U.S. patent application number 13/229106 was filed with the patent office on 2012-01-05 for therapeutic uses of derivatives of piperidinyl-and piperidinyl-alkyl carbamates.
This patent application is currently assigned to SANOFI-AVENTIS. Invention is credited to Ahmed Abouabdellah, Philippe Burnier, Christian Hoornaert, Jean Jeunesse, Frederic Puech.
Application Number | 20120004207 13/229106 |
Document ID | / |
Family ID | 33306203 |
Filed Date | 2012-01-05 |
United States Patent
Application |
20120004207 |
Kind Code |
A1 |
Abouabdellah; Ahmed ; et
al. |
January 5, 2012 |
THERAPEUTIC USES OF DERIVATIVES OF PIPERIDINYL-AND
PIPERIDINYL-ALKYL CARBAMATES
Abstract
Compound corresponding to the general formula (I): ##STR00001##
in which A=N or CR.sub.2; R.sub.2.dbd.H, F, OH, CN, CF.sub.3,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy; n=2 or 3 and m=2 when A=N; n=1,
2 or 3 and m=1 or 2 when A=CR.sub.2; B=covalent bond or
C.sub.1-8-alkylene; R.sub.1=optionally substituted heteroaryl;
R.sub.3.dbd.CHR.sub.4CONHR.sub.5; R.sub.4.dbd.H or C.sub.1-6-alkyl;
R.sub.5.dbd.H, C.sub.1-6-alkyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-C.sub.6-alkylene; in the form of a
base, an acid-addition salt, a hydrate or a solvate. Therapeutic
uses thereof.
Inventors: |
Abouabdellah; Ahmed;
(Thiais, FR) ; Burnier; Philippe;
(Maisons-Laffitte, FR) ; Hoornaert; Christian;
(Antony, FR) ; Jeunesse; Jean; (Paris, FR)
; Puech; Frederic; (La Celle Saint-Cloud, FR) |
Assignee: |
SANOFI-AVENTIS
Paris
FR
|
Family ID: |
33306203 |
Appl. No.: |
13/229106 |
Filed: |
September 9, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11670690 |
Feb 2, 2007 |
8034818 |
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13229106 |
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11262211 |
Oct 28, 2005 |
7214798 |
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11670690 |
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PCT/FR04/01102 |
May 6, 2004 |
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11262211 |
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Current U.S.
Class: |
514/210.01 ;
514/218; 514/252.02; 514/252.11; 514/252.14; 514/253.01;
514/253.09; 514/254.03; 514/255.03; 544/238; 544/295; 544/357;
544/360; 544/364; 544/367; 544/393 |
Current CPC
Class: |
A61P 25/18 20180101;
C07D 401/14 20130101; A61P 25/08 20180101; A61P 37/06 20180101;
A61P 11/00 20180101; A61P 31/18 20180101; C07D 295/13 20130101;
A61P 43/00 20180101; A61P 11/02 20180101; C07D 401/04 20130101;
A61P 9/06 20180101; A61P 7/06 20180101; A61P 13/00 20180101; A61P
17/06 20180101; C07D 471/04 20130101; A61P 1/08 20180101; A61P
19/02 20180101; A61P 25/14 20180101; A61P 29/00 20180101; A61P
37/02 20180101; A61P 1/04 20180101; A61P 21/04 20180101; A61P 31/00
20180101; C07D 413/04 20130101; A61P 37/08 20180101; A61P 13/12
20180101; A61P 25/00 20180101; A61P 27/06 20180101; A61P 11/06
20180101; A61P 13/08 20180101; C07D 213/38 20130101; A61P 7/00
20180101; A61P 25/20 20180101; A61P 19/10 20180101; A61P 25/22
20180101; A61P 27/16 20180101; C07D 491/04 20130101; A61P 9/10
20180101; A61P 3/00 20180101; A61P 19/06 20180101; A61P 1/00
20180101; A61P 9/00 20180101; A61P 1/12 20180101; A61P 35/00
20180101; A61P 17/04 20180101; A61P 31/04 20180101; A61P 25/02
20180101; A61P 37/00 20180101; A61P 1/14 20180101; A61P 25/16
20180101; A61P 25/28 20180101; A61P 37/04 20180101; A61P 27/02
20180101; A61P 17/00 20180101; A61P 33/00 20180101; C07D 211/26
20130101; C07D 417/04 20130101; A61P 9/12 20180101; A61P 13/10
20180101; A61P 31/12 20180101; C07D 495/04 20130101 |
Class at
Publication: |
514/210.01 ;
544/393; 544/360; 544/295; 544/367; 544/364; 544/357; 544/238;
514/255.03; 514/253.01; 514/252.14; 514/254.03; 514/253.09;
514/252.11; 514/252.02; 514/218 |
International
Class: |
A61K 31/495 20060101
A61K031/495; C07D 401/12 20060101 C07D401/12; C07D 403/12 20060101
C07D403/12; C07D 417/12 20060101 C07D417/12; C07D 403/14 20060101
C07D403/14; A61K 31/496 20060101 A61K031/496; A61K 31/497 20060101
A61K031/497; A61K 31/501 20060101 A61K031/501; A61K 31/551 20060101
A61K031/551; A61K 31/397 20060101 A61K031/397; A61P 25/00 20060101
A61P025/00; A61P 1/08 20060101 A61P001/08; A61P 3/00 20060101
A61P003/00; A61P 25/28 20060101 A61P025/28; A61P 25/08 20060101
A61P025/08; A61P 9/00 20060101 A61P009/00; A61P 9/10 20060101
A61P009/10; A61P 35/00 20060101 A61P035/00; A61P 37/00 20060101
A61P037/00; A61P 37/08 20060101 A61P037/08; A61P 33/00 20060101
A61P033/00; A61P 31/12 20060101 A61P031/12; A61P 31/04 20060101
A61P031/04; A61P 29/00 20060101 A61P029/00; A61P 19/10 20060101
A61P019/10; A61P 27/02 20060101 A61P027/02; A61P 1/00 20060101
A61P001/00; A61P 13/00 20060101 A61P013/00; C07D 295/15 20060101
C07D295/15 |
Foreign Application Data
Date |
Code |
Application Number |
May 7, 2003 |
FR |
0305540 |
Claims
1. A compound corresponding to formula (I) ##STR00119## in which A
is a nitrogen atom or a CR.sub.2 group in which R.sub.2 is a
hydrogen or fluorine atom or a hydroxyl, cyano, trifluoromethyl,
C.sub.1-6-alkyl or C.sub.1-6-alkoxy group; when A is a nitrogen
atom, n is an integer equal to 3 and m is 2; when A is a CR.sub.2
group, n is an integer equal to 1, 2 or 3 and m is an integer equal
to 1 or 2; B is a covalent bond or a C.sub.1-8-alkylene group;
R.sub.1 is a group selected from phenyl, pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl,
tetrahydroisoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, cinnolyl, imidazopyrimidinyl, thienopyrimidinyl,
benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl,
pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl,
dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl,
oxazolopyridyl, isoxazolopyridyl and thiazolopyridyl, said R.sub.1
group being optionally substituted with one or more groups selected
from R' and R''; R' is a halogen atom or a cyano, nitro, hydroxyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-thioalkyl,
C.sub.1-6-fluoroalkyl, C.sub.1-6-fluoroalkoxy,
C.sub.1-6-fluorothioalkyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-6-alkylene, azetidinyl, piperidyl,
pyrrolidinyl, morpholinyl, piperazinyl, azepinyl, NH.sub.2,
NHR.sub.6, NR.sub.6R.sub.7, NR.sub.6COR.sub.7,
NR.sub.6SO.sub.2R.sub.7, COR.sub.6, CO.sub.2R.sub.6,
SO.sub.2R.sub.6, SO.sub.2NR.sub.6R.sub.7 or
--O--(C.sub.1-6-alkylene)-O-- group; R'' is a phenyl, imidazolyl,
pyridyl or pyrimidinyl group; each R'' group is optionally
substituted with one or more R'groups, which may be identical to or
different from each other; R.sub.3 is a group of general formula
CHR.sub.4CONHR.sub.5 in which: R.sub.4 is a hydrogen atom or a
C.sub.1-6-alkyl group and R.sub.5 is a hydrogen atom or a
C.sub.1-6-alkyl, C.sub.3-7-cycloalkyl or
C.sub.3-7-cycloalkyl-C.sub.1-6-alkylene group; and each of R.sub.6
and R.sub.7 is, independently, a C.sub.1-6-alkyl group; in the form
of a base, an acid-addition salt, a hydrate or a solvate.
2. A compound of formula (I) according to claim 1, wherein: A is a
nitrogen atom; n is 3; m is 2; B is a C.sub.1-8-alkylene group;
R.sub.1 is a group selected from phenyl, pyridyl, pyrimidinyl,
thiadiazolyl and naphthyl, said R.sub.1 group being optionally
substituted with one or more groups selected from R' and R''; R' is
a halogen atom or a nitro or C.sub.1-6-fluoroalkyl group; R'' is a
phenyl, optionally substituted with one or more groups, which may
be identical to or different from each other, selected from halogen
cyano, C.sub.1-6-alkoxy and C.sub.1-6-fluoroalkoxy; R.sub.3 is a
group of general formula CHR.sub.4CONHR.sub.5 in which: R.sub.4 is
a hydrogen atom and R.sub.5 is a hydrogen atom or a
C.sub.1-6-alkyl, C.sub.3-7-cycloalkyl or
C.sub.3-7-cycloalkyl-C.sub.1-6-alkylene group; in the form of a
base, an acid-addition salt, a hydrate or a solvate.
3. A compound of formula (I) according to claim 1, wherein: A is a
CR.sub.2 group in which R.sub.2 is a hydrogen or fluorine atom or a
hydroxyl group; each of m and n is an integer equal to 1 or 2; B is
a covalent bond or a C.sub.1-4-alkylene group; R.sub.1 is a group
selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
thiazolyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, furopyridyl, thienopyrimidinyl,
imidazopyrimidinyl, benzothiazolyl, benzimidazolyl and
benzoxazolyl, said R.sub.1 group being optionally substituted with
one or more groups selected from R' and R''; R' is a halogen atom,
or a cyano or C.sub.1-6-alkyl, a C.sub.1-6-alkoxy,
C.sub.1-6-fluoroalkyl, C.sub.1-6-fluoroalkoxy,
C.sub.3-7-cycloalkyl, pyrrolidinyl, NH.sub.2, NR.sub.6R.sub.7 or
COR.sub.6 group; R'' is phenyl, imidazolyl or pyridyl; each R''
group is optionally substituted with one or more R' groups selected
from chlorine and fluorine atoms; R.sub.3 is a group of general
formula CHR.sub.4CONHR.sub.5 in which R.sub.4 is a hydrogen atom or
a C.sub.1-6-alkyl group, and R.sub.5 is a hydrogen atom or a
C.sub.1-6-alkyl, C.sub.3-7-cycloalkyl or
C.sub.3-7-cycloalkyl-C.sub.1-C.sub.6-alkylene group; and each of
R.sub.6 and R.sub.7 is, independently, a C.sub.1-6-alkyl group; in
the form of a base, an acid-addition salt, a hydrate or a
solvate.
4. A compound of formula (I) according to claim 1, wherein: A is
CH; each of m and n is equal to 2; B is an ethyl group; R.sub.1 is
selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
thiazolyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, furopyridyl, thienopyrimidinyl,
imidazopyrimidinyl, benzothiazolyl, benzimidazolyl and
benzoxazolyl, said R.sub.1 group being optionally substituted with
one or more groups selected from R' and R''; R' represents a
halogen atom or a cyano or C.sub.1-6-alkyl, a C.sub.1-6-alkoxy,
C.sub.1-6-fluoroalkyl, C.sub.1-6-fluoroalkoxy,
C.sub.3-7-cycloalkyl, pyrrolidinyl, NH.sub.2, NR.sub.6R.sub.7 or
COR.sub.6 group; R'' represents a phenyl, imidazolyl or pyridyl;
each R'' group is optionally substituted with one or more R' groups
selected from chlorine and fluorine atoms; R.sub.3 is a group of
general formula CH2CONHR.sub.5 in which R.sub.5 is a hydrogen atom
or a C.sub.1-C.sub.6-alkyl group; and each of R.sub.6 and R.sub.7
is, independently, a C.sub.1-6-alkyl group; in the form of the
base, an acid-addition salt, a hydrate or a solvate.
5. A process for preparing a compound of formula (I) according to
claim 1, comprising the step of subjecting a carbamate ester of
general formula (Ia) ##STR00120## in which n, m, A, B, R.sub.1 and
R.sub.4 are as defined in claim 1 and R represents a methyl or
ethyl group, to aminolysis using an amine of general formula
R.sub.5NH.sub.2 in which R.sub.5 is as defined in claim 1.
6. A process for preparing a compound of formula (I) according to
claim 1, comprising the step of subjecting an oxazolidinedione
derivative of general formula (V) ##STR00121## in which n, m, A, B,
R.sub.1 and R.sub.4 are as defined in claim 1, to aminolysis using
an amine of general formula R.sub.5NH.sub.2 in which R.sub.5 is as
defined in claim 1.
7. A compound corresponding to the general formula (Ia)
##STR00122## in which A is a nitrogen atom or a CR.sub.2 group in
which R.sub.2 is a hydrogen or fluorine atom or a hydroxyl, cyano,
trifluoromethyl, C.sub.1-6-alkyl or C.sub.1-6-alkoxy group; when A
is a nitrogen atom, n is an integer equal to 3 and m is 2; when A
is a CR.sub.2 group, n is an integer equal to 1, 2 or 3 and m is an
integer equal to 1 or 2; B is a covalent bond or a
C.sub.1-8-alkylene group; R.sub.1 is a group selected from phenyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl,
thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl,
isoquinolyl, tetrahydroisoquinolyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, cinnolyl, imidazopyrimidinyl,
thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl,
benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,
indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl,
thienopyridyl, dihydrothienopyridyl, imidazopyridyl,
pyrazolopyridyl, oxazolopyridyl, isoxazolopyridyl and
thiazolopyridyl, said R.sub.1 group being optionally substituted
with one or more groups selected from R' and R''; R' is a halogen
atom or a cyano, nitro, hydroxyl, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, C.sub.1-6-thioalkyl, C.sub.1-6-fluoroalkyl,
C.sub.1-6-fluoroalkoxy, C.sub.1-6-fluorothioalkyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-6-alkylene,
azetidinyl, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl,
azepinyl, NH.sub.2, NHR.sub.6, NR.sub.6R.sub.7, NR.sub.6COR.sub.7,
NR.sub.6SO.sub.2R.sub.7, COR.sub.6, CO.sub.2R.sub.6,
SO.sub.2R.sub.6, SO.sub.2NR.sub.6R.sub.7 or
--O--(C.sub.1-6-alkylene)-O-- group; R'' is a phenyl, imidazolyl,
pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl group; each R''
group is optionally substituted with one or more R'groups, which
may be identical to or different from each other; R.sub.4 is a
hydrogen atom or a C.sub.1-6-alkyl group; each of R.sub.6 and
R.sub.7 is, independently, a C.sub.1-6-alkyl group; and R is a
methyl or ethyl group.
