[0235] moisturizing agents, such as glycerol. PEG 400,
thiamorpholinone and its derivatives, or urea;
[0236] antiseborrhoeic or antiacne agents, such as
S-carboxymethylcysteine, S-benzylcysteamine, salts thereof or
derivatives thereof, or benzoyl peroxide.
[0237] Of course, those skilled in the art will take care to select
the optional compound(s) to be added to these compositions in such
a way that the advantageous properties intrinsically associated
with the present invention are not, or not substantially, impaired
by the envisaged addition.
[0238] Several examples of the preparation of compounds of general
formula (I) according to the invention, results for biological
activity of these compounds and also various formulations based on
such compounds will now be given by way of illustration and without
any limiting nature.
EXAMPLE 1
3-(2,4-Dihydroxyphenyl)azetidine-1-carboxylic acid tort-butyl
ester
a) 2,4-Bis(benzyloxy)-1-bromobenzene
[0239] 106.6 g (0.771 mol, 3 eq) of potassium carbonate (325 mesh)
are added to a solution of 50.1 g (0.257 mol, 1 eq) of
4-bromoresorcinol at 97% in 500 ml of acetone. The reaction medium
is cooled to 5-10.degree. C. and 75 ml (0.630 mol, 2.45 eq) of
benzyl bromide are added dropwise. The reaction medium is stirred
at ambient temperature overnight and is then heated at 50.degree.
C. for 2 hours. The solvent is evaporated off and the residue is
then taken up with a water/ethyl acetate mixture. The aqueous phase
is extracted with ethyl acetate, and the organic phases are
combined, washed with a saturated solution of sodium chloride,
dried over magnesium sulphate, filtered and evaporated. The residue
(114.34 g) is chromatographed on silica gel (600 g), elution being
carried out with 90/10 heptane/dichloromethane.
94.4 g of 2,4-bis(benzyloxy)-1-bromobenzene are obtained in the
form of white crystals.
Yield=99%.
b) 3-(2,4-Bis(benzyloxy)phenyl)-3-hydroxyazetidine-1-carboxylic
acid tert-butyl ester
[0240] In a 100 ml three-necked flask, 5 g of
2,4-bis(benzyloxy)-1-bromobenzene are dissolved in 60 ml of
tetrahydrofuran. The mixture is cooled to -70.degree. C. and then
11.4 ml of 2.5M n-butyllithium in hexane are added. The reaction
medium is stirred at -70.degree. C. for 1 hour, and then 2.8 g of
1-Boc-azetidine-3-one dissolved in 4 ml of THF are added dropwise.
The reaction medium is stirred at -70.degree. C. for 2 hours and
then left at ambient temperature overnight. The reaction medium is
poured into 40 ml of a 2M solution of hydrochloric acid and then
extracted with 100 ml of ethyl acetate. The organic phases are
combined, washed with 50 ml of water and then dried over magnesium
sulphate and evaporated.
The residue is chromatographed on silica gel (AnaLogix SF40-80 g
column), elution being carried out with 80/20 heptanelethyl
acetate. 2.2 g of
3-(2,4-bis(benzyloxy)phenyl)-3-hydroxyazetidine-1-carboxylic acid
tert-butyl ester are obtained. Yield: 37%.
c) 3-(2,4-Dihydroxyphenyl)azetidine-1-carboxylic acid tert-butyl
ester
[0241] 1 g of
3-(2,4-bis(benzyloxy)phenyl)-3-hydroxyazetidine-1-carboxylic acid
tert-butyl ester are dissolved in a mixture of 20 ml of ethyl
acetate/10 ml of methanol, and then 0.2 g of palladium-on-charcoal
at 10% is added. The reaction mixture is stirred for 24 hours under
a hydrogen atmosphere. The reaction mixture is filtered and then
the residue is chromatographed on silica gel (7/3 heptane/ethyl
acetate). 0.16 g of 3-(2,4-dihydroxyphenyl)azetidine-1-carboxylic
acid tert-butyl ester is obtained. Yield=28%.
[0242] .sup.1H NMR (DMSO, 400 MHz): 1.38 (s, 9H): 3.72 (m, 1H);
3.85 (bm, 2H); 4.07 (bm, 2H); 6.17 (dd, J=8.4 & 2.4 Hz, 1H);
6.27 (d, J=2.4 Hz, 1H); 6.92 (d, J=8.4 Hz, 1H); 9.12 (s, 1H); 9.32
(s, 1H).
[0243] .sup.13C NMR (DMSO, 100 MHz): 28.1, 55, 102.4, 105.9, 117.9,
127.6, 155.8, 156.0, 157.0.
EXAMPLE 2
[3-(2,4-Dihydroxyphenyl)azetidin-1-yl]phenylmethanone
a) 3-(2,4-Bis(benzyloxy)phenyl)azetidine-1-carboxylic acid
tert-butyl ester
[0244] In a 25 ml round-bottomed flask, 1.35 g of potassium
carbonate are added in small portions to a solution of 0.86 g of
3-(2,4-dihydroxyphenyl)azetidine-1-carboxylic acid tert-butyl ester
(Example 1) in 9 ml of methyl ethyl ketone.
0.93 ml of benzyl bromide are added dropwise and the reaction
mixture is then stirred for 2 hours at reflux. The reaction mixture
is filtered and the residue is then chromatographed on silica gel
(70/30 heptane/ethyl acetate).
[0245] 1.1 g of 3-(2,4-bis(benzyloxy)phenyl)azetidine-1-carboxylic
acid tert-butyl ester are obtained. Yield=76%.
b) 3-(2,4-Bis(benzyloxy)phenyl)azetidine trifluoroacetate
[0246] In a 25 ml round-bottomed flask, 1 g of
3-(2,4-bis(benzyloxy)phenyl)azetidine-1-carboxylic acid tert-butyl
ester is dissolved in 10 ml of dichloromethane and then 2.5 ml of
trifluoroacetic acid are added. The reaction mixture is stirred for
2 hours. The solvents are evaporated off and the residue is then
taken up in isopropyl ether. 0.92 g of
3-(2,4-bis(benzyloxy)phenyl)azetidine trifluoroacetate is obtained.
Yield=90%.
c) [3-(2,4-Bis(benzyloxy)phenyl)azetidin-1-yl]phenylmethanone
[0247] In a 10 ml round-bottomed flask, 0.25 g of
3-(2,4-bis(benzyloxy)phenyl)azetidine trifluoroacetate in 5 ml of
tetrahydrofuran is dissolved in the presence of 0.1 ml of
N,N-diisopropylethylamine. 0.07 ml of benzoyl chloride is added and
the mixture is then stirred for 24 hours at ambient temperature.
The reaction mixture is extracted with ethyl acetate and the
organic phases are then combined and dried over magnesium sulphate.
The residue is chromatographed on silica gel (9/1 heptane/ethyl
acetate). 0.2 g of
[3-(2,4-bis(benzyloxy)phenyl)azetidin-1-yl]phenylmethanone is
obtained. Yield=82%.
d) [3-(2,4-Dihydroxyphenyl)azetidin-1-yl]phenylmethanone
[0248] In a 10 ml round-bottomed flask, 0.2 g of
[3-(2,4-bis(benzyloxy)phenyl)azetidin-1-yl]phenylmethanone is
dissolved in 6 ml of methanol in the presence of 0.1 g of
palladium-on-charcoal at 10%. The reaction mixture is stirred for
18 hours under a hydrogen atmosphere. The reaction mixture is
filtered and the residue is then chromatographed on silica gel (1/1
heptane/ethyl acetate).
0.08 g of [3-(2,4-dihydroxyphenyl)azetidin-1-yl]phenylmethanone is
obtained. Yield=67%.
[0249] .sup.1H NMR (DMSO, 400 MHz): 3.86 (m, 1H): 4.04 (m, 1H);
4.29 (m, 2H); 4.58 (t, J=8.6 Hz, 1H); 6.19 (dd, J=8.4 & 2.4 Hz,
1H); 6.28 (d. J=2.4 Hz, 1H); 6.98 (d, J=8.4 Hz, 1H); 7.47 (m, 3H);
7.63 (d, J=8 Hz, 2H) 9.14 (s, 1H); 9.37 (s, 1H).
[0250] .sup.13C NMR (DMSO, 100 MHz): 29.3, 54.2, 58.7, 102.4,
105.9, 117.8, 127.7, 127.8, 128.3, 130.7, 133.3, 156.0, 157.0,
168.9.
EXAMPLE 3
3-(2,4-Dihydroxyphenyl)azetidine-1-carboxylic acid pentylamide
a) 3-(2,4-Bis(benzyloxy)phenyl)azetidine-1-carboxylic acid
pentylamide
[0251] In a 10 ml round-bottomed flask, 0.15 g of
3-(2,4-bis(benzyloxy)phenyl)azetidine trifluoroacetate is dissolved
in 3 ml of tetrahydrofuran in the presence of 0.1 ml of
N,N-diisopropylethylamine. 0.04 ml of pentyl isocyanate is added
and the reaction mixture is then stirred for 20 minutes at ambient
temperature. The reaction mixture is extracted with ethyl acetate
and the organic phases are then combined and dried over magnesium
sulphate. The residue is chromatographed on silica gel (9/1
heptane/ethyl acetate). 0.1 g of
3-(2,4-bis(benzyloxy)phenyl)azetidine-1-carboxylic acid pentylamide
is obtained. Yield=67%.
b) 3-(2,4-Dihydroxyphenyl)azetidine-1-carboxylic acid
pentylamide
[0252] In a 10 ml round-bottomed flask, 0.2 g of
3-(2,4-bis(benzyloxy)phenyl)azetidine-1-carboxylic acid pentylamide
is dissolved in 6 ml of methanol in the presence of 0.1 g of
palladium-on-charcoal at 10%. The reaction mixture is stirred for 6
hours under a hydrogen atmosphere. The reaction mixture is filtered
and the residue is then chromatographed on silica gel (95/5
dichloromethane/methanol).
0.02 g of 3-(2,4-dihydroxyphenyl)azetidine-1-carboxylic acid
pentylamide is obtained. Yield=33%.
[0253] .sup.1H NMR (DMSO, 400 MHz): 0.85 (t, J=7 Hz, 3H); 1.22 (m,
4H); 1.34 (m, 2H); 2.94 (bm, 2H); 3.59 (bm, 1H); 3.73 (bm, 2H);
4.02 (bm, 2H); 6.17 (m, 3H); 6.26 (d, J=2.4 Hz, 1H); 6.91 (d, J=8.4
Hz, 1H); 9.1 (bs, 1H); 9.27 (s, 1H).
[0254] .sup.13C NMR (DMSO, 100 MHz): 13.9, 21.9, 27.6, 28.5, 29.6,
55.0, 102.3, 106.0, 118.5, 127.3, 155.8, 156.8, 159.9.
EXAMPLE 4
3-(2,4-Dihydroxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl
ester
a) 3-Oxo-pyrrolidine-1-carboxylic acid tert-butyl ester
[0255] In a 1 l three-necked flask, 10 g of
N-Boc-3-hydroxypyrrolidine are dissolved in 350 ml of dimethyl
sulphoxide in the presence of 52.3 ml of triethylamine. 28 g of
pyridine-sulphur trioxide complex dissolved in 350 ml of dimethyl
sulphoxide are added dropwise to the above solution. The reaction
mixture is stirred for 4 hours at ambient temperature. The reaction
medium is acidified to pH 4.5-5 with a 1M solution of hydrochloric
acid and the reaction mixture is then extracted with ethyl acetate.
