U.S. patent application number 10/714447 was filed with the patent office on 2004-07-15 for novel compounds with analgesic effect.
This patent application is currently assigned to AstraZeneca Canada Inc.. Invention is credited to Plobeck, Niklas, Roberts, Edward, Wahlestedt, Claes.
Application Number | 20040138228 10/714447 |
Document ID | / |
Family ID | 20400739 |
Filed Date | 2004-07-15 |
United States Patent
Application |
20040138228 |
Kind Code |
A1 |
Roberts, Edward ; et
al. |
July 15, 2004 |
Novel compounds with analgesic effect
Abstract
Compounds of the formula (I) 1 as well as their pharmaceutically
acceptable salts, and pharmaceutical compositions comprising the
novel compounds. The novel compounds of the formula (I) are useful
in the management of pain.
Inventors: |
Roberts, Edward; (St Lazare
de Vaudreuil, CA) ; Plobeck, Niklas; (Ville St
Laurent, CA) ; Wahlestedt, Claes; (Montreal,
CA) |
Correspondence
Address: |
Michael A. Sanzo
Fitch, Even, Tabin & Flannery
Suite 401L
1801 K Street, N.W.
Washington
DC
20006-1201
US
|
Assignee: |
AstraZeneca Canada Inc.
|
Family ID: |
20400739 |
Appl. No.: |
10/714447 |
Filed: |
November 17, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10714447 |
Nov 17, 2003 |
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09631116 |
Aug 2, 2000 |
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6680321 |
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09631116 |
Aug 2, 2000 |
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08836830 |
Apr 24, 1997 |
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6130222 |
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08836830 |
Apr 24, 1997 |
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PCT/SE96/01635 |
Dec 11, 1996 |
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Current U.S.
Class: |
514/253.06 ;
514/252.12; 514/254.11; 514/314; 514/317; 514/320; 546/176;
546/196; 546/205 |
Current CPC
Class: |
C07D 295/112 20130101;
A61P 23/00 20180101; C07D 295/096 20130101; C07C 2601/14 20170501;
C07D 295/155 20130101; A61P 25/04 20180101; C07D 295/135 20130101;
C07D 295/205 20130101; C07D 215/14 20130101; C07D 295/185 20130101;
A61P 29/00 20180101; C07D 307/81 20130101; A61K 31/496 20130101;
A61K 31/495 20130101 |
Class at
Publication: |
514/253.06 ;
514/254.11; 514/252.12; 514/314; 514/317; 514/320; 546/176;
546/196; 546/205 |
International
Class: |
C07D 215/12; A61K
031/496; A61K 031/495 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 22, 1995 |
SE |
9504661-1 |
Claims
1. A compound of the general formula (I) 29wherein G is a carbon
atom or a nitrogen atom; A is selected from (i) phenyl substituted
by any of --COOH, --CONH.sub.2, COOCH.sub.3, --CN, NH.sub.2 or
--COCH.sub.3; (ii) naphtyl, benzofuranyl, and quinolinyl; and 30
wherein the phenyl ring of each A substituent may be optionally and
independently substituted by 1 or 2 substituents selected from
hydrogen, CH.sub.3, (CH.sub.2).sub.oCF.sub.3, halogen,
CONR.sup.7R.sup.8, CO.sub.2R.sup.7, COR.sup.7,
(CH.sub.2).sub.oNR.sup.7R.sup.8, (CH.sub.2).sub.oCH.sub.3(CH.s-
ub.2).sub.oSOR.sup.7, (CH.sub.2).sub.oSO.sub.2R.sup.7 and
(CH.sub.2).sub.oSO.sub.2NR.sup.7R.sup.8 wherein o is 0, 1, or 2,
and R.sup.7 and R.sup.8 are as defined below; R.sup.1 is selected
from hydrogen; a branched or straight C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkenyl, --CO(C.sub.1-C.sub.6 alkyl);
(C.sub.1-C.sub.6 alkyl)-B wherein B is as defined below;
C.sub.3-C.sub.8 cycloalkyl, C.sub.4-C.sub.8 (alkyl-cycloalkyl)
wherein alkyl is C.sub.1-C.sub.2 alkyl and cycloalkyl is
C.sub.3-C.sub.6 cycloalkyl; C.sub.6-C.sub.10 aryl; and heteroaryl
having from 5-10 atoms selected from any of C, S, N and O; and
whereby the C.sub.6-C.sub.10 aryl and the heteroaryl may optionally
be substituted by 1 or 2 substituents selected from hydrogen,
CH.sub.3, (CH.sub.2).sub.oCF.sub.3, halogen, CONR.sup.7R.sup.8,
CO.sub.2R.sup.7, COR.sup.7, (CH.sub.2).sub.oNR.sup.7R.sup.8,
(CH.sub.2).sub.oCH.sub.3(CH.s- ub.2).sub.oSOR.sup.7,
(CH.sub.2).sub.oSO.sub.2R.sup.7 and
(CH.sub.2).sub.oSO.sub.2NR.sup.7R.sup.8 wherein o is 0, 1, or 2,
and R.sup.7 and R.sup.8 are as defined below; R.sup.7 and R.sup.8
is each and independently as defined for R.sup.1 above; R.sup.2 is
selected from hydrogen, CH.sub.3, OR.sup.1, CO.sub.2R.sup.1, and
CH.sub.2CO.sub.2R.sup.1 wherein R.sup.1 is as defined above;
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, R.sup.17, and R.sup.18, is each and
independently as defined for R1 above; B is a substituted or
unsubstituted aromatic; an optionally substituted C.sub.5-C.sub.10
hydroaromatic; a heteroaromatic or a heterohydroaromatic moiety,
each having from 5 to 10 atoms selected from any of C, S, N and O,
and each being optionally substituted by 1 or 2 substituents
independently selected from hydrogen, CH.sub.3, CF.sub.3, halogen,
(CH.sub.2).sub.pCONR.sup.7R.sup.8, (CH.sub.2).sub.pNR.sup.7R.sup-
.8, (CH.sub.2).sub.pCOR.sup.7, (CH.sub.2).sub.pCO.sub.2R.sup.7,
(CH.sub.2).sub.pSOR.sup.7, (CH.sub.2).sub.pSO.sub.2R.sup.7, and
(CH.sub.2).sub.pSO.sub.2NR.sup.7R.sup.8; wherein p is 0, 1, 2 or 3
and wherein R.sup.7 and R.sup.8 are as defined above; R.sup.3,
R.sup.4, R.sup.5 and R.sup.6 is each and independently selected
from R.sup.7, (CH.sub.2).sub.pCONR.sup.7R.sup.8,
(CH.sub.2).sub.pNR.sup.7R.sup.8, (CH.sub.2).sub.pCONR.sup.7R.sup.8,
(CH.sub.2).sub.pCO.sub.2R.sup.7, (CH.sub.2).sub.pPh,
(CH.sub.2).sub.p(p-OH Ph), (CH.sub.2).sub.p-3-indolyl- ,
(CH.sub.2).sub.pSR.sup.7, and (CH.sub.2).sub.pOR.sup.7; wherein p
is 0, 1, 2, 3, or 4, and R.sup.7 and R.sup.8 are as defined above;
as well as pharmaceutically acceptable salts of the compounds of
the formula (I), isomers, hydrates, isoforms and prodrugs thereof;
with the proviso that when A is a phenyl ring substituted by a --CN
group or by a --NH.sub.2 group, B may not be 31 wherein Z.sup.1 is
hydroxy, and esters thereof; hydroxymethyl, and esters thereof; or
amino, and carboxamides and sulfonamides.
2. A compound of the formula I according to claim 1, wherein G is a
carbon atom or a nitrogen atom; A is selected from (i) phenyl
substituted by any of --COOH, --CONH.sub.2, COOCH.sub.3, --CN,
NH.sub.2 or --COCH.sub.3; (ii) naphtyl, benzofuranyl, and
quinolinyl; and (iii) 32 wherein the phenyl ring of each A
substituent may be optionally and independently substituted by 1 or
2 substituents selected from hydrogen, CH.sub.3,
(CH.sub.2).sub.oCF.sub.3, halogen CONR.sup.7R.sup.8,
CO.sub.2R.sup.7, COR.sup.7, (CH.sub.2).sub.oNR.sup.7R.sup.8,
(CH.sub.2).sub.oCH.sub.3(CH.s- ub.2).sub.oSOR.sup.7,
(CH.sub.2).sub.oSO.sub.2R.sup.7 and
(CH.sub.2).sub.oSO.sub.2NR.sup.7R.sup.8 wherein o is 0, 1, or 2,
and R.sup.7 and R.sup.8 are as defined below; R.sup.1, R.sup.7 and
R.sup.8 is each and independently selected from hydrogen; a
branched or straight C.sub.1-C.sub.4 alkyl, allyl,
--CO--(C.sub.1-C.sub.6 alkyl); (C.sub.1-C.sub.6 alkyl)-B wherein B
is as defined below, C.sub.3-C.sub.5 cycloalkyl, C.sub.4-C.sub.8
(alkyl-cycloalkyl) wherein alkyl is C.sub.1-C.sub.2 alkyl and
cycloalkyl is C.sub.3-C.sub.6 cycloalkyl; and phenyl; R.sup.2 is
hydrogen, methyl, or OR.sup.1 wherein R.sup.1 is as defined above;
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, R.sup.17, and R.sup.18 is each and
independently as defined for R.sup.1 above; B is selected from
phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl,
benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl,
cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl,
indenyl, tetrahydronaphthyl, tetrahydroquinyl,
tetrahydroisoquinolinyl, tetrahydrofuranyl, pyrrolidinyl,
indazolinyl, and 33 each B group being optionally substituted by
1-2 substituents independently selected from hydrogen, CH.sub.3,
CF.sub.3, halogen, (CH.sub.2).sub.pCONR.sup.7R.sup.8,
(CH.sub.2).sub.pNR.sup.7R.sup.8, (CH.sub.2).sub.pCOR.sup.7,
(CH.sub.2).sub.p(CO.sub.2R.sup.7, and OR.sup.7, wherein p is 0 or
1, and wherein R.sup.7 and R.sup.8 are as defined above; and
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is each and independently
selected from hydrogen, CH.sub.3, CH(Me).sub.2,
CH.sub.2CH(Me).sub.2,
CH(Me)CH.sub.2CH.sub.3(CH.sub.2).sub.pCONR.sup.7R.s- up.8,
(CH.sub.2).sub.pNR.sup.7R.sup.8, (CH.sub.2).sub.pCONR.sup.7R.sup.8,
(CH.sub.2).sub.pCO.sub.2R.sup.7, (CH.sub.2).sub.pPh,
(CH.sub.2).sub.p(p-OH Ph), (CH.sub.2).sub.p-3-indolyl,
(CH.sub.2).sub.pSR.sup.7, and (CH.sub.2).sub.pOR.sup.7, wherein p
is 0, 1, 2, or 3, and wherein R.sup.7 and R.sup.8 are as defined
above; with the proviso that when A is a phenyl ring substituted by
a --CN group or by a --NH.sub.2 group, B may not be 34 wherein
Z.sup.1 is hydroxy, and esters thereof; hydroxymethyl, and esters
thereof; or amino, and carboxamides and sulfonamides.
3. A compound of the formula I according to claim 1, wherein G is a
nitrogen atom; A is selected from 35 wherein R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16,
R.sup.17, and R.sup.18 is each an ethyl group; R.sup.1 is selected
from hydrogen, methyl, ethyl, allyl, or CH.sub.2-cyclopropyl;
R.sup.2 is H, methyl, or OR.sup.1; B is selected from phenyl,
naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl,
benzothiophenyl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl,
cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl,
tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl,
tetrahydrofuranyl, indazolinyl, and 36 each B group being
optionally substituted by 1-2 substituents-independently selected
from hydrogen, methyl, CF.sub.3, halogen,
(CH.sub.2)CONR.sup.7R.sup.8, (CH.sub.2).sub.pNR.sup.7R.sup.8,
(CH.sub.2).sub.pCOR.sup.7, (CH.sub.2).sub.pC.sub.2R.sup.7, and
OR.sup.7, wherein p is 0, 1, or 2, and wherein R.sup.7 and R.sup.8
are as defined for R.sup.1 above; R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 is each and independently selected from H, CH.sub.3,
CH(Me).sub.2, CH.sub.2CH(Me).sub.2,
CH(Me)CH.sub.2CH.sub.3(CH.sub.2).sub.pCONR.sup.7R.sup.8,
(CH.sub.2).sub.pNR.sup.7R.sup.8, (CH.sub.2).sub.pCONR.sup.7R.sup.8,
(CH.sub.2).sub.pCO.sub.2R.sup.7, (CH.sub.2).sub.pPh,
(CH.sub.2).sub.p(p-OH Ph), (CH.sub.2).sub.pSR.sup.7, and
(CH.sub.2).sub.pOR.sup.7 wherein p is 0, 1 or 2, and wherein
R.sup.7 and R.sup.8 are as defined above.