8. A compound corresponding to the general formula (V) ##STR00123##
in which A is a nitrogen atom or a CR.sub.2 group in which R.sub.2
is a hydrogen or fluorine atom or a hydroxyl, cyano,
trifluoromethyl, C.sub.1-6-alkyl or C.sub.1-6-alkoxy group; when A
is a nitrogen atom, n is an integer equal to 3 and m is 2; when A
is a CR.sub.2 group, n is an integer equal to 1, 2 or 3 and m is an
integer equal to 1 or 2; B is a covalent bond or a
C.sub.1-8-alkylene group; R.sub.1 is a group selected from phenyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl,
thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl,
isoquinolyl, tetrahydroisoquinolyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, cinnolyl, imidazopyrimidinyl,
thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl,
benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,
indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl,
thienopyridyl, dihydrothienopyridyl, imidazopyridyl,
pyrazolopyridyl, oxazolopyridyl, isoxazolopyridyl and
thiazolopyridyl, said R.sub.1 group being optionally substituted
with one or more groups selected from R' and R''; R' is a halogen
atom or a cyano, nitro, hydroxyl, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, C.sub.1-6-thioalkyl, C.sub.1-6-fluoroalkyl,
C.sub.1-6-fluoroalkoxy, C.sub.1-6-fluorothioalkyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-6-alkylene,
azetidinyl, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl,
azepinyl, NH.sub.2, NHR.sub.6, NR.sub.6R.sub.7, NR.sub.6COR.sub.7,
NR.sub.6SO.sub.2R.sub.7, COR.sub.6, CO.sub.2R.sub.6,
SO.sub.2R.sub.6, SO.sub.2NR.sub.6R.sub.7 or
--O--(C.sub.1-6-alkylene)-O-- group; R'' is a phenyl, imidazolyl,
pyridyl or pyrimidinyl group; each R'' group is optionally
substituted with one or more R'groups, which may be identical to or
different from each other; R.sub.3 is a group of general formula
CHR.sub.4CONHR.sub.5 in which: R.sub.4 is a hydrogen atom or a
C.sub.1-6-alkyl group; and each of R.sub.6 and R.sub.7 is,
independently, a C.sub.1-6-alkyl group.
9. A medicament comprising a compound of formula (I) according to
claim 1, in the form of the base or of a pharmaceutically
acceptable acid-addition salt, hydrate or solvate.
10. A pharmaceutical composition containing at least one compound
of formula (I) according to claim 1, in the form of a base or of a
pharmaceutically acceptable acid-addition salt, hydrate or solvate,
and one or more pharmaceutically acceptable excipients.
11. A method of preventing or treating a pathology in which the
endogenous cannabinoids and/or any other substrate metabolized by
the enzyme FAAH are involved, comprising administering to a patient
in need thereof an effective amount of a compound of formula (I)
according to claim 1, in the form of a base or of a
pharmaceutically acceptable acid-addition salt, hydrate or
solvate.
12. The method of claim 11 for preventing or treating acute or
chronic pain, vertigo, vomiting, nausea, eating disorders,
neurological and psychiatric pathologies, acute or chronic
neurodegenerative diseases, epilepsy, sleeping disorders,
cardiovascular diseases, renal ischaemia, cancers, immune system
disorders, allergic diseases, parasitic, viral or bacterial
infectious diseases, inflammatory diseases, osteoporosis, ocular
complaints, pulmonary complaints, gastrointestinal diseases or
urinary incontinence.
13. A compound chosen from the group consisting of; ##STR00124##
##STR00125## ##STR00126## ##STR00127## ##STR00128## ##STR00129##
##STR00130## ##STR00131## ##STR00132## ##STR00133## ##STR00134##
##STR00135## ##STR00136## ##STR00137## ##STR00138## ##STR00139##
##STR00140## ##STR00141## ##STR00142## in the form of a base, an
acid-addition salt, a hydrate or a solvate.
14. A medicament comprising a compound according to claim 13, in
the form of the base or of a pharmaceutically acceptable
acid-addition salt, hydrate or solvate.
15. A pharmaceutical composition containing at least one compound
according to claim 13, in the form of a base or of a
pharmaceutically acceptable acid-addition salt, hydrate or solvate,
and one or more pharmaceutically acceptable excipients.
16. A method of preventing or treating a pathology in which the
endogenous cannabinoids and/or any other substrate metabolized by
the enzyme FAAH are involved, comprising administering to a patient
in need thereof an effective amount of a compound according to
claim 13, in the form of a base or of a pharmaceutically acceptable
acid-addition salt, hydrate or solvate.
17. The method of claim 16 for preventing or treating acute or
chronic pain, vertigo, vomiting, nausea, eating disorders,
neurological and psychiatric pathologies, acute or chronic
neurodegenerative diseases, epilepsy, sleeping disorders,
cardiovascular diseases, renal ischaemia, cancers, immune system
disorders, allergic diseases, parasitic, viral or bacterial
infectious diseases, inflammatory diseases, osteoporosis, ocular
complaints, pulmonary complaints, gastrointestinal diseases or
urinary incontinence.
Description
CROSS-REFERENCE
[0001] This application is a divisional of U.S. patent application
Ser. No. 11/670,690, filed Feb. 2, 2008 which is a divisional of
U.S. patent application Ser. No. 11/262,211 now U.S. Pat. No.
7,214,798 which claims the benefit of WO International Application
No. PCT/FR 2004/001102, filed May 6, 2004, which WO application
claims the benefit of priority of French Patent Application No.
03/05540, filed May 7, 2003, all of which are incorporated by
reference in their entireties.
BACKGROUND OF THE INVENTION
[0002] The invention relates to piperidyl- and
piperazinyl-alkylcarbamate derivatives and to the preparation and
therapeutic application thereof.
SUMMARY OF THE INVENTION
[0003] The compounds of the invention correspond to the general
formula (I):
##STR00002##
in which [0004] A represents a nitrogen atom or a group CR.sub.2 in
which R.sub.2 represents a hydrogen or fluorine atom or a hydroxyl,
cyano, trifluoromethyl, C.sub.1-6-alkyl or C.sub.1-6-alkoxy group;
[0005] n represents an integer equal to 2 or 3 and m represents an
integer equal to 2 when A represents a nitrogen atom; [0006] n
represents an integer equal to 1, 2 or 3 and m represents an
integer equal to 1 or 2 when A represents a group CR.sub.2; [0007]
B represents a covalent bond or a C.sub.1-8-alkylene group; [0008]
R.sub.1 represents a group chosen from phenyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl,
thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl,
isoquinolyl, tetrahydroisoquinolyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, cinnolyl, imidazopyrimidinyl,
thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl,
benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,
indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl,
thienopyridyl, dihydrothienopyridyl, imidazopyridyl,
pyrazolopyridyl, oxazolopyridyl, isoxazolopyridyl and
thiazolopyridyl; [0009] the group R.sub.1 optionally being
substituted with one or more groups R' and/or R''; [0010] R'
represents a halogen atom or a cyano, nitro, hydroxyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-thioalkyl,
C.sub.1-6-fluoroalkyl, C.sub.1-6-fluoroalkoxy,
C.sub.1-6-fluorothioalkyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-6-alkylene, azetidinyl, piperidyl,
pyrrolidinyl, morpholinyl, piperazinyl, azepinyl, NH.sub.2,
NHR.sub.6, NR.sub.6R.sub.7, NR.sub.6COR.sub.7,
NR.sub.6SO.sub.2R.sub.7, COR.sub.6, CO.sub.2R.sub.6,
SO.sub.2R.sub.6, SO.sub.2NR.sub.6R.sub.7 or
--O--(C.sub.1-6-alkylene)-O-- group; [0011] R'' represents a
phenyl, imidazolyl, pyridyl, pyridazinyl, pyrazinyl or pyrimidinyl;
[0012] the group(s) R'' being optionally substituted with one or
more groups R', which may be identical to or different from each
other; [0013] R.sub.3 represents a group of general formula
CHR.sub.4CONHR.sub.5 in which [0014] R.sub.4 represents a hydrogen
atom or a C.sub.1-6-alkyl group and [0015] R.sub.5 represents a
hydrogen atom or a C.sub.1-6-alkyl, C.sub.3-7-cycloalkyl or
C.sub.3-7-cycloalkyl-C.sub.1-6-alkylene group; [0016] R.sub.6 and
R.sub.7 represent, independently of each other, a C.sub.1-6-alkyl
group.
DETAILED DESCRIPTION
[0017] Among the compounds of general formula (I), a first subgroup
of compounds consists of compounds for which: [0018] A represents a
nitrogen atom; and/or [0019] n represents an integer equal to 2 or
3 and m represents an integer equal to 2; and/or [0020] B
represents a C.sub.1-8-alkylene group, more particularly an ethyl
or propyl; and/or [0021] R.sub.1 represents a group chosen from
phenyl, pyridyl, pyrimidinyl, thiadiazolyl and naphthyl; [0022] the
group R.sub.1 being optionally substituted with one or more groups
R' and/or R''; and/or [0023] R' represents a halogen atom, more
particularly a chlorine, or a nitro or C.sub.1-6-fluoroalkyl group,
more particularly a trifluoromethyl; and/or [0024] R'' represents a
phenyl optionally substituted with one or more groups, which may be
identical to or different from each other, chosen from a halogen
atom, more particularly a chlorine, and a cyano, C.sub.1-6-alkoxy,
more particularly a methoxy, or C.sub.1-6-fluoroalkoxy, more
particularly a trifluoromethoxy, group; and/or [0025] R.sub.3
represents a group of general formula CHR.sub.4CONHR.sub.5 in which
[0026] R.sub.4 represents a hydrogen atom and [0027] R.sub.5
represents a hydrogen atom or a C.sub.1-6-alkyl group, more
particularly a methyl or an ethyl, a C.sub.3-7-cycloalkyl group,
more particularly a cyclopropyl, or a
C.sub.3-7-cycloalkyl-C.sub.1-6-alkylene group, more particularly a
cyclopropyl-methylene.
[0028] Among the compounds of general formula (I), a second
subgroup of compounds consists of compounds for which: [0029] A
represents a group CR.sub.2 in which R.sub.2 represents a hydrogen
or fluorine atom or a hydroxyl group; and/or [0030] m represents an
integer equal to 1 or 2 and n represents an integer equal to 1 or
2; and/or [0031] B represents a covalent bond or a
C.sub.1-4-alkylene group, more particularly a methyl, ethyl or
n-propyl; and/or [0032] R.sub.1 represents a group chosen from
phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,
quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, furopyridyl, thienopyrimidinyl, imidazopyrimidinyl,
benzothiazolyl, benzimidazolyl and benzoxazolyl; [0033] the group
R.sub.1 being optionally substituted with one or more groups R'
and/or R''; and/or [0034] R' represents a halogen atom, more
particularly a fluorine, a chlorine or a bromine, or a cyano group,
C.sub.1-6-alkyl, more particularly a methyl, ethyl, n-propyl or
isobutyl, a C.sub.1-6-alkoxy, more particularly a methoxy,
C.sub.1-6-fluoroalkyl, more particularly a trifluoromethyl,
C.sub.1-6-fluoroalkoxy, more particularly a trifluoromethoxy,
C.sub.3-7-cycloalkyl, more particularly a cyclopropyl or
cyclopentyl, pyrrolidinyl, NH.sub.2, NR.sub.6R.sub.7 or COR.sub.6;
and/or [0035] R'' represents a phenyl, imidazolyl or pyridyl; the
group(s) R'' being optionally substituted with one or more groups
R', which may be identical to or different from each other, more
particularly with one or more chlorine or fluorine atoms; and/or
[0036] R.sub.3 represents a group of general formula
CHR.sub.4CONHR.sub.5 in which [0037] R.sub.4 represents a hydrogen
atom or a C.sub.1-6-alkyl group, more particularly a methyl, and
[0038] R.sub.5 represents a hydrogen atom or a C.sub.1-6-alkyl
group, more particularly a methyl or an ethyl,
C.sub.3-7-cycloalkyl, more particularly a cyclopropyl,
C.sub.3-7-cycloalkyl-C.sub.1-C.sub.6-alkylene, more particularly a
cyclopropyl-methylene; and/or [0039] R.sub.6 and R.sub.7 represent,
independently of each other, a C.sub.1-6-alkyl group, more
particularly a methyl.
[0040] Among the compounds of general formula (I), a third subgroup
of compounds consists of compounds for which: [0041] A represents a
group CR.sub.2 in which R.sub.2 represents a hydrogen atom; and/or
[0042] m is equal to 2 and n is equal to 2; and/or [0043] B
represents an ethyl group; and/or [0044] R.sub.1 represents a group
chosen from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
thiazolyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, furopyridyl, thienopyrimidinyl,
imidazopyrimidinyl, benzothiazolyl, benzimidazolyl and
benzoxazolyl; [0045] the group R.sub.1 being optionally substituted
with one or more groups R' and/or R''; and/or [0046] R' represents
a halogen atom, more particularly a fluorine, a chlorine or a
bromine, or a cyano group, C.sub.1-6-alkyl, more particularly a
methyl, ethyl, n-propyl or isobutyl, a C.sub.1-6-alkoxy, more
particularly a methoxy, C.sub.1-6-fluoroalkyl, more particularly a
trifluoromethyl, C.sub.1-6-fluoroalkoxy, more particularly a
trifluoromethoxy, C.sub.3-7-cycloalkyl, more particularly a
cyclopropyl or cyclopentyl, pyrrolidinyl, NH.sub.2, NR.sub.6R.sub.7
or COR.sub.6; and/or [0047] R'' represents a phenyl, imidazolyl or
pyridyl; [0048] the group(s) R'' being optionally substituted with
one or more groups R', which may be identical to or different from
each other, more particularly with one or more chlorine or fluorine
atoms; and/or [0049] R.sub.3 represents a group of general formula
CHR.sub.4CONHR.sub.5 in which [0050] R.sub.4 represents a hydrogen
atom and [0051] R.sub.5 represents a hydrogen atom or a
C.sub.1-C.sub.6-alkyl group, more particularly a methyl or an
ethyl; and/or [0052] R.sub.6 and R.sub.7 represent, independently
of each other, a C.sub.1-6-alkyl group, more particularly a
methyl.
[0053] A subject of the invention is also, among the compounds of
general formula (I), compounds corresponding to the general formula
(I'):
##STR00003##
in which [0054] A represents a nitrogen atom or a group CR.sub.2 in
which R.sub.2 represents a hydrogen or fluorine atom or a hydroxyl,
cyano, trifluoromethyl, C.sub.1-5-alkyl or C.sub.1-5-alkoxy group;
[0055] n represents an integer equal to 2 or 3 and m represents an
integer equal to 2 when A represents a nitrogen atom; [0056] n
represents an integer equal to 1, 2 or 3 and m represents an
integer equal to 1 or 2 when A represents a group CR.sub.2; [0057]
B represents a covalent bond or a C.sub.1-8-alkylene group; [0058]
R.sub.1 represents a group chosen from phenyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, thiazolyl,
imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, naphthyl,
quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl,
phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolyl,
imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,
benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl,
dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl,
imidazopyridyl, pyrazolopyridyl, oxazolopyridyl, isoxazolopyridyl
and thiazolopyridyl; [0059] optionally substituted with one or more
substituents chosen from a halogen atom and a cyano, nitro,
C.sub.1-5-alkyl, C.sub.1-3-alkoxy, C.sub.1-5-thioalkyl,
C.sub.1-5-fluoroalkyl, C.sub.1-3-fluoroalkoxy,
C.sub.1-3-fluorothioalkyl, C.sub.3-5-cycloalkyl,
C.sub.3-5-cycloalkyl-C.sub.1-3-alkylene, piperidyl, pyrrolidinyl,
morpholinyl, NH.sub.2, NHR.sub.6, NR.sub.6R.sub.7, NHCOR.sub.6,
COR.sub.6, CO.sub.2R.sub.6, SO.sub.2R.sub.6,
--O--(C.sub.1-3-alkylene)-O--, phenyl, pyridyl or pyrimidinyl
group; [0060] the phenyl, pyridyl and pyrimidinyl groups possibly
being substituted with one or more substituents chosen from a
halogen atom and a cyano, nitro, hydroxyl, C.sub.1-5-alkyl,
C.sub.1-3-alkoxy, C.sub.1-5-thioalkyl, C.sub.1-5-fluoroalkyl,
C.sub.1-3-fluoroalkoxy, C.sub.1-3-fluorothioalkyl,
C.sub.3-5-cycloalkyl, C.sub.3-5-cycloalkyl-C.sub.1-3-alkylene,
piperidyl, pyrrolidinyl, morpholinyl, NH.sub.2, NHR.sub.6,
NR.sub.6R.sub.7, NHCOR.sub.6, COR.sub.6, CO.sub.2R.sub.6,
SO.sub.2R.sub.6, or --O--(C.sub.1-3-alkylene)-O-- group; [0061]
R.sub.3 represents a group of general formula CHR.sub.4CONHR.sub.5
in which [0062] R.sub.4 represents a hydrogen atom or a
C.sub.1-3-alkyl group and [0063] R.sub.5 represents a hydrogen atom
or a C.sub.1-3-alkyl, C.sub.3-5-cycloalkyl or
C.sub.3-5-cycloalkyl-C.sub.1-3-alkylene group; [0064] R.sub.6 and
R.sub.7 represent, independently of each other, a C.sub.1-3-alkyl
group.