The organic phases are combined and then dried over anhydrous
sodium sulphate. The residue is filtered through silica gel (1/1
heptane/ethyl acetate). 5.7 g of 3-oxo-pyrrolidine-1-carboxylic
acid tert-butyl ester are obtained. Yield: 58%.
b) 3-(2,4-Dihydroxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl
ester
[0256] In a manner analogous to Examples 1b and 1c, but using
3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester,
3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl
ester is obtained.
[0257] .sup.1H NMR (DMSO, 400 MHz): 1.40 (s, 9H); 1.89 (m, 2H);
3.04 (t, J=9.5 Hz, 1H); 3.23 (m, 1H); 3.36 (m, 2H): 3.57 (dd, J=7.6
& 10 Hz, 1H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.28 (d, J=2.4
Hz, 1H): 6.82 (m, 1H); 9.06 (s, 1H): 9.27 (s, 1H).
[0258] .sup.13C NMR (DMSO, 100 MHz): 28.1, 29.9 & 30.8, 36.2
& 37.2, 45.2 & 45.4, 50.7 & 51.1, 78.0, 102.5, 106.0,
127.1, 153.5, 155.5, 156.7.
EXAMPLE 5
3-(2,4-Dihydroxyphenyl)pyrrolidine-1-carboxylic acid isobutyl
ester
a) 3-(2,4-Bis(benzyloxy)phenyl)pyrrolidinium trifluoroacetate
[0259] In a 50 ml round-bottomed flask, 1 g of
3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid
tert-butyl ester (Example 4) are dissolved in 16 ml of
dichloromethane and then 4 ml of trifluoroacetic acid are added.
The reaction mixture is stirred for 1 hour. The solvents are
evaporated off and the residue is then taken up in isopropyl ether.
1.26 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidinium
trifluoroacetate are obtained. Yield=76%.
b) 3-(2,4-Bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid
isobutyl ester
[0260] In a 10 ml round-bottomed flask, 0.25 g of
3-(2,4-bis(benzyloxy)phenyl)pyrrolidinium trifluoroacetate is
dissolved in 5 ml of tetrahydrofuran in the presence of 0.25 ml of
N,N-diisopropylethylamine. 0.108 g of isobutyl chloroformate is
added and the reaction mixture is stirred for 30 minutes at ambient
temperature. The reaction mixture is extracted with ethyl acetate
and the organic phases are then combined and dried over magnesium
sulphate. The residue is chromatographed on silica gel (8/2
heptane/ethyl acetate). 0.22 g of
3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid isobutyl
ester is obtained. Yield=66%.
c) 3-(2,4-Dihydroxyphenyl)pyrrolidine-1-carboxylic acid isobutyl
ester
[0261] In a 25 ml round-bottomed flask, 0.22 g of
3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid isobutyl
ester is dissolved in 6 ml of methanol in the presence of 0.1 g of
palladium-on-charcoal at 10%. The reaction mixture is stirred for
18 hours under a hydrogen atmosphere. The reaction mixture is
filtered and the residue is then chromatographed on silica gel (1/1
heptane/ethyl acetate).
0.1 g of 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid
isobutyl ester is obtained. Yield=75%.
[0262] .sup.1H NMR (DMSO, 400 MHz): 0.88 (t, J=7 Hz, 6H); 1.80-2.07
(m, 3H); 3.10 (q, J=9 Hz, 1H); 3.23-3.48 (m, 3H); 3.63 (m, 1H);
3.75 (m, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.28 (d, J=2.4 Hz,
1H); 6.82 (m, 1H); 9.07 (s, 1H); 9.29 (s, 1H).
[0263] .sup.13C NMR (DMSO, 100 MHz): 18.9, 27.6, 30.0 & 30.8,
36.4 & 37.3, 45.0 & 45.5, 50.6 & 51.0, 70.1, 102.5,
106.0, 117.5, 127.0, 154.1, 155.9, 156.7.
EXAMPLE 6
3-(2,4-Dihydroxyphenyl)pyrrolidine-1-carboxylic acid
cyclohexylamide
a) 3-(2,4-Bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid
cyclohexylamide
[0264] In a 10 ml round-bottomed flask, 0.25 g of
3-(2,4-bis(benzyloxy)phenyl)pyrrolidinium trifluoroacetate is
dissolved in 5 ml of tetrahydrofuran in the presence of 0.25 ml of
N,N-diisopropylethylamine. 0.1 g of cyclohexyl isocyanate is added
and the reaction mixture is stirred for 30 minutes at ambient
temperature. The reaction mixture is extracted with ethyl acetate
and the organic phases are then combined and dried over magnesium
sulphate. The residue is chromatographed on silica gel (7/3
heptane/ethyl acetate). 0.23 g of
3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid
cyclohexylamide is obtained. Yield=66%.
b) 3-(2,4-Dihydroxyphenyl)pyrrolidine-1-carboxylic acid
cyclohexylamide
[0265] In a 25 ml round-bottomed flask, 0.23 g of
3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid
cyclohexylamide is dissolved in 4 ml of methanol in the presence of
3 ml of ethyl acetate and of 0.1 g of palladium-on-charcoal at 10%.
The reaction mixture is stirred for 18 hours under a hydrogen
atmosphere. The reaction mixture is filtered and the residue is
then chromatographed on silica gel (7/3 heptane/ethyl acetate).
0.095 g of 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid
cyclohexylamide is obtained. Yield=100%.
[0266] .sup.1H NMR (DMSO, 400 MHz): 1.17 (m, 4H); 1.55 (m, 1H);
1.60 (m, 4H); 1.86 (m, 1H); 1.99 (m, 1H); 3.03 (t, J=9.2 Hz, 1H);
3.21 (q, J=9.2 Hz, 1H); 3.38 (m, 3H); 3.56 (t, J=8 Hz, 1H); 5.67
(d, J=7.9 Hz, 1H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.28 (d,
J=2.4 Hz, 1H); 6.85 (d, J=8.2 Hz, 1H); 9.04 (s, 1H); 9.25 (s,
1H).
[0267] .sup.13C NMR (DMSO, 100 MHz): 25.1, 25.3, 30.6, 33.3, 36.9,
45.0, 48.7, 50.7, 102.4, 105.9, 118.0, 127.0, 155.8, 155.9,
156.6.
EXAMPLE 7
3-(2,4-Dihydroxyphenyl)pyrrolidine-1-carboxylic acid
phenylamide
[0268] In a manner analogous to Example 6, but using phenyl
isocyanate, 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid
phenylamide is obtained.
[0269] .sup.1H NMR (DMSO, 400 MHz): 1.94-2.09 (m, 2H); 3.23 (t,
J=9.4 Hz, 1H); 3.37 (m, 1H); 3.48 (m, 1H); 3.54 (m, 1H); 3.76 (dd,
J=7.7 & 9.5 Hz, 1H); 6.17 (dd, J=8.4 & 2.4 Hz, 1H); 6.30
(d, J=2.4 Hz, 1H); 6.89 (m, 2H); 7.21 (t, J=7.6 Hz, 2H); 7.51 (d,
J=7.6 Hz, 2H), 9.08 (s, 1H); 9.31 (s, 1H).
[0270] .sup.13C NMR (DMSO, 100 MHz). 30.5, 37.0, 45.4, 51.0, 102.4,
106.0, 117.7, 119.3, 121.4, 127.2, 128.2, 140.6, 153.8, 156.0,
156.7.
EXAMPLE 8
3-(2,4-Dihydroxyphenyl)pyrrolidine-1-carboxylic acid
(4-fluorophenyl)amide
[0271] In a manner analogous to Example 6, but using 4-fluorophenyl
isocyanate, 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid
(4-fluorophenyl)amide is obtained.
[0272] .sup.1H NMR (DMSO, 400 MHz): 1.93-2.08 (m, 2H); 3.24 (t,
J=9.4 Hz, 1H); 3.37 (m, 1H): 3.44 (m, 1H); 3.53 (m, 1H); 3.76 (dd,
J=7.7 & 9.5 Hz, 1H); 6.17 (dd, J=8.4 & 2.4 Hz, 1H): 6.30
(d, J=2.4 Hz, 1H); 6.91 (d, J=8.3 Hz, 1H); 7.05 (t, J=8.8 Hz, 2H);
7.51 (m, 2H); 8.15 (s, 1H); 9.08 (s, 1H); 9.31 (s, 1H).
[0273] .sup.13C NMR (DMSO, 100 MHz): 30.5, 37.0, 45.4, 51.0, 102.5,
106.0, 114.7, 117.7, 121.0, 127.1, 137.0, 155.9, 156.7, 158.3.
EXAMPLE 9
3-(2,4-Dihydroxyphenyl)pyrrolidine-1-carboxylic acid
(4-trifluoromethylphenyl)amide
[0274] In a manner analogous to Example 6, but using
4-trifluoromethylphenyl isocyanate,
3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid
(4-trifluoromethylphenyl)amide is obtained.
[0275] .sup.1H NMR (DMSO, 400 MHz): 1.95-2.08 (m, 2H); 3.26 (t,
J=9.4 Hz, 1H); 3.37 (m, 1H); 3.44 (m, 1H); 3.57 (m, 1H); 3.77 (dd,
J=7.7 & 9.5 Hz, 1H); 6.17 (dd, J=8.4 & 2.4 Hz, 1H); 6.30
(d, J=2.4 Hz, 1H); 6.90 (d, J=8.3 Hz, 1H); 7.56 (d. J=8.7 Hz, 1H);
7.76 (d, J=8.7 Hz, 2H); 8.52 (s, 1H); 9.08 (s, 1H); 9.33 (s,
1H).
[0276] .sup.13C NMR (DMSO, 100 MHz): 30.4, 37.0, 45.5, 51.0, 102.5,
106.0, 117.5, 118.6, 121.1 (q), 124.6 (q), 125.4, 127.2, 153.38,
156.0, 156.7.
EXAMPLE 10
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid ethyl ester
a) 4-(2,4-Bis(benzyloxy)phenyl)-4-hydroxypiperidine-1-carboxylic
acid ethyl ester
[0277] In a 500 ml three-necked flask. 20 g of
2,4-bis(benzyloxy)-1-bromobenzene are dissolved in 240 ml of
tetrahydrofuran. The mixture is cooled to -70.degree. C. and then
26 ml of 2.5M n-butyllithium in hexane are added. The reaction
medium is stirred at -70.degree. C. for 1 hour, and then 11.1 g of
4-oxo-piperidine-1-carboxylic acid ethyl ester are added dropwise.
The reaction medium is stirred at -70.degree. C. for 2 hours and
then left at ambient temperature overnight. The reaction medium is
poured into 100 ml of a 2M solution of hydrochloric acid and then
extracted with 400 ml of ethyl acetate. The organic phases are
combined, washed with 150 ml of water and then dried over magnesium
sulphate and evaporated.