4. A compound of the formula (I) of claim 1 above, being anyone of
(.+-.)-trans-1-(3-methoxy-.alpha.-(naphthyl)benzyl)-2,5-dimethylpiperazin-
e (compound 3);
(.+-.)-3-((.alpha.R*/S*)-.alpha.-((2S*,5R*)-4-Allyl-2,5-di-
methyl-1-piperazinyl)-1-naphthyl)anisole (compound 4 and 5);
(.+-.)-trans-1-(3-methoxy-.alpha.-(2-naphthyl)benzyl)-2,5-dimethylpiperaz-
ine (compound 8);
(.+-.)-3-((.alpha.R*/S*)-.alpha.-((2S*,5R*)-4-Allyl-2,5--
dimethyl-1-piperazinyl)-2-naphthyl)anisole (compound 9 and 10);
(.+-.)-trans-1-(3-methoxy-.alpha.-(2'-benzofuranyl)benzyl)-2,5-dimethylpi-
perazine (compound 13);
(.+-.)-3-((.alpha.R*/S*)-.alpha.-((2S*,5R*)-4-Ally-
l-2,5-dimethyl-1-piperazinyl)-2-benzofuranyl)anisole (compound 14
and 15);
(.+-.)-3-((.alpha.R*/S*)-.alpha.-((2S*,5R*)-4-Cyclopropylmethyl-2,5-dimet-
hyl-1-piperazinyl)-2-benzofuranyl)anisole (compound 16 and 17);
(.+-.)-trans-1-(3-methoxy-.alpha.-(6'-quinolinyl)benzyl)-2,5-dimethylpipe-
razine (compound 20 and 21);
(.+-.)-3-((.alpha.R*/S*)-.alpha.-((2S*,5R*)-4-
-Allyl-2,5-dimethyl-1-piperazinyl)-6-quinolinyl)anisole (compound
22);
(.+-.)-3-((.alpha.R*/S*)-.alpha.-((2S*,5R*)-4-Allyl-2,5-dimethyl-1-pipera-
zinyl)-6-quinolinyl)anisole (compound 23);
(.+-.)-3-((.alpha.R*/S*)-.alpha-
.-((2S*,5R*)-4-Cyclopropylmethyl-2,5-dimethyl-1-piperazinyl)-6-quinolinyl)-
anisole (compound 24 and 25);
(.+-.)-trans-1-(3-methoxy-.alpha.-(4-quinoli-
nyl)benzyl)-2,5-dimethyl-piperazine (compound 28);
(.+-.)-3-((.alpha.R*/S*- )-.alpha.-((2S*,5R*) Allyl-2,
ethyl-1-piperazinyl)-4-quinolinyl)anisole (compound 29 and 30);
(.+-.)4-((.alpha.-(1-Piperazinyl))-4-chlorobenzyl)--
N,N-diethylbenzamide (compound 33);
(.+-.)4-((.alpha.-((4-Allyl)-1-piperaz-
inyl))-4-chlorobenzyl)-N,N-diethylbenzamide.2hcl (compound 34);
(.+-.)4-((.alpha.-(1-Piperazinyl))-2-naphtylmethyl)-N,N-diethylbenzamide
(compound 37);
(.+-.)4-((.alpha.-((4-Allyl)-1-piperazinyl)-2-naphtylmethy-
l)-N,N-diethylbenzamide (compound 38);
(.+-.)4-((.alpha.-(1-Piperazinyl))-- 4-xylyl)-N,N-diethylbenzamide,
(compound 41); (.+-.)4-((.alpha.-((4-Allyl)-
-1-piperazinyl))-4-xylyl)-N,N-diethylbenzamide.2HCl (compound 42);
(.+-.)4-((.alpha.-(1-Piperazinyl))-3-xylyl)-N,N-diethylbenzamide.2HCl
(compound 45);
(.+-.)4-((.alpha.-(1-Piperazinyl))-cyclohexylmethyl)-N,N-d-
iethylbenzamide (compound 48);
(.+-.)4-((.alpha.-(1-Piperazinyl))-3,4-dime-
thylbenzyl)-N,N-diethylbenzamide (compound 51);
(.+-.)4-((.alpha.-(1-Piper-
azinyl))-1-naphtylmethyl)-N,N-diethylbenzamide (compound 54);
4-(4-(2-Dimethyl-5-methyl-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzam-
ide dihydrochloride (compound 57);
4-(4-(1-Allyl-2-dimethyl-5-methyl-piper-
azinyl)-3-methoxybenzyl)-N,N-diethylbenzamide dihydrochloride
(compound 58);
4-(1-(4-Allyl-2-dimethyl-5-methyl-piperazinyl)-3-methoxybenzyl)-N,N--
diethylbenzamide dihydrochloride (compound 60);
4-(1-(2-dimethyl-5-methyl--
piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide dihydrochloride
(compound 61); 4-((1-piperazinyl)-benzyl) N,N-diethylbenzamide
dihydrochloride (compound 64);
4-((4-Allyl-1-piperazinyl)-benzyl)-N,N-die- thylbenzamide
dihydrochloride (compound 65); 4-((4-Acetyl-1-piperazinyl)-b-
enzyl)-N,N-diethylbenzamide hydrochloride (compound 77);
4-(4-(2-Hydroxymethyl-5-methyl)piperazinyl-benzyl)-N,N-diethyl-benzamide
dihydrochloride (compound 69);
4-((4-(2-Hydroxymethyl-5-methyl)piperaziny-
l)-3-methoxybenzyl)-N,N-diethylbenzamide dihydrochloride (compound
70);
4-((4-(1-Allyl-2-hydroxymethyl-5-methyl)piperazinyl)-3-methoxybenzyl)-N,N-
-diethylbenzamide dihydrochloride (compound 71); Methyl
3-((2-naphtyl)(3-methyl-piperazinyl)methyl)phenyl ether
dihydrochloride (compound 75); Methyl
3-((2-naphtyl)(4-Allyl-2-methyl-piperazinyl)methyl)- phenyl ether
dihydrochloride (compound 76); 4-((1-piperazinyl)benzyl)benzo- ic
acid dihydrochloride (compound 79);
4-((1-piperazinyl)benzyl-N,N-diethy- lbenzamide hydrochloride
(compound 83); Methyl 4-((4-t-butoxycarbonyl-pipe-
razinyl)-benzyl)benzoate (compound 80); Methyl
4-((1-piperazinyl)benzyl)be- nzoate dihydrochloride (compound 81);
4-(1-piperazinyl-benzyl)benzonitrile dihydrochloride (compound 84);
4-(1-piperazinyl-benzyl)-acetophenone dihydrochloride (compound
85); 4-((.alpha.-piperidinyl)-benzyl)-N,N-dieth- ylbenzmide
(compound 88); N,N-Diethyl-4-(3-methoxybenzyl-1-piperazinyl)-be-
nzamide (Example 50);
N,N-Diethyl-4-[(4-allyl-1-piperazinyl)-3-methoxybenz- yl]-benzamide
(Example 51); 4-[(N-benzyl-1-piperazinyl)-benzyl]-aniline (compound
91); 4-[(N-benzyl-1-piperazinyl)-benzyl]-acetanilide (compound 92);
4-[(N-benzyl-1-piperazinyl)-benzyl]-methanesulfonamide (Example
54); Methyl-N-4-[(N-benzyl-1-piperazinyl)-benzyl]-2-methylacetate
Example 55); and
4-[(N-benzyl-1-piperazinyl)-3-fluorobenzyl]-acetanilide (compound
95).
5. A compound according to any of claims 1-4, in form of its
hydrochloride salt.
6. A compound according to any of claims 1-5, for use in
therapy.
7. A compound according to claim 6, wherein the therapy is pain
management.
8. A compound according to claim 6, wherein the therapy is directed
towards gastrointestinal disorders.
9. A compound according to claim 6, wherein the therapy is directed
towards spinal injuries.
10. A compound according to claim 6, wherein the therapy is
directed to disorders of the sympathetic nervous system.
11. Use of a compound according to any of claims 1-5 for the
manufacture of a medicament for use in the treatment of pain.
12. Use of a compound according to any of claims 1-5 for the
manufacture of a medicament for use in the treatment of
gastrointestinal disorders.
13. Use of a compound according to any of claims 1-5 for the
manufacture of a medicament for use in the treatment of spinal
injuries.
14. A compound according to any of claims 1-5, further
characterized in that it is isotopically labelled.
15. Use of a compound according to claim 14 as a diagnostic
agent.
16. A pharmaceutical composition comprising a compound according to
any of claims 1-5 as an active ingredient, together with a
pharmaceutically acceptable carrier.
17. A process for the preparation of a compound according to any of
claims 1-5, whereby A) (i) An aldehyde or ketone is treated with a
nucleophile, giving the corresponding alcohol; (ii) the alcohol is
converted into a suitable leaving group, which in turn is displaced
with a nucleophile; and (iii) a N-(4)-unsubstituted piperazine
derivative is substituted via its organo halide or equivalent
species, or acylated; or B) (i) A N-protected amino acid ester is
reacted with a second amino acid ester, and thereafter treated with
an acid, giving a piparazinedione; (ii) the dione is reduced to the
corresponding pip raze; and (iii) the piperazine is alkylated or
acylated on one or more of the nitrogens.
18. A method for the treatment of pain, whereby an effective amount
of a compound according to any of claims 1-5 is administered to a
subject in need of pain management.
Description
FIELD OF THE INVENTION
[0001] The present invention is related to novel compounds, to a
process for their preparation, their use and pharmaceutical
compositions comprising the novel compounds. The novel compounds
are used in therapy, and in particular for the treatment of
pain.
BACKGROUND AND PRIOR ART
[0002] The .delta. receptor has been identified as having a role,
in many bodily functions such as circulatory and pain systems.
Ligands for the .delta. receptor may therefore find potential use
as analgesics, and/or as antihypertensive agents. Ligands for the
.delta. receptor have also been shown to posess immunomodulatory
activities.
[0003] The identification of at least three different populations
of opioid receptors (.mu., .delta. and .kappa.) is now well
established and all three are apparent in both central and
peripheral nervous systems of many species including man. Analgesia
has been observed in various animal models when one or more of
these receptors has been activated.
[0004] With few exceptions, currently available selective opioid
.delta. ligands are peptidic in nature and are unsuitable for
administration by systemic routes. Some non-peptidic .delta.
antagonists have been available for some time (see Takemori and
Portoghese, 1992, Ann. Rev. Pharmacol. Tox., 32: 239-269. for
review). These compounds, e.g. naltrindole, suffer from rather poor
(i.e., <10-fold) selectivity for the .delta. receptor vs .mu.
receptor binding and exhibit no analgesic activity, a fact which
underscores the need for the development of highly selective
non-peptidic .delta. agonists.
[0005] Recently, a non-peptidic .delta. agonist, BW 373U86, was
described by Chang et al., 1993, J. Pharmacol. Exp. Ther., 267:
852-857., as the first .delta.-selective non-peptide with analgesic
activity, however, it shows significant affinity for the .mu.
receptor.
[0006] Thus, the problem underlying the present invention was to
find new analgesics having excellent analgesic effects, but also
with an improved side-effect profile over current .mu. agonists and
potential oral efficacy.
[0007] Analgesics that have been identified and are existing in the
prior art have many disadvantages in that they suffer from poor
pharmacokinetics and are not analgesic when administered by
systemic routes. Also, it has been documented that preferred
compounds, described within the prior art, show significant
convulsive effects when administered systemically.
[0008] In WO 93/15062 and WO 95/045051, some diarylmethylpiperazine
and diarylmethylpiperidine compounds, including BW 373U86, are
disclosed, but these prior art compounds are structurally distinct
from the compounds acccording to the present invention.
[0009] The problem mentioned above has been solved by developing
novel piperazine and piperidine compounds, as will be described
below.