[0065] The compounds of general formula (I) may comprise one or
more asymmetric carbons. They may exist in the form of enantiomers
or diastereoisomers. These enantiomers and diastereoisomers, and
also mixtures thereof, including racemic mixtures, form part of the
invention.
[0066] The compounds of general formula (I) may exist in the form
of bases or of acid-addition salts. Such addition salts form part
of the invention.
[0067] These salts are advantageously prepared with
pharmaceutically acceptable acids, but the salts of other acids
that are useful, for example, for the purification or isolation of
the compounds of formula (I) also form part of the invention.
[0068] The compounds of general formula (I) may be in the form of
hydrates or solvates, i.e. in the form of associations or
combinations with one or more water molecules or with a solvent.
Such hydrates and solvates also form part of the invention.
[0069] In the context of the invention, the following definitions
apply: [0070] C.sub.t-z in which t and z may take values from 1 to
8, a carbon-based chain possibly containing from t to z carbon
atoms, for example a C.sub.1-3 carbon-based chain which may contain
from 1 to 3 carbon atoms, [0071] alkyl, a saturated, linear or
branched aliphatic group, for example a C.sub.1-3-alkyl group
represents a linear or branched carbon-based chain of 1 to 3 carbon
atoms, more particularly a methyl, ethyl, propyl or 1-methylethyl,
[0072] alkylene, a saturated, linear or branched divalent alkyl
group, for example a C.sub.1-3-alkylene group represents a linear
or branched divalent carbon-based chain of 1 to 3 carbon atoms,
more particularly a methylene, ethylene, 1-methylethylene or
propylene, [0073] cycloalkyl, a cyclic alkyl group, for example a
C.sub.3-5-cycloalkyl group represents a cyclic carbon-based group
of 3 to 5 carbon atoms, more particularly a cyclopropyl, cyclobutyl
or cyclopentyl, [0074] alkoxy, an --O-alkyl group containing a
saturated, linear or branched aliphatic chain, [0075] thioalkyl, an
--S-alkyl group containing a saturated, linear or branched
aliphatic chain, [0076] fluoroalkyl, an alkyl group in which one or
more hydrogen atoms have been replaced with a fluorine atom, [0077]
fluoroalkoxy, an alkoxy group in which one or more hydrogen atoms
have been replaced with a fluorine atom, [0078] fluorothioalkyl, a
thioalkyl group in which one or more hydrogen atoms have been
replaced with a fluorine atom, [0079] halogen atom, a fluorine, a
chlorine, a bromine or an iodine.
[0080] The compounds of the invention may be prepared according to
various methods, illustrated by the schemes that follow.
[0081] Thus, a first method (Scheme 1) consists in reacting an
amine of general formula (II), in which A, B, R.sub.1, n and m are
as defined above, with a carbonate of general formula (IIIa) in
which Z represents a hydrogen atom or a nitro group, R.sub.4 is as
defined above and R represents a methyl or ethyl group. The
carbamate ester of general formula (Ia) thus obtained is then
converted into a compound of general formula (I), via aminolysis
using an amine of general formula R.sub.5NH.sub.2 in which R.sub.5
is as defined above. The aminolysis reaction may be performed in a
solvent such as methanol or a mixture of solvents such as methanol
and tetrahydrofuran or methanol and dioxane.
[0082] One variant for obtaining the compounds of general formula
(I) (Scheme 1) consists in reacting an amine of general formula
(II), as defined above, with a carbonate of general formula (IIIb),
in which Z represents a hydrogen atom or a nitro group and R.sub.4
and R.sub.5 are as defined above, in a solvent such as toluene or
dichloroethane, at a temperature of between 0.degree. C. and
80.degree. C.
[0083] The carbonates of general formula (IIIa) and (IIIb) may be
prepared according to any method described in the literature, for
example by reacting an alcohol of general formula HOCHR.sub.4COOR,
in which R represents a methyl or ethyl group, or
HOCHR.sub.4CONHR.sub.5 in which R.sub.4 and R.sub.5 are as defined
above, with phenyl chloroformate or 4-nitrophenyl chloroformate, in
the presence of a base such as triethylamine or
diisopropylethylamine.
##STR00004##
[0084] A second method for obtaining the compounds of general
formula (I) (Scheme 2) consists in reacting a derivative of general
formula (IIa) in which Y represents a hydroxyl, mesylate or
tosylate group or a chlorine, bromine or iodine atom and A, B,
R.sub.1, n and m are as defined above, with an oxazolidinedione of
general formula (IV) in which R.sub.4 is as defined above, to give
the oxazolidinedione derivative of general formula (V). In the case
where Y represents a hydroxyl group, the reaction may be performed
according to the Mitsunobu conditions (Synthesis, 1981, 1-28), for
example via the action of diethyl or diisopropyl azodicarboxylate
in the presence of triphenylphosphine. In the case where Y
represents a chlorine, bromine or iodine atom or a mesylate or
tosylate group, the reaction may be performed in the presence of a
base such as 1,1,3,3-tetramethylguanidine, sodium hydride or sodium
tert-butoxide in a solvent such as tetrahydrofuran, acetonitrile or
dimethylformamide, at a temperature of between 0.degree. C. and the
reflux temperature of the solvent. The oxazolidinedione derivative
of general formula (V) thus obtained is then converted into a
compound of general formula (I), via aminolysis using an amine of
general formula R.sub.5NH.sub.2 in which R.sub.5 is as defined
above.
##STR00005##
[0085] The compounds of general formulae (I), (Ia), (II), (IIIa)
and (V), in which R.sub.1 is substituted with a group R'', may also
be prepared by reacting the corresponding compounds of general
formulae (I), (Ia), (II), (IIIa) and (V), for which R.sub.1 is
substituted with a chlorine, bromine or iodine atom or with a
triflate group in the position into which the group R'' is to be
introduced, with an aryl- or heteroaryl-boronic acid derivative
according to the Suzuki reaction conditions (Chem. Rev. 1995, 95,
2457-2483) or with an aryl- or heteroaryl-trialkylstannane
derivative according to the Stille reaction conditions (Angew.
Chem. Int. Ed. 1986, 25, 504-524).
[0086] The compounds of general formulae (II), (IIa) and (IV), when
their preparation method is not described, are commercially
available or are described in the literature, or alternatively may
be prepared according to methods that are described therein or
known to those skilled in the art.
[0087] The amines of general formula R.sub.5NH.sub.2 are
commercially available.
[0088] According to another of its aspects, a subject of the
invention is also the compounds of formula (Ia) in which n, m, A,
B, R.sub.1 and R.sub.4 are as defined above and R represents a
methyl or ethyl group. The compounds of formula (Ia) are useful as
synthetic intermediates for the preparation of the compounds of
formula (I).
[0089] According to another of its aspects, a subject of the
invention is also the compounds of formula (V) in which n, m, A, B,
R.sub.1 and R.sub.4 are as defined above, the following compounds
being excluded: [0090]
3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-2,4-oxazo-
lidinedione [0091]
3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-5-methyl-2,4-oxa-
zolidinedione [0092]
3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-5-ethyl-2,4-oxaz-
olidinedione [0093]
3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-5-propyl-2,4-oxa-
zolidinedione [0094]
3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-5-(1-methylethyl-
)-2,4-oxazolidinedione.
[0095] The compounds of formula (V) are useful as synthetic
intermediates for the preparation of the compounds of formula
(I).
[0096] The examples that follow illustrate the preparation of a
number of compounds of the invention. These examples are not
limiting and are given merely to illustrate the invention. The
microanalyses and the IR, NMR and/or LC/MS (Liquid Chromatography
coupled to Mass Spectroscopy) spectra confirm the structures and
purities of the compounds obtained.
[0097] m.p. (.degree. C.) represents the melting point in degrees
Celsius.
[0098] The numbers indicated in parentheses in the example titles
correspond to those in the first column of the table
hereinbelow.
[0099] The IUPAC (International Union of Pure and Applied
Chemistry) nomenclature has been used for the naming of the
compounds in the examples that follow.
EXAMPLE 1
Compound 38
2-(Methylamino)-2-oxoethyl
2-[4-(1-naphthyl)-1-piperazinyl]ethylcarbamate hydrochloride
##STR00006##
[0100] 1.1.
2-{2-[4-(1-Naphthyl)-1-piperazinyl]ethyl}-1H-isoindole-1,3(2H)-dione
[0101] A suspension of 1.17 g (5.52 mmol) of
1-(1-naphthyl)piperazine (Tetrahedron Letters, 1998, 39(15),
2219-2222), 0.99 g (7.15 mol) of potassium carbonate and 1.68 g
(6.62 mmol) of 2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione in 15 ml
of N,N-dimethylformamide is heated at 90.degree. C. for 2
hours.
[0102] The mixture is allowed to cool to room temperature and is
concentrated under reduced pressure. The residue is taken up in
ethyl acetate and water, the aqueous phase is separated out and
extracted three times with ethyl acetate, and the combined organic
phases are washed with saturated aqueous sodium chloride solution
and dried over sodium sulfate. After evaporating off the solvent,
the residue obtained is purified by chromatography on silica gel,
eluting with a 40/60 mixture of ethyl acetate and cyclohexane.
[0103] 1.14 g of pure product are thus obtained in the form of an
oil.
1.2. 2-[4-(1-Naphthyl)-1-piperazinyl]ethanamine
[0104] 0.17 ml (3.55 mmol) of hydrazine monohydrate is added slowly
at room temperature to a solution of 1.14 g (2.96 mmol) of
2-{2-[4-(1-naphthyl)-1-piperazinyl]ethyl}-1H-isoindole-1,3(2H)-dione,
prepared in step 1.1, in 15 ml of ethanol. The reaction mixture is
then refluxed for 1 hour.
[0105] The mixture is allowed to cool to room temperature, the
insoluble material is separated out by filtration and the filtrate
is concentrated under reduced pressure. The residue is taken up in
20 ml of ether and stirred at room temperature for 20 minutes. The
insoluble material is again separated out and the filtrate is
concentrated under reduced pressure. The residue obtained is
purified by chromatography on silica gel, eluting with a 90/10/1
mixture of dichloromethane, methanol and 28% aqueous ammonia.
[0106] 0.45 g of amine is thus obtained in the form of a colourless
oil.
1.3. Ethyl[(phenyloxycarbonyl)oxy]acetate
[0107] 32 ml (256 mmol) of phenyl chloroformate are added slowly at
room temperature to a solution of 25 g (240 mmol) of ethyl
glycolate and 55 ml (315 mmol) of diisopropylethylamine in 500 ml
of toluene. Stirring is continued at room temperature for 2
hours.
[0108] The salt formed is separated out and the filtrate is
concentrated under reduced pressure.
[0109] 53.7 g of oily product are obtained, and are used without
further purification in the following step.
1.4.
Ethyl[({2,4-(1-naphthyl)-1-piperazinyl]ethyl}amino)carbonyl]oxyacetat-
e
[0110] A solution of 0.45 g (1.76 mmol) of
2-[4-(1-naphthyl)-1-piperazinyl]ethanamine, prepared in step 1.2,
and 0.48 g (2.16 mmol) of ethyl [(phenyloxycarbonyl)oxy]acetate,
obtained in step 1.3, in 15 ml of toluene is heated at 50.degree.
C. for 6 hours.
[0111] The mixture is allowed to cool to room temperature, the
insoluble material is separated out by filtration and the filtrate
is concentrated under reduced pressure. The residue is taken up in
dichloromethane and water, the aqueous phase is separated out and
extracted three times with dichloromethane, and the combined
organic phases are washed with saturated aqueous sodium chloride
solution and dried over sodium sulfate. After evaporating off the
solvent, the residue obtained is purified by chromatography on
silica gel, eluting with a 97/3 and then 93/7 mixture of
dichloromethane and methanol. 0.49 g of pure product is thus
obtained in the form of an oil.
1.5. 2-(Methylamino)-2-oxoethyl
2-[4-(1-naphthyl)-1-piperazinyl]ethylcarbamate
[0112] 1.9 ml (3.75 mmol) of a solution (2M) of methylamine in
tetrahydrofuran are added to a solution of 0.48 g (1.25 mmol) of
ethyl[({2,4-(1-naphthyl)-1-piperazinyl]ethyl}amino)carbonyl]oxyacetate,
prepared in step 1.4, in 5 ml of methanol. Stirring is continued at
room temperature for 1 hour.
[0113] After concentrating under reduced pressure, the residue
obtained is purified by chromatography on silica gel, eluting with
a 97/3 mixture of dichloromethane and methanol. An oily residue is
obtained, which is taken up with a solution of hydrochloric acid
(5N) in isopropanol. The mixture is concentrated to dryness and the
salt obtained is then recrystallized from a 1/1 mixture of acetone
and diisopropyl ether.
[0114] 0.23 g of pure monohydrochloride product is thus obtained in
the form of a white solid.
[0115] LC-MS: M+H=371
[0116] m.p. (.degree. C.): 166.degree. C.
[0117] .sup.1H NMR (DMSO) .delta. (ppm): 2.55 (d, 3H); 3.20-3.75
(unresolved peak, 12H); 4.40 (s, 2H); 7.10 (d, 1H); 7.35-7.70
(unresolved peak, 4H); 7.80-8.05 (unresolved peak, 2H); 8.15 (dd,
1H); 10.90 (broad s, 1H).
EXAMPLE 2
Compound 157
2-(Methylamino)-2-oxoethyl
3-[1-(1-isoquinolyl)-4-piperidyl]propylcarbamate hydrochloride
##STR00007##
[0118] 2.1. 2-[1-(1-Isoquinolyl)-4-piperidyl]ethanol
[0119] 4.17 g (25.50 mmol) of 1-chloroisoquinoline, 3.62 g (28
mmol) of 2-(4-piperidyl)ethanol, 5.90 g (61.20 mmol) of sodium
tert-butoxide and 0.476 g (0.765 mmol) of BINAP
(2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) suspended in 50 ml of
toluene are introduced under an inert atmosphere. 0.233 g (0.255
mmol) of tris(dibenzylideneacetone)dipalladium is then added. The
reaction mixture is then refluxed for 12 hours.
[0120] The salts are separated out by filtration through Celite and
the filtrate is then concentrated under reduced pressure. The
residue is taken up in ethyl acetate and water, the aqueous phase
is separated out and extracted twice with ethyl acetate, and the
combined organic phases are washed with saturated aqueous sodium
chloride solution and dried over sodium sulfate. After evaporating
off the solvent, the residue obtained is purified by chromatography
on silica gel, eluting with a 97/3 mixture of dichloromethane and
methanol.
[0121] 3.34 g of product are obtained in the form of a grey
paste.
2.2. 1-[4-(2-Chloroethyl)-1-piperidyl]isoquinoline
[0122] 2.20 ml (30.10 mmol) of thionyl chloride are added dropwise
to a solution of 3.09 g (12.10 mmol) of
2-[1-(1-isoquinolyl)-4-piperidyl]ethanol, prepared in step 2.1, in
30 ml of dichloromethane. The reaction mixture is then refluxed for
5 hours.