The residue is crystallized with a dichloromethane/heptane mixture.
16 g of
4-(2,4-bis(benzyloxy)phenyl)-4-hydroxypiperidine-1-carboxylic acid
ethyl ester are obtained.
Yield: 62%.
b) 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid ethyl
ester
[0278] 1 g of
4-(2,4-bis(benzyloxy)phenyl)-4-hydroxypiperidine-1-carboxylic acid
ethyl ester is dissolved in a mixture of 50 ml of methanol, and
then 0.5 g of palladium-on-charcoal at 10% is added. The reaction
mixture is stirred for 2 hours under a hydrogen atmosphere. The
reaction mixture is filtered and the residue is then crystallized
with dichloromethane. 0.5 g of
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid ethyl ester is
obtained. Yield=86%.
[0279] .sup.1H NMR (DMSO, 400 MHz): 1.17 (t, J=7 Hz, 3H); 1.38 (m,
2H); 1.64 (m, 2H); 2.84 (m, 3H) 4.01 (m, 4H); 6.12 (dd, J=8.4 &
2.4 Hz, 1H); 6.25 (d, J=2.4 Hz, 1H); 6.79 (d, J=8.3 Hz, 1H); 8.96
(s, 1H); 9.14 (s, 1H).
[0280] .sup.13C NMR (DMSO, 100 MHz): 14.6, 31.6, 34.6, 44.2, 60.5,
102.3, 106.0, 122.1, 126.7, 154.6, 155.2, 156.2.
EXAMPLE 11
[4-(2,4-Dihydroxyphenyl)piperidin-1-yl]phenylmethanone
a) 4-(2,4-Bis(benzyloxy)phenyl)piperidine-1-carboxylic acid ethyl
ester
[0281] In a 100 ml round-bottomed flask. 9.7 g of potassium
carbonate are added in small portions to a solution of 6.2 g of
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid ethyl ester
(Example 10) in 62 ml of methyl ethyl ketone.
6.7 ml of benzyl bromide are added dropwise and the reaction
mixture is then stirred for 2 hours at reflux. The reaction mixture
is filtered and the residue is then chromatographed on silica gel
(80/20 heptane/ethyl acetate). 9.8 g of
4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid ethyl
ester are obtained. Yield=92%.
b) 4-(2,4-Bis(benzyloxy)phenyl)piperidine
[0282] In a 500 ml three-necked flask, 9 g of
4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid ethyl
ester are dissolved in 180 ml of ethanol, and then 40 ml of a 5M
solution of sodium hydroxide are added. The reaction mixture is
brought to reflux for 48 hours.
The reaction mixture is poured into 400 ml of water. The solid is
filtered off and then chromatographed on silica gel (98/2
dichloromethane/methanol). 3.8 g of
4-(2,4-bis(benzyloxy)phenyl)piperidine are obtained.
c) [4-(2,4-Bis(benzyloxy)phenyl)piperidin-1-yl]phenylmethanone
[0283] In a 25 ml round-bottomed flask, 0.5 g of
4-(2,4-bis(benzyloxy)phenyl)piperidine in 10 ml of tetrahydrofuran
is dissolved in the presence of 0.26 ml of
N,N-diisopropylethylamine. 0.17 ml of benzoyl chloride is added and
the mixture is then stirred for 24 hours at ambient temperature.
The reaction mixture is extracted with ethyl acetate and then the
organic phases are combined and dried over magnesium sulphate. The
residue is chromatographed on silica gel (8/2 heptane/ethyl
acetate). 0.5 g of
[4-(2,4-bis(benzyloxy)phenyl)piperidin-1-yl]phenylmethanone is
obtained. Yield=80%.
d) [4-(2,4-Dihydroxyphenyl)piperidin-1-yl]phenylmethanone
[0284] In a 25 ml round-bottomed flask, 0.5 g of
[4-(2,4-bis(benzyloxy)phenyl)piperidin-1-yl]phenylmethanone is
dissolved in 15 ml of methanol in the presence of 0.2 g of
palladium-on-charcoal at 10%. The reaction mixture is stirred for
48 hours under a hydrogen atmosphere. The reaction mixture is
filtered and the residue is then chromatographed on silica gel (1/1
heptane/ethyl acetate).
0.3 g of [4-(2,4-dihydroxyphenyl)piperidin-1-yl]phenylmethanone is
obtained. Yield=96%.
[0285] .sup.1H NMR (DMSO, 400 MHz): 1.50 (bm, 2H); 1.59 (bm, 1H);
1.75, (bm, 1H); 2.79 (bm, 1H); 2.97 (m, 1H); 3.11 (bm, 1H); 3.62
(bm, 1H); 4.59 (bm, 1H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.27
(d, J=2.4 Hz, 1H); 6.85 (d, J=8.3 Hz, 1H); 7.41 (m, 5H); 8.98 (s,
1H), 9.17 (s, 1H).
[0286] .sup.13C NMR (DMSO, 100 MHz): 31.7, 34.6, 47.9, 102.4,
106.0, 122.0, 126.6, 126.9, 128.3, 129.2, 136.6, 139.6, 155.1,
156.1, 168.8, 170.3.
EXAMPLE 12
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid butylamide
a) 4-(2,4-Bis(benzyloxy)phenyl)piperidine-1-carboxylic acid
butylamide
[0287] In a 10 ml round-bottomed flask, 0.25 g of
4-(2,4-bis(benzyloxy)phenyl)piperidine is dissolved in 5 ml of
tetrahydrofuran in the presence of 0.23 ml of
N,N-diisopropylethylamine. 0.08 ml of butyl isocyanate is added and
the reaction mixture is then stirred for 20 minutes at ambient
temperature. The reaction mixture is extracted with ethyl acetate,
and then the organic phases are combined and dried over magnesium
sulphate. The residue is chromatographed on silica gel (8/2
heptanelethyl acetate). 0.25 g of
4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid butylamide
is obtained. Yield=78%.
b) 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
butylamide
[0288] In a 25 ml round-bottomed flask, 0.25 g of
4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid butylamide
is dissolved in 9 ml of methanol in the presence of 0.1 g of
palladium-on-charcoal at 10%. The reaction mixture is stirred for 4
hours under a hydrogen atmosphere. The reaction mixture is
filtered.
0.14 g of 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
butylamide is obtained. Yield=90%.
[0289] .sup.1H NMR (DMSO, 400 MHz): 0.86 (t, J=7 Hz, 3H); 1.30 (m,
2H); 1.37 (m, 4H); 1.60 (m, 2H); 2.62 (m, 2H); 2.80 (m, 1H); 3.00
(m, 2H); 4.03 (m, 2H); 6.12 (dd, J=8.4 & 2.4 Hz, 1H); 6.25 (d,
J=2.4 Hz, 1H); 6.38 (t, J=5.4 Hz, 1H): 6.77 (d, J=8.2 Hz, 1H); 8.95
(s, 1H): 9.11 (s, 1H).
[0290] .sup.13C NMR (DMSO, 100 MHz): 13.8, 19.6, 31.7, 32.0, 34.7,
44.3, 102.3, 106.0, 122.5, 126.7, 155.2, 156.0, 157.3.
EXAMPLE 13
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid propylamide
[0291] In a manner analogous to Example 12a, but using propyl
isocyanate, 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
propylamide is obtained.
[0292] .sup.1H NMR (DMSO, 400 MHz): 0.86 (t, J=7 Hz, 3H): 1.37 (m,
4H); 1.59 (m, 2H); 2.65 (m, 2H); 2.79 (m, 1H); 2.97 (m, 2H): 4.03
(m, 2H); 6.12 (dd, J=8.4 & 2.4 Hz, 1H); 6.25 (d, J=2.4 Hz, 1H);
6.41 (t, J=5.4 Hz, 1H); 6.77 (d, J=8.2 Hz, 1H); 8.95 (s, 1H); 9.12
(s, 1H).
[0293] .sup.13C NMR (DMSO, 100 MHz): 11.3, 23.0, 31.7, 34.7, 41.9,
44.3, 102.3, 106.0, 122.5, 126.7, 155.2, 156.0, 157.3.
EXAMPLE 14
1-[4-(2,4-Dihydroxyphenyl)piperidin-1-yl]butan-1-one
[0294] In a manner analogous to Example 11c, but using butanoyl
chloride, 1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]butan-1-one is
obtained.
[0295] .sup.1H NMR (DMSO, 400 MHz): 0.86 (t, J=7.5 Hz, 3H);
1.29-1.55 (m, 4H); 1.67 (m, 2H); 2.27 (t. J=8 Hz, 2H); 2.48 (bm,
1H); 2.90 (t, J=11.6 Hz, 1H); 3.02 (t, J=12.8 Hz, 1H); 3.91 (bd,
J=12.8 Hz, 1H); 4.50 (bd, J=13.2 Hz, 1H); 6.13 (dd. J=8.4 & 2.4
Hz, 1H); 6.24 (d, J=2.4 Hz, 1H); 6.77 (d, J=8.3 Hz, 1H); 8.93 (s,
1H), 9.11 (s, 1H).
[0296] .sup.13C NMR (DMSO, 100 MHz): 14.3, 18.8, 32.1 & 32.9,
34.8, 35.1, 42.3 & 46.3, 102.8, 106.5, 122.6, 127.2, 155.6,
156.6, 170.5.
EXAMPLE 15
1-[4-(2,4-Dihydroxyphenyl)piperidin-1-yl]-2-methylpropan-1-one
[0297] In a manner analogous to Example 11c, but using
2-methylpropanoyl chloride,
1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-methylpropan-1-one is
obtained.
[0298] .sup.1H NMR (DMSO, 400 MHz): 0.96 (2t, J=7.5 Hz, 6H);
1.28-1.46 (m, 2H); 1.68 (m, 2H); 2.51 (bm, 1H); 2.87 (m, 2H); 3.05
(t, J=12.8 Hz, 1H); 4.01 (bd, J=12.8 Hz, 1H); 4.53 (bd, J=13.2 Hz,
1H); 6.13 (dd, J=8.4 & 2.4 Hz, 1H); 6.25 (d, J=2.4 Hz, 1H);
6.79 (d, J=8.3 Hz, 1H); 8.97 (s, 1H), 9.15 (s, 1H).
[0299] .sup.13C NMR (DMSO, 100 MHz): 19.3, 19.6, 28.9, 31.6 &
32.6, 34.7, 42.0 & 45.6, 102.3, 106.0, 122.0, 126.7, 155.2,
156.1, 173.9.
EXAMPLE 16
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid phenylamide
[0300] In a manner analogous to Example 12a, but using phenyl
isocyanate, 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
phenylamide is obtained.
[0301] .sup.1H NMR (DMSO, 400 MHz): 1.46 (m, 2H); 1.70 (d, J=11.6
Hz, 2H); 2.82 (t, J=11.4 Hz, 2H); 2.90 (m, 1H); 4.23 (d, J=13.1 Hz,
2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.25 (d, J=2.4 Hz, 1H);
6.82 (d, J=8.3 Hz, 1H); 6.91 (t, J=8.2 Hz, 1H); 7.21 (t, J=8 Hz,
2H); 7.45 (d, J=8 Hz, 2H); 8.47 (s, 1H); 8.97 (s, 1H); 9.16 (s,
1H).