[0010] Outline of the Invention
[0011] The novel compounds according to the present invention are
defined by the formula (I) 2
[0012] wherein
[0013] G is a carbon atom or a nitrogen atom;
[0014] A is selected from
[0015] (i) phenyl substituted by any of --COOH, --CONH.sub.2,
COOCH.sub.3, --CN, NH.sub.2 or --COCH.sub.3;
[0016] (ii) naphtyl, benzofuranyl, and quinolinyl; and 3
[0017] wherein the phenyl ring of each A substituent may be
optionally and independently substituted by 1 or 2 substituents
selected from hydrogen, CH.sub.3, (CH.sub.2).sub.oCF.sub.3,
halogen, CONR.sup.7R.sup.8, CO.sub.2R.sup.7, COR.sup.7,
(CH.sub.2).sub.oNR.sup.7R.sup.8,
(CH.sub.2).sub.oCH.sub.3(CH.sub.2).sub.oSOR.sup.7,
(CH.sub.2).sub.oSO.sub.2R.sup.7 and
(CH.sub.2).sub.oSO.sub.2NR.sup.7R.sup- .8 wherein o is 0, 1, or 2,
and R.sup.7 and R.sup.8 are defined below;
[0018] R.sup.1 is selected from hydrogen; a branched or straight
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkenyl,
--CO(C.sub.1-C.sub.6 alkyl); (C.sub.1-C.sub.6 alkyl)-B wherein B is
as defined below, C.sub.3-C.sub.8 cycloalkyl, C.sub.4-C.sub.8
(alkyl-cycloalkyl) wherein alkyl is C.sub.1-C.sub.2 alkyl and
cycloalkyl is C.sub.3-C.sub.6 cycloalkyl; C.sub.6-C.sub.10 aryl;
and heteroaryl having from 5-10 atoms selected from any of C, S, N
and O; and whereby the C.sub.6-C.sub.10 aryl and the heteroaryl may
optionally be substituted by 1 or 2 substituents selected from
hydrogen, CH.sub.3, (CH.sub.2).sub.oCF.sub.3, halogen,
CONR.sup.7R.sup.8, CO.sub.2R.sup.7, COR.sup.7,
(CH.sub.2).sub.oNR.sup.7R.- sup.8,
(CH.sub.2).sub.oCH.sub.3(CH.sub.2).sub.oSOR.sup.7,
(CH.sub.2).sub.oSO.sub.2R.sup.7 and
(CH.sub.2).sub.oSO.sub.2NR.sup.7R.sup- .8, wherein o is 0, 1, or 2,
and R.sup.7 and R.sup.8 are as defined below;
[0019] R.sup.7 and R.sup.8 is each and independently as defined for
R.sup.1 above;
[0020] R.sup.2 is selected from hydrogen, CH.sub.3, OR.sup.1,
CO.sub.2R.sup.1, and CH.sub.2CO.sub.2R.sup.1 wherein
[0021] R.sup.1 is as defined above;
[0022] R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, R.sup.17, and R.sup.18, is each and
independently as defined for R.sup.1 above;
[0023] B is a substituted or unsubstituted aromatic; an optionally
substituted C.sub.5-C.sub.10 hydroaromatic; a heteroaromatic or a
heterohydroaromatic moiety, each having from 5 to 10 atoms selected
from any of C, S, N and O, and each being optionally and
independently substituted by 1 or 2 substituents independently
selected from hydrogen, CH.sub.3, CF.sub.3, halogen,
(CH.sub.2).sub.pCONR.sup.7R.sup.8, (CH.sub.2).sub.pNR.sup.7R.sup.8,
(CH.sub.2).sub.pCOR.sup.7R.sup.8, (CH.sub.2).sub.pCO.sub.2R.sup.7,
OR.sup.7, (CH.sub.2).sub.pSOR.sup.7,
(CH.sub.2).sub.pSO.sub.2R.sup.7, and
(CH.sub.2).sub.pSO.sub.2NR.sup.7R.su- p.8;
[0024] wherein p is 0, 1, 2 or 3 and wherein R.sup.7 and R.sup.8
are as defined above;
[0025] R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is each and
independently selected from
[0026] R.sup.7, (CH.sub.2).sub.pCONR.sup.7R.sup.8,
(CH.sub.2).sub.pNR.sup.- 7R.sup.8,
(CH.sub.2).sub.pCONR.sup.7R.sup.8, (CH.sub.2).sub.pCO.sub.2R.sup-
.7, (CH.sub.2).sub.pPh, (CH.sub.2).sub.p(p-OH Ph),
(CH.sub.2).sub.p-3-indo- lyl, (CH.sub.2).sub.pSR.sup.7, and
(CH.sub.2).sub.pOR.sup.7;
[0027] wherein p is 0, 1, 2, 3, or 4, and R.sup.7 and R.sup.8 are
as defined above;
[0028] with the proviso that when A is a phenyl ring substituted by
a --CN group or by a --NH.sub.2 group, B may not be 4
[0029] wherein
[0030] Z.sup.1 is hydroxy, and esters thereof;
[0031] hydroxymethyl, and esters thereof; or
[0032] amino, and carboxamides and sulfonamides.
[0033] Within the scope of the invention are also pharmaceutically
acceptable salts of the compounds of the formula (I), as well as
isomers, hydrates, isoforms and prodrugs thereof.
[0034] Preferred compounds according to the invention are compounds
of the formula (I) wherein
[0035] G is a carbon atom or a nitrogen atom;
[0036] A is selected from
[0037] (i) phenyl substituted by any of --COOH, --CONH.sub.2,
COOCH.sub.3, --CN, NH.sub.2 or --COCH.sub.3;
[0038] (ii) naphtyl, benzofuranyl, and quinolinyl; and 5
[0039] wherein the phenyl ring of each A substituent may be
optionally and independently substituted by 1 or 2 substituents
selected from hydrogen, CH.sub.3, (CH.sub.2).sub.oCF.sub.3,
halogen, CONR.sup.7R.sup.8, COR.sup.7, COR.sup.7,
(CH.sub.2).sub.oNR.sup.7R.sup.8,
(CH.sub.2)CH.sub.3(CH.sub.2).sub.oOR.sup.7,
(CH.sub.2).sub.oOR.sup.7 and (CH.sub.2 NR.sup.7R.sup.8, wherein 0
is 0, 1, or 2, and R.sup.7 and R.sup.8 are as defined below;
[0040] R.sup.1, R.sup.7 and R.sup.8 is each and independently
selected from hydrogen; a branched or straight C.sub.1-C.sub.4
alkyl, allyl, --CO(C.sub.1-C.sub.6 alkyl); (C.sub.1-C.sub.6
alkyl)-B wherein B is as defined below; C.sub.3-C.sub.5 cycloalkyl,
C.sub.4-C.sub.8 (alkyl-cycloalkyl) wherein alkyl is C.sub.1-C.sub.2
alkyl and cycloalkyl is C.sub.3-C.sub.6 cycloalkyl; and phenyl;
[0041] R.sup.2 is hydrogen, methyl, or OR.sup.1 wherein R.sup.1 is
as defined above;
[0042] R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, R.sup.17, and R.sup.18 is each and
independently as defined for R.sup.1 above;
[0043] B is selected from phenyl, naphthyl, indolyl, benzofuranyl,
dihydrobenzofuranyl benzothiophenyl, pyrryl, furanyl, quinolinyl,
isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl,
cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl,
tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl,
pyrrolidinyl, indazolinyl, and 6
[0044] each B group being optionally substituted by 1-2
substituents independently selected from hydrogen, CH.sub.3,
CF.sub.3, halogen, (CH.sub.2).sub.pCONR.sup.7R.sup.8,
(CH.sub.2).sub.pNR.sup.7R.sup.8, (CH.sub.2).sub.pCOR.sup.7,
(CH.sub.2).sub.pCO.sub.2R.sup.7, and OR.sup.7;
[0045] wherein p is 0 or 1, and wherein R.sup.7 and R.sup.8 are as
defined above; and
[0046] R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is each and
independently selected from hydrogen, CH.sub.3, CH(Me).sub.2,
CH.sub.2CH(Me).sub.2, CH(Me)CH.sub.2CH.sub.3(CH.sub.2)CONR.sup.7,
(CH.sub.2).sub.pNR.sup.7R.sup- .8,
(CH.sub.2).sub.pCONR.sup.7R.sup.8, (CH.sub.2).sub.pCO.sub.2R.sup.7,
(CH.sub.2).sub.pPh, (CH.sub.2).sub.p(p-OH Ph),
(CH.sub.2)-3-indolyl, (CH.sub.2).sub.pSR.sup.7, and
(CH.sub.2).sub.pOR.sup.7, wherein p is 0, 1, 2, or 3, and wherein
R.sup.7 and R.sup.8 are as defined above;
[0047] with the proviso that when A is a phenyl ring substituted by
a --CN group or by a --NH.sub.2 group, B may not be. 7
[0048] wherein
[0049] Z.sup.1 is hydroxy, and esters thereof;
[0050] hydroxymethyl, and esters thereof; or
[0051] amino, and carboxamides and sulfonamides.
[0052] Especially preferred compounds according to the invention
are compounds of the formula (I) wherein
[0053] G is a nitrogen atom;
[0054] A is selected from 8
[0055] wherein
[0056] R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, R.sup.17, and R.sup.18 is each an ethyl
group;
[0057] R.sup.1 is selected from hydrogen, methyl, ethyl, allyl, or
CH.sub.2-cyclopropyl;
[0058] R.sup.2 is H, methyl, or OR.sup.1, wherein R1 is as defined
above;
[0059] B is selected from phenyl, naphthyl, indolyl, benzofuranyl,
dihydrobenzofuranyl, benzothiophenyl, furanyl, quinolinyl,
isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl,
cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl,
tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl,
indazolinyl, and 9
[0060] each B group being optionally substituted by 1-2
substituents independently selected from hydrogen, methyl,
CF.sub.3, halogen, (CH.sub.2).sub.pCONR.sup.7R.sup.8,
(CH.sub.2).sub.pNR.sup.7R.sup.8, (CH.sub.2).sub.pCOR.sup.7,
(CH.sub.2).sub.pCO.sub.2R.sup.7, and OR.sup.7,
[0061] wherein p is 0, 1, or 2, and wherein R.sup.7 and R.sup.8 are
as defined for R.sup.1 above;
[0062] R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is each and
independently selected from H, CH.sub.3, CH(Me).sub.2, is
CH.sub.2CH(Me).sub.2,
CH(Me)CH.sub.2CH.sub.3(CH.sub.2).sub.pCONR.sup.7R.sup.8,
(CH.sub.2).sub.pNR.sup.7R.sup.8, (CH.sub.2).sub.pCONR.sup.7R.sup.8,
(CH.sub.2).sub.pCO.sub.2R.sup.7, (CH.sub.2).sub.pPh,
(CH.sub.2).sub.p(p-OH Ph), (CH.sub.2).sub.p-3-indolyl,
(CH.sub.2).sub.pSR.sup.7, and (CH.sub.2).sub.pOR.sup.7
[0063] wherein p is 0, 1 or 2, and wherein R.sup.7 and R.sup.8 are
as defined above;
[0064] The substituents A and B respectively, may optionally be
substituted at any position of the ring.
[0065] By "halogen" we mean chloro, fluoro, bromo and iodo.
[0066] By "aryl" we mean an aromatic ring having from 6-10 carbon
atoms, such as phenyl and naphtyl.
[0067] By "heteroaryl" we mean an aromatic ring in which one or
more of the 5-10 atoms in the ring are elements other than carbon,
such as N, S and O.
[0068] By "hydroaromatic" we mean a partly or fully saturated
aromatic ring structure having 5-10 carbon atoms in the ring.
[0069] By "heterohydroaromatic" we mean a partly or fully saturated
aromatic ring structure in which one or more of the 5-10 atoms in
the ring are-elements other than carbon, such as N, S and O.
[0070] By "isomers" we mean compounds of the formula (I), which
differ by the position of their functional group and/or
orientation. By "orientation" we mean stereoisomers,
diastereoisomers, regioisomers and enantiomers.
[0071] By "isoforms" we mean compounds of the formula (I) which
differ by their crystal lattice, such as crystalline compound and
amorphous compounds.
[0072] By "prodrug" we mean pharmacologically acceptable
derivatives, e.g. esters and amides, such the resulting
biotransformation product of the derivative is the active drug. The
reference by Goodman and Gilmans, The Pharmacological basis of
Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992,
"Biotransformation of Drugs, p. 13-15, describing prodrugs
generally, is hereby incorporated.
[0073] The novel compounds of the present invention are useful in
therapy, especially for the treatment of pain.
[0074] The compounds are also useful for modulating the analgesic
effects acting at the .mu. opioid receptor subtype, the modulation
of side effects seen with agents acting at the .mu. opioid receptor
subtype such as morphine, especially respiratory depression, gut
motility and abuse liability.
[0075] Compounds of the invention are also useful as
immunomodulators, especially for autoimmune diseases, such as
arthritis, for skin grafts, organ transplants and similar surgical
needs, for collagen diseases, various allergies, for use as anti
tumour agents and anti viral agents.
[0076] Compounds of the invention are useful in disease states
where degeneration or dysfunction of opioid receptors is present or
implicated in that paradigm. This may involve the use of
isotopically labeled versions of the compounds of the invention in
diagnostic techniques and imaging applications such as positron
emission tomography (PET).
[0077] Compounds of the invention are useful for the treatment of
diarrhea, depression, urinary incontinence, various mental
illnesses, cough, lung oedema, various gastrointestinal disorders,
spinal injury and drug addiction, including the treatment of
alcohol, nicotine, opioid and other drug abuse and for disorders of
the sympathetic nervous system for example hypertension.
[0078] The best mode of performing the present invention known at
present, is to use the compounds according to Example 21 (compound
33), Example 22 (compound 34), Example 23 (compound 37), Example 24
(compound 38), Example 25 (compound 41), Example 26 (compound 42),
Example 27 (compound 45), Example 29 (compound 51), Example 30
(compound 54), Example 35 (compound 64), Example 36 (compound 65),
Example 50, and Example 51. The numbering of the compounds is in
accordance with the Examples below, as well as in accordance with
the numbering in the Schemes presented in the following.