[0123] The mixture is concentrated to dryness under reduced
pressure. The residue is taken up in 40 ml of dichloromethane and
30 ml of aqueous sodium hydroxide solution (1M). The aqueous phase
is separated out and extracted twice with dichloromethane, the
combined organic phases are washed with saturated aqueous sodium
chloride solution and dried over sodium sulfate, and the filtrate
is concentrated under reduced pressure. 2.70 g of product are
obtained in the form of a brown paste, which is used without
further purification in the following step.
2.3. 3-[1-(1-Isoquinolyl)-4-piperidyl]propanenitrile
[0124] 0.63 g (9.57 mmol) of potassium cyanide is added portionwise
to a suspension of 2.63 g (9.57 mmol) of
1-[4-(2-chloroethyl)-1-piperidyl]isoquinoline, prepared in step
2.2, and 0.048 g (0.29 mmol) of potassium iodide in 30 ml of 2 5
dimethyl sulfoxide. The reaction mixture is maintained at about
120.degree. C. for 16 hours. The mixture is allowed to cool to room
temperature and 90 ml of water and ethyl acetate are then added.
The aqueous phase is separated out and extracted three times with
ethyl acetate, the combined organic phases are washed with
saturated aqueous sodium chloride solution and dried over sodium
sulfate, and the filtrate is concentrated under reduced pressure.
The residue thus obtained is purified by chromatography on silica
gel, eluting with a 30/70 mixture of ethyl acetate and
cyclohexane.
[0125] 0.77 g of product is obtained in the form of a yellow
solid.
[0126] m.p. (.degree. C.): 141-143.degree. C.
2.4. 3-[1-(1-Isoquinolyl)-4-piperidyl]propanamine
[0127] A solution of 0.77 g (2.90 mmol) of
3-[1-(1-isoquinolyl)-4-piperidyl]propanenitrile, prepared in step
2.3, in 16 ml of tetrahydrofuran is added dropwise to a suspension
of 0.22 g (5.80 mmol) of lithium aluminium hydride in 8 ml of
tetrahydrofuran. The reaction mixture is then refluxed for 5
hours.
[0128] The reaction medium is cooled to about 0.degree. C. and 15
ml of aqueous sodium hydroxide solution (1M) are then added slowly.
The mixture is stirred at room temperature for 30 minutes, followed
by portionwise addition of wet sodium sulfate. The salts are
separated out by filtration through paper and the phases are then
allowed to separate by settling. The aqueous phase is extracted
three times with ethyl acetate, the combined organic phases are
dried over sodium sulfate and the filtrate is concentrated under
reduced pressure. The residue thus obtained is purified by
chromatography on silica gel, eluting with a 93/7/0.7 mixture of
dichloromethane, methanol and 28% aqueous ammonia.
[0129] 0.329 g of product is obtained in the form of a yellow oil
that crystallizes at room temperature.
2.5.
Ethyl[{3-[1-(1-isoquinolyl)-4-piperidyl]propyl}amino)carbonyl]oxyacet-
ate
[0130] The process is performed as in Example 1 (step 1.4).
Starting with 0.350 g (1.30 mmol) of
3-[1-(1-isoquinolyl)-4-piperidyl]propanamine, obtained in step 2.4,
and 0.32 g (1.43 mmol) of ethyl[(phenyloxycarbonyl)oxy]acetate,
prepared in step 1.3 of Example 1, and after chromatography on
silica gel, eluting with a 20/80 and then 30/70 mixture of ethyl
acetate and cyclohexane, 0.383 g of product is obtained in the form
of a yellow paste.
2.6. 2-(Methylamino)-2-oxoethyl
3-[1-(1-isoquinolyl)-4-piperidyl]propylcarbamate
[0131] The process is performed as described in Example 1 (step
1.5). Starting with 0.380 g (0.95 mmol) of ethyl
[{3-[1-(1-isoquinolyl)-4-piperidyl]propyl}-amino)carbonyl]oxyacetate,
obtained in step 2.5, and 4.8 ml (9.51 mmol) of a solution (2M) of
methylamine in tetrahydrofuran, and after chromatography on silica
gel, eluting with a 98/2 and then 95/5 mixture of dichloromethane
and methanol, 0.277 g of product is obtained in the form of an oil.
This oily residue is then taken up in a solution of hydrochloric
acid (5N) in isopropanol and the salt formed is filtered off and
then washed with ethyl acetate.
[0132] After drying under vacuum at about 40.degree. C., 0.204 g of
hydrochloride is obtained in the form of an amorphous white
solid.
[0133] LC-MS: M+H=385
[0134] .sup.1H NMR (DMSO+D.sub.2O) .delta. (ppm): 1.30 (m, 2H);
1.40-1.80 (unresolved peak, 5H); 1.90 (broad d, 2H); 2.60 (s, 3H);
3.05 (m, 2H); 3.40 (t, 2H); 4.05 (broad d, 2H); 4.30 (s, 2H); 7.50
(d, 1H); 7.80 (m, 2H); 7.95 (t, 1H); 8.05 (d, 1H); 8.20 (d,
1H).
EXAMPLE 3
Compound 44
2-Amino-2-oxoethyl
2-{1-[3-(trifluoromethyl)phenyl]-4-piperidyl}ethylcarbamate
##STR00008##
[0135] 3.1.
2-{1-[3-(Trifluoromethyl)phenyl]-4-piperidyl}ethanol
[0136] The process is performed as described in Example 2 (step
2.1). Starting with 25.6 g (113.90 mmol) of
1-bromo-3-(trifluoromethyl)benzene, 17.66 g (136.60 mmol) of
2-(4-piperidyl)ethanol, 26.24 g (273 mmol) of sodium tert-butoxide,
2.12 g (3.41 mmol) of BINAP and 1.04 g (1.14 mmol) of
tris-(dibenzylideneacetone)dipalladium, and after chromatography on
silica gel, eluting with a 25/75 mixture of ethyl acetate and
cyclohexane, 17.90 g of an orange-coloured oily residue are
obtained. This residue is then taken up in 100 ml of methanol, a
solution of 4.24 g of potassium hydroxide in 15 ml of methanol is
then added and stirring is continued at room temperature for 1
hour. The mixture is concentrated under reduced pressure and the
residue is then taken up in chloroform and aqueous hydrochloric
acid solution (1N). The organic phase is separated out and dried
over sodium sulfate, and the filtrate is concentrated under reduced
pressure. 14 g of product are obtained in the form of a dark yellow
oil, which is used without further purification in the following
step.
3.2. 2-{1-[3-(Trifluoromethyl)phenyl]-4-piperidyl}ethyl
methanesulfonate
[0137] A solution of 1 g (8.78 mmol) of mesyl chloride in 5 ml of
dichloromethane is added dropwise under an inert atmosphere to a
solution of 2 g (7.32 mmol) of
2-{1-[3-(trifluoromethyl)phenyl]-4-piperidyl}ethanol, obtained in
step 3.1, and 1.53 ml (10.98 mmol) of triethylamine in 40 ml of
dichloromethane, cooled to about 0.degree. C. Stirring is continued
at 0.degree. C. for 1 hour and then at room temperature for 2
hours.
[0138] Water is added to the reaction medium, the aqueous phase is
separated out and extracted three times with dichloromethane, the
combined organic phases are washed with saturated aqueous sodium
chloride solution and dried over sodium sulfate, and the filtrate
is concentrated under reduced pressure.
[0139] 2.5 g of product are thus obtained in the form of an oil,
which is used without further purification in the following
step.
3.3.
3-(2-{1-[3-(Trifluoromethyl)phenyl]-4-piperidyl}ethyl)-1,3-oxazolidin-
e-2,4-dione
[0140] A solution of 2.3 g (6.545 mmol) of
2-{1-[3-(trifluoromethyl)phenyl]-4-piperidyl}ethyl
methanesulfonate, prepared in step 3.2, 0.694 g (6.87 mmol) of
1,3-oxazolidine-2,4-dione (J. Med. Chem., 1991, 34, 1538-1544) and
1.5 g (13.09 mmol) of 1,1,3,3-tetramethylguanidine in 30 ml of
tetrahydrofuran is refluxed for 12 hours under an inert
atmosphere.
[0141] The mixture is concentrated under reduced pressure. The
residue is taken up in dichloromethane and water, the aqueous phase
is separated out and extracted twice with dichloromethane, and the
combined organic phases are washed with saturated aqueous sodium
chloride solution and dried over sodium sulfate. After evaporating
off the solvent, the residue obtained is purified by chromatography
on silica gel, eluting with a 20/80 and then 40/60 mixture of ethyl
acetate and cyclohexane.
[0142] 1.61 g of pure product are obtained in the form of an
oil.
3.4. 2-Amino-2-oxoethyl
2-{1-[3-(trifluoromethyl)phenyl]-4-piperidyl}ethylcarbamate
[0143] 9.3 ml (64.82 mmol) of a solution of aqueous ammonia (7N) in
methanol are added to a solution of 0.77 g (2.16 mmol) of
3-(2-{1-[3-(trifluoromethyl)-phenyl]-4-piperidyl}ethyl)-1,3-oxazolidine-2-
,4-dione, obtained in step 3.3, in 10 ml of a 1/1 mixture of
methanol and tetrahydrofuran. Stirring is continued at room
temperature for 24 hours.
[0144] After concentrating under reduced pressure, the residue
obtained is purified by chromatography on silica gel, eluting with
a 97/3 and then 95/5 mixture of dichloromethane and methanol,
followed by recrystallization from a mixture of ethyl acetate and
diisopropyl ether.
[0145] 0.370 g of pure product is obtained in the form of a white
solid.
[0146] LC-MS: M+H=374
[0147] m.p. (.degree. C.): 140-142.degree. C.
[0148] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 1.30-1.55
(unresolved peak, 5H); 1.90 (broad d, 2H); 2.80 (t, 2H); 3.35 (q,
2H); 3.80 (broad d, 2H); 4.60 (s, 2H); 4.90 (broad s, 1H); 5.55
(broad s, 1H); 6.05 (broad s, 1H); 7.10 (m, 3H); 7.35 (t, 1H).
EXAMPLE 4
Compound 47
2-(Methylamino)-2-oxoethyl
2-[1-(6-methyl-2-pyridyl)-4-piperidyl]ethylcarbamate
hydrochloride
##STR00009##
[0149] 4.1. 2-[1-(6-Methyl-2-pyridyl)-4-piperidyl]ethanol
[0150] 1 g (7.74 mmol) of 2-(4-piperidyl)ethanol and 0.987 g (7.74
mmol) of 2-chloro-6-methylpyridine are introduced into an
autoclave. The mixture is then heated at 130.degree. C. for 17
hours.
[0151] The reaction mixture is allowed to cool to room temperature
and is then taken up in chloroform and saturated aqueous sodium
hydrogen carbonate solution. The aqueous phase is separated out and
extracted twice with chloroform, the combined organic phases are
washed with saturated aqueous sodium chloride solution and dried
over sodium sulfate, and the filtrate is concentrated under reduced
pressure.
[0152] 1.21 g of product are thus obtained in the form of an
orange-coloured liquid, which is used without further purification
in the following step.
4.2. 2-[1-(6-Methyl-2-pyridyl)-4-piperidyl]ethyl
methanesulfonate
[0153] The process is performed as in Example 3 (step 3.2).
Starting with 0.661 g (3 mmol) of
2-[1-(6-methyl-2-pyridyl)-4-piperidyl]ethanol, obtained in step
4.1, 0.378 g (3.30 mmol) of mesyl chloride and 0.63 ml (4.50 mmol)
of triethylamine, 0.779 g of product is obtained in the form of an
orange-coloured oil, which is used without further purification in
the following step.
4.3.
3-{2-[1-(6-Methyl-2-pyridyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-d-
ione
[0154] The process is performed according to the method described
in Example 3 (step 3.3). Starting with 0.776 g (2.60 mmol) of
2-[1-(6-methyl-2-pyridyl)-4-piperidyl]ethyl methanesulfonate,
obtained in step 4.2, 0.315 g (3.12 mmol) of
1,3-oxazolidine-2,4-dione and 0.65 ml (5.20 mmol) of
1,1,3,3-tetramethylguanidine, and after chromatography on silica
gel, eluting with a 30/70 mixture of ethyl acetate and cyclohexane,
0.76 g of pure product is obtained in the form of a yellow oil.
4.4. 2-(Methylamino)-2-oxoethyl
2-[1-(6-methyl-2-pyridyl)-4-piperidyl]ethylcarbamate
[0155] The process is performed according to the procedure
described in Example 1 (step 1.5). Starting with 0.841 g (2.77
mmol) of
3-{2-[1-(6-methyl-2-pyridyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione-
, obtained in step 4.3, and 6.9 ml (13.86 mmol) of a solution (2M)
of methylamine in tetrahydrofuran, 0.598 g of pure product is
obtained in the form of an oil, after chromatography on silica gel,
eluting with a 95/5 mixture of dichloromethane and methanol. This
oily residue is then taken up with a solution of hydrochloric acid
(5N) in isopropanol and the salt formed is filtered off and then
washed successively with acetone and then with ether.
[0156] After drying under vacuum at about 80.degree. C., 0.492 g of
hydrochloride is obtained in the form of a white powder.
[0157] LC-MS: M+H=335
[0158] m.p. (.degree. C.): 95-100.degree. C.
[0159] .sup.1H NMR (DMSO+D.sub.2O) .delta. (ppm): 0.95-1.45
(unresolved peak, 4H); 1.60 (m, 1H); 1.80 (broad d, 2H); 2.40 (s,
3H); 2.60 (s, 3H); 2.90-3.20 (unresolved peak, 4H); 4.10 (broad d,
2H); 4.30 (s, 2H); 6.70 (d, 1H); 7.10 (d, 1H); 7.75 (dd, 1H).
EXAMPLE 5
Compound 154
2-(Methylamino)-2-oxoethyl
[1-(1-isoquinolyl)-4-piperidyl]methylcarbamate hydrochloride
##STR00010##
[0160] 5.1. [1-(1-Isoquinolyl)-4-piperidyl]methanol
[0161] The process is performed as described in Example 2 (step
2.1). Starting with 2.50 g (15.28 mmol) of 1-chloroisoquinoline,
1.94 g (136.6 mmol) of 4-piperidylmethanol, 3.53 g (36.67 mmol) of
sodium tert-butoxide, 0.285 g (0.46 mmol) of BINAP and 0.140 g
(0.15 mmol) of tris(dibenzylideneacetone)dipalladium, and after
chromatography on silica gel, eluting with a 98/2/0.2 and then
95/5/0.5 mixture of dichloromethane, methanol and 28% aqueous
ammonia, 2.40 g of pure product are obtained in the form of a
viscous orange oil.
5.2.
3-{[1-(1-Isoquinolyl)-4-piperidyl]methyl}-1,3-oxazolidine-2,4-dione
[0162] A solution of 2.01 g (9.95 mmol) of diisopropyl
azodicarboxylate (DIAD) in 5 ml of tetrahydrofuran is added
dropwise, under an inert atmosphere, to a solution of 2.4 g (9.95
mmol) of [1-(1-isoquinolyl)-4-piperidyl]methanol, prepared in step
5.1, 2.87 g (10.94 mmol) of triphenylphosphine and 1.21 g (11.93
mmol) of 1,3-oxazolidine-2,4-dione in 40 ml of tetrahydrofuran,
cooled to about -10.degree. C., the temperature of the reaction
medium being maintained throughout between -10.degree. C. and
0.degree. C. Stirring is then continued at 0.degree. C. for 1 hour
and then at 25.degree. C. for 18 hours.
[0163] The mixture is concentrated under reduced pressure and the
residue is taken up in dichloromethane and 10 ml of aqueous 5%
sodium hydroxide solution. The aqueous phase is separated out and
then extracted twice with dichloromethane. The organic phases are
combined and washed successively with aqueous hydrochloric acid
solution (1N) and then with saturated aqueous sodium hydrogen
carbonate solution and with saturated aqueous sodium chloride
solution. The organic phase is dried over sodium sulfate and the
filtrate is concentrated under reduced pressure. The residue thus
obtained is purified by chromatography on silica gel, eluting with
a 99/1/0.1 and then 98/2/0.2 mixture of dichloromethane, methanol
and 28% aqueous ammonia.