[0302] .sup.13C NMR (DMSO, 100 MHz): 31.8, 34.7, 44.7, 102.4,
106.0, 119.5, 121.4, 122.3, 126.8, 128.2, 140.7, 154.9, 155.2,
156.1.
EXAMPLE 17
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
(4-fluorophenyl)amide
[0303] In a manner analogous to Example 12a, but using
4-fluorophenyl isocyanate,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(4-fluorophenyl)amide is obtained.
[0304] .sup.1H NMR (DMSO, 400 MHz): 1.46 (m, 2H); 1.69 (d, J=11.6
Hz, 2H); 2.82 (t, J=11.4 Hz, 2H); 2.90 (m, 1H); 4.22 (d, J=13.1 Hz,
2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.28 (d, J=2.4 Hz, 1H);
6.81 (d, J=8.3 Hz, 1H); 7.08 (t, J=8.2 Hz, 2H); 7.46 (m, 2H); 8.51
(s, 1H); 9.00 (s, 1H); 9.16 (s, 1H).
[0305] .sup.13C NMR (DMSO, 100 MHz): 31.8, 34.7, 44.6, 102.4,
106.0, 114.6, 121.2, 122.3, 126.8, 137.0, 154.9, 155.2, 156.0,
156.1, 158.4.
EXAMPLE 18
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
p-tolylamide
[0306] In a manner analogous to Example 12a, but using p-tolyl
isocyanate, 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
p-tolylamide is obtained.
[0307] .sup.1H NMR (DMSO, 400 MHz): 1.46 (m, 2H); 1.69 (d, J=11.6
Hz, 2H); 2.22 (s, 3H); 2.83 (t, J=11.4 Hz, 2H); 2.90 (m, 1H); 4.22
(d, J=13.1 Hz, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.27 (d.
J=2.4 Hz, 1H); 6.82 (d, J=8.3 Hz, 1H); 7.02 (d, J=8.2 Hz, 2H); 7.34
(d, J=8 Hz, 2H); 8.37 (s, 1H); 8.97 (s, 1H); 9.15 (s, 1H).
[0308] .sup.13C NMR (DMSO, 100 MHz): 20.3, 31.8, 34.7, 44.6, 102.4,
106.0, 119.7, 122.3, 126.8, 128.6, 130.2, 138.1, 154.9, 155.2,
156.1.
EXAMPLE 19
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
phenethylamide
[0309] In a manner analogous to Example 12a, but using phenethyl
isocyanate, 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
phenethylamide is obtained.
[0310] .sup.1H NMR (DMSO, 400 MHz): 1.34 (m, 2H); 1.60 (d, J=11.6
Hz, 2H); 2.64-2.73 (m, 4H); 2.83 (m, 1H); 3.22 (m, 2H); 4.02 (d,
J=13.1 Hz, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d, J=2.4
Hz, 1H); 6.54 (m, 1H); 6.78 (d, J=8.3 Hz, 1H); 7.18 (m, 3H); 7.28
(m, 2H); 8.97 (s, 1H): 9.12 (s, 1H).
[0311] .sup.13C NMR (DMSO, 100 MHz): 31.7, 34.7, 36.0, 41.9, 44.3,
102.4, 106.0, 122.5, 125.8, 126.7, 128.2, 128.6, 139.9, 155.4.1,
156.0, 157.2.
EXAMPLE 20
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
(3-fluorophenyl)amide
[0312] In a manner analogous to Example 12a, but using
3-fluorophenyl isocyanate,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(3-fluorophenyl)amide is obtained.
[0313] .sup.1H NMR (DMSO, 400 MHz): 1.46 (m, 2H); 1.69 (d, J=11.6
Hz, 2H); 2.82 (t, J=11.4 Hz, 2H); 2.90 (m, 1H); 4.22 (d, J=13.1 Hz,
2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.27 (d, J=2.4 Hz, 1H);
6.70 (m, 1H); 6.81 (d, J=8.3 Hz, 1H); 7.24 (m, 2H); 7.47 (d, J=18
Hz, 1H); 8.70 (s, 1H); 9.00 (s, 1H); 9.17 (s, 1H).
[0314] .sup.13C NMR (DMSO, 100 MHz): 31.8, 34.7, 44.7, 102.4,
106.0, 107.6, 114.9, 122.2, 126.8, 129.6, 142.7, 154.5, 155.2,
156.1, 162.1.
EXAMPLE 21
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
((R)-1-phenylethyl)amide
[0315] In a manner analogous to Example 12a, but using
((R)-1-isocyanatoethyl)benzene,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
((R)-1-phenylethyl)amide is obtained.
[0316] .sup.1H NMR (DMSO, 400 MHz): 1.35 (d, J=7.1 Hz, 3H); 1.38
(m, 2H); 1.62 (m, 2H); 2.82 (t. J=13 Hz, 2H); 2.83 (m, 1H); 4.22
(d, J=12.3 Hz, 2H); 4.84 (m, 1H); 6.13 (dd, J=8.4 & 2.4 Hz,
1H); 6.26 (d, J=2.4 Hz, 1H); 6.73 (d, J=7.9 Hz, 1H); 6.78 (d, J=8.3
Hz, 1H); 7.18 (m, 1H); 7.32 (m, 4H); 8.96 (s, 1H); 9.13 (s,
1H).
[0317] .sup.13C NMR (DMSO, 100 MHz): 22.8, 31.7, 31.8, 44.4, 49.3,
102.4, 106.0, 122.5, 125.9, 126.1, 126.7, 127.9, 146.3, 155.2,
156.0, 156.6.
EXAMPLE 22
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
methylphenylamide
[0318] .sup.1H NMR (DMSO, 400 MHz): 1.28 (m, 2H); 1.48 (d, J=12 Hz,
2H); 2.62 (t, J=12.6 Hz, 2H); 2.77 (m, 1H); 3.09 (s, 3H); 3.80 (d,
J=13 Hz, 2H); 6.13 (dd, J=8.4 & 2.4 Hz, 1H); 6.22 (d, J=2.4 Hz,
1H); 6.70 (d. J=7.9 Hz, 1H); 7.11 (m, 3H); 7.35 (m, 2H); 8.96 (s,
1H); 9.09 (s, 1H).
[0319] .sup.13C NMR (DMSO, 100 MHz): 31.2, 34.4, 38.8, 46.0, 102.3,
106.0, 122.2, 122.6, 123.6, 126.6, 129.2, 146.7, 155.1, 156.0,
160.0.
EXAMPLE 23
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
pyridin-2-ylamide
a) Pyridin-2-ylcarbamic acid 4-nitrophenyl ester
[0320] 0.5 g of 2-aminopyridine is dissolved in 10 ml of
dichloromethane and then 1.18 g of 4-nitrophenyl chloroformate are
added, as are 1.85 ml of N,N-diisopropylethylamine. The reaction
mixture is stirred for one hour at ambient temperature. 50 ml of
water are added to the reaction mixture and then the medium is
extracted with 50 ml of dichloromethane. The solvents are
evaporated off and then the solid is used in the next stage without
further purification.
b) 4-(2,4-Bis(benzyloxy)phenyl)piperidine-1-carboxylic acid
pyridin-2-ylamide
[0321] 0.5 g of 4-(2,4-bis(benzyloxy)phenyl)piperidinium chloride
is suspended in 5 ml of dimethylformamide and then 0.43 ml of
N,N-diisopropylethylamine is added, as is 0.38 g of
pyridin-2-ylcarbamic acid 4-nitrophenyl ester in solution in 2 ml
of dimethylformamide. The reaction mixture is stirred for 24 hours
at 80'C.
It is heated at 80.degree. C. for 24 hours. 50 ml of water are
added, and the reaction mixture is then extracted with 50 ml of
ethyl acetate. The solvents are evaporated off and then the residue
is chromatographed on silica gel (70/30 heptane/ethyl acetate). 20
mg of 4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid
pyridin-2-ylamide are obtained.
c) 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
pyridin-2-ylamide
[0322] 20 mg of 4-(2,4-Bis(benzyloxy)phenyl)piperidine-1-carboxylic
acid pyridin-2-ylamide are dissolved in 20 ml of ethyl acetate and
then 1 ml of methanol is added. 10 mg of palladium-on-charcoal at
10% are added, and then the reaction mixture is stirred for 18
hours under a hydrogen atmosphere. The mixture is filtered and the
residue is then crystallized from an ethyl acetate/heptane mixture.
5 mg of 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
pyridin-2-ylamide. Yield: 39%
[0323] .sup.1H NMR (DMSO, 400 MHz): 1.458 (m, 2H); 1.68 (m, 2H);
2.85 (m, 3H); 4.26 (d, J=13.6 Hz, 2H); 6.14 (dd, J=8.4 & 2.4
Hz, 1H); 6.25 (d, J=2.4 Hz, 1H); 6.81 (d, J=7.9 Hz, 1H): 6.95 (m,
1H); 7.66 (m, 1H); 7.78 (d, J=7.9 Hz, 1H); 8.21 (m, 1H); 8.97 (s,
1H); 9.09 (s, 1H), 9.15 (s, 1H).
EXAMPLE 24
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-phenylethyl)amide
[0324] In a manner analogous to Example 12a, but using
((S)-1-isocyanatoethyl)benzene,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-phenylethyl)amide is obtained.
[0325] .sup.1H NMR (DMSO, 400 MHz): 1.35 (d, J=7.1 Hz, 3H); 1.38
(m, 2H); 1.62 (m, 2H); 2.82 (t, J=13 Hz, 2H); 2.83 (m, 1H); 4.22
(d, J=12.3 Hz, 2H); 4.84 (m, 1H); 6.13 (dd, J=8.4 & 2.4 Hz,
1H); 6.26 (d, J=2.4 Hz, 1H); 6.73 (d, J=7.9 Hz, 1H); 6.78 (d, J=8.3
Hz, 1H); 7.18 (m, 1H); 7.32 (m, 4H); 8.96 (s, 1H); 9.13 (s,
1H).
[0326] .sup.13C NMR (DMSO, 100 MHz): 22.8, 31.7, 31.8, 44.4, 49.3,
102.4, 106.0, 122.5, 125.9, 126.1, 126.7, 127.9, 146.3, 155.2,
156.0, 156.6.
EXAMPLE 25
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-phenylpropyl)amide
[0327] In a manner analogous to Example 12a, but using
((S)-1-isocyanatopropyl)benzene,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-phenylpropyl)amide is obtained.
[0328] .sup.1H NMR (DMSO, 400 MHz): 0.82 (t, J=7.1 Hz, 3H): 1.37
(m, 2H); 1.67 (m, 4H); 2.67 (m, 2H); 2.83 (m, 1H); 4.12 (d, J=12.3
Hz, 2H); 4.56 (m, 1H); 6.13 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d,
J=2.4 Hz, 1H); 6.65 (d, J=7.9 Hz, 1H); 6.77 (d, J=8.3 Hz, 1H); 7.18
(m, 1H); 7.29 (m, 4H); 8.96 (s, 1H); 9.11 (s, 1H).
[0329] .sup.13C NMR (DMSO, 100 MHz): 11.4, 29.3, 31.7, 34.7, 44.5,
55.8, 102.4, 106.0, 122.5, 126.1, 126.4, 126.7, 127.9, 145.4,
155.1, 156.0, 156.9.