[0079] Methods of Preparation
[0080] Generalized Method A
[0081] An aldehyde or ketone is treated with a nucleophile such as
a Grignard or organolithium species to produce the corresponding
alcohol. This alcohol may then be converted into a suitable leaving
group (X), such as an ester, sulphonate or halide which may in turn
be displaced with a nucleophilic species such as a substituted or
unsubstituted piperazine. N-(4)-unsubstituted piperazine
derivatives may then be suitably substituted with a variety of
groups via their organo halide or equivalent species, or acylated
with a number of different acylating compounds. This sequence of
events will give rise to compounds according to general formula
I.
[0082] Generalized Method B
[0083] An N-protected amino acid, as its activated ester, may be
reacted with a second amino acid ester. On treatment with an acid
this species may then cyclize to form a piperazinedione. This dione
may be reduced via a number of standard methods to the
corresponding piperazine (e.g. a reducing agent such as lithium
aluminium hydride, by conversion to the thioamide and subsequent
desulphurization, hydrogenation in the presence of POCl.sub.3 etc.)
This piperazine may then be alkylated or acylated on one or more of
the nitrogens and/or may be used subsequently in generalized method
A.
[0084] Deprotection of functional groups or further modifications
may then be necessary, these are described for each individual
case. Specific examples for the above transformations are given in
the experimental.
[0085] All transformations contemplated use reagents (including
salts) and solvents known to the art of chemistry and to
biotransformations carried out in a suitable biological medium to
bring about these transformations and includes all reaction
enhancing agents (e.g. HMPA), and chiral resolutions using chiral
salt formation and chiral biological resolutions.
DETAILED DESCRIPTION OF THE INVENTION
[0086] The invention will now be described in more detail by the
following examples, which are not to be construed as limiting the
invention. 10
EXAMPLES
[0087] The compounds according to Examples 1-3 were synthesized as
shown in Scheme 1 above.
[0088] A.
[0089] I. Preparation of 3-methoxy-.alpha.-(1-naphthyl)benzyl
Alcohol (Compound 1)
[0090] To a solution of 3-bromoanisole (5.61 g, 30.0 mmol) in dry
THF (80 mL) was dropwise added n-butyl lithium-hexane solution (1.6
M, 37.5 ml., 60 mmol) under nitrogen at -78.degree. C. The reaction
mixture was allowed to warm to r.t. in 2 h and cooled down again to
-78.degree. C. prior to addition of 1-naphthaldehyde (4.69 g, 30.0
mmol, in 10 mL THF). The mixture was warmed to r.t. in 3 h, and
then quenched with aqueous NH.sub.4Cl solution, extracted with
ethyl acetate (3.times.50 mL). The combined organic phases were
washed with brine, dried over MgSO.sub.4. Removal of solvents in
vacuo provided 3-methoxy-.alpha.-(1-naphthyl)benzy- l alcohol (4.25
g, 54%). GC-MS (R.sub.t=10.41 min) 264 (M.sup.+), 245, 231, 215,
202, 155, 135, 128, 109.
[0091] II. Preparation of 3-methoxy-.alpha.-(1-naphthyl)benzyl
Chloride (Compound 2)
[0092] To a solution of 3-methoxy-.alpha.-(1-naphthyl)benzyl
alcohol (2.5 g, 9.5 mmol) in diethyl ether (5 mL) was added 35%
hydrochloric acid (10 mL) at 0.degree. C. The reaction mixture was
warmed to r.t. in 1 h, and then extracted with ethyl acetate
(3.times.50 mL). The combined organic layers were washed with
aqueous NH.sub.4Cl solution and brine, dried over MgSO.sub.4.
Evaporation of solvents gave 3-methoxy-.alpha.-(1-naphthyl)be- nzyl
chloride (1.94 g, 72%). GC-MS (R.sub.t=10.30 min) 282 (M.sup.+),
247, 232, 215, 202, 189, 163, 151, 139, 123, 101.
Example 1
[0093] Preparation of
(.+-.)-trans-1-(3-methoxy-.alpha.-(1-naphthyl)benzyl-
)-2,5-dimethylpiperazine (Compound 3)
[0094] A mixture of trans-2,5-dimethylpiperazine (456 mg, 4.0
mmol), 3-methoxy-.alpha.-(1-naphthyl)benzyl chloride (430 mg, 1.5
mmol) and triethylamine (2 mL) in dry DMF (10 mL) was refluxed for
2 h under nitrogen. after cooling down to r.t., the reaction
mixture was quenched with 1 N aqueous NH.sub.4OH solution, and
extracted with ethyl acetate (3.times.50 mL). The combined organic
layers were washed with 0.5 N aqueous NaOH solution, saturated
aqueous NH.sub.4C and brine, dried over MgSO.sub.4. Removal of
solvents gave (.+-.)-trans-1-(3-methoxy-.alpha.-(1-
'-naphthyl)benzyl)-2,5-dimethylpiperazine, which was used directly
in the next step: GC-MS (two isomers: R.sub.t=12.98 & 13.10
min) 360 (M.sup.+), 301, 276, 247, 232, 215, 189, 165, 131,
113.
Example 2 and 3
[0095] Preparation of
(.+-.)-3-((.alpha.R*/S*)-.alpha.-((2S*,5R)-4-Allyl-2-
,5-dimethyl-piperazinyl)-1-naphthyl)anisole (Compounds 4 &
5)
[0096] A mixture of above
(.+-.)-trans-1-(3-methoxy-.alpha.-(1-naphthyl)be-
nzyl)-2,5-dimethylpiperazine, K.sub.2CO.sub.3 (276 mg, 2.0 mmol)
and allyl bromide (242 mg, 2.0 mmol) in DMF (5 mL)/THF (10 mL) was
stirred for 3 h at r.t. The reaction mixture was quenched with 1 N
NH.sub.4OH and extracted with ethyl acetate (3.times.50 mL). The
combined organic layers were washed with saturated aqueous
NH.sub.4Cl and brine, dried over MgSO.sub.4. Evaporation of
solvents provided crude
(.+-.)-3-((.alpha.R*/S*)-.alpha.-((2S*,5R*)-4-Allyl-2-methyl-piperazinyl)-
-1-naphthyl)anisole, which were purified by silica gel column
eluting with AcOEt-Hexane (2:98.fwdarw.100:0) to yield the two
isomers (totally 267 mg, 45% from 2):
[0097] The first isomer, compound 4: GC-MS (R.sub.t=14.84 min)
401.15 (M.sup.++1, 0.3%), 400.15 (M.sup.+, 0.9), 359.15 (0.6),
330.15 (0.4), 302.15 (3.2), 274.15 (8.0), 247.05 (23.0), 215.10
(12.7), 202.05 (7.8), 153.15 (100), 126.15 (10.1); .delta..sub.H
(400 MHz, CDCl.sub.3) 1.02 (d, J=6.4 Hz, 6H), 2.15 (dd, J=11.2, 6.4
Hz, 1H), 2.31 (dd, J=11.2, 6.4 Hz, 1H), 2.60 (m, 1H), 2.74 (dd,
J=11.2, 3.2 Hz, 1H), 2.80 (dd, J=11.2, 3.2 Hz, 1H), 2.94 (dd,
J=13.6, 7.2 Hz, 1H), 3.03 (dt, J=6.4, 3.2 Hz, 1H), 3.20 (dd,
J=13.6, 5.6 Hz, 1H), 3.73 (s, 3H), 5.12. (m, 2H), 5.73 (brs, 1H),
5.83 (m, 1H), 6.68 (dd, J=8.0, 2.4 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H),
7.12 (m, 2H), 7.42 (m, 3H), 7.62 (d, J=7.2 Hz, 1H), 7.71 (d, J=8.0
Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 8.28 (brs, 1H); .delta..sub.C-13
(100 MHz, CDCl.sub.3) 13.2, 14.2, 35.6, 52.1, 53.0, 55.1, 55.2,
57.2, 63.8, 111.6, 114.4, 117.2, 121.1, 123.8, 125.2, 125.7, 125.8,
127.2, 127.5, 127.8, 128.9, 132.1, 134.0, 135.5, 137.4, 145.5,
159.5.
[0098] Its HCl salt: m.p. 124-135.degree. C. (Ether); v.sub.max
(KBr) cm.sup.-1 3483, 1601, 1264; Anal.Calcd.for
C.sub.27H.sub.32N.sub.2O.2HCl.- 1.0H.sub.2O: C, 65.98; H, 7.38; N,
5.70. Found: C, 66.12; H, 7.25; N, 5.42.
[0099] The second isomer, compound 5: GC-MS (R.sub.t=14.65 min)
401.25 (M.sup.++1, 0.2%), 400.25 (M.sup.+, 0.8), 359.15 (0.4),
330.15 (0.4), 302.15 (3.1), 274.15 (8.0), 247.05 (21.7), 215.10
(13.0), 202.05 (7.0), 153.15 (100), 126.15 (9.7); .delta..sub.H
(400 MHz, CDCl.sub.3) 0.93 (d, J=6.4 Hz, 3H), 1.15 (d, J=6.4 Hz,
3H), 2.14 (m, 2H), 2.37 (m, 1H), 2.60 (dd, J=11.6, 2.8 Hz, 1H),
2.84 (m, 2H), 2.96 (m, 1H), 3.35 (dd, J=13.2, 5.2 Hz, 1H), 5.13 (m,
2H), 5.81 (s, 1H), 5.86 (m, 1H), 6.73 (dd, J=8.0, 2.8 Hz, H), 6.81
(s, 1H), 6.84 (d, J=8.0 Hz, 1H), 7.16 (m, 1H), 7.40 (m, 3H), 7.70
(m, 2H), 7.80 (d, J=8.0 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H);
.delta..sub.C-13 (100 MHz, CDCl.sub.3 15.7, 16.3, 38.8, 53.6, 55.0,
55.6, 56.8, 59.3, 63.6, 111.5, 115.6, 117.4, 121.9, 124.6, 125.0,
125.1, 125.4, 126.2, 127.4, 128.5, 128.9, 131.6, 133.9, 135.0,
138.3, 142.2, 159.4.
[0100] Its HCl salt m.p. 150.5-153.degree. C. (Ether); v.sub.max
(KBr) cm.sup.-1 3483, 1600, 1262; Anal.Calcd.for
C.sub.27H.sub.32N.sub.2O.2HCl.- 0.75H.sub.2O: C, 66.59; H, 7.35; N,
5.75. Found: C, 66.41; H, 7.03; N, 5.48. 11
[0101] The compounds according to Examples 46 were synthesized as
shown in Scheme 2 above.
[0102] B.
[0103] I. Preparation of 3-methoxy-.alpha.-(2-naphthyl)benzyl
Alcohol (Compound 6)
[0104] The compound 6 was prepared by following the synthesis
procedure as described for compound 1, but substituting
1-naphtaldehyde for 2-naphtaldehyde.
[0105] GC-MS (R.sub.t=10.68 min) 264 (M.sup.+), 247, 231, 215, 202,
155, 135, 128, 109; .delta..sub.H (400 MHz, CDCl.sub.3) 3.15 (brs,
1H), 3.59 (s, 3H), 5.71 (s, 1H), 6.69 (dd, J=8.4, 2.8 Hz, 1H), 6.87
(m, 2H), 7.11 (t, J=8.0 Hz, 1H), 7.29 (dd, J=8.4, 1.2 Hz, 1H), 7.35
(m, 2H), 7.63 (d, J=8.4 Hz, 1H), 7.70 (m, 3H); .delta..sub.C-13
(100 MHz, CDCl.sub.3) 55.0, 75.9, 112.1, 112.8, 118.9, 124.6,
124.9, 125.7, 125.9, 127.5, 127.9, 128.1, 12943, 132.7, 133.1,
141.0, 145.2, 159.5.
[0106] II. Preparation of 3-methoxy-.alpha.-(2-naphthyl)benzyl
Chloride (Compound 7)
[0107] The compound 7 was prepared by following the synthesis
procedure as described for compound 2, but substituting compound 1
for compound 6.
[0108] GC-MS (R.sub.t=10.58 min) 282 (M.sup.+), 247, 231, 215, 202,
189, 151, 123, 101.
Example 4
[0109] Preparation of
(.+-.)-trans-1-(3-methoxy-.alpha.-(2-naphthyl)benzyl-
)-2,5-dimethylpiperazine (Compound 8)
[0110] The compound 8 was prepared by following the synthesis
procedure as described for compound 3, but substituting compound 2
for compound 7.
[0111] Used directly in the next step: GC-MS (R.sub.t=14.03 min)
360 (M.sup.+), 331, 301, 276, 247, 219, 169, 131, 113.
Example 5 and 6
[0112] Preparation of
(.+-.)-3-((.alpha.R*/S*)-.alpha.-((2S*,5R*)-4-Allyl--
2,5-dimethyl-1-piperazinyl)-2-naphthyl)anisole (Compounds 9 &
10)
[0113] The compounds of these Examples were prepared by following
the synthesis procedure as described for Examples 2 and 3, but
substituting compound 3 for compound 8.