[0164] 3.57 g of oxazolidinedione are thus obtained in the form of
an orange paste.
5.3. 2-(Methylamino)-2-oxoethyl
[1-(1-isoquinolyl)-4-piperidyl]methylcarbamate
[0165] The process is performed according to the procedure
described in Example 1 (step 1.5). Starting with 3.57 g (10.97
mmol) of
3-{[1-(1-isoquinolyl-4-piperidyl]methyl}-1,3-oxazolidine-2,4-dione,
obtained in step 5.2, and 27 ml (54.86 mmol) of a solution (2M) of
methylamine in tetrahydrofuran, and after chromatography on silica
gel, eluting with a 95/5/0.5 mixture of dichloromethane, methanol
and 28% aqueous ammonia, 0.90 g of pure product is obtained in the
form of a yellow paste. This residue is then taken up in a solution
of hydrochloric acid (5N) in isopropanol, and the salt formed is
filtered off and then washed with acetone.
[0166] After drying under vacuum at about 80.degree. C., 0.728 g of
hydrochloride is obtained in the form of a pale yellow solid.
[0167] LC-MS: M+H=357
[0168] m.p. (.degree. C.): 208-212.degree. C. (decomposition)
[0169] .sup.1H NMR (D.sub.2O) .delta. (ppm): 1.55 (m, 2H); 1.95 (m,
3H); 2.70 (s, 3H); 3.20 (broad d, 2H); 3.45 (t, 2H); 4.10 (broad d,
2H); 4.50 (s, 2H); 7.35 (d, 1H); 7.55 (d, 1H); 7.70 (m, 1H); 7.90
(d, 2H); 8.20 (d, 1H).
EXAMPLE 6
Compound 158
2-Amino-2-oxoethyl
2-[1-(6-fluoro-1-isoquinolyl)-4-piperidyl]ethylcarbamate
##STR00011##
[0170] 6.1. 2-[1-(6-Fluoro-1-isoquinolyl)-4-piperidyl]ethanol
[0171] The process is performed as described in Example 4 (step
4.1). Starting with 1.52 g (8.39 mmol) of
1-chloro-6-fluoroisoquinoline and 1.20 g (9.23 mmol) of
2-(4-piperidyl)ethanol, and after chromatography on silica gel,
eluting with a 95/5/0.5 mixture of dichloromethane, methanol and
28% aqueous ammonia, 0.90 g of pure product is obtained in the form
of a yellow paste.
6.2. 2-[1-(6-Fluoro-1-isoquinolyl)-4-piperidyl]ethyl
methanesulfonate
[0172] The process is performed as described in Example 3 (step
3.2). Starting with 1.47 g (5.36 mmol) of
2-[1-(6-fluoro-1-isoquinolyl)-4-piperidyl]ethanol, obtained in step
6.1, 0.675 g (5.89 mmol) of mesyl chloride and 1.13 ml (8.04 mmol)
of triethylamine, 1.80 g of product are obtained in the form of an
oil, which is used without further purification in the following
step.
6.3.
3-{2-[1-(6-Fluoro-1-isoquinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2-
,4-dione
[0173] The process is performed according to the method described
in Example 3 (step 3.3). Starting with 1.8 g (5.10 mmol) of
2-[1-(6-fluoro-1-isoquinolyl)-4-piperidyl]ethyl methanesulfonate,
obtained in step 6.2, 0.62 g (6.13 mmol) of
1,3-oxazolidine-2,4-dione and 1.30 ml (10.21 mmol) of
1,1,3,3-tetramethylguanidine, and after chromatography on silica
gel, eluting with a 40/60 mixture of ethyl acetate and cyclohexane,
1.34 g of pure product are obtained in the form of an amorphous
white solid.
6.4. 2-Amino-2-oxoethyl
2-[1-(6-fluoro-1-isoquinolyl)-4-piperidyl]ethylcarbamate
[0174] The process is performed according to the procedure
described in Example 3 (step 3.4). Starting with 0.597 g (1.67
mmol) of
3-{2-[1-(6-fluoro-1-isoquinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-d-
ione, obtained in Step 6.3, and 14.30 ml (100.20 mmol) of a
solution (7M) of aqueous ammonia in methanol, and after
chromatography on silica gel, eluting with a 95/5 mixture of
dichloromethane and methanol, followed by recrystallization from
diisopropyl ether, 0.168 g of pure product is obtained in the form
of a white solid.
[0175] LC-MS: M+H=375
[0176] m.p. (.degree. C.): 135-139.degree. C.
[0177] .sup.1H NMR (DMSO) .delta. (ppm): 1.20-1.70 (unresolved
peak, 5H); 1.80 (broad d, 2H); 2.85 (t, 2H); 3.10 (broad d, 2H);
3.70 (broad d, 2H); 4.30 (s, 2H); 6.95-7.20 (unresolved peak, 3H);
7.30 (d, 1H); 7.45 (td, 1H); 7.60 (dd, 1H); 8.10 (m, 2H).
EXAMPLE 7
Compound 172
2-(Methylamino)-2-oxoethyl
2-[1-(4-isoquinolyl)-4-piperidyl]ethylcarbamate hydrochloride
##STR00012##
[0178] 7.1. 2-[1-(4-Isoquinolyl)-4-piperidyl]ethanol
[0179] The process is performed according to the protocol described
in Example 2 (step 2.1). Starting with 1 g (4.81 mmol) of
4-bromoisoquinoline, 0.683 g (5.29 mmol) of 2-(4-piperidyl)ethanol,
1.11 g (11.50 mmol) of sodium tert-butoxide, 0.090 g (0.144 mmol)
of BINAP and 0.044 g (0.048 mmol) of
tris(dibenzylideneacetone)dipalladium, and after chromatography on
silica gel, eluting with a 97/3 and then 95/5 mixture of
dichloromethane and methanol, 0.810 g of product is obtained in the
form of a viscous green liquid.
7.2.
3-{2-[1-(4-Isoquinolyl)-4-piperidyl]ethyl)-1,3-oxazolidine-2,4-dione
[0180] The procedure described in Example 5 (step 5.2) is used.
Starting with 0.801 g (3.12 mmol) of
2-[1-(4-isoquinolyl)-4-piperidyl]ethanol, prepared in step 7.1,
0.902 g (3.44 mmol) of triphenylphosphine, 0.379 g (3.75 mmol) of
1,3-oxazolidine-2,4-dione and 0.632 g (3.12 mmol) of diisopropyl
azodicarboxylate (DIAD), and after chromatography on silica gel,
eluting with a 98/2 mixture of dichloromethane and methanol, 1 g of
product is obtained in the form of a green paste.
7.3. 2-(Methylamino)-2-oxoethyl
2-[1-(4-isoquinolyl)-4-piperidyl]ethylcarbamate
[0181] The procedure described in Example 1 (step 1.5) is used.
Starting with 1 g (2.95 mmol) of
3-{2-[1-(4-isoquinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione,
obtained in step 7.2, and 7.40 ml (14.73 mmol) of a solution (2M)
of methylamine in tetrahydrofuran, and after chromatography on
silica gel, eluting with a 95/5 mixture of dichloromethane and
methanol, 0.410 g of pure product is obtained in the form of an
amorphous white solid. This oily residue is then taken up in a
solution of hydrochloric acid (5N) in isopropanol and the salt
formed is filtered off and then washed successively with acetone
and then with diisopropyl ether.
[0182] After drying under vacuum at about 90.degree. C., 0.359 g of
hydrochloride is obtained in the form of a yellow solid.
[0183] LC-MS: M+H=371
[0184] m.p. (.degree. C.): 205-210.degree. C.
[0185] .sup.1H NMR (DMSO) .delta. (ppm): 1.30-1.70 (unresolved
peak, 5H); 1.90 (broad d, 2H); 2.60 (d, 3H); 2.90 (t, 2H); 3.15 (m,
2H); 3.50 (broad d, 2H); 4.35 (s, 2H); 7.25 (broad t, 1H); 7.80
(broad s, 1H); 8.0 (dd, 1H); 8.05-8.30 (unresolved peak, 3H); 8.45
(d, 1H); 9.45 (s, 1H).
EXAMPLE 8
Compound 126
2-(Methylamino)-2-oxoethyl
2-[1-(2-quinolyl)-4-piperidyl]ethylcarbamate
##STR00013##
[0186] 8.1. 2-[1-(2-Quinolyl)-4-piperidyl]ethanol
[0187] The process is performed as in Example 4 (step 4.1).
Starting with 2 g (12.20 mmol) of 2-chloroquinoline and 1.58 g
(12.20 mmol) of 2-(4-piperidyl)-ethanol, and after chromatography
on silica gel, eluting with a 98/2/0.2 and then 95/5/0.5 mixture of
dichloromethane, methanol and 28% aqueous ammonia, 2.36 g of pure
product are obtained in the form of a pale yellow oil that
crystallizes at room temperature.
8.2.
3{2-[1-(2-Quinolyl)-4-piperidyl]ethyl-1,3-oxazolidine-2,4-dione
[0188] The process is performed according to the procedure
described in Example 5 (step 5.2). Starting with 2.22 g (8.65 mmol)
of 2-[1-(2-quinolyl)-4-piperidyl]-ethanol, prepared in step 8.1,
2.50 g (9.52 mmol) of triphenylphosphine, 1.05 g (10.38 mmol) of
1,3-oxazolidine-2,4-dione and 1.75 g (8.65 mmol) of diisopropyl
azodicarboxylate (DIAD), and after chromatography on silica gel,
eluting with a 30/70 and then 40/60 mixture of ethyl acetate and
cyclohexane, 2.63 g of product are obtained in the form of an
amorphous white solid.
8.3. 2-(Methylamino)-2-oxoethyl
2-[1-(2-quinolyl)-4-piperidyl]ethylcarbamate
[0189] The process is performed according to the procedure
described in Example 1 (step 1.5). Starting with 1.5 g (4.42 mmol)
of 3{2-[1-(2-quinolyl)-4-piperidyl]ethyl-1,3-oxazolidine-2,4-dione,
obtained in step 8.2, and 11 ml (22.10 mmol) of a solution (2M) of
methylamine in tetrahydrofuran, and after chromatography on silica
gel, eluting with a 98/2/0.2 and then 95/5/0.5 mixture of
dichloromethane, methanol and 28% aqueous ammonia, followed by
crystallization from ethyl acetate, 0.405 g of pure product is
obtained in the form of a white solid.
[0190] LC-MS: M+H=371
[0191] m.p. (.degree. C.): 125-128.degree. C.
[0192] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 1.20-1.60
(unresolved peak, 5H); 1.85 (broad d, 2H); 2.85 (d, 3H); 3.0 (broad
t, 2H); 3.30 (broad q, 2H); 4.55 (broad d, 2H); 4.60 (s, 2H); 4.85
(broad s, 1H); 6.10 (broad s, 1H); 7.0 (d, 1H); 7.20 (t, 1H); 7.55
(m, 2H); 7.70 (d, 1H); 7.90 (d, 1H).
EXAMPLE 9
Compound 127
2-Amino-2-oxoethyl 2-[1-(2-quinolyl)-4-piperidyl]ethylcarbamate
##STR00014##
[0194] The process is performed according to the procedure
described in Example 3 (step 3.4). Starting with 1.14 g (3.36 mmol)
of
3{2-[1-(2-quinolyl)-4-piperidyl]-ethyl}-1,3-oxazolidine-2,4-dione,
described in Example 8 (step 8.2), and 9.60 ml (67.20 mmol) of a
solution (7M) of aqueous ammonia in methanol, and after
chromatography on silica gel, eluting with a 95/5 mixture of
dichloromethane and methanol, followed by recrystallization from
ethyl acetate, 0.360 g of pure product is obtained in the form of a
white solid.
[0195] LC-MS: M+H=357
[0196] m.p. (.degree. C.): 135-137.degree. C.
[0197] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 1.15-1.70
(unresolved peak, 5H); 1.85 (broad d, 2H); 2.95 (t, 2H); 3.35 (q,
2H); 4.55 (broad d, 2H); 4.60 (s, 2H); 4.85 (broad s, 1H); 5.55
(broad s, 1H); 6.05 (broad s, 1H); 7.0 (d, 1H); 7.20 (t, 1H); 7.55
(t, 1H); 7.60 (d, 1H); 7.70 (d, 1H); 7.90 (d, 1H).
EXAMPLE 10
Compound 137
2-Amino-2-oxoethyl
2-[1-(6-chloro-2-quinolyl)-4-piperidyl]ethylcarbamate
##STR00015##
[0198] 10.1. 2-[1-(6-Chloro-2-quinolyl)-4-piperidyl]ethanol
[0199] The process is performed as described in Example 4 (step
4.1). Starting with 2 g (10.10 mmol) of 2,6-dichloroquinoline and
1.44 g (11.10 mmol) of 2-(4-piperidyl)ethanol, and after
chromatography on silica gel, eluting with a 98/2 mixture of
dichloromethane and methanol, 2.54 g of pure product are obtained
in the form of a white solid.
10.2. 2-[1-(6-Chloro-2-quinolyl)-4-piperidyl]ethyl
methanesulfonate
[0200] The process is performed as described in Example 3 (step
3.2). Starting with 2.49 g (8.56 mmol) of
2-[1-(6-chloro-2-quinolyl)-4-piperidyl]ethanol, obtained in step
10.1, 1.08 g (9.42 mmol) of mesyl chloride and 1.81 ml (12.84 mmol)
of triethylamine, 3.10 g of product are obtained in the form of an
oil, which is used without further purification in the following
step.
10.3.
3-{2-[1-(6-Chloro-2-quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-
-dione
[0201] The process is performed according to the method described
in Example 3 (step 3.3). Starting with 3 g (8.13 mmol) of
2-[1-(6-chloro-2-quinolyl)-4-piperidyl]ethyl methanesulfonate,
obtained in step 10.2, 1.09 g (10.8 mmol) of
1,3-oxazolidine-2,4-dione and 2.30 ml (18 mmol) of
1,1,3,3-tetramethylguanidine, and after chromatography on silica
gel, eluting with a 98/2 mixture of dichloromethane and methanol,
2.57 g of product are obtained.
10.4. 2-Amino-2-oxoethyl
2-[1-(6-chloro-2-quinolyl)-4-piperidyl]ethylcarbamate
[0202] The process is performed according to the procedure
described in Example 3 (step 3.4). Starting with 1.28 g (3.42 mmol)
of
3-{2-[1-(6-chloro-2-quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dion-
e, obtained in step 10.3, and 22.10 ml (154.08 mmol) of a solution
(7M) of aqueous ammonia in methanol, and after crystallization from
ethanol, 0.64 g of pure product is obtained in the form of a white
solid.
[0203] LC-MS: M+H=391
[0204] m.p. (.degree. C.): 189-191.degree. C.
[0205] .sup.1H NMR (DMSO) .delta. (ppm): 1.10 (m, 2H); 1.40 (m,
2H); 1.60 (m, 1H); 1.80 (broad d, 2H); 2.90 (broad t, 2H); 3.05 (m,
2H); 4.30 (s, 2H); 4.50 (broad d, 2H); 7.15 (m, 3H); 7.25 (d, 1H);
7.50 (m, 2H); 7.75 (d, 1H); 7.95 (d, 1H).
EXAMPLE 11
Compound 166
2-(Methylamino)-2-oxoethyl
2-[1-(3-isoquinolyl)-4-piperidyl]ethylcarbamate
##STR00016##
[0206] 11.1. 2-[1-(3-Isoquinolyl)-4-piperidyl]ethanol
[0207] The process is performed as described in Example 4 (step
4.1). Starting with 1 g (6.11 mmol) of 3-chloroisoquinoline and
0.869 g (6.72 mmol) of 2-(4-piperidyl)ethanol, and after
chromatography on silica gel, eluting with a 98/2 mixture of
dichloromethane and methanol, 0.34 g of pure product is obtained in
the form of an oil.