EXAMPLE 26
(R)-2-Amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-one
a)
(R)-1-Benzyl-2-[4-(2,4-bis(benzyloxy)phenyl)piperidin-1-yl]-2-oxoethyl)-
carbamic acid benzyl ester
[0330] In a 50 ml round-bottomed flask, 0.615 g of
Z-L-phenylalanine is dissolved in 10 ml of dimethylformamide, and
0.43 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and
also 0.305 g of 1-hydroxybenzotriazole (HOBT) are added, and the
reaction mixture is then stirred for 5 minutes at ambient
temperature.
1 g of 4-(2,4-bis(benzyloxy)phenyl)piperidinium hydrochloride and
also 0.36 ml of diisopropylamine are added. The reaction mixture is
stirred for 1 hour at ambient temperature. The reaction medium is
washed with 20 ml of 5% citric acid and then extracted with 20 ml
of ethyl acetate, the organic phase is washed with 20 ml of a 1M
solution of sodium hydroxide, and the organic phase is dried over
magnesium sulphate. After evaporation of the solvents, the crude
product is chromatographed on silica gel. 1.23 g of
{(R)-1-benzyl-2-[4-(2,4-bis(benzyloxy)phenyl)piperidin-1-yl]-2-oxoet-
hyl}carbamic acid benzyl ester are obtained.
b)
(R)-2-Amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1--
one
[0331] In a 25 ml round-bottomed flask, 1.23 g of
{(R)-1-benzyl-2-[4-(2,4-bis(benzyloxy)phenyl)piperidin-1-yl]-2-oxoethyl}c-
arbamic acid benzyl ester are dissolved in 15 ml of methanol and
also 15 ml of ethyl acetate in the presence of 0.25 g of
palladium-on-charcoal at 10%. The reaction mixture is stirred for
18 hours under a hydrogen atmosphere. The reaction mixture is
filtered. The residue is chromatographed on silica gel (95/5
dichloromethane/methanol). 0.625 g of
(R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-on-
e is obtained. Yield=64%.
[0332] .sup.1H NMR (DMSO, 400 MHz): 0.6 (m, 1H); 1.09 (m, 1H);
1.30-1.75 (m, 5H); 2.56-2.97 (m, 4H); 3.94 (m, 2H); 4.51 (d, J=12.8
Hz, 1H); 6.11 (m, 1H); 6.24 (m, 1H); 6.57 & 6.77 (d, J=8.3 Hz,
1H); 7.18-7.40 (m, 5H); 8.97 (s, 1H); 9.11 & 9.15 (s, 1H).
[0333] .sup.13C NMR (DMSO, 100 MHz): (hindrance of rotation) 31.6,
32.3, 31.1, 34.6, 42.0, 42.2, 42.7, 45.3, 45.6, 51.3, 51.6, 102.3,
105.9, 121.9, 126.0, 126.7, 127.9, 128.1, 129.4, 138.5, 155.0,
156.0, 172.6.
EXAMPLE 27
1-[4-(2,4-Dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-one
[0334] In a manner analogous to Example 11c, but using
3-phenylpropionyl chloride,
1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-one is
obtained.
[0335] .sup.1H NMR (DMSO, 400 MHz): 1.33 (m, 2H): 1.63 (m, 2H);
2.50-2.70 (m, 3H); 2.80-3.0 (m, 4H); 3.92 (d, J=12.8 Hz, 1H); 4.53
(d, J=12.8 Hz, 1H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d,
J=2.4 Hz, 1H); 6.75 (d, J=7.9 Hz, 1H); 7.15-7.29 (m, 5H); 8.97 (s,
1H); 9.11 (s, 1H).
[0336] .sup.13C NMR (DMSO, 100 MHz): 30.9, 31.6, 32.2, 33.9, 34.5,
42.0, 45.8, 102.4, 106.0, 122.1, 125.8, 126.7, 128.2, 128.4, 141.5,
155.2, 156.1, 169.5.
EXAMPLE 28
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
2-fluorobenzylamide
[0337] In a manner analogous to Example 12a, but using
2-fluorobenzyl isocyanate,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
2-fluorobenzylamide is obtained.
[0338] .sup.1H NMR (DMSO, 400 MHz): 1.40 (m, 2H); 1.63 (m, 2H);
2.76 (t, J=13 Hz, 2H); 2.84 (m, 1H); 4.02 (d, J=12.3 Hz, 2H): 4.28
(d, J=5.5 Hz, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d,
J=2.4 Hz, 1H); 6.73 (d, J=7.9 Hz, 1H); 7.03 (t. J=5.6 Hz, 1H); 7.16
(m, 2H); 7.28 (m, 2H); 8.96 (s, 1H); 9.13 (s, 1H).
[0339] .sup.13C NMR (DMSO, 100 MHz): 31.7, 34.7, 37.0, 44.4, 102.4,
106.0, 114.7, 122.4, 124.1, 126.7, 127.7, 128.2, 129.0, 155.2,
156.0, 157.2, 158.6, 161.0
EXAMPLE 29
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
3-fluorobenzylamide
[0340] In a manner analogous to Example 12a, but using
3-fluorobenzyl isocyanate,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
3-fluorobenzylamide is obtained.
[0341] .sup.1H NMR (DMSO, 400 MHz): 1.38 (m, 2H); 1.63 (m, 2H);
2.73 (t, J=13 Hz, 2H); 2.86 (m, 1H); 4.04 (d, J=12.3 Hz, 2H); 4.23
(d, J=5.5 Hz, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d,
J=2.4 Hz, 1H); 6.79 (d, J=7.9 Hz, 1H); 7.06 (m, 4H); 7.34 (m, 1H);
8.96 (s, 1H); 9.13 (s, 1H).
[0342] .sup.13C NMR (DMSO, 100 MHz): 31.8, 24.7, 43.1, 44.5, 102.5,
106.1, 113.0 & 113.2, 113.5 & 113.7, 122.5, 123.0, 126.8,
130.0, 144.6, 155.3, 156.1, 157.3.
EXAMPLE 30
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
4-fluorobenzylamide
[0343] In a manner analogous to Example 12a, but using
4-fluorobenzyl isocyanate,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
4-fluorobenzylamide is obtained.
[0344] .sup.1H NMR (DMSO, 400 MHz): 1.38 (m, 2H); 1.63 (m, 2H);
2.71 (t, J=13 Hz, 2H); 2.84 (m, 1H); 4.04 (d, J=12.3 Hz, 2H); 4.21
(d, J=5.5 Hz, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d,
J=2.4 Hz, 1H); 6.78 (d, J=7.9 Hz, 1H); 7.05 (t, J=5.6 Hz, 1H); 7.13
(m, 2H); 7.28 (m, 2H); 8.96 (s, 1H); 9.13 (s, 1H).
[0345] .sup.13C NMR (DMSO, 100 MHz): 31.7, 34.7, 42.8, 44.4, 102.4,
106.0, 114.7, 122.4, 126.7, 128.8, 137.4, 155.2, 156.0, 157.2,
159.7 & 162.1.
EXAMPLE 31
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid benzylamide
[0346] In a manner analogous to Example 12a, but using benzyl
isocyanate, 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
benzylamide is obtained.
[0347] .sup.1H NMR (DMSO, 400 MHz): 1.41 (m, 2H); 1.63 (m, 2H);
2.72 (t. J=13 Hz, 2H); 2.85 (m, 1H); 4.02 (d, J=12.3 Hz, 2H); 4.24
(d, J=5.5 Hz, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H); 6.26 (d,
J=2.4 Hz, 1H); 6.79 (d, J=7.9 Hz, 1H); 7.05 (t, J=5.6 Hz, 1H); 7.24
(m, 5H); 7.28 (m, 2H); 8.96 (s, 1H); 9.13 (s, 1H).
[0348] .sup.13C NMR (DMSO, 100 MHz): 31.7, 34.7, 43.5, 44.4, 102.4,
106.0, 122.4, 126.3, 126.7, 126.9, 128.0, 141.2, 155.2, 156.0,
157.3.
EXAMPLE 32
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
2-methylbenzylamide
[0349] In a manner analogous to Example 12a, but using
2-methylbenzyl isocyanate,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
2-methylbenzylamide is obtained.
[0350] .sup.1H NMR (DMSO, 400 MHz): 1.40 (m, 2H); 1.62 (m, 2H);
2.27 (s, 3H); 2.73 (t, J=13 Hz, 2H); 2.85 (m, 1H); 4.10 (d, J=12.3
Hz, 2H); 4.22 (d, J=5.5 Hz, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H);
6.26 (d, J=2.4 Hz, 1H); 6.79 (d, J=7.9 Hz, 1H); 6.90 (t. J=5.6 Hz,
1H); 7.09-7.20 (m, 4H); 7.28 (m, 2H); 9 (bs, 1H); 9.12 (bs,
1H).
[0351] .sup.13C NMR (DMSO, 100 MHz): 18.6, 31.8, 34.7, 41.4, 44.5,
102.4, 106.0, 122.4, 125.5, 126.2, 126.7, 126.9, 129.6, 135.0,
138.7, 155.2, 156.0, 157.3.
EXAMPLE 33
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
3-methylbenzylamide
[0352] In a manner analogous to Example 12a, but using
3-methylbenzyl isocyanate,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
3-methylbenzylamide is obtained.
[0353] .sup.1H NMR (DMSO, 400 MHz): 1.40 (m, 2H); 1.62 (m, 2H);
2.28 (s, 3H); 2.72 (t, J=13 Hz, 2H); 2.86 (m, 1H); 4.02 (d, J=12.3
Hz, 2H): 4.20 (d, J=5.5 Hz, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H);
6.26 (d, J=2.4 Hz, 1H); 6.78 (d, J=7.9 Hz, 1H); 7.00-7.06 (m, 4H);
7.18 (t, J=7.6 Hz, 1H); 8.99 (s, 1H); 9.13 (s, 1H).
[0354] .sup.13C NMR (DMSO, 100 MHz): 21.0, 31.7, 34.7, 43.4, 44.5,
102.4, 106.0, 122.5, 124.1, 126.7, 126.9, 127.6, 127.9, 136.9,
141.1, 155.2, 156.0, 157.3.
EXAMPLE 34
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
4-methylbenzylamide
[0355] In a manner analogous to Example 12a, but using
4-methylbenzyl isocyanate,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
4-methylbenzylamide is obtained.
[0356] .sup.1H NMR (DMSO, 400 MHz): 1.41 (m, 2H); 1.62 (m, 2H);
2.27 (s, 3H); 2.71 (t, J=13 Hz, 2H); 2.84 (m, 1H); 4.08 (d, J=12
Hz, 2H); 4.19 (d, J=5.5 Hz, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H);
6.26 (d, J=2.4 Hz, 1H); 6.78 (d, J=7.9 Hz, 1H); 6.99 (t, J=5.6 Hz,
1H); 7.12 (2d, J=8 Hz, 4H); 8.96 (s, 1H); 9.13 (s, 1H).