[0114] Compound 9 (one pure isomer): GC-MS (R.sub.t=16.05 min)
401.25 (0.2%), 400.25 (0.8), 359.15 (0.4), 330.15 (0.4), 302.15
(3.1), 274.15 (8.0), 247.05 (21.7), 215.10 (13.0), 202.05 (7.0),
153.15 (100), 126.15 (9.7); .delta..sub.H (400 MHz, CDCl.sub.3)
1.36 (d, J=6.4 Hz, 3H), 1.41 (d, J=6.4 Hz, 3H), 3.16 (dd, J=13.2,
2.4 Hz, 1H), 3.26 (d, J=13.2 Hz, 1H), 3.46 (m, 1H), 3.86 (s, 3H),
3.94 (dd, J=11.2, 2.8 Hz, 1H), 4.10 (m, 2H), 4.46 (m, 2H), 5.58 (m,
2H), 5.78 (s, 1H), 6.05 (m, 1H), 6.96 (dd, J=8.0, 2.0 Hz, 1H), 7.18
(s, 1H), 7.33 (m, 1H), 7.44 (m, 1H), 7.50 (m, 2H), 7.83 (m, 3H),
8.04 (d, J=8.0 Hz, 1H), 8.13 (s, 1H), 13.6 (brs, 2H).
[0115] Its HCl salt m.p. 129-138.degree. C. (Ether); v.sub.max
(KBr) cm.sup.-1 3426, 1600, 1262; Anal.Calcd.for
C.sub.27H.sub.32N.sub.2O.2HCl.- 0.75H.sub.2O: C, 66.59; H, 7.35; N,
5.75. Found: C, 66.80; H, 7.11; N, 5.42.
[0116] Compound 10 (a mixture of two isomers) Its HCl salt: m.p.
160-162.5.degree. C. (Ether); v.sub.max (KBr) cm.sup.-1 3380, 1600,
1261; Anal.Calcd.for C.sub.27H.sub.32N.sub.2O.2HCl.0.50H.sub.2O: C,
67.21; H, 7.31; N, 5.81. Found: C, 67.13; H, 6.97; N, 5.47. 12
[0117] The compounds according to Examples 7-11 were synthesized as
shown in Scheme 3 above.
[0118] C.
[0119] I. Preparation of 3-methoxy-.alpha.-(2-benzofuranyl)benzyl
Alcohol (Compound 11)
[0120] The compound of this Example was prepared by following the
synthesis procedure as described for Example 1.
[0121] GC-MS (R.sub.t=9.54 min) 254.15 (M.sup.+, 100%), 237.10
(73.8), 221.05 (19.6), 194.10 (17.8), 165.10 (30.3), 147.05 (76.7),
135.10 (69.2), 118.10 (35.4), 108.10 (26.5), 91.10 (47.1);
.delta..sub.H (400 MHz, CDCl.sub.3) 3.21 (brs, 1H), 3.72 (s, 3H),
5.82 (s, 1H), 6.47 (s, 1H), 6.80-7.50 (m, 8H).
[0122] II. Preparation of 3-methoxy-.alpha.-(2-benzofuranyl)benzyl
Chloride (Compound 12)
[0123] The compound 12 was prepared by following the synthesis
procedure as described for compound 2, but substituting compound 1
for compound 11.
[0124] GC-MS (R.sub.t=9.08 min) 272.05 (M.sup.+, 4.1%), 237.10
(100), 221.05 (4.5), 194.10 (14.7), 165.10 (23.1); .delta..sub.H
(400 MHz, CDCl.sub.3) 3.78 (s, 3H), 6.11 (s, 1H), 6.56 (s, 1H),
6.85-7.50 (m, 8H).
Example 7
[0125] Preparation of
(.+-.)-trans-1-(3-methoxy-.alpha.-(2'-benzofuranyl)b-
enzyl)-2,5-dimethylpiperazine (Compound 13)
[0126] The compound 13 was prepared by following the synthesis
procedure as described for compound 3, but substituting compound 2
for compound 12.
[0127] GC-MS (R.sub.t=11.87 min & R.sub.t=12.09 inn) 351.15
(M.sup.++1, 2.2%), 350.15 (M.sup.+, 8.6), 321.20 (0.4), 308.15
(0.2), 294.20 (18.3), 266.10 (58.6), 231.10 (100), 221.05 (3.0),
194.10 (10.0), 178.05 (4.1), 165.10 (13.0), 131.05 (2.9), 113.10
(43.8); .delta..sub.H (400 MHz, CDCl.sub.3) (isomer at
R.sub.t=11.87 min) 0.92 (d, J=6.4 Hz, 3H), 1.20 (d, J=6.4 Hz, 3H),
1.92 (dd, J=11.2, 10.8 Hz, 1H), 2.44 (m, 1H), 2.69 (dd, J=11.2,
10.8 Hz, 1H), 2.83 (m, 2H), 2.90 (m, 1H), 3.78 (s, 3H), 5.56 (s,
1H), 6.61 (s, 1H), 6.80 (d, J=8.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H),
7.10 (s, 1H), 7.24 (m, 3H), 7.46 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.0
Hz, 1H); (isomer at R.sub.t=12.09 min) 0.96 (d, J=6.4 Hz, 3H), 1.22
(d, J=6.4 Hz, 3H), 1.83 (dd, J=11.2, 10.8 Hz, 1H), 2.40 (m, 1H),
2.65 (m, 1H), 2.90 (m, 3H), 3.80 (s, 3H), 5.47 (s, 1H), 6.63 (s,
1H), 6.84 (m, 2H), 7.21 (m, 2H), 7.24 (m, 2H). 7.46 (d, J=8.0 Hz,
1H), 7.51 (d, J=8.0 Hz, 1H).
[0128] Its HCl salt: m.p. 115-125.degree. C. (Ether); v.sub.max
(KBr) cm.sup.-1 3373, 1595, 1257; Anal.Calcd.for
C.sub.22H.sub.26N.sub.2.1.70HC- l.0.20H.sub.2O: C, 63.51; H, 6.81;
N, 6.73. Found: C, 63.60; H, 6.80; N, 6.70.
Example 8 and 9
[0129] Preparation of
(.+-.)-3-((.alpha.R*/S*)-.alpha.-((2S*,5R*)-4-Allyl--
2,5-dimethyl-1-piperazinyl)-2-benzofuranyl)anisole (Compounds 14
& 15)
[0130] The compounds of these Examples were prepared by following
the synthesis procedure as described for Examples 2 and 3, but
substituting compound 3 for compound 13.
[0131] The first isomer, compound 14: GC-MS (R.sub.t=13.03 min)
390.20 (M.sup.+, 1.5%), 349.15 (0.4), 320.10 (0.3), 292.10 (1.7),
264.10 (4.2), 237.10 (25.1), 221.05 (1.4), 194.10 (5.2), 165.10
(5.5), 153.15 (100), 126.15 (4.8), 98.05 (8.7), 84.10 (17.8);
.delta..sub.H (400 MHz, CDCl.sub.3) 0.97 (d, J=6.4 Hz, 3H), 1.21
(d, J=6.4 Hz, 3H), 2.12 (m, 2H), 2.35 (m, 1H), 2.65 (m, 1H), 2.75
(dd, J=11.6, 2.4 Hz, 1H), 2.81 (m, 3H), 3.42 (dd, J=13.6, 5.2 Hz,
1H), 3.78 (s, 3H), 5.14 (m, 2H), 5.51 (s, 1H), 5.85 (m, 1H), 6.61
(s, 1H), 6.81 (dd, J=8.0, 2.4 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 7.11
(s, 1H), 7.24 (m, 3H), 7.44 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.0 Hz,
1H); .delta..sub.C-13 (100 MHz, CDCl.sub.3) 17.2, 17.5, 53.1, 54.4,
55.2, 56.0, 56.6, 59.2, 60.4, 106.8, 111.3, 112.1, 114.2, 117.8,
120.6, 120.7, 122.6, 123.8, 128.1, 129.0, 134.8, 141.4, 154.9,
155.2, 159.6.
[0132] Its HCl salt: m.p. 122-128.degree. C. (Ether); v.sub.max
(KBr) cm.sup.-1 13490, 1602, 1253; Anal.Calcd.for
C.sub.25H.sub.30N.sub.2O.sub.- 2.2HCl.0.25H.sub.2O: C, 64.17; H,
7.00; N, 5.99. Found: C, 64.27; H, 6.92; N, 5.92.
[0133] The second isomer, compound 15: GC-MS (R.sub.t=13.23 min)
390.20 (M.sup.+, 3.1%), 349.15 (0.5), 292.10 (2.2), 264.10 (5.5),
237.10 (33.2), 221.05 (1.8), 194.10 (7.1), 165.10 (7.7), 153.15
(100), 126.15 (7.1), 98.15 (18.4), 84.10 (25.0); .delta..sub.H (400
MHz, CDCl.sub.3) 1.00 (d, J=6.4 Hz, 3H), 1.21 (d, J=6.4 Hz, 3H),
2.12 (m, 2H), 2.48 (m, 1H), 2.61 (m, 1H), 2.78 (dd, J=11.6, 2.4 Hz,
1H), 2.83 (m, 3H), 3.42 (dd, J=13.6, 5.6 Hz, 1H), 3.79 (s, 3H),
5.15 (m, 2H), 5.40 (s, 1H), 5.85 (m, 1H), 6.64 (s, 1H), 6.86(m,
3H), 7.20 (m, 3H), 7.44 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz,
1H).
[0134] Its HCl salt: m.p. 97-104.degree. C. (Ether); v.sub.max
(KBr) cm.sup.-1 3438, 1601 (s), 1260; Anal.Calcd.for
C.sub.25H.sub.30N.sub.2O.s- ub.2.2HCl.0.50H.sub.2O: C, 63.56; H,
7.04; N, 5.93. Found: C, 63.70; H, 6.68; N, 5.83.
Example 10 and 11
[0135] Preparation of
(.+-.)-3-((.alpha.R*/S*)-.alpha.-((2S*,5R*)-4-Cyclop-
ropylmethyl-2,5-dimethyl-1-piperazinyl)-2-benzofuranyl)anisole
(Compounds 16 & 17)
[0136] The compounds of these Examples were prepared by following
the synthesis procedure as described for Examples 2 and 3, except
using cyclopropyl methyl iodide and substituting compound 3 for
compound 13.
[0137] The first isomer, compound 16: GC-MS (R.sub.t=14.87 min)
405.25 (M.sup.++1, 2.3%), 404.25 (M.sup.+, 8.2), 362.20 (0.5),
349.15 (0.4), 320.20 (0.8), 292.20 (4.1), 291.10 (3.4), 265.10
(16.5), 237.10 (65.9), 194.10 (11.5), 167.20 (100), 140.20 (3.9),
124.15 (4.6), 98.15 (44.0); .delta..sub.H (400 MHz, CDCl.sub.3)
0.05 (m, 2H), 0.46 (m, 2H), 0.80 (m, 1H), 0.92 (d, J=6.0 Hz, 3H),
1.21 (d, J=6.0 Hz, 3H), 2.01 (dd, J=12.8, 7.2 Hz, 1H), 2.17 (m,
2H), 2.35 (m, 1H), 2.64 (dd, J=13.2, 6.4 Hz, 1H), 2.66 (m, 1H),
2.72 (dd, J=12.0, 2.4 Hz, 1H), 3.04 (dd, J=11.2, 3.2 Hz, 1H), 3.75
(s, 3H), 5.50 (s, 1H), 6.58 (s, 1H), 6.79 (dd, J=8.0, 2.4 Hz, 1H),
7.01 (d, J=8.0 Hz, 1H), 7.09 (s, 1H), 7.20 (m, 3H), 7.41 (d, J=8.0
Hz, 1H), 7.51 (m, 1H); .delta..sub.C-13 (100 MHz, CDCl.sub.3) 3.2,
4.7, 7.4, 17.4, 17.7, 53.1, 54.5, 55.2, 56.0, 58.3, 59.2, 60.8,
106.8, 111.3, 112.0, 114.2, 120.6, 120.7, 122.6, 123.7, 128.0,
129.0, 141.4, 154.8, 155.2, 159.6.
[0138] Its HCl sa t: m.p. 162-164.degree. C. (Ether); v.sub.max
(KBr) cm.sup.-1 3414, 1599, 1255; Anal.Calcd.for
C.sub.26H.sub.32N.sub.2O.sub.2- .2HCl.0.5H.sub.2O: C, 64.19; H,
7.25; N, 5.76. Found: C, 64.43; H, 7.30; N, 5.78.
[0139] The second isomer, compound 17: GC-MS (R.sub.t=15.17 min)
405.25 (M.sup.++1, 2.2%), 404.25 (M.sup.+, 8.9), 362.10 (0.6),
349.15 (0.4), 320.10 (0.8), 292.10 (5.0), 291.10 (3.9), 265.10
(19.4), 237.10 (72.2), 194.10 (12.8), 167.20 (100), 140.10 (3.9),
124.15 (4.8), 98.15 (45.5); .delta..sub.H (400 MHz, CDCl.sub.3)
0.08 (m, 2H), 0.48 (m, 2H), 0.82 (m, 1H), 0.97 (d, J=6.4 Hz, 3H),
1.25 (d, J=6.4 Hz, 3H), 2.10 (m, 2H), 2.28 (dd, J=11.2, 10.0 Hz,
1H), 2.49 (m, 1H), 2.62 (dd, J=13.2, 6.0 Hz, 1H), 2.63 (m, 1H),
2.83 (dd, J=11.2, 2.8 Hz, 1H), 3.02 (dd, J=11.2, 3.2 Hz, 1H), 3.78
(s, 3H), 5.43 (s, 1H), 6.64 (s, 1H), 6.87 (m, 3H), 7.21 (m, 3H),
7.45 (dd, J=7.6, 1.2 Hz, 1H), 7.50 (m, 1H); .delta..sub.C-13 (100
MHz, CDCl.sub.3) 3.3, 4.6, 7.4, 17.0, 17.6, 52.6, 55.2, 55.4, 55.6,
58.3, 60.3, 61.6, 105.7, 111.3, 112.5, 115.9, 120.5, 122.1, 112.5,
123.5, 128.4; 128.9, 137.3, 155.0, 158.3, 159.3.