11.2. 2-[1-(3-Isoquinolyl)-4-piperidyl]ethyl methanesulfonate
[0208] The process is performed as described in Example 3 (step
3.2). Starting with 0.34 g (1.33 mmol) of
2-[1-(3-isoquinolyl)-4-piperidyl]ethanol, obtained in step 11.1,
0.18 g (1.59 mmol) of mesyl chloride and 0.30 ml (1.99 mmol) of
triethylamine, 0.44 g of product is obtained in the form of an oil,
which is used without further purification in the following
step.
11.3.
3-{2-[1(3-Isoquinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione
[0209] The process is performed according to the method described
in Example 3 (step 3.3). Starting with 0.44 g (1.32 mmol) of
2-[1-(3-isoquinolyl)-4-piperidyl]-ethyl methanesulfonate, obtained
in step 11.2, 0.16 g (1.58 mmol) of 1,3-oxazolidine-2,4-dione and
0.30 g (2.63 mmol) of 1,1,3,3-tetramethylguanidine, and after
chromatography on silica gel, eluting with a 98/2 mixture of
dichloromethane and methanol, 0.25 g of product is obtained.
11.4. 2-(Methylamino)-2-oxoethyl
2-[1-(3-isoquinolyl)-4-piperidyl]ethylcarbamate
[0210] The process is performed according to the procedure
described in Example 1 (step 1.5). Starting with 0.24 g (0.71 mmol)
of
3-{2-[1-(3-isoquinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione,
obtained in step 11.3, and 1.8 ml (3.53 mmol) of a solution (2M) of
methylamine in tetrahydrofuran, and after chromatography on silica
gel, eluting with a 98/2 and then 96/4 mixture of dichloromethane
and methanol, followed by crystallization from diisopropyl ether,
0.16 g of pure product is obtained in the form of a white
solid.
[0211] LC-MS: M+H=371
[0212] m.p. (.degree. C.): 156-158.degree. C.
[0213] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 1.20-1.70
(unresolved peak, 5H); 1.85 (d, 2H); 2.90 (m, 5H); 3.30 (q, 2H);
4.40 (d, 2H); 4.60 (s, 2H); 4.85 (broad s, 1H); 6.10 (broad s, 1H);
6.80 (s, 1H); 7.30 (m, 1H); 7.60 (m, 2H); 7.80 (d, 1H); 8.95 (s,
1H).
EXAMPLE 12
Compound 128
2-(Methylamino)-2-oxoethyl
2-[4-fluoro-1-(2-quinolyl)-4-piperidyl]ethylcarbamate
##STR00017##
[0214] 12.1. tert-Butyl
4-hydroxy-4-(2-hydroxyethyl)-1-piperidinecarboxylate
[0215] A solution of 31.20 g (108.50 mmol) of tert-butyl
4-(2-ethoxy-2-oxoethyl)-4-hydroxy-1-piperidinecarboxylate (WO
02/16352) in 150 ml of tetrahydrofuran is added dropwise to a
suspension of 4.12 g (108.50 mmol) of lithium aluminium hydride in
150 ml of tetrahydrofuran. The mixture is stirred at room
temperature for 2 hours and is then worked up as described in
Example 2 (step 2.4).
[0216] 26 g of product are obtained in the form of a yellow oil,
which is used without further purification in the following
step.
12.2. tert-Butyl
4-(2-{[tert-butyldiphenylsilyl]oxy}ethyl)-4-hydroxy-1-piperidine-carboxyl-
ate
[0217] A solution of 21.50 ml (82.50 mmol) of
tert-butyldiphenylsilyl chloride in 15 ml of dichloromethane is
added dropwise, under an inert atmosphere, to a solution of 18.4 g
(75 mmol) of tert-butyl
4-hydroxy-4-(2-hydroxyethyl)-1-piperidinecarboxylate, obtained in
step 12.1, and 11.60 ml (82.50 mmol) of triethylamine in 100 ml of
dichloromethane, cooled to about 0.degree. C. The mixture is
allowed to warm to room temperature and stirring is then continued
for 12 hours. Saturated aqueous ammonium chloride solution is added
to the reaction medium. The aqueous phase is separated out and
extracted twice with dichloromethane, the combined organic phases
are washed with saturated aqueous sodium chloride solution and
dried over sodium sulfate, and the filtrate is concentrated under
reduced pressure. The residue thus obtained is purified by
chromatography on silica gel, eluting with a 10/90 and then 20/80
mixture of ethyl acetate and cyclohexane.
[0218] 33.48 g of product are thus obtained in the form of a yellow
oil.
12.3. tert-Butyl
4-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-4-fluoro-1-piperidinecarboxyl-
ate
[0219] A solution of 1.70 ml (13.40 mmol) of
1,1'-[(trifluoro-.lamda..sup.4-sulfanyl)imino]diethane (DAST) in 10
ml of dichloromethane is added dropwise, under an inert atmosphere,
to a solution of 5 g (10.34 mmol) of tert-butyl
4-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-4-hydroxy-1-piperidinecarboxy-
late, obtained in step 12.2, in 100 ml of dichloromethane, cooled
to about 0.degree. C. The mixture is allowed to warm to room
temperature and stiffing is then continued for 12 hours. Saturated
aqueous sodium hydrogen carbonate solution is added to the reaction
medium. The aqueous phase is separated out and extracted three
times with dichloromethane, and the combined organic phases are
washed with saturated aqueous sodium chloride solution and dried
over sodium sulfate. The filtrate is concentrated under reduced
pressure and the residue thus obtained is then purified by
chromatography on silica gel, eluting with a 10/90 mixture of ethyl
acetate and cyclohexane. 4.65 g of product are thus obtained in the
form of an orange-coloured oil. 0.60 ml of a solution of osmium
tetroxide (2.5%) in tert-butanol is added at room temperature to a
solution of 4.50 g of this oily residue and 1.25 g (10.7 mmol) of
N-methylmorpholine oxide (NMO) in a mixture of 8 ml of acetone and
6 ml of water. Stiffing is continued for 21 hours. The residue is
taken up in ethyl acetate and water, the aqueous phase is separated
out and extracted twice with ethyl acetate, and the combined
organic phases are washed with saturated aqueous sodium chloride
solution and dried over sodium sulfate. After evaporating off the
solvent, the residue obtained is purified by chromatography on
silica gel, eluting with a 6/94 mixture of ethyl acetate and
cyclohexane.
[0220] 3.40 g of product are thus obtained in the form of a pale
yellow oil.
12.4.
4-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-4-fluoropiperidine
[0221] 2.80 ml (37.06 mmol) of trifluoroacetic acid are added
slowly to a solution of 3 g (6.17 mmol) of tert-butyl
4-(2-{[tert-butyldiphenylsilyl]oxy}ethyl)-4-fluoro-1-piperidinecarboxylat-
e, obtained in step 12.3, in 20 ml of dichloromethane. Stirring is
continued at room temperature for 5 hours. The reaction mixture is
poured into a mixture of ice-water and 28% aqueous ammonia. The
phases are separated by settling, the aqueous phase is extracted
twice with dichloromethane and the combined organic phases are
washed with saturated aqueous sodium chloride solution, dried over
sodium sulfate and concentrated under reduced pressure.
[0222] 2.30 g of product are obtained in the form of a yellow oil,
which is used without further purification in the following
step.
12.5.
2-[4-(2-{[tert-butyldiphenylsilyl]oxy}ethyl)-4-fluoro-1-piperidyl]qu-
inoline
[0223] The process is performed as described in Example 2 (step
2.1). Starting with 1.18 g (5.68 mmol) of 2-bromoquinoline (Eur. J.
Org. Chem. 2002, 4181-4184), 2.30 g (5.98 mmol) of
4-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-4-fluoropiperidine,
obtained in step 12.4, 0.66 g (6.81 mmol) of sodium tert-butoxide,
0.149 g (0.239 mmol) of BINAP and 0.074 g (0.081 mmol) of
tris(dibenzylideneacetone)dipalladium, and after chromatography on
silica gel, eluting with a 10/90 mixture of ethyl acetate and
cyclohexane, 2.15 g of pure product are obtained in the form of an
orange-coloured oil.
12.6. 2-[4-Fluoro-1-(2-quinolyl)-4-piperidyl]ethanol
[0224] 0.40 g (1.26 mmol) of n-tetrabutylammonium fluoride
trihydrate is added to a solution of 2.15 g (4.19 mmol) of
2-[4-(2-{[tert-butyldiphenylsilyl]oxy}ethyl)-4-fluoro-1-piperidyl]quinoli-
ne, obtained in step 12.5, in 20 ml of tetrahydrofuran. Stirring is
continued at room temperature for 4 hours. The mixture is
concentrated to dryness and the residue obtained is then purified
by chromatography on silica gel, eluting with a 35/65 and then
40/60 mixture of ethyl acetate and cyclohexane.
[0225] 0.61 g of product is obtained in the form of an
orange-coloured oil.
12.7. 2-[4-Fluoro-1-(2-quinolyl)-4-piperidyl]ethyl
methanesulfonate
[0226] The process is performed as described in Example 3 (step
3.2). Starting with 0.61 g (2.22 mmol) of
2-[4-fluoro-1-(2-quinolyl)-4-piperidyl]ethanol, obtained in step
12.6, 0.280 g (2.45 mmol) of mesyl chloride and 0.35 ml (2.45 mmol)
of triethylamine, 0.80 g of product is obtained in the form of an
orange-coloured oil, which is used without further purification in
the following step.
12.8.
3-{2-[4-Fluoro-1-(2-quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-
-dione
[0227] The process is performed according to the method described
in Example 3 (step 3.3). Starting with 0.780 g (2.22 mmol) of
2-[4-fluoro-1-(2-quinolyl)-4-piperidyl]ethyl methanesulfonate,
obtained in step 12.7, 0.27 g (2.66 mmol) of
1,3-oxazolidine-2,4-dione and 0.51 g (4.43 mmol) of
1,1,3,3-tetramethylguanidine, and after chromatography on silica
gel, eluting with a 99/1 mixture of dichloromethane and methanol,
0.520 g of pure product is obtained in the form of a beige-coloured
solid.
12.9. 2-(Methylamino)-2-oxoethyl
2-[4-fluoro-1-(2-quinolyl)-4-piperidyl]ethylcarbamate
[0228] The process is performed according to the procedure
described in Example 1 (step 1.5). Starting with 0.52 g (1.46 mmol)
of
3-{2-[4-fluoro-1-(2-quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dion-
e, obtained in step 12.8, and 3.6 ml (7.28 mmol) of a solution (2M)
of methylamine in tetrahydrofuran, and after chromatography on
silica gel, eluting with a 99/1 mixture of ethyl acetate and
methanol, followed by crystallization from diethyl ether, 0.390 g
of pure product is obtained in the form of a white solid.
[0229] LC-MS: M+H=389
[0230] m.p. (.degree. C.): 147-149.degree. C.
[0231] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 1.70-2.10
(unresolved peak, 6H); 2.90 (d, 3H); 3.40 (broad t, 2H); 3.50 (q,
2H); 4.40 (broad d, 2H); 4.60 (s, 2H); 5.15 (broad s, 1H); 6.15
(broad s, 1H); 7.05 (d, 1H); 7.25 (t, 1H); 7.55 (t, 1H); 7.65 (d,
1H); 7.75 (d, 1H); 7.95 (d, 1H).
EXAMPLE 13
Compound 49
2-(Methylamino)-2-oxoethyl
2-[1-(6-isobutyl-2-pyridyl)-4-piperidyl]ethylcarbamate
##STR00018##
[0232] 13.1. 2-[1-(6-Bromo-2-pyridyl)-4-piperidyl]ethanol
[0233] The process is performed as described in Example 4 (step
4.1). Starting with 30.20 g (127 mmol) of 2,6-dibromopyridine and
16.45 g (127 mmol) of 2-(4-piperidyl)ethanol, and after
chromatography on silica gel, eluting with a 30/70 mixture of ethyl
acetate and cyclohexane, 7 g of pure product are obtained in the
form of an oil.
13.2. 2-[1-(6-Bromo-2-pyridyl)-4-piperidyl]ethyl
methanesulfonate
[0234] The process is performed as described in Example 3 (step
3.2). Starting with 7 g (24.50 mmol) of
2-[1-(6-bromo-2-pyridyl)-4-piperidyl]ethanol, obtained in step
13.1, 2.50 ml (26.90 mmol) of mesyl chloride and 3.80 ml (26.90
mmol) of triethylamine, 8.68 g of product are obtained in the form
of an oil, which is used without further purification in the
following step.
13.3.
3-{2-[1-(6-Bromo-2-pyridyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-d-
ione
[0235] The process is performed according to the method described
in Example 3 (step 3.3). Starting with 8.68 g (23.80 mmol) of
2-[1-(6-bromo-2-pyridyl)-4-piperidyl]ethyl methanesulfonate,
obtained in step 13.2, 2.90 g (28.60 mmol) of
1,3-oxazolidine-2,4-dione and 6 ml (47.60 mmol) of
1,1,3,3-tetramethylguanidine, and after chromatography on silica
gel, eluting with a 97/3 mixture of dichloromethane and methanol,
4.52 g of product are obtained in the form of an oil.
13.4.
3-{2-[1-(6-Isobutyl-2-pyridyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,-
4-dione
[0236] 2 g (5.43 mmol) of
3-{2-[1-(6-bromo-2-pyridyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione,
prepared in step 13.3, and 0.20 g (0.271 mmol) of
dichlorobis(triphenylphosphine)palladium
(Pd(PPh.sub.3).sub.2Cl.sub.2) suspended in 10 ml of tetrahydrofuran
are introduced under an inert atmosphere. 22 ml (10.80 mmol) of a
solution (0.5 M) of bromo(isobutyl)zinc in tetrahydrofuran are then
added. Stirring is continued at room temperature for 17 hours. The
reaction mixture is poured into water and ethyl acetate. The phases
are separated by settling, the aqueous phase is extracted twice
with ethyl acetate, the combined organic phases are dried over
sodium sulfate and the filtrate is concentrated under reduced
pressure. The residue thus obtained is purified by chromatography
on silica gel, eluting with a 20/80 mixture of ethyl acetate and
cyclohexane.
[0237] 1.41 g of product are obtained in the form of a white
solid.
[0238] m.p. (.degree. C.): 94-96.degree. C.
13.5. 2-(Methylamino)-2-oxoethyl
2-[1-(6-isobutyl-2-pyridyl)-4-piperidyl]ethyl-carbamate
[0239] The process is performed according to the procedure
described in Example 1 (step 1.5). Starting with 0.72 g (2.08 mmol)
of
3-{2-[1-(6-isobutyl-2-pyridyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dio-
ne, obtained in step 13.4, and 5.20 ml (10.40 mmol) of a solution
(2M) of methylamine in tetrahydrofuran, and after chromatography on
silica gel, eluting with a 95/5/0.5 mixture of dichloromethane,
methanol and 28% aqueous ammonia, followed by crystallization from
diisopropyl ether, 0.540 g of pure product is obtained in the form
of a white solid.
[0240] LC-MS: M+H=377
[0241] m.p. (.degree. C.): 97-99.degree. C.
[0242] .sup.1H NMR (DMSO) .delta. (ppm): 0.85 (d, 6H); 1.05 (m,
2H); 1.20-1.60 (unresolved peak, 3H); 1.70 (broad d, 2H); 2.0 (m,
1H); 2.40 (d, 2H); 2.55 (d, 3H); 2.70 (broad t, 2H); 3.05 (broad q,
2H); 4.20 (broad d, 2H); 4.30 (s, 2H); 6.35 (d, 1H); 6.55 (d, 1H);
7.15 (broad t, 1H); 7.40 (dd, 1H); 7.75 (broad s, 1H).
EXAMPLE 14
Compound 58
2-Amino-2-oxoethyl
2-[1-(6-phenyl-2-pyridyl)-4-piperidyl]methylcarbamate
##STR00019##
[0243] 14.1.