[0357] .sup.13C NMR (DMSO, 100 MHz): 20.8, 31.9, 34.9, 43.4, 44.6,
102.6, 106.2, 122.7, 126.9, 127.2, 128.7, 135.4, 138.4, 155.4,
156.3, 157.5.
EXAMPLE 35
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
2-methoxybenzylamide
[0358] In a manner analogous to Example 12a, but using
2-methoxybenzyl isocyanate,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
2-methoxybenzylamide is obtained.
[0359] .sup.1H NMR (DMSO, 400 MHz): 1.41 (m, 2H); 1.63 (m, 2H);
2.74 (t, J=13 Hz, 2H); 2.86 (m, 1H); 3.79 (s, 3H); 4.11 (d, J=12.3
Hz, 2H); 4.22 (d, J=5.5 Hz, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H);
6.26 (d, J=2.4 Hz, 1H); 6.79-6.95 (m, 4H); 7.13-7.22 (m, 2H); 9.00
(bs, 1H); 9.14 (bs, 1H).
[0360] .sup.13C NMR (DMSO, 100 MHz): 31.7, 34.7, 38.3, 44.5, 55.2,
102.4, 106.0, 110.1, 119.9, 122.5, 126.7, 126.9, 127.3, 128.6,
155.2, 156.1, 156.3, 157.4.
EXAMPLE 36
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
3-methoxybenzylamide
[0361] In a manner analogous to Example 12a, but using
3-methoxybenzyl isocyanate,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
3-methoxybenzylamide is obtained.
[0362] .sup.1H NMR (DMSO, 400 MHz): 1.41 (m, 2H); 1.63 (m, 2H);
2.72 (t, J=13 Hz, 2H); 2.86 (m, 1H); 3.73 (s, 3H); 4.09 (d, J=12.3
Hz, 2H); 4.21 (d, J=5.5 Hz, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H);
6.26 (d, J=2.4 Hz, 1H); 6.79 (m, 4H); 7.03 (t, J=5.6 Hz, 1H); 7.22
(t, J=8 Hz, 1H); 9.02 (bs, 1H): 9.10 (bs, 1H).
[0363] .sup.13C NMR (DMSO, 100 MHz): 31.7, 34.7, 43.4, 44.5, 54.9,
102.4, 106.0, 111.6, 112.6, 119.1, 122.5, 126.7, 129.0, 142.9,
155.2, 156.0, 157.3, 159.2.
EXAMPLE 37
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
4-methoxybenzylamide
[0364] In a manner analogous to Example 12a, but using
4-methoxybenzyl isocyanate,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
4-methoxybenzylamide is obtained.
[0365] .sup.1H NMR (DMSO, 400 MHz): 1.41 (m, 2H); 1.62 (m, 2H):
2.70 (t, J=13 Hz, 2H): 2.84 (m, 1H); 3.72 (s, 3H); 4.08 (d, J=12
Hz, 2H); 4.16 (d, J=5.5 Hz, 2H); 6.14 (dd, J=8.4 & 2.4 Hz, 1H);
6.26 (d, J=2.4 Hz, 1H); 6.78 (d, J=7.9 Hz, 1H); 6.87 (d, J=8 Hz,
2H); 7.12 (t, J=5.6 Hz, 1H); 7.18 (d, J=8 Hz, 2H); 9.06 (s,
2H).
[0366] .sup.13C NMR (DMSO, 100 MHz): 31.7, 34.7, 42.9, 44.4, 55.0,
102.4, 106.0, 113.4, 122.4, 126.7, 128.3, 133.2, 155.2, 156.1,
157.3, 157.9.
EXAMPLE 38
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-p-tolylethyl)amide
[0367] In a manner analogous to Example 12a, but using
((S)-1-isocyanatoethyl)-4-methylbenzene,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-p-tolylethyl)amide is obtained.
[0368] .sup.1H NMR (DMSO, 400 MHz): 1.35 (d, J=7.1 Hz, 3H); 1.38
(m, 2H); 1.62 (m, 2H); 2.26 (s, 3H); 2.67 (t, J=13 Hz, 2H); 2.83
(m, 1H); 4.11 (d, J=12.3 Hz, 2H); 4.84 (m, 1H); 6.14 (dd, J=8.4
& 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.67 (d, J=7.9 Hz, 1H);
6.77 (d, J=8.3 Hz, 1H); 7.09 (d, J=8 Hz, 2H); 7.20 (d, J=8 Hz, 2H);
8.96 (s, 1H); 9.12 (s, 1H).
[0369] .sup.13C NMR (DMSO, 100 MHz): 18.5, 20.6, 22.9, 31.8, 34.7,
44.4, 49.0, 102.4, 106.0, 122.5, 125.8, 126.7, 128.5, 135.0, 143.2,
155.2, 156.0, 156.6.
EXAMPLE 39
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
[(S)-1-(4-fluorophenyl)ethyl]amide
[0370] In a manner analogous to Example 12a, but using
1-fluoro-4-((S)-1-isocyanatoethyl)benzene,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
[(S)-1-(4-fluorophenyl)ethyl]amide is obtained.
[0371] .sup.1H NMR (DMSO, 400 MHz): 1.35 (d, J=7.1 Hz, 3H); 1.38
(m, 2H); 1.62 (m, 2H); 2.67 (t, J=13 Hz, 2H); 2.83 (m, 1H); 4.09
(d, J=12.3 Hz, 2H); 4.84 (m, 1H); 6.14 (dd, J=8.4 & 2.4 Hz,
1H); 6.26 (d, J=2.4 Hz, 1H); 6.74 (d, J=7.9 Hz, 1H); 6.78 (d, J=8.3
Hz, 1H); 7.09 (t, J=8.9 Hz, 2H); 7.35 (m, 2H); 8.96 (s, 1H); 9.12
(s, 1H).
[0372] .sup.13C NMR (DMSO, 100 MHz): 22.8, 31.7, 34.7, 44.4, 48.7,
102.4, 106.0, 114.5, 122.4, 126.7, 127.8, 142.4, 155.2, 156.0,
156.5, 160.7 (d, J=241 Hz).
EXAMPLE 40
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
(S)-indan-1-ylamide
[0373] In a manner analogous to Example 12a, but using
(S)-1-isocyanatoindane,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
(S)-indan-1-ylamide is obtained.
[0374] .sup.1H NMR (DMSO, 400 MHz): 1.38 (m, 2H); 1.62 (m, 2H);
1.86 (m, 1H); 2.36 (m, 1H); 2.68-2.93 (m, 5H); 4.13 (d, J=12.3 Hz,
2H); 5.23 (m, 1H); 6.14 (dd. J=8.4 & 2.4 Hz, 1H); 6.26 (d,
J=2.4 Hz, 1H); 6.71 (d, J=7.9 Hz, 1H); 6.80 (d, J=8.3 Hz, 1H); 7.20
(m, 4H); 9.07 (bs, 2H).
[0375] .sup.13C NMR (DMSO, 100 MHz): 29.6, 31.7, 33.2, 34.7, 44.5,
55.3, 102.4, 106.0, 122.5, 123.9, 124.3, 126.1, 126.7, 126.9,
142.6, 145.4, 155.2, 156.0, 157.4.
EXAMPLE 41
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-naphthalen-1-ylethyl)amide
[0376] In a manner analogous to Example 12a, but using
1-((S)-1-isocyanatoethyl)naphthalene,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-naphthalen-1-ylethyl)amide is obtained.
[0377] .sup.1H NMR (DMSO, 400 MHz): 1.37 (m, 2H); 1.49 (d, J=7.1
Hz, 3H); 1.62 (m, 2H); 2.70 (t, J=13 Hz, 2H); 2.84 (m, 1H); 4.14
(t, J=12 Hz, 2H); 5.66 (m, 1H); 6.13 (dd, J=8.4 & 2.4 Hz, 1H);
6.26 (d, J=2.4 Hz, 1H); 6.75 (d, J=7.9 Hz, 1H); 6.91 (d, J=7.7 Hz,
1H); 7.53 (m, 4H); 7.79 (d, J=8 Hz, 1H); 7.93 (d, J=8 Hz, 1H); 8.16
(d, J=8 Hz, 1H); 8.97 (s, 1H); 9.13 (s, 1H).
[0378] .sup.13C NMR (DMSO, 100 MHz): 22.0, 31.7, 34.6, 44.6, 45.5,
102.4, 106.0, 122.2, 122.5, 123.3, 125.3, 125.4, 125.9, 126.7,
126.7, 128.5, 130.4, 133.3, 141.8, 155.2, 156.0, 156.5.
EXAMPLE 42
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-naphthalen-2-ylethyl)amide
[0379] In a manner analogous to Example 23a, but using
(S)-1-naphthalen-2-ylethylamine, and then repeating the sequence
23b and 23c, 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-naphthalen-2-ylethyl)amide is obtained.
[0380] .sup.1H NMR (DMSO, 400 MHz): 1.35 (m, 2H); 1.46 (d, J=7.1
Hz, 3H): 1.62 (m, 2H); 2.70 (t, J=13 Hz, 2H); 2.85 (m, 1H); 4.14
(d. J=12.9 Hz, 2H); 5.01 (m, 1H); 6.13 (dd, J=8.4 & 2.4 Hz,
1H); 6.26 (d, J=2.4 Hz, 1H): 6.77 (d, J=7.9 Hz, 1H); 6.85 (d. J=7.7
Hz, 1H); 7.43-7.50 (m, 3H); 7.77 (s, 1H); 7.85 (m, 3H); 8.97 (s,
1H); 9.13 (s, 1H).
[0381] .sup.13C NMR (DMSO, 100 MHz): 22.6, 31.2, 34.6, 44.5, 49.5,
102.4, 106.0, 122.5, 123.8, 125.1, 125.3, 125.9, 126.7, 127.4,
127.5, 131.9, 132.8, 143.8, 155.2, 156.0, 156.7.
EXAMPLE 43
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
[(S)-1-(4-methoxyphenyl)ethyl]amide
[0382] In a manner analogous to Example 12a, but using
1-((S)-1-isocyanatoethyl)-4-methoxybenzene,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
[(S)-1-(4-methoxyphenyl)ethyl]amide is obtained.
[0383] .sup.1H NMR (DMSO, 400 MHz): 1.33 (d, J=7.1 Hz, 3H); 1.38
(m, 2H); 1.62 (m, 2H); 2.66 (t, J=13 Hz, 2H); 2.83 (m, 1H); 3.72
(s, 3H); 4.06 (d, J=12.3 Hz, 2H); 4.79 (m, 1H); 6.13 (dd, J=8.4
& 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.64 (d, J=7.9 Hz, 1H);
6.78 (d, J=8.3 Hz, 1H); 6.85 (d, J=8.6 Hz, 2H); 7.23 (d, J=8.6 Hz,
2H): 8.96 (s, 1H): 9.13 (s, 1H).
[0384] .sup.13C NMR (DMSO, 100 MHz): 22.9, 31.7, 34.7, 44.4, 48.6,
55.0, 102.4, 106.0, 113.3, 122.5, 126.7, 127.0, 138.2, 155.2,
156.0, 156.6, 157.7.
EXAMPLE 44
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid
[(S)-1-(3-methoxyphenyl)ethyl]amide
[0385] In a manner analogous to Example 12a, but using
1-((S)-1-isocyanatoethyl)-3-methoxybenzene,
4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
[(S)-1-(3-methoxyphenyl)ethyl]amide is obtained.