[0140] Its HCl salt: m.p. 92-105.degree. C. (Ether); v.sub.max
(KBr) cm.sup.-1 3398, 1599, 1257; Anal.Calcd.for
C.sub.26H.sub.32N.sub.2.2HCl.0- .5H.sub.2O: C, 64.19; H, 7.25; N,
5.76. Found: C, 64.38; H, 7.14; N, 5.73. 13
[0141] D.
[0142] I. Preparation of 6-Quinolinecarboxaldehyde
[0143] A mixture of 6-methylquinoline (5.72 g, 40.0 mmol) and
selenium oxide (4.44 g, 40.0 mmol) was heated to 220.degree. C. for
1 h. After cooling down the residue was dissolved in ethyl acetate
(100 mL). The organic solution was washed with brine, dried over
MgSO.sub.4. Evaporation of solvents provided a solid, which was
recrystalized from ether-hexane (1:1) mixture to give
6-quinolinecarboxaldehyde (3.45 g, 55%).
[0144] GC-MS (R.sub.t=5.29 min) 157.15 (M.sup.+, 100%), 156.15
(92.2), 128.15 (62.9), 101.15 (16.0); .delta..sub.H (400 MHz,
CDCl.sub.3) 7.53 (m, 1H), 8.21 (m, 2H), 8.33 (m, 2H), 9.06 (m, 1H),
10.21 (s, 1H); .delta..sub.C-13 (100 MHz, CDCl.sub.3) 122.1, 126.6,
127.6, 130.7, 133.5, 134.2, 137.3, 150.8, 153.0, 191.3.
[0145] The compounds according to Examples 12-17 were synthesized
as shown in Scheme 4 above.
[0146] II. Preparation of 3-methoxy-.alpha.-(6-(quinolinyl)benzyl
Alcohol (Compound 18)
[0147] The compound 18 was prepared by following the synthesis
procedure as described for compound 1, but substituting
1-naphtaldehyde for 6-quinolinecarboxaldehyde.
[0148] GC-MS (R.sub.t=11.13 min) 265.10 (M.sup.+, 49.0%), 248.05
(2.3), 204.05 (9.7), 156.05 (37.6), 135.00 (100), 109.00 (43.5);
.delta..sub.H (400 MHz, CDCl.sub.3) 3.73 (s, 3H), 5.94 (s, 1H),
6.78 (d, J=8.4 Hz, 1H), 6.95 (m, 2H), 7.22 (m, 1H), 7.31 (m, 1H),
7.61 (d, J=8.4 Hz, 1H), 7.83 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 8.07
(d, J=8.0 Hz, 1H), 8.73 (m, 1H); .delta..sub.C-13 (100 MHz,
CDCl.sub.3) 55.2, 75.7, 112.3, 113.1, 119.1, 121.2, 124.6, 128.5,
129.4, 129.6, 136.3, 142.1, 145.2, 147.6, 150.1, 159.8.
[0149] III. Preparation of 3-methoxy-.alpha.-(6-quinolinyl)benzyl
Chloride (Compound 19)
[0150] The compound 19 was prepared by following the synthesis
procedure as described for compound 2, but substituting compound 1
for compound 18.
[0151] Used directly in the next step: .delta..sub.H (400 MHz,
CDCl.sub.3) 3.73 (s, 3H), 5.98 (s, 1H), 6.8-8.2 (m, 9H), 8.80 (s,
1H).
Example 12 and 13
[0152] Preparation of
(.+-.)-trans-1-(3-methoxy-.alpha.-(6'-quinolinyl)ben-
zyl)-2,5-dimethylpiperazine (Compounds 20 & 21)
[0153] The compounds of these Examples were prepared by following
the synthesis procedure as described for compound 3, but
substituting compound 2 for compound 19.
[0154] GC-MS (R.sub.t=14.91 min) 361.20 (M.sup.+, 0.8%), 332.15
(0.3), 306.15 (0.6), 302.15 (14.4), 277.15 (52.5), 248.05 (100),
233.00 (10.6), 204.05 (17.1), 176.05 (2.7), 151.05 (1.4), 142.10
(1.8), 113.10 (19.9).
[0155] The first isomer, compound 20: .delta..sub.H (400 MHz,
CDCl.sub.3) 1.06 (d, J=6.4 Hz, 3H)' 1.24 (d, J=6.4 Hz, 3H), 1.84
(dd, J=11.6, 9.2 Hz, 1H), 2.60 (m, 2H), 2.77 (m, 2H), 3.06 (m, 2H),
3.80 (s, 3H), 5.44 (s, 1H), 6.77 (s, 1H), 6.83 (d, J=8.0 Hz, 1H),
6.88 (dd, J=8.0, 2.4 Hz, 1H), 7.31 (m, 1H), 7.37 (m, 1H), 7.82 (s,
1H), 7.84 (m, 1H), 8.03 (d, J=8.8 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H),
8.87 (m, 1H).
[0156] Compound 21 (a mixture of two isomers, .about.25% compound
20): .delta..sub.H (400 MHz, CDCl.sub.3) 1.20 (m, 6H), 2.05 (m,
1H), 2.73 (m, 2H), 2.87 (m, 1H), 3.13 (m, 2H), 3.73 & 3.76 (s,
3H), 5.38 (s, 1H), 6.38 (brs, NH), 6.70-8.15 (m, 9H), 8.84 (m,
1H).
Example 14
[0157] Preparation of
(.+-.)-3-((.alpha.R*/S*)-.alpha.-((2S*,5R*)-4-Allyl--
2,5-dimethyl-1-piperazinyl)-6-quinolinyl)anisole (Compound 22)
[0158] The compound of this Example was prepared by following the
synthesis procedure as described for Examples 2 and 3, but
substituting compound 3 for compound 20.
[0159] GC-MS (R.sub.t=17.22 min) 401.25 (M.sup.+, 0.3%), 360.20
(0.3), 331.10 (0.2), 303.20 (1.7), 276.10 (4.5), 248.10 (17.2),
233.10 (4.5), 204.10 (8.0), 176.10 (1.3), 153.20 (100), 126.20
(5.4); .delta..sub.H (400 MHz, CDCl.sub.3) 1.0 (d, J=6.4 Hz, 3H),
1.21 (d, J=6.4 Hz, 3H), 1.99 (m, 1H), 2.20 (m, 1H), 2.56 (m, 1H),
2.66 (m, 1H), 2.71 (m, 1H), 2.85 (m, 1H), 2.90 (m, 1H), 3.37 (dd,
J=13.2, 4.0 Hz, 1H), 3.78 (s, 3H), 5.17 (m, 2H), 5.35 (s, 1H), 5.87
(m, 1H), 6.82 (m, 3H), 7.26 (t, J=7.6 Hz, 1H), 7.36 (m, 1H), 7.81
(s, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 8.09 (d,
J=7.6 Hz, 1H), 8.87 (m, 1H); .delta..sub.C-13 (100 MHz, CDCl.sub.3)
15.7, 16.4, 52.0, 53.7, 55.2, 55.5, 56.8, 58.9, 65.9, 112.1, 116.3,
117.8, 120.9, 122.5, 126.5, 127.9, 128.9, 129.0, 130.2, 134.8,
136.0, 139.2, 141.1, 147.6, 150.0, 159.5.
[0160] Its HCl salt m.p. 128-140.degree. C. (Ether); v.sub.max
(KBr) cm.sup.-1 3376, 1596, 1263; Anal.Calcd.for
C.sub.26H.sub.31N.sub.3O.2.30H- Cl.0.1H.sub.2O: C, 64.10; H, 6.93;
N, 8.62. Found: C, 64.08; H, 6.92; N, 8.35.
Example 15
[0161] Preparation of
(.+-.)-3-((.alpha.R*/S*)-.alpha.-((2S*,5R*)-4-Allyl--
2,5-dimethyl-1-piperazinyl)-6-(quinolinyl)anisole (Compound 23)
[0162] The compound of this Example was prepared by following the
synthesis procedure as described for Examples 2 and 3, but
substituting compound 3 for compound 21.
[0163] GC-MS (R.sub.t=17.21 min) 401.35 (M.sup.+, 0.4%), 360.30
(0.2), 331.20 (0.2), 303.20 (1.6), 276.10 (4.8), 248.10 (17.3),
233.10 (4.4), 204.10 (8.1), 176.10 (1.3), 153.20 (100), 126.20
(5.6); .delta..sub.H (400 MHz, CDCl.sub.3) 1.01 (d, J=6.0 Hz, 3H),
1.21 (d, J=6.0 Hz, 3H), 1.95 (m, 1H), 2.16 (m, 1H), 2.56 (m, 1H),
2.66 (m, 1H), 2.74 (m, 1H), 2.80 (m, 1H), 2.87 (m, 1H), 3.30 (dd,
J=13.6, 5.6 Hz, 1H), 3.77 (s, 3H), 5.13 (m, 2H), 5.34 (s, 1H), 5.82
(m, 1H), 6.77 (dd, J=8.0, 2.4 Hz, 1H), 6.99 (d, J=7.6 Hz, 1H), 7.11
(s, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.38 (dd, J=8.4, 4.0 Hz, 1H), 7.59
(d, J=8.4 Hz, 1H), 7.66 (s, 1H), 8.03 (d, J=8.8 Hz, 1H), 8.11 (d,
J=8.4 Hz, 1H), 8.88 (m, 1H); .delta..sub.C-13 (100 MHz, CDCl.sub.3)
15.3, 16.2, 51.9, 53.4, 55.2, 55.3, 56.8, 58.5, 66.1, 111.8, 114.0,
117.6, 120.6, 121.1, 127.9, 128.3, 128.9, 129.1, 131.4, 134.9,
136.0, 137.1, 144.1, 147.7, 150.2, 159.6.
[0164] Its HCl salt: m.p. 177-182.degree. C. (Ether); v.sub.max
(KBr) cm.sup.-1 3405, 1597, 1260; Anal.Calcd.for
C.sub.26H.sub.31N.sub.30.2.80H- Cl: C, 62.01; H, 6.76; N, 8.34.
Found: C, 61.98; H, 6.77; N, 8.03.
Example 16 and 17
[0165] Preparation of
(.+-.)-3-((.alpha.R*/S*)-.alpha.-((2S*,5R*)-4-Cyclop-
ropylmethyl-25-dimethyl-1-piperazinyl)-4-quinolinyl)anisole
(Compounds 24 & 25)
[0166] The compounds of these Examples were prepared by following
the synthesis procedure as described for Examples 2 and 3, but
substituting allylbromide for cyclopropylmethylioidide.
[0167] The first isomer, compound 24: GC-MS (R.sub.t=20.77 min)
415.25 (M.sup.+, 3.8%), 344.15 (2.4), 302.10 (9.5), 276.10 (58.8),
248.15 (79.1), 233.10 (17.2), 204.10 (29.4), 176.10 (4.2), 167.15
(100), 138.15 (14.2), 112.15 (47.0); .delta..sub.H (400 MHz,
CDCl.sub.3) 0.10 (m, 2H), 0.51 (m, 2H), 0.86 (m, 1H), 0.97 (d,
J=6.4 Hz, 3H), 1.25 (d, J=6.4 Hz, 3H), 1.98 (dd, J=11.2, 8.8 Hz,
1H), 2.14 (dd, J=13.2, 6.4 Hz, 1H), 2.32 (dd, J=10.8, 5.6 Hz, 1H),
2.58 (m, 2H), 2.66 (dd, J=11.6, 2.8 Hz, 1H), 2.73 (m, 1H), 3.07
(dd, J=11.2, 3.2 Hz, 1H), 3.78 (s, 3H), 5.39 (s, 1H), 6.79 (s, 1H),
6.84 (m, 2H), 7.26 (t, J=8.0 Hz, 1H), 7.35 (dd, J=8.4, 4.0 Hz, 1H),
7.83 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 8.03 (d, J=9.2 Hz, 1H), 8.09
(d, J=8.0 Hz, 1H), 8.86 (dd, J=4.0, 2.0 Hz, 1H); .delta..sub.C-13
(100 MHz, CDCl.sub.3) 3.4, 4.4, 7.6, 16.2, 16.9, 52.1, 53.8, 55.2,
55.6, 58.5, 59.7, 65.6, 112.0, 116.3, 120.9, 122.6, 126.5, 127.9,
128.8, 129.0, 130.2, 136.0, 139.1, 141.1, 147.6, 149.9, 159.4.