3-{2-[1-(6-Phenyl-2-pyridyl)-4-piperidyl]methyl}-1,3-oxazolidine-2,4-dion-
e
[0244] 0.20 g (0.56 mmol) of
3-{2-[1-(6-bromo-2-pyridyl)-4-piperidyl]methyl}-1,3-oxazolidine-2,4-dione-
, prepared according to the procedure described in Example 13
(steps 13.1, 13.2 and 13.3), 0.089 g (0.73 mmol) of phenylboronic
acid and 0.480 g (2.25 mmol) of hydrated potassium phosphate
suspended in 3 ml of 1,2-dimethoxyethane are introduced under an
inert atmosphere. 0.040 g (0.0346 mmol) of
tetrakis(triphenylphosphine)palladium is then added. The reaction
mixture is then maintained at about 85.degree. C. for 16 hours. The
resulting mixture is concentrated under reduced pressure. The
residue is taken up in ethyl acetate and water, the aqueous phase
is separated out and extracted twice with ethyl acetate, the
combined organic phases are dried over sodium sulfate and the
filtrate is concentrated under reduced pressure. The residue thus
obtained is purified by chromatography on silica gel, eluting with
a 40/60 mixture of ethyl acetate and cyclohexane.
[0245] 0.175 g of product is obtained.
14.2. 2-Amino-2-oxoethyl
2-[1-(6-phenyl-2-pyridyl)-4-piperidyl]methylcarbamate
[0246] The process is performed according to the procedure
described in Example 3 (step 3.4). Starting with 0.175 g (0.499
mmol) of
3-{2-[1-(6-phenyl-2-pyridyl)-4-piperidyl]methyl}-1,3-oxazolidine-2,4-dion-
e, obtained in step 14.1, and 2.5 ml (17.45 mmol) of a solution
(7M) of aqueous ammonia in methanol, 0.070 g of pure product is
obtained in the form of a white solid, after crystallization from
ethyl acetate.
[0247] LC-MS: M+H=369
[0248] m.p. (.degree. C.): 131-132.degree. C.
[0249] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 1.20-1.90
(unresolved peak, 5H); 2.90 (broad t, 2H); 3.20 (t, 2H); 4.50
(broad d, 2H); 4.60 (s, 2H); 5.0 (broad s, 1H); 5.55 (broad s, 1H);
6.15 (broad s, 1H); 6.65 (d, 1H); 7.10 (d, 1H); 7.35-7.60 (m, 4H);
8.15 (dd, 2H).
EXAMPLE 15
Compound 130
2-(Methylamino)-2-oxoethyl
2-[1-(5-chloro-2-quinolyl)-4-piperidyl]ethylcarbamate
##STR00020##
[0250] 15.1. 2-[1-(5-Chloro-2-quinolyl)-4-piperidyl]ethanol
[0251] The process is performed as described in Example 4 (step
4.1). Starting with 4.78 g (24.14 mmol) of
2-chloro-5-chloroquinoline (J. Med. Chem., 2002, 45, 3130-3137) and
3.43 g (26.55 mmol) of 2-(4-piperidyl)ethanol, 7 g of product are
obtained in the form of an oil, which is used without further
purification in the following step.
15.2. 2-[1-(5-Chloro-2-quinolyl)-4-piperidyl]ethyl
methanesulfonate
[0252] The process is performed as described in Example 3 (step
3.2). Starting with 7 g (24.07 mmol) of
2-[1-(5-chloro-2-quinolyl)-4-piperidyl]ethanol, obtained in step
15.1, 3.31 g (28.89 mmol) of mesyl chloride and 5.10 ml (36.11
mmol) of triethylamine, 8.70 g of product are obtained in the form
of an oil, which is used without further purification in the
following step.
15.3.
3-{2-[1-(5-Chloro-2-quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-
-dione
[0253] The process is performed according to the method described
in Example 3 (step 3.3). Starting with 8.7 g (23.58 mmol) of
2-[1-(5-chloro-2-quinolyl)-4-piperidyl]ethyl methanesulfonate,
obtained in step 15.2, 2.86 g (28.30 mmol) of
1,3-oxazolidine-2,4-dione and 5.43 g (47.17 mmol) of
1,1,3,3-tetramethyl-guanidine, and after chromatography on silica
gel, eluting with a 99.5/0.5 mixture of dichloromethane and
methanol, 6.40 g of product are obtained in the form of a white
solid.
[0254] m.p. (.degree. C.): 136.degree. C.
15.4. 2-(Methylamino)-2-oxoethyl
2-[1-(5-chloro-2-quinolyl)-4-piperidyl]ethylcarbamate
[0255] The process is performed according to the procedure
described in Example 1 (step 1.5). Starting with 6.40 g (17.12
mmol) of
3-{2-[1-(5-chloro-2-quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dion-
e, obtained in step 15.3, and 60 ml (119.84 mmol) of a solution
(2M) of methylamine in tetrahydrofuran, and after chromatography on
silica gel, eluting with a 98/2 and then 96/4 mixture of
dichloromethane and methanol, followed by crystallization from
diisopropyl ether, 5.14 g of product are obtained in the form of a
white solid.
[0256] LC-MS: M+H=405
[0257] m.p. (.degree. C.): 158-162.degree. C.
[0258] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 1.10-1.80
(unresolved peak, 5H); 1.9 (broad d, 2H); 2.90 (d, 3H); 3.0 (m,
2H); 3.30 (q, 2H); 4.60 (m, 4H); 4.85 (broad s, 1H); 6.10 (broad s,
1H); 7.05 (d, 1H); 7.25 (d, 1H); 7.40 (dd, 1H); 7.60 (d, 1H); 8.30
(s, 1H).
[0259] Table 1 below illustrates the chemical structures and
physical properties of a number of compounds according to the
invention.
[0260] In this table: [0261] in the "base or salt" column, "base"
represents a compound in free base form, whereas "HCl" represents a
compound in hydrochloride form; [0262] OMe represents a methoxy
group.
TABLE-US-00001 [0262] TABLE 1 ( I ) ##STR00021## base or No R.sub.1
m n A B R.sub.3 salt m.p. (.degree. C.) 1. ##STR00022## 2 2 N
(CH.sub.2).sub.3 CH.sub.2CONHCH.sub.3 base 131 2. 3. ##STR00023## 2
2 2 2 N N (CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONHCH.sub.3 base base 417* 165-166 4. 5. ##STR00024## 2 2
2 2 N N (CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONHCH.sub.3 base base 144-145 138-139 6. 7. ##STR00025## 2
2 2 2 N N (CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONHCH.sub.3 base base 173-174 196-197 8. 9. ##STR00026## 2
2 2 2 N N (CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONHCH.sub.3 base base 157-158 225-226 10. 11. ##STR00027##
2 2 2 2 N N (CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONHCH.sub.3 base base 121-122 141-142 12. 13. ##STR00028##
2 2 2 2 N N (CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONHCH.sub.3 base base 139-140 170-171 14. 15. ##STR00029##
2 2 2 2 N N (CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONHCH.sub.3 base base 128-129 153-154 16. 17. ##STR00030##
2 2 2 2 N N (CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONHCH.sub.3 base base 160-161 148-149 18. 19. ##STR00031##
2 2 2 2 N N (CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONHCH.sub.3 base base 156-157 157-158 20. 21. ##STR00032##
2 2 2 2 N N (CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONHCH.sub.3 base base 178-179 432* 22. 23. ##STR00033## 2
2 2 2 N N (CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONHCH.sub.3 base base 158-159 180-181 24. 25. ##STR00034##
2 2 2 2 N N (CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONHCH.sub.3 base base 185-186 193-194 26. 27. ##STR00035##
2 2 2 2 N N (CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONHCH.sub.3 base base 153-154 125-126 28. 29. ##STR00036##
2 2 2 2 N N (CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONHCH.sub.3 base base 193-194 176-177 30. 31. ##STR00037##
2 2 2 2 N N (CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONHCH.sub.3 base base 160-161 156-157 32. 33. ##STR00038##
2 2 2 2 N N (CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONHCH.sub.3 base base 189-190 196-197 34. ##STR00039## 2 3
N (CH.sub.2).sub.3 CH.sub.2CONHCH.sub.3 base 100 (dec.) 35.
##STR00040## 2 3 N (CH.sub.2).sub.3 CH.sub.2CONHCH.sub.3 HCl 451*
36. ##STR00041## 2 3 N (CH.sub.2).sub.3 CH.sub.2CONHCH.sub.3 HCl
172-174 37. ##STR00042## 2 3 N (CH.sub.2).sub.3
CH.sub.2CONHCH.sub.3 base 118-122 38. 39. ##STR00043## 2 2 2 2 N N
(CH.sub.2).sub.2 (CH.sub.2).sub.3 CH.sub.2CONHCH.sub.3
CH.sub.2CONHCH.sub.3 HCl HCl 166 167 40. 41. 42. 43. 44. 45.
##STR00044## 1 1 1 2 2 2 1 1 1 2 2 2 CH CH CH CH CH CF CH.sub.2
CH.sub.2 CH.sub.2 (CH.sub.2).sub.2 (CH.sub.2).sub.2
(CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONHCH.sub.3
CH.sub.2CONHCH.sub.2 (cyclopropyl) CH.sub.2CONHCH.sub.3
CH.sub.2CONH.sub.2 CH.sub.2CONHCH.sub.3 base base base base base
base 149-151 137-139 119-121 110-112 140-142 127-128 46.
##STR00045## 2 2 CH (CH.sub.2).sub.2 CH.sub.2CONHCH.sub.3 HCl
168-170 47. ##STR00046## 2 2 CH (CH.sub.2).sub.2
CH.sub.2CONHCH.sub.3 HCl 95-100 48. ##STR00047## 2 2 CH
(CH.sub.2).sub.2 CH.sub.2CONHCH.sub.3 base 113-115 49. 50.
##STR00048## 2 2 2 2 CH CH (CH.sub.2).sub.2 (CH.sub.2).sub.2
CH.sub.2CONHCH.sub.3 CH.sub.2CONH.sub.2 base base 97-99 107-109 51.
##STR00049## 2 2 CH (CH.sub.2).sub.2 CH.sub.2CONHCH.sub.3 base
108-110 52. ##STR00050## 2 2 CH (CH.sub.2).sub.2
CH.sub.2CONHCH.sub.3 base 98-100 53. ##STR00051## 2 2 CH
(CH.sub.2).sub.2 CH.sub.2CONHCH.sub.3 base 123-125 54. 55. 56.
##STR00052## 2 2 2 2 2 2 CH CH CH -- CH.sub.2 (CH.sub.2).sub.2
CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2 base base
base 169 148-149 131-132 57. 58. 59. ##STR00053## 2 2 2 2 2 2 CH CH
CH -- CH.sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2 base base base 153 131-132
116-117 60. 61. 62. ##STR00054## 2 2 2 2 2 2 CH CH CH -- CH.sub.2
(CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONH.sub.2 base base base 190-191 155-156 155-156 63. 64.
65. ##STR00055## 2 2 2 2 2 2 CH CH CH -- CH.sub.2 (CH.sub.2).sub.2
CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2 base base
base 159-160 132 134-135 66. 67. ##STR00056## 2 2 2 2 CH CH
CH.sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2
base base 146-147 332* 68. 69. 70. ##STR00057## 2 2 2 2 2 2 CH CH
CH -- CH.sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2 base base base 131-132
129-130 86-87 71. 72. 73. ##STR00058## 2 2 2 2 2 2 CH CH CH --
CH.sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONH.sub.2 base base base 58-59 387* 58-59 74. 75.
##STR00059## 2 2 2 2 CH CH CH.sub.2 (CH.sub.2).sub.2
CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2 base base 152-153 163 76. 77.
##STR00060## 2 2 2 2 CH CH (CH.sub.2).sub.2 (CH.sub.2).sub.2
CH.sub.2CONHCH.sub.3 CH.sub.2CONH.sub.2 base base 121-123 137-139
78. 79. ##STR00061## 2 2 2 2 CH CH CH.sub.2 (CH.sub.2).sub.2
CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2 base base 327* 162-163 80.
81. 82. ##STR00062## 2 2 2 2 2 2 CH CH CH -- CH.sub.2
(CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONH.sub.2 base base base 168 176 174-175 83. 84.
##STR00063## 2 2 2 2 CH CH CH.sub.2 (CH.sub.2).sub.2
CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2 base base 169-170 145-146 85.
86. ##STR00064## 2 2 2 2 CH CH (CH.sub.2).sub.2 (CH.sub.2).sub.2
CH.sub.2CONH.sub.2 CH.sub.2CONHCH.sub.3 base base 119-121 109-111
87. 88. ##STR00065## 2 2 2 2 CH CH CH.sub.2 (CH.sub.2).sub.2
CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2 base base 169-170 164-165 89.
##STR00066## 2 2 CH CH.sub.2 CH.sub.2CONH.sub.2 base 174-175 90.
91. ##STR00067## 2 2 2 2 CH CH CH.sub.2 (CH.sub.2).sub.2
CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2 base base 162-163 151-152 92.
93. ##STR00068## 2 2 2 2 CH CH -- CH.sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONH.sub.2 base base 195-196 229-230 94. 95. 96.
##STR00069## 2 2 2 2 2 2 CH CH CH -- CH.sub.2 (CH.sub.2).sub.2
CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2 base base
base 194-195 222-223 182 97. 98. ##STR00070## 2 2 2 2 CH CH
(CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONHCH.sub.3 base base 196-199 161-163 99. 100.
##STR00071## 2 2 2 2 CH CH CH.sub.2 (CH.sub.2).sub.2
CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2 base base 157-158 175-176
101. ##STR00072## 2 2 CH CH.sub.2 CH.sub.2CONH.sub.2 base 163-164
102. ##STR00073## 2 2 CH (CH.sub.2).sub.2 CH.sub.2CONH.sub.2 base
418* 103. ##STR00074## 2 2 CH CH.sub.2 CH.sub.2CONH.sub.2 base
190-191 104. ##STR00075## 2 2 CH (CH.sub.2).sub.2
CH.sub.2CONH.sub.2 base 165-166 105. 106. ##STR00076## 2 2 2 2 CH
CH CH.sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2
base base 323* 202-203 107. ##STR00077## 2 2 CH CH.sub.2
CH.sub.2CONH.sub.2 base 172-173 108. ##STR00078## 2 2 CH CH.sub.2
CH.sub.2CONH.sub.2 base 370* 109. ##STR00079## 2 2 CH CH.sub.2
CH.sub.2CONH.sub.2 base 177-178 110. 111. ##STR00080## 2 2 2 2 CH
CH CH.sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2
base base 202-203 185-186 112. 113. ##STR00081## 2 2 2 2 CH CH
CH.sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2
base base 165-166 126-127 114. 115. ##STR00082## 2 2 2 2 CH CH
CH.sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2
base base 309* 159-160 116. 117. ##STR00083## 2 2 2 2 CH CH
CH.sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2
base base 161-162 126-127 118. 119. ##STR00084## 2 2 2 2 CH CH
CH.sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2
base base 158-159 174-175 120. ##STR00085## 2 2 CH (CH.sub.2).sub.2
CH.sub.2CONH.sub.2 base 204-205 121. 122. ##STR00086## 2 2 2 2 CH
CH CH.sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2
base base 229-230 228-229 123. 124. 125. 126. 127. 128. 129.
##STR00087## 2 2 2 2 2 2 2 2 2 2 2 2 2 2 CH CH CH CH CH CF C(OH)
CH.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.2 (CH.sub.2).sub.2
(CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONHCH.sub.3
CH.sub.2CONH.sub.2 CH(CH.sub.3)CONHCH.sub.3 CH.sub.2CONHCH.sub.3
CH.sub.2CONH.sub.2 CH.sub.2CONHCH.sub.3 CH.sub.2CONHCH.sub.3 base
base base base base base base 153-157 206-212 129-130 126-128
135-137 147-149 82-90 130. 131. ##STR00088## 2 2 2 2 CH CH
(CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONHCH.sub.3
CH.sub.2CONH.sub.2 base base 158-162 171-175 132. ##STR00089## 2 2
CH (CH.sub.2).sub.2 CH.sub.2CONHCH.sub.3 base 162-163 133.