[0386] .sup.1H NMR (DMSO, 400 MHz): 1.33 (d, J=7.1 Hz, 3H); 1.38
(m, 2H); 1.62 (m, 2H); 2.68 (t, J=13 Hz, 2H); 2.84 (m, 1H); 3.73
(s, 3H); 4.10 (d, J=12.3 Hz, 2H); 4.81 (m, 1H); 6.13 (dd, J=8.4
& 2.4 Hz, 1H): 6.26 (d, J=2.4 Hz, 1H); 6.70-6.79 (m, 5H); 7.20
(t, J=8.1 Hz, 1H); 8.96 (s, 1H); 9.13 (s, 1H).
[0387] .sup.13C NMR (DMSO, 100 MHz): 22.9, 31.8, 34.6, 44.4, 49.3,
54.9, 102.4, 106.0, 111.3, 111.8, 118.2, 122.5, 126.7, 129.0,
148.0, 155.2, 156.0, 156.7, 159.1.
EXAMPLE 45
(S)-2-Amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-one
[0388] In a manner analogous to Example 26, but using
Z-D-phenylalanine,
(S)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-on-
e is obtained.
[0389] .sup.1H NMR (DMSO, 400 MHz): 0.6 (m, 1H); 1.09 (m, 1H);
1.30-1.75 (m, 5H); 2.56-2.97 (m, 4H); 3.94 (m, 2H); 4.51 (d, J=12.8
Hz, 1H); 6.11 (m, 1H); 6.24 (m, 1H); 6.57 & 6.77 (d, J=8.3 Hz,
1H); 7.18-7.40 (m, 5H); 8.97 (s, 1H); 9.11 & 9.15 (s, 1H).
[0390] .sup.13C NMR (DMSO, 100 MHz): (hindrance of rotation) 31.6,
32.3, 31.1, 34.6, 42.0, 42.2, 42.7, 45.3, 45.6, 51.3, 51.6, 102.3,
105.9, 121.9, 126.0, 126.7, 127.9, 128.1, 129.4, 138.5, 155.0,
156.0, 172.6.
EXAMPLE 46
4-(5-Fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-phenylethyl)amide
a) 1,5-Bis(benzyloxy)-2-fluoro-4-nitrobenzene
[0391] 2.82 g (70.6 mmol, 2.5 eq) of sodium hydride at 60% are
added to a solution of 7.6 g (70.6 mmol, 2.5 eq) of benzyl alcohol
in 100 ml of tetrahydrofuran. The reaction medium is stirred at
ambient temperature for 11/2 hours and then 5.0 g (28.2 mmol, 1 eq)
of 1,2,4-trifluoro-5-nitrobenzene in solution in 50 ml of
tetrahydrofuran are added dropwise. The reaction medium is refluxed
for 3 hours. The reaction medium is treated with 150 ml of 1M
hydrochloric acid and extracted with ethyl acetate. The organic
phases are combined, washed with a saturated solution of sodium
chloride, dried over magnesium sulphate, filtered and evaporated.
The residue is chromatographed on silica gel, elution being carried
out with 90/10 heptane/ethyl acetate.
1.68 g of 1,5-bis(benzyloxy)-2-fluoro-4-nitrobenzene are
obtained.
Yield=17%.
b) 1,5-Bis(benzyloxy)-2-fluoro-4-aminobenzene
[0392] 508 mg (9.5 mmol, 2 eq) of ammonium chloride, followed by
2.23 g (34.2 mmol, 7.2 eq) of zinc powder, are added to a solution
of 1.68 g (4.75 mmol, 1 eq) of
1,5-bis(benzyloxy)-2-fluoro-4-nitrobenzene in 50 ml of water. The
reaction medium is refluxed for 4 hours. The cooled reaction medium
is extracted with ethyl acetate. The organic phases are combined,
washed with a saturated solution of sodium chloride, dried over
magnesium sulphate, filtered and evaporated. The residue is
chromatographed on silica gel, elution being carried out with 85/15
heptane/ethyl acetate.
930 mg of 1,5-bis(benzyloxy)-2-fluoro-4-aminobenzene are
obtained.
Yield=61%.
c) 1,5-Bis(benzyloxy)-2-fluoro-4-iodobenzene
[0393] 7 ml of 6M hydrochloric acid are added to a solution of 3.20
g (9.9 mmol, 1 eq) of 1,5-bis(benzyloxy)-2-fluoro-4-aminobenzene in
40 ml of N,N-dimethylformamide, cooled to 0.degree. C. 683 mg (9.9
mmol, 1 eq) of sodium nitrite in solution in 7 ml of water are
added and the reaction medium is stirred at 0.degree. C. for 1
hour. 1.64 g (9.9 mmol, 1 eq) of potassium iodide in solution in 8
ml of water are added, followed by 190 mg (1.0 mmol, 0.1 eq) of
copper iodide, and then the reaction medium is stirred at ambient
temperature overnight. The reaction medium is treated with a
saturated solution of ammonium chloride and extracted with ethyl
acetate. The organic phases are combined, washed with a saturated
solution of sodium chloride, dried over magnesium sulphate,
filtered and evaporated. The residue is chromatographed on silica
gel, elution being carried out with 75/25 heptane/dichloromethane.
3.59 g of 1,5-bis(benzyloxy)-2-fluoro-4-iodobenzene are
obtained.
Yield=68%.
d) 4-(2,4-Bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic
acid tert-butyl ester
[0394] 4.0 ml (9.9 mmol, 1.2 eq) of 2.5M n-butyllithium in hexane
are added to a solution of 3.59 g (8.26 mmol, 1 eq) of
1,5-bis(benzyloxy)-2-fluoro-4-iodobenzene in 40 ml of
tetrahydrofuran, cooled to -70'C. The reaction medium is stirred at
-70.degree. C. for 25 minutes and 1.97 g (9.9 mmol, 1.2 eq) of
1-boc-4-piperidone in solution in 20 ml of tetrahydrofuran are
added. The reaction medium is stirred at -70.degree. C. for 1 hour
and is then left to return to ambient temperature overnight. 30 ml
of a saturated solution of ammonium chloride, to which 4 ml of 2M
hydrochloric acid have been added, are added to the reaction
medium, which is stirred for 20 minutes and is then extracted with
ethyl acetate. The organic phases are combined, dried over
magnesium sulphate and evaporated. The residue is chromatographed
on silica gel, elution being carried out with 95/5 heptane/ethyl
acetate then 75/25 heptane/ethyl acetate (with 0.1% of TEA).
860 mg of a mixture of
4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acid
tert-butyl ester (25%) and of 1-boc-4-piperidone are obtained in
the form of a yellow oil which crystallizes. Yield=5%.
e)
4-(5-Fluoro-2,4-dihydroxyphenyl)-3,6-dihydro-2H-pyridine-1-carboxylic
acid tert-butyl ester
[0395] A mixture of 860 mg (0.42 mmol, 1 eq) of
4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acid
tert-butyl ester at 35% in 10 ml of ethyl acetate, in the presence
of 200 mg of palladium-on-charcoal at 10%, is stirred at ambient
temperature under a hydrogen pressure of 5 bar for 17 hours. 5 ml
of methanol are added and the reaction medium is stirred at ambient
temperature under a hydrogen pressure of 5 bar for 29 hours. The
reaction medium is filtered through filter paper and the filtrate
is evaporated off. The residue is chromatographed on silica gel,
elution being carried out with 60/40 heptane/ethyl acetate. 192 mg
of
4-(5-fluoro-2,4-dihydroxyphenyl)-3,6-dihydro-2H-pyridine-1-carboxylic
acid tert-butyl ester are obtained. Yield=100%.
f) 4-(2,4-Bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic
acid tert-butyl ester
[0396] 241 mg (1.74 mmol, 3 eq) of potassium carbonate (325 mesh)
are added to a solution of 181 mg (0.58 mmol, 1 eq) of
4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
tert-butyl ester in 3 ml of acetone. 152 .mu.l (1.28 mmol, 2.2 eq)
of benzyl bromide are added dropwise. The reaction medium is heated
at 50.degree. C. for 20 hours. The solvent is evaporated off and
then the residue is taken up with a water/ethyl acetate mixture.
The aqueous phase is extracted with ethyl acetate, and the organic
phases are combined, washed with a solution of sodium hydrogen
carbonate and then with a saturated solution of sodium chloride,
dried over magnesium sulphate, filtered and evaporated. The residue
is chromatographed on silica gel, elution being carried out with
85/15 heptane/ethyl acetate.
188 mg of
4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acid
tert-butyl ester are obtained. Yield=66%.
g) 4-(2,4-Bis(benzyloxy)-5-fluorophenyl)piperidine
[0397] 280 .mu.l (3.7 mmol, 10 eq) of trifluoroacetic acid are
added to a solution of 184 mg (0.37 mmol, 1 eq) of
4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acid
tert-butyl ester in 3 ml of dichloromethane. The reaction medium is
stirred at ambient temperature for 1 hour. The reaction medium is
treated with 10 ml of water and then extracted with
dichloromethane. The organic phases are combined, washed with a
saturated solution of sodium hydrogen carbonate and then with a
saturated solution of sodium chloride, dried over magnesium
sulphate and evaporated. 150 mg of
4-(2,4-bis(benzyloxy)-5-fluorophenyl)pipendine are obtained.
Yield=100%.
h) 4-(2,4-Bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic
acid ((S)-1-phenylethyl)amide
[0398] 65 .mu.l (0.45 mmol, 1.2 eq) of (S)-(-)-phenylethyl
isocyanate are added to a solution of 147 mg (0.37 mmol, 1 eq) of
4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine in 3 ml of
tetrahydrofuran in the presence of 64 .mu.l (0.37 mmol, 1 eq) of
dimethylethylamine. The reaction medium is stirred at ambient
temperature for 50 minutes. The reaction is stopped by adding 5 ml
of water, and then extracted with ethyl acetate. The organic phases
are combined and dried over magnesium sulphate. The solvent is
evaporated off and the residue is chromatographed on silica gel,
elution being carried out with 60/40 heptane/ethyl acetate. 178 mg
of 4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic
acid phenylamide are obtained. Yield=89%.
i) 4-(5-Fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-phenylethyl)amide
[0399] A mixture of 174 mg (0.32 mmol, 1 eq) of
4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acid
phenylamide in 1 ml of ethyl acetate and of 2 ml of methanol in the
presence of 51 mg (30% by mass) of palladium-on-charcoal at 10% is
stirred at ambient temperature under atmospheric hydrogen pressure
for 8 hours. The reaction medium is filtered through filter paper
and the filtrate is evaporated off. The residue is chromatographed
on silica gel, elution being carried out with 30/70 heptane/ethyl
acetate. 83 mg of
4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
((S)-1-phenylethyl)amide are obtained.
Yield=72%.
[0400] .sup.1H NMR (DMSO, 400 MHz): 1.35-1.45 (m, 5H); 1.53 (m,
2H); 2.67 (t, J=13 Hz, 2H); 2.83 (m, 1H); 4.11 (d, J=12.3 Hz, 2H):
4.83 (m, 1H); 6.43 (d, J=8.0 Hz, 1H); 6.73 (m, 2H); 7.14-7.40 (m,
5H); 9.11 (s, 1H); 9.40 (s, 1H).