[0168] Its HCl salt: m.p. 127-157.degree. C. (Ether); v.sub.max
(KBr) cm.sup.-1 13402, 1596, 1262; Anal.Calcd.for
C.sub.27H.sub.33N.sub.3O.3HCl- .0.75H.sub.2O: C, 60.23; H, 7.02; N,
7.80. Found: C, 60.49; H, 7.00; N, 7.73.
[0169] The second isomer, compound 25: GC-MS (R.sub.t=20.73 min)
415.25 (M.sup.+, 3.2%), 344.05 (2.3), 302.10 (7.7), 276.10 (48.5),
248.15 (69.6), 233.10 (15.7), 204.10 (25.8), 176.10 (3.7), 167.15
(100), 138.15 (12.2), 112.15 (46.8); .delta..sub.H (400 MHz,
CDCl.sub.3) 0.17 (m, 2H), 0.56 (m, 2H), 0.97 (m, 1H), 1.11 (brs,
3H), 1.27 (brs, 3H), 2.24 (m, 1H), 2.38 (m, 1H), 2.51 (m, 1H), 2.61
(m, 1H), 2.87 (m, 3H), 3.13 (m, 1H), 3.77 (s, 3H), 5.34 (s, 1H),
6.78 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 7.08 (s, 1H), 7.22
(t, J=8.0 Hz, 1H), 7.39 (dd, J=8.4, 4.4 Hz, 1H), 7.60 (d, J=8.4 Hz,
1H), 7.73 (s, 1H), 8.04 (d, J=8.8 Hz, 1H), 8.16 (d, J=8.4 Hz, 1H),
8.89 (d, J=4.0 Hz, 1H); .delta..sub.C-13 (100 MHz, CDCl.sub.3)
4.07, 4.37, 6.9, 14.8, 15.1, 51.4, 55.2, 56.2, 58.2, 60.3, 66.4,
111.8, 114.2, 120.6, 121.2, 128.0, 128.1, 129.2, 131.0, 136.0,
137.0, 143.8, 147.7, 150.3, 159.6.
[0170] Its HCl salt: m.p. 92-105.degree. C. (Ether); v.sub.max
(KBr) cm.sup.-1 13345, 1596, 1259. 14
[0171] The compounds according to Examples 18-20 were synthesized
as shown in Scheme 5 above.
[0172] E.
[0173] I. Preparation of 3-methoxy-.alpha.-(4-quinolinyl)benzyl
Alcohol (Compound 26)
[0174] The compound 26 was prepared by following the synthesis
procedure as described for compound 1, but substituting
1-naphtaldehyde for 4-quinolinecarboxaldehyde.
[0175] GC-MS (R.sub.t=10.81 min) 266.10 (M.sup.++1, 11.8%), 265.10
(M.sup.+, 61.0), 248.05 (6.1), 232.00 (6.2), 216.05 (4.7), 204.00
(10.5), 191.05 (2.0), 176.00 (3.8), 156.00 (13.9), 135.10 (100),
129.10 (86.6), 109.10 (68.2). 102.10 (25.5): .delta..sub.H (400
MHz. CDCl.sub.3) 3.67 (s, 3H), 5.30 (brs, 1H), 6.41 (s, 1H), 6.76
(d, J=7.2 Hz, 1H), 6.90 (m, 2H), 7.18 (t, J=7.6 Hz, 1H), 7.38 (m,
1H), 7.56 (t, J=7.6 Hz, 1H), 7.62 (m, 1H), 7.92 (d, J=8.4 Hz, 1H),
8.00 (d, J=8.4 Hz, 1H), 8.64 (dd, J=4.4, 1.2 Hz, 1H);
.delta..sub.C-13 (100 MHz, CDCl.sub.3) 55.1, 72.1, 113.0, 113.2,
118.5, 119.5, 123.9, 125.7, 126.5, 129.0, 129.5, 129.7, 143.8,
147.8, 149.1, 149.9, 159.7.
[0176] II. Preparation of 3-methoxy-.alpha.-(4-quinolinyl)benzyl
Chloride (Compound 27)
[0177] The compound 27 was prepared by following the synthesis
procedure as described for compound 2, but substituting compound 1
for compound 26.
[0178] Used directly in the next step: GC-MS (R.sub.t=10.54 min)
285.10 (M.sup.++2, 11.5%), 283.10 (M.sup.+, 33.10), 268.05 (0.2),
248.15 (100), 233.10 (37.0), 217.05 (27.2), 204.10 (45.5), 178.10
(5.9), 176.10 (11.5), 151.10 (5.7), 139.05 (2.1), 108.60 (11.0),
102.10 (17.4).
Example 18
[0179] Preparation of
(.+-.)-trans-1-(3-methoxy-.alpha.-(4-quinolinyl)benz-
yl)-2,5-dimethylpiperazine (Compound 28)
[0180] The compound of this Example was prepared by following the
synthesis procedure as described for compound 3, but substituting
compound 2 for compound 27.
[0181] GC-MS (R.sub.t=13.96 min) 362.20 (M.sup.++1, 1.4%), 361.20
(M.sup.+, 6.6), 306.10 (2.0), 302.15 (18.3), 277.15 (59.6), 248.15
(100), 233.10 (15.8), 204.10 (20.9), 176.10 (3.8), 151.00 (1.8),
143.15 (1.4), 113.15 (15.8); .delta..sub.H (400 MHz, CDCl.sub.3)
0.92 (d, J=6.4 Hz, 3H), 1.12 (d, J=6.4 Hz, 3H), 1.82 (dd, J=11.6,
10.0 Hz, 1H), 2.52 (brs, 1H), 2.62 (dd, J=11.6, 2.8 Hz, 1H), 2.72
(m, 1H), 2.77 (m, 1H), 2.88 (m, 1H), 2.98 (dd, J=11.6, 2.0 Hz, 1H),
3.72 (s, 3H), 5.86 (s, 1H), 6.69 (s, 1H), 6.72 (d, J=8.0, 1H), 6.78
(dd, J=8.0, 2.4 Hz, 1H), 7.20 (t, J=8.0 Hz, 1H), 7.37 (t, J=8.0 Hz,
1H), 7.60 (t, J=8.0 Hz, 1H), 7.65 (d, J=4.4 Hz, 1H), 7.99 (d, J=8.8
Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 8.89 (d, J=4.4 Hz, 1H).
Example 19 and 20
[0182] Preparation of
(.+-.)-3-((.alpha.R*/S*)-.alpha.-((2S*,5R*)-4-Allyl-- 25-dim
ethyl-1-piperazinyl)-4-quinolinyl)anisole (Compounds 29 &
30)
[0183] The compounds of these Examples were prepared by following
the synthesis procedure as described for Examples 2 and 3, but
substituting compound 3 for compound 28.
[0184] The first isomer, compound 29: GC-MS (R.sub.t=15.97 min)
401.15 (M.sup.+, 0.8%), 360.20 (0.8), 303.15 (3.3), 27615 (5.7),
248.05 (15.3), 217.05 (6.3). 204.10 (10.4), 176.00 (2.2), 153.20
(100), 126.10 (5.3), 98.10 (13.8); .delta..sub.H (400 MHz,
CDCl.sub.3) 0.96 (d, J=6.0 Hz, 3H), 1.14 (d, J=6.0 Hz, 3H), 2.01
(m, 1H), 2.16 (t, J=10.0 Hz, 1H), 2.47 (m, 1H), 2.59 (d, J=11.2 Hz,
1H), 2.86 (m, 2H), 2.95 (t, J=6.0 Hz, 1H), 3.36 (dd, J=13.6, 4.4
Hz, 1H), 3.72 (s, 3H), 5.15 (m, 2H), 5.77 (s, 1H), 5.85 (m, 1H),
6.74 (m, 3H), 7.17 (t, J=7.6 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.60
(dd, J=7.2, 0.8 Hz, 1H), 7.73 (d, J=4.4 Hz, 1H), 8.00 (d, J=8.4 Hz,
1H), 8.08 (d, J=8.8 Hz, 1H), 8.90 (d, J=3.6 Hz, 1H);
.delta..sub.C-13 (100 MHz, CDCl.sub.3) 15.9, 16.6, 53.8, 55.1,
55.5, 56.7, 59.4, 63.2, 112.0, 115.7, 117.7, 120.6, 121.9, 124.4,
126.0, 126.8, 128.6, 129.3, 130.1, 134.8, 140.3, 148.5, 148.6,
150.2, 159.5.
[0185] Its HCl salt: m.p. 158-166.degree. C. (AcOEt-Ether);
v.sub.max (KBr) cm.sup.-1 3400, 1596, 1263; Anal.Calcd.for
C.sub.26H.sub.31N.sub.3O- .3.0HCl.0.9H.sub.2O: C, 59.24; H, 6.85;
N, 7.97. Found: C, 59.31; H, 6.94; N, 7.80.
[0186] The second isomer, compound 30: GC-MS (R.sub.t=16.19 min)
401.25 (M.sup.+, 0.5%), 386.20 (0.2), 360.20 (0.7), 331.10 (0.3),
303.15 (3.3), 276.15 (4.7), 248.15 (13.7), 233.10 (5.8), 217.05
(4.9), 204.10 (9.8), 176.10 (1.8), 153.20 (100), 126.20 (5.2),
98.10 (13.9); .delta..sub.H (400 MHz, CDCl.sub.3); .delta..sub.C-13
(100 MHz, CDCl.sub.3).
[0187] Its HCl salt: m.p. 155-165.degree. C. (AcOEt-Ether). 15
[0188] The compounds according to Examples 21-22 were synthesized
as shown in Scheme 6 above.
[0189] F.
[0190] I. Preparation of
(.+-.)4-((.alpha.-Hydroxy)-4-chlorobenzyl)-N,N-di- ethylbenzamide
(Compound 31)
[0191] 4-Formyl-N,N-diethylbenzamide (2.088 g, 10.1 mmol) was
dissolved in 45 ml of anhydrous THF. The solution was cooled down
to -78.degree. C., followed by a dropwise addition of 10.1 ml (10.1
mmol) of a 1.0 M solution of 4-Chloro-phenylmagnesium bromide in
ether. The mixture was warmed up to room temperature within 3
hours. Then 50 ml of a saturated NH.sub.4Cl-solution was added and
the mixture was extracted with ethyl acetate (3.times.30 ml). The
combined organic layers were washed with water (2.times.30 ml) and
brine (1.times.30 ml), dried (Na.sub.2SO.sub.4), filtered and the
solvent was removed in vacuo. The residue was chromatographed on
silica gel eluting with methanol:dichloromethane (1:125-3:125) to
yiled the title compound as a colorless oil.
[0192] v.sub.max (KBr)/cm.sup.-1 13329, 2977, 1595, 1461, 1289,
1094, 1051, 830: .delta..sub.H (400 MHz, CDCl.sub.3) 1.09 (3H, br
s), 1.21 (3H, br s), 3.22 (2H, br s), 3.33 (1H, d, J 3), 3.50 (2H,
br s), 5.74 (1H, d, J 3), 7.22-7.34 (m, 8H);
[0193] II. Preparation of
(.+-.)4-((.alpha.-Chloro)-4-chlorobenzyl)-N,N-di- ethylbenzamide
(Compound 32)
[0194] The compound 32 was prepared by following the synthesis
procedure as described for compound 2, but substituting compound 1
for compound 31.
[0195] Used for the next step without further purification.
Example 21
[0196] Preparation of
(.+-.)4-((.alpha.-(1-Piperazinyl)-4-chlorobenzyl)-N,-
N-diethylbenzamide (Compound 33)
[0197] The compound of this Example was prepared by following the
synthesis procedure as described for compound 3, but substituting
compound 2 for compound 32.
[0198] m.p. 112-113.degree. C. (from acetonitrile), v.sub.max
(KBr)/cm.sup.-1 3347, 2947, 2809, 1615, 1451, 1318, 1284, 1094,
836; .delta..sub.H (400 MHz, CDCl.sub.3) 1.10 (3H, br s), 1.21 (3H,
br s), 1.69 (1H, br s), 2.33 (4H, br s), 2.86-2.89 (4H, m), 3.24
(2H, br s), 3.51 (2H, br s), 4.22 (1H, s), 7.23-7.41 (8H, m);
C.sub.22H.sub.28N.sub.3- OCl.0.3H.sub.2O requires:
[0199] C, 67.52; H, 7.37; N, 10.74. Found: C, 67.68; H, 7.37; N,
10.73.
Example 22
[0200] Preparation of
(.+-.)4-((.alpha.-((4-Allyl)-1-piperazinyl))-4-chlor-
obenzyl)-N,N-diethylbenzamide.2HCl (Compound 34)
[0201] The compound of this Example was prepared by following the
synthesis procedure as described for Examples 2 and 3, but
substituting compound 3 for compound 33.