##STR00090## 2 2 CH (CH.sub.2).sub.2 CH.sub.2CONHCH.sub.3 base
154-156 134. 135. 136. 137. ##STR00091## 2 2 2 2 2 2 2 2 CH CH CH
CH CH.sub.2 CH.sub.2 (CH.sub.2).sub.2 (CH.sub.2).sub.2
CH.sub.2CONHCH.sub.3 CH.sub.2CONH.sub.2 CH.sub.2CONHCH.sub.3
CH.sub.2CONH.sub.2 base base base base 147-151 207-208 155-157
189-191 138. 139. 140. 141. ##STR00092## 2 2 2 2 2 2 2 2 CH CH CH
CH (CH.sub.2).sub.2 (CH.sub.2).sub.2 (CH.sub.2).sub.2
(CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONHCH.sub.3
CH.sub.2CONHCH.sub.2CH.sub.3 CH.sub.2CONHCH.sub.2 (cyclopropyl)
base base base base 163-165 135-137 114-116 95-100 142. 143.
##STR00093## 2 2 2 2 CH CH (CH.sub.2).sub.2 (CH.sub.2).sub.2
CH.sub.2CONH.sub.2 CH.sub.2CONHCH.sub.3 base base 191-193 149-151
144. 145. ##STR00094## 2 2 2 2 CH CH (CH.sub.2).sub.2
(CH.sub.2).sub.2 CH.sub.2CONHCH.sub.3 CH.sub.2CONH.sub.2 base base
146-150 171-173 146. 147. ##STR00095## 2 2 2 2 CH CH
(CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONHCH.sub.3
CH.sub.2CONH.sub.2 base base 140-142 160-162 148. 149. ##STR00096##
2 2 2 2 CH CH (CH.sub.2).sub.2 (CH.sub.2).sub.2
CH.sub.2CONHCH.sub.3 CH.sub.2CONH.sub.2 HCl HCl 148-150 219-221
150. ##STR00097## 2 2 CH (CH.sub.2).sub.2 CH.sub.2CONHCH.sub.3 base
130-132
151. 152. 153. 154. 155. 156. 157. ##STR00098## 1 1 2 2 2 2 2 2 2 2
2 2 2 2 CH CH CH CH CH CH CH CH.sub.2 CH.sub.2 -- CH.sub.2
(CH.sub.2).sub.2 (CH.sub.2).sub.2 (CH.sub.2).sub.3
CH.sub.2CONH.sub.2 CH.sub.2CONHCH.sub.3 CH.sub.2CONHCH.sub.3
CH.sub.2CONHCH.sub.3 CH.sub.2CONHCH.sub.3 CH.sub.2CONH.sub.2
CH.sub.2CONHCH.sub.3 base base HCl HCl HCl HCl HCl 109-111 99-102
232-237 208-212 132-136 120-124 385* 158. 159. ##STR00099## 2 2 2 2
CH CH (CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2
CH.sub.2CONHCH.sub.3 base base 135-139 144-148 160. ##STR00100## 2
2 CH (CH.sub.2).sub.2 CH.sub.2CONHCH.sub.3 base 134-136 161. 162.
163. ##STR00101## 2 2 2 2 2 2 CH CH CH CH.sub.2 (CH.sub.2).sub.2
(CH.sub.2).sub.2 CH.sub.2CONHCH.sub.3 CH.sub.2CONHCH.sub.3
CH.sub.2CONH.sub.2 HCl base base 387* 100-104 118-120 164.
##STR00102## 2 2 CH (CH.sub.2).sub.2 CH.sub.2CONHCH.sub.3 HCl
186-188 165. ##STR00103## 2 2 CH (CH.sub.2).sub.2
CH.sub.2CONHCH.sub.3 base 80-86 166. 167. ##STR00104## 2 2 2 2 CH
CH (CH.sub.2).sub.2 (CH.sub.2).sub.2 CH.sub.2CONHCH.sub.3
CH.sub.2CONH.sub.2 base base 156-158 176-178 168. ##STR00105## 2 2
CH (CH.sub.2).sub.2 CH.sub.2CONHCH.sub.3 base 148-150 169.
##STR00106## 2 2 CH (CH.sub.2).sub.2 CH.sub.2CONHCH.sub.3 base
154-156 170. 171. ##STR00107## 2 2 2 2 CH CH (CH.sub.2).sub.2
(CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONHCH.sub.3 base base
156-158 156-158 172. ##STR00108## 2 2 CH (CH.sub.2).sub.2
CH.sub.2CONHCH.sub.3 HCl 205-210 173. 174. ##STR00109## 2 2 2 2 CH
CH CH.sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2
base base 419* 105-106 175. 176. ##STR00110## 2 2 2 2 CH CH
CH.sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2
base base 129-130 112-113 177. ##STR00111## 2 2 CH CH.sub.2
CH.sub.2CONH.sub.2 base 180-181 178. 179. 180. ##STR00112## 2 2 2 2
2 2 CH CH CH CH.sub.2 (CH.sub.2).sub.2 (CH.sub.2).sub.2
CH.sub.2CONH.sub.2 CH.sub.2CONHCH.sub.3 CH.sub.2CONH.sub.2 base
base base 244-245 146-150 169-171 181. 182. ##STR00113## 2 2 2 2 CH
CH CH.sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2
base base 137-138 208-209 183. 184. ##STR00114## 2 2 2 2 CH CH
CH.sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2
base base 183-184 172-173 185. 186. ##STR00115## 2 2 2 2 CH CH
CH.sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2
base base 187-188 191-192 187. ##STR00116## 2 2 CH CH.sub.2
CH.sub.2CONH.sub.2 base 222-223 188. 189. ##STR00117## 2 2 2 2 CH
CH CH.sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2
base base 149-150 167-168 190. 191. ##STR00118## 2 2 2 2 CH CH
CH.sub.2 (CH.sub.2).sub.2 CH.sub.2CONH.sub.2 CH.sub.2CONH.sub.2
base base 220-221 201-202 *M + H (LC-MS) dec. = decomposition of
the product
[0263] The compounds of the invention underwent pharmacological
trials to determine their inhibitory effect on the enzyme FAAH
(Fatty Acid Amide Hydrolase).
[0264] The inhibitory activity was demonstrated in a radioenzymatic
test based on measuring the product of hydrolysis (ethanolamine
[1-.sup.3H]) of anandamide [ethanolamine 1-.sup.3H] with FAAH (Life
Sciences (1995), 56, 1999-2005 and Journal of Pharmacology and
Experimented Therapeutics (1997), 283, 729-734). Thus, mouse brains
(minus the cerebellum) are removed and stored at -80.degree. C.
Membrane homogenates are prepared extemporaneously by homogenizing
the tissues using a Polytron blender in 10 mM tris-HCl buffer (pH
8.0) containing 150 mM NaCl and 1 mM EDTA. The enzymatic reaction
is then performed in 70 .mu.l of buffer containing fatty-acid-free
bovine serum albumin (1 mg/ml). To test compounds at different
concentrations, anandamide [ethanolamine 1-.sup.3H] (specific
activity of 15-20 Ci/mmol) diluted to 10 .mu.M with cold
anandamide, and the membrane preparation (400 .mu.g of frozen
tissue per test) are successively added. After 15 minutes at
25.degree. C., the enzymatic reaction is quenched by adding 140
.mu.L of chloroform/methanol (2:1). The mixture is stirred for 10
minutes and then centrifuged for 15 minutes at 3500 g. An aliquot
(30 .mu.L) of the aqueous phase containing the ethanolamine
[1-.sup.3H] is counted by liquid scintillation. Under these
conditions, the most active compounds of the invention have
IC.sub.50 values (concentration that inhibits 50% of the control
enzymatic activity of FAAH) of between 0.001 and 1 .mu.M.
[0265] Table 2 below shows the IC.sub.50 values of a few compounds
according to the invention.
TABLE-US-00002 TABLE 2 Compound No. IC.sub.50 47 85 .mu.M 126 113
.mu.M 166 87 .mu.M
[0266] It is thus seen that the compounds according to the
invention have inhibitory activity on the enzyme FAAH.
[0267] The in vivo activity of the compounds of the invention was
evaluated in a test of analgesia.
[0268] Thus, the intraperitoneal (i.p.) administration of PBQ
(phenylbenzoquinone, 2 mg/kg in 0.9% sodium chloride solution
containing 5% ethanol) to male OF1 mice weighing 25 to 30 g, causes
abdominal tractions, on average 30 torsions or contractions during
the period of 5 to 15 minutes after injection. The test compounds
are administered orally or intraperitoneally as a 0.5% suspension
in Tween 80, 60 minutes or 120 minutes before the administration of
PBQ. Under these conditions, the most powerful compounds of the
invention produce a 35% to 70% reduction in the number of tractions
induced with PBQ, within a dose range of between 1 and 30
mg/kg.
[0269] Table 3 below shows the results of the analgesia test for a
few compounds according to the invention.
TABLE-US-00003 TABLE 3 Reduction in the number of tractions
Compound No. (%) 47 -63% (b) 126 -43% (b) 166 -62% (a) (a) 1 mg/kg
p.o. at 2 hours; (b) 3 mg/kg p.o. at 1 hour
[0270] The enzyme FAAH (Chemistry and Physics of Lipids, (2000),
108, 107-121) catalyses the hydrolysis of the endogenous amide and
ester derivatives of various fatty acids such as
N-arachidonoylethanolamine (anandamide), N-palmitoylethanolamine,
N-oleoylethanolamine, oleamide or 2-arachidonoylglycerol. These
derivatives exert different pharmacological activities by
interacting, inter alia, with the cannabinoid and vanilloid
receptors.
[0271] The compounds of the invention block this degradation
pathway and increase the tissue content of these endogenous
substances. They may be used in this respect in the prevention and
treatment of pathologies in which the endogenous cannabinoids,
and/or any other substrates metabolized by the enzyme FAAH, are
involved. Examples that may be mentioned include the following
diseases and complaints: [0272] pain, especially acute or chronic
pain of neurogenic type: migraine, neuropathic pain including the
forms associated with the herpes virus and diabetes, acute or
chronic pain associated with inflammatory diseases: arthritis,
rheumatoid arthritis, osteoarthritis, spondylitis, gout,
vascularitis, Crohn's disease, irritable bowel syndrome, [0273]
acute or chronic peripheral pain, [0274] vertigo, vomiting, nausea,
in particular post-chemotherapy nausea, [0275] eating disorders, in
particular anorexia and cachexia of diverse nature, [0276]
neurological and psychiatric pathologies: tremor, dyskinaesia,
dystonia, spasticity, [0277] compulsive and obsessive behaviour,
Tourette's syndrome, all forms of depression and anxiety of any
nature or origin, mood disorders, psychoses, [0278] acute and
chronic neurodegenerative diseases: Parkinson's disease,
Alzheimer's disease, senile dementia, Huntington's chorea, lesions
associated with cerebral ischaemia and cranial and medullary
trauma, [0279] epilepsy, [0280] sleeping disorders, including sleep
apnoea, [0281] cardiovascular diseases, in particular hypertension,
cardiac arrhythmia, [0282] arteriosclerosis, heart attack, cardiac
ischaemia, [0283] renal ischaemia, [0284] cancers: benign skin
tumours, papillomas and cerebral tumours, prostate tumours,
cerebral tumours (gliobastomas, medullo-epitheliomas,
medullo-blastomas, neuroblastomas, tumours of embryonic origin,
astrocytomas, astroblastomas, ependyomas, oligodendrogliomas,
plexus tumour, neuroepitheliomas, pineal gland tumours,
ependymoblastomas, malignant meningiomas, sarcomatoses, malignant
melanomas, schwennomas), [0285] immune system disorders, especially
autoimmune diseases: psoriasis, lupus erythematosus, connective
tissue diseases, Sjogrer's syndrome, ankylosing spondylitis,
undifferentiated spondylitis, Behcet's disease, haemolytic
autoimmune anaemias, multiple sclerosis, amyotrophic lateral
sclerosis, amylosis, graft rejection, diseases affecting the
plasmocytic line, [0286] allergic diseases: immediate or delayed
hypersensitivity, allergic rhinitis or allergic conjunctivitis,
contact dermatitis, [0287] parasitic, viral or bacterial infectious
diseases: AIDS, meningitis, inflammatory diseases, especially
articular diseases: arthritis, rheumatoid arthritis,
osteoarthritis, spondylitis, gout, vascularitis, Crohn's disease,
irritable bowel syndrome, osteoporosis, ocular complaints: ocular
hypertension, glaucoma, [0288] pulmonary complaints: respiratory
pathway diseases, bronchospasms, coughing, asthma, chronic
bronchitis, chronic obstruction of the respiratory pathways,
emphysema, [0289] gastrointestinal diseases: irritable bowel
syndrome, intestinal inflammatory disorders, ulcers, diarrhoea,
[0290] urinary incontinence and inflammation of the bladder.
[0291] The use of the compounds according to the invention, in the
form of the base, or a pharmaceutically acceptable acid-addition
salt, hydrate or solvate, for the preparation of a medicinal
product for treating the pathologies mentioned above forms an
integral part of the invention.
[0292] A subject of the invention is also medicinal products
comprising a compound of formula (I), or an acid-addition salt, or
alternatively a pharmaceutically acceptable hydrate or solvate of
the compound of formula (I). These medicinal products find their
therapeutic use especially in the treatment of the pathologies
mentioned above.
[0293] According to another of its aspects, the present invention
relates to pharmaceutical compositions containing, as active
principal, at least one compound according to the invention. These
pharmaceutical compounds contain an effective dose of a compound
according to the invention, or a pharmaceutically acceptable
acid-addition salt, hydrate or solvate of the said compound, and
optionally one or more pharmaceutically acceptable excipients.
[0294] The said excipients are chosen, according to the
pharmaceutical form and the desired administration form, from the
usual excipients known to those skilled in the art.
[0295] In the pharmaceutical compositions of the present invention
for oral, sublingual, subcutaneous, intramuscular, intravenous,
topical, local, intrathecal, intranasal, transdermal, pulmonary,
ocular or rectal administration, the active principal of formula
(I) above, or the possible acid-addition salt, solvate or hydrate
thereof, may be administered in a unit administration form, as a
mixture with standard pharmaceutical excipients, to man and animals
for the prophylaxis or treatment of the above disorders or
diseases.
[0296] The appropriate unit administration forms comprise oral
forms such as tablets, soft or hard gel capsules, powders,
granules, chewing gums and oral solutions or suspensions,
sublingual, buccal, intratracheal, intraocular and intranasal
administration forms, forms for administration by inhalation,
sub-cutaneous, intramuscular or intravenous administration forms
and rectal or vaginal administration forms. For topical
administration, the compounds according to the invention may be
used in creams, ointments or lotions.
[0297] By way of example, a unit administration form of a compound
according to the invention in the form of a tablet may comprise the
following components:
TABLE-US-00004 Compound according to the invention 50.0 mg Mannitol
223.75 mg Sodium croscarmellose 6.0 mg Maize starch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg
[0298] The said unit forms are dosed to allow a daily
administration of from 0.01 to 20 mg of active principal per kg of
body weight, depending on the presentation form.
[0299] There may be particular cases in which higher or lower doses
are suitable, and such doses also form part of the invention.
According to the usual practice, the dose that is suitable for each
patient is determined by the doctor according to the mode of
administration and the weight and response of the said patient.
[0300] According to another of its aspects, the invention also
relates to a method for treating the pathologies mentioned above,
which comprises the administration of an effective dose of a
compound according to the invention, a pharmaceutically acceptable
acid-addition salt thereof or a solvate or hydrate of the said
compound.
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