[0401] .sup.13C NMR (DMSO, 100 MHz): 23.0, 31.6, 34.6, 44.2, 49.3,
104.5, 113.3 (d, J=19 Hz), 122.4, (d, J=5 Hz), 125.9, 126.1, 127.9,
142.4, 144.6 (d, J=228 Hz), 146.3, 150.4, 155.5.
EXAMPLE 47
(R)-1-[4-(2,4-Dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylethanone
[0402] In a manner analogous to Example 26, but using
(R)-hydroxyphenylacetic acid,
(R)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylethanone
is obtained.
[0403] .sup.1H NMR (DMSO, 400 MHz): (hindrance of rotation) 0.6 (m,
0.5H); 1.30-1.70 (m, 3.5H): 2.5-3 (m, 2H); 4.0 (m, 1H); 4.51 (m,
1H); 5.37-5.57 (m, 2H); 6.07 (m, 1H); 6.24 (m, 1H); 6.48 & 6.72
(2d, J=8.2 Hz, 1H); 7.29-7.38 (m, 5H); 8.98 (2s, 1H); 9.11 (2s,
1H)
[0404] .sup.13C NMR (DMSO, 100 MHz): (hindrance of rotation) 30.9
& 31.4, 31.5 & 31.9, 34.1 & 34.4, 42.9, 45.2, 71.1,
102.4, 105.9, 121.8, 126.3, 126.4, 126.9, 127.5, 128.1, 128.3,
128.4, 128.9, 140.5, 155.1, 156.1, 170.0.
EXAMPLE 48
(S)-1-[4-(2,4-Dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylethanone
[0405] In a manner analogous to Example 26, but using
(S)-hydroxyphenylacetic acid,
(S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-2-phenylethanone
is obtained.
[0406] .sup.1H NMR (DMSO, 400 MHz): (hindrance of rotation) 0.6 (m,
0.5H); 1.30-1.70 (m, 3.5H); 2.5-3 (m, 2H); 4.0 (m, 1H); 4.51 (m,
1H); 5.37-5.57 (m, 2H); 6.07 (m, 1H); 6.24 (m, 1H); 6.48 & 6.72
(2d, J=8.2 Hz, 1H); 7.29-7.38 (m, 5H); 8.98 (2s, 1H); 9.11 (2s,
1H)
[0407] .sup.13C NMR (DMSO, 100 MHz): (hindrance of rotation) 30.9
& 31.4, 31.5 & 31.9, 34.1 & 34.4, 42.9, 45.2, 71.1,
102.4, 105.9, 121.8, 126.3, 126.4, 126.9, 127.5, 128.1, 128.3,
128.4, 128.9, 140.5, 155.1, 156.1, 170.0.
EXAMPLE 49
(R)-1-[4-(2,4-Dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-3-phenylpropan-1-o-
ne
[0408] In a manner analogous to Example 26, but using
(R)-2-hydroxy-3-phenylpropionic acid,
(R)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-3-phenylpropan-1--
one is obtained.
[0409] .sup.1H NMR (DMSO, 400 MHz): (hindrance of rotation)
1.04-1.70 (m, 4H); 2.50-3.34 (m, 5H); 4.02 (m, 1H); 4.52 (m, 2H);
4.97 (m, 1H); 6.14 (d, J=8.2 Hz, 1H); 6.25 (m, 1H); 6.67 &
6.782 (2d, J=8.2 Hz, 1H); 7.14-7.28 (m, 5H); 8.97 (2s, 1H); 9.15
(2s, 1H).
[0410] .sup.13C NMR (DMSO, 100 MHz): (hindrance of rotation) 31.6
& 31.7, 34.5 & 34.7, 40.3 & 40.6, 42.5, 45.6, 68.6
& 68.9, 102.5, 106.1, 122.1, 126.1, 126.8, 128.1, 129.6, 138.1
& 138.4, 155.3, 156.2, 171.0.
EXAMPLE 50
(S)-1-[4-(2,4-Dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-3-phenylpropan-1-o-
ne
[0411] In a manner analogous to Example 26, but using
(S)-2-hydroxy-3-phenylpropionic acid,
(S)-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-2-hydroxy-3-phenylpropan-1--
one is obtained.
[0412] .sup.1H NMR (DMSO, 400 MHz): (hindrance of rotation)
1.04-1.70 (m, 4H); 2.50-3.34 (m, 5H); 4.02 (m, 1H); 4.52 (m, 2H);
4.97 (m, 1H); 6.14 (d, J=8.2 Hz, 1H); 6.25 (m, 1H); 6.67 &
6.782 (2d, J=8.2 Hz, 1H); 7.14-7.28 (m, 5H); 8.97 (2s, 1H); 9.15
(2s, 1H).
[0413] .sup.13C NMR (DMSO, 100 MHz): (hindrance of rotation) 31.6
& 31.7, 34.5 & 34.7, 40.3 & 40.6, 42.5, 45.6, 68.6
& 68.9, 102.5, 106.1, 122.1, 126.1, 126.8, 128.1, 129.6, 138.1
& 138.4, 155.3, 156.2, 171.0.
EXAMPLE 51
Tyrosinase activity inhibition assay
[0414] The activity of the inhibitors is measured using a lysate of
B16F1 cells (murine melanoma line). In the presence of the
L-tyrosine substrate, the tyrosinase present in these cells
catalyses the hydroxylation of L-tyrosine to give L-DOPA and then
the oxidation of the L-DOPA to give dopaquinone. In the presence of
MBTH (3-methyl-2-benzothiazolinone hydrazone), the dopaquinone is
trapped so as to form a pink complex which absorbs at 520 nm.
[0415] The B16F1 cells are cultured in DMEM medium+10% foetal calf
serum+10.sup.-9 M .alpha.-MSH for 4 days at 37.degree. C. under 7%
CO.sub.2. They are treated with trypsin, washed in PBS, counted and
pelleted. The pellet is taken up at 10.sup.7 cells/mL in lysis
buffer (10 mM sodium phosphate, pH 6.8 --1% Igepal) and the
suspension is treated with ultrasound for 10 seconds. After
centrifugation for 30 minutes at 4000 rpm, the supernatant obtained
constitutes the cell lysate used as tyrosinase source in the
enzymatic assay.
[0416] The assays are carried out in duplicate in 384-well plates
in a total volume of 50 .mu.l. Each well contains: [0417] 40 .mu.l
of solution containing 1.25 mM L-tyrosine, 6.25 .mu.M L-DOPA
(cofactor) and 3.75 mM MBTH in buffer B (62.25 mM sodium phosphate,
pH 6.8--2.5% dimethylformamide), [0418] 5 .mu.l of inhibitor
diluted in DMSO, [0419] 5 .mu.l of cell lysate diluted to 1/2 in 50
mM Tris HCl buffer, pH 7.5.
[0420] The plate is incubated at 37.degree. C. and a
spectrophotometric reading is carried out at 520 nm after 6 hours
of incubation. In order to avoid any possible absorption of the
products, the system uses corrected absorbance (absorbance at time
6 h--absorbance at time zero).
[0421] The inhibitors are assayed in terms of dose-response so as
to calculate an IC.sub.50 (dose which inhibits 50% of the enzymatic
activity).
[0422] Several internal controls are added to each experiment:
[0423] control for 100% activity: the 5 .mu.l of inhibitor are
replaced with 5 .mu.l of DMSO, [0424] control for 50% activity: the
5 .mu.l of inhibitor are replaced with 5 .mu.l of phenylthiourea at
300 .mu.M in DMSO, [0425] control for 0% activity: the L-tyrosine
substrate is replaced with buffer B.
[0426] The results obtained for the compounds of the invention are
shown in Table A:
TABLE-US-00001 TABLE A Tyrosine hydroxylase/ Dopa oxidase IC.sub.50
Name Structure (.mu.M) 4-Butylresorcinol (Rucinol) ##STR00015## 3
Compound 48 ##STR00016## 0.2 Compound 24 ##STR00017## 0.15
EXAMPLE 52
Melanogenesis Inhibition assay
[0427] The inhibition of melanogenesis is measured in MNT1 human
melanoma cells according to a protocol adapted from Reigner et al.,
Cell Mol Biol (1999) 45: 969-980. The assay is based on the
concomitant incorporation of 2 radiolabelled tracers:
.sup.14C-thiouracil is incorporated into the neosynthesized melanin
and reflects melanogenesis, whereas .sup.3H-leucine is incorporated
into the proteins and reflects cell viability and, consequently,
the toxicity of the compounds tested.
[0428] The MNT1 cells are seeded into 96-well plates in the
presence of the test compounds and of the radioisotopes. After
incubation for 24 h at 37.degree. C., the cells are washed and the
amount of the 2 radioisotopes is measured. The test compounds are
evaluated in terms of dose-response so as to calculate an IC.sub.50
for inhibition of melanogenesis on the basis of the .sup.14C
incorporation which is standardized through the .sup.3H
incorporation. An IC.sub.50 for cell toxicity is also calculated on
the basis of the .sup.3H incorporation.
[0429] This assay therefore makes it possible to distinguish the
products that specifically inhibit melanogenesis from those which
are cytotoxic to melanocytes.
TABLE-US-00002 IC.sub.50 IC.sub.50 Name Formula melanogenesis
toxicity 4-Butyl- resorcinol (Rucinol) ##STR00018## 15 .mu.M 55
.mu.M Compound 48 ##STR00019## 0.7 .mu.M >999 .mu.M Compound 24
##STR00020## 0.3 .mu.M >999 .mu.M
EXAMPLE 53
Formulations
[0430] This example illustrates various formulations based on the
compounds according to the invention.
Topically
TABLE-US-00003 [0431] (a) Ointment Compound 16 0.020 g Isopropyl
myristate 81.700 g Liquid petroleum jelly 9.100 g Silica (Aerosil
200) 9.180 g (b) Ointment Compound 6 0.300 g White petroleum jelly,
qs 100 g pharmaceutical grade (c) Nonionic water-in-oil cream
Compound 16 0.100 g Mixture of emulsive lanolin alcohols, of 39.900
g waxes and of oils (Anhydrous eucerin) Methyl para-hydroxybenzoate
0.075 g Propyl para-hydroxybenzoate 0.075 g Sterile demineralized
water qs 100 g (d) Lotion Compound 6 0.100 g Polyethylene glycol
(PEG 400) 69.900 g 95% ethanol 30.000 g (e) Hydrophobic ointment
Compound 22 0.300 g Isopropyl myristate 36.400 g Silicone oil
(Rhodorsil 47 V 300) 36.400 g Beeswax 13.600 g Silicone oil (Abil
300,000 cst) qs 100 g (f) Nonionic oil-in-water cream Compound 4
1.000 g Cetyl alcohol 4.000 g Glyceryl monostearate 2.500 g PEG 50
stearate 2.500 g Shea butter 9.200 g Propylene glycol 2.000 g
Methyl para-hydroxybenzoate 0.075 g Propyl para-hydroxybenzoate
0.075 g Sterile demineralized water qs 100 g
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