[0202] m.p. 147-163.degree. C. (from ether), v.sub.max
(KBr)/cm.sup.-1 3418, 2974, 2355, 1626, 1435, 1286, 1092, 945, 812;
.delta..sub.H (400 MHz. CDCl.sub.3) 1.06 (3H, br s), 1.19 (3H, br
s). 3.0-3.7 (14H, m), 5.4-5.6 (2H, m), 6.0-6.2 (1H, br m), 7.2-7.8
(9H, m); C.sub.25H.sub.34N.sub.3O.sub.0C.sub.3 requires:
[0203] C, 60.18; H, 6.87; N, 8.42. Found: C, 60.48; H, 6.89; N,
8.31. 16
[0204] The compounds according to Examples 23-24 were synthesized
as shown in Scheme 7 above.
[0205] G.
[0206] I. Preparation of
(.+-.)4-((.alpha.-Hydroxy)-2-naphtylmethyl)-N,N-d- iethylbenzamide
(Compound 35)
[0207] The compound 35 was prepared by following the synthesis
procedure as described for compound 1, but substituting
3-bromoanisole for 2-bromoanisole, and 1-naphtaldehyde for
N,N-diethyl-4-carboxybenzamide.
[0208] v.sub.max (KBr)/cm.sup.-1 3302, 2976, 1607, 1430, 1290,
1098, 813; .delta..sub.H (400 MHz, CDCl.sub.3) 1.09 (3H, br s),
1.22 (3H, br s), 2.60 (1H, d, J 3), 3.24 (2H, br s), 3.52 (2H, br
s), 6.00 (1H, d, J 3), 7.30-7.50 (7H, m), 7.76-7.88 (4H, m);
[0209] II. Preparation of
(.+-.)4-((.alpha.-Chloro)-2-naphtyl-methyl)-N,N-- diethylbenzamide
(Compound 36)
[0210] The compound 36 was prepared by following the synthesis
procedure as described for Used for the next step without further
purification.
Example 23
[0211] Preparation of
(.+-.)4-((.alpha.-(1-piperazinyl))-2-naphtylmethyl)--
N,N-diethylbenzamide (Compound 37)
[0212] The compound of this Example was prepared by following the
synthesis procedure as described for Example 1, but substituting
compound 2 for compound 36.
[0213] m.p. 106-108.degree. C. (from acetonitrile), v.sub.max
(KBr)/cm.sup.-1 3324, 3052, 2964, 2810, 2774, 1613, 1465, 1287,
1130, 1098; .delta..sub.H (400 MHz, CDCl.sub.3) 1.07 (3H, br s),
1.19 (3H, br s), 1.89 (1H, br s), 2.40 (4H, br s), 2.89-2.92 (4H,
m), 3.21 (2H, br s), 3.50 (2H, br s), 4.41 (1H, s), 7.24-7.84 (11H,
3m); C.sub.26H.sub.31N.sub.3O.0.9H.sub.2O requires:
[0214] C, 74.75; H, 7.91; N, 10.06. Found: C, 74.68; H, 7.56; N,
10.38.
Example 24
[0215] Preparation of
(.+-.)4-((.alpha.-((4-Allyl)-1-piperazinyl))-2-napht-
ylmethyl)-N,N-diethylbenzamide (Compound 38)
[0216] The compound of this Example was prepared by following the
synthesis procedure as described for Examples 2 and 3, but
substituting compound 3 for compound 37.
[0217] v.sub.max (KBr)/cm.sup.-1 3053, 2968, 2805, 1629, 1426,
1288, 1141, 1095, 921, 817; .delta..sub.H (400 MHz, CDCl.sub.3)
1.06 (3H, br s), 1.19 (3H, br s), 2.49 (6H, br s), 3.00 (2H, m),
3.20 (2H, br s), 3.49 (2H, br s), 4.41 (1H, s), 5.08-5.22 (2H, m),
5.78-5.92 (1H, m), 7.26-7.84 (11H, m);
C.sub.25H.sub.34N.sub.3OCl.sub.3. 0.6H.sub.2O requires:
[0218] C, 76.99; H, 8.07; N, 9.29. Found: C, 77.06; H, 8.09; N,
9.32%. 17
[0219] The compounds according to Examples 25-26 were synthesized
as shown in Scheme 8 above.
[0220] H.
[0221] I. Preparation of
(.+-.)4-((.alpha.-Hydroxy)-4-xylyl)-N,N-diethylbe- nzamide
(Compound 39)
[0222] The compound 39 was prepared by following the synthesis
procedure as described for compound 31, but substituting
4-chlorophenylmagnesiumbro- mide for 4-toluylmagnesiumbromide.
[0223] v.sub.max (KBr)/cm.sup.-1 3364, 2970, 1602, 1455, 1381,
1291, 1101, 1054, 802; .delta..sub.H (400 MHz, CDCl.sub.3) 1.09
(3H, br s), 1.22 (3H, br s), 2.33 (3H, s), 2.55 (1H, br s), 3.24
(2H, br s), 3.52 (2H, br s), 5.78 (1H, d, J 3), 7.11-7.41 (8H,
m);
[0224] II. Preparation of
(.+-.)4-((.alpha.-Chloro)-4-xylyl)-N,N-diethylbe- nzamide (Compound
40)
[0225] The compound 40 was prepared by following the synthesis
procedure as described for compound 2.
[0226] Used for the next step without further purification.
Example 25
[0227] Preparation of
(.+-.)4-((.alpha.-(1-Piperazinyl))-4-xylyl)-N,N-diet- hylbenzamide
(Compound 41)
[0228] The compound of this Example was prepared by following the
synthesis procedure as described for compound 3.
[0229] m.p. 129-132.degree. C. (from acetonitrile), v.sub.max
(KBr)/cm.sup.-1 3320, 2957, 2811, 1610, 1437, 1285, 1128, 1010,
838; .delta..sub.H (400 MHz, CDCl.sub.3) 1.10 (3H, br s), 1.20 (3H,
br s), 1.83 (1H, br s), 2.30 (3H, s), 2.34 (4H, br s), 2.86-2.89
(4H, m), 3.24 (2H, br s), 3.51 (2H, br s), 4.20 (1H, s), 7.06-7.46
(8H, 3m); C.sub.23H.sub.31N.sub.3O requires:
[0230] C, 75.58; H, 8.55; N, 11.50. Found: C, 75.30; H, 8.54; N,
11.56.
Example 26
[0231] Preparation of
(.+-.)4-((.alpha.-((4-Allyl)-1-piperazinyl))-4-xylyl-
)-N,N-diethylbenzamide.2HCl (Compound 42)
[0232] The compound of this Example was prepared by following the
synthesis procedure as described for Examples 2 and 3.
[0233] m.p. >160.degree. C. dec. (from ether); v.sub.max
(KBr)/cm.sup.-1 3437, 2973, 2402, 1625, 1433, 1289, 1097, 944, 809;
.delta..sub.H (400 MHz, CDCl.sub.3, free base) 1.10 (3H, br s),
1.20 (3H, br s), 2.29 (3H, s), 2.35-2.60 (6H, m), 3.03 (2H, m),
3.24 (2H, br s), 3.52 (2H, br s), 4.22 (1H, s), 5.12-5.23 (2H, m),
5.81-5.93 (1H, m), 7.05-7.45 (8H, 3m); 18
[0234] The compounds according to Examples 27 were synthesized as
shown in Scheme 9 above.
[0235] I.
[0236] I. Preparation of
(.+-.)4-((.alpha.-Hydroxy)-3-xylyl)-N,N-diethylbe- nzamide
(Compound 43)
[0237] The compound 43 was prepared by following the synthesis
procedure as described for compound 31, but substituting
4-chlorophenylmagnesiumbro- mide for m-toluylmagnesiumbromide.
[0238] v.sub.max (KBr)/cm.sup.-1 3406, 2972, 1613, 1429, 1360,
1287, 1097, 1053, 789; .delta..sub.H (400 MHz, CDCl.sub.3) 1.10
(3H, br s), 1.22 (3H, br s), 2.34 (3H, s), 2.55 (1H, d, J 3.5),
3.25 (2H, br s), 3.52 (2H, br s), 5.80 (1H, d, J 3), 7.12-7.42 (8H,
m);
[0239] II. Preparation of
(.+-.)4-((.alpha.-Chloro)-3-xylyl)-N,N-diethylbe- nzamide (Compound
44)
[0240] The compound 44 was prepared by following the synthesis
procedure as described for compound 2.
[0241] Used for the next step without further purification.
Example 27
[0242] Preparation of
(.+-.)4-((.alpha.-(1-piperazinyl))-4-xylyl)-N,N-diet-
hylbenzamide.2HCl (Compound 45)
[0243] The compound of this Example was prepared by following the
synthesis procedure as described for compound 3.
[0244] m.p. >130.degree. C. dec. (from ether), v.sub.max
(Kbr)/cm.sup.-1 2971, 2805, 2715, 1624, 1434, 1289, 1096, 783;
.delta..sub.H (400 MHz, CDCl.sub.3, free base) 1.10 (3H, br s),
1.20 (3H, br s), 2.31 (3H, s), 2.35-2.45 (5H, m), 2.89-2.92 (4H,
m), 3.25 (2H, br s), 3.51 (2H, br s), 4.19 (1H, s), 6.98-7.46 (8H,
4m); 19
[0245] The compounds according to Example 28 were synthesized as
shown in Scheme 10 above.
[0246] J.
[0247] I. Preparation of
(.+-.)4-((.alpha.-Hydroxy)-cyclohexylmethyl)-N,N-- diethylbenzamide
(Compound 46)
[0248] The compound 46 was prepared by following the synthesis
procedure as described for compound 31.
[0249] .delta..sub.H (400 MHz, CDCl.sub.3) 0.85-2.0 (18H, m), 3.26
(2H, br s), 3.53 (2H, br s), 4.35-4.43 (1H, m), 7.28-7.36 (4H,
m);
[0250] II. Preparation of
(.+-.)4-((.alpha.-Chloro)-cyclohexylmethyl)-N,N-- diethylbenzamide
(Compound 47)
[0251] The compound 47 was prepared by following the synthesis
procedure as described for compound 2.
[0252] Used for the next step without further purification.
Example 28
[0253] Preparation of
(.+-.)4-((.alpha.-(1-piperazinyl))-cyclohexylmethyl)-
-N,N-diethylbenzamide (Compound 48)
[0254] The compound of this Example was prepared by following the
synthesis procedure as described for compound 3.
[0255] m.p. 113-116.degree. C. (from acetonitrile), v.sub.max
(KBr)/cm.sup.-1 3330, 2936, 2845, 1623, 1431, 1286, 1096, 823;
.delta..sub.H (400 MHz, CDCl.sub.3) 0.64-2.02 (18H, m), 2.18-2.40
(4H, m), 2.75-2.87 (4H, m), 3.06 (1H, d, J 8.8), 3.27 (2H, br s),
3.52 (2H, br s), 7.11 (2H, d, J 8.4), 7.29 (2H, d, J 8.4); 20
[0256] The compounds according to Examples 29 were synthesized as
shown in Scheme 11 above.
[0257] K.
[0258] I. Preparation of
(.+-.)4-((.alpha.-Hydroxy)-3,4-dimethylbenzyl)-N,-
N-diethylbenzamide (Compound 49)
[0259] The compound 49 was prepared by following the synthesis
procedure as described for compound 1.
[0260] .delta..sub.H (400 MHz, CDCl.sub.3) 1.09 (3H, br s), 2.23
(6H, s), 2.85 (1H, d, J 3), 3.24 (2H, br s), 3.51 (2H, br s), 5.73
(1H, d, J 2), 7.03-7.12 (m, 3H), 7.26-7.39 (m, 4H);
[0261] II. Preparation of
(.+-.)4-((.alpha.-Chloro)-3,4-dimethylbenzyl)-N,-
N-diethylbenzamide (Compound 50)
[0262] The compound 50 was prepared by following the synthesis
procedure as described for compound 2.
[0263] Used for the next step without further purification.
Example 29
[0264] Preparation of
(.+-.)4-((.alpha.-(1-Piperazinyl))-3,4-dimethylbenzy-
l)-N,N-diethylbenzamide (Compound 51)
[0265] The compound of this Example was prepared by following the
synthesis procedure as described for compound 3.
[0266] v.sub.max (KBr)/cm.sup.-1 3304, 2939, 2810, 1626, 1429,
1286, 1096, 846; .delta..sub.H (400 MHz, CDCl.sub.3) 1.11 (3H, br
s), 1.20 (3H, br s), 1.87 (1H, br s), 2.20 (3H, s), 2.22 (3H, s),
2.34 (4H, br s), 2.86-2.89 (4H, m), 3.25 (2H, br s), 3.51 (2H, br
s), 4.15 (1H, s), 7.02-7.15 (3H, m), 7.26-7.30 (2H, m), 7.42-7.46
(2H, m); 21
[0267] The compounds according to Examples 30 were synthesized as
shown in Scheme 12 above.
[0268] L.
[0269] I. Preparation of
(.+-.)4-(.alpha.-Hydroxy)-1-naphtylmethyl)-N,N-di- ethylbenzamide
(Compound 52)
[0270] The compound 52 was prepared by following the synthesis
procedure as described for compound 1.
[0271] .delta..sub.H (400 MHz, CDCl.sub.3) 1.06 (3H, br s), 1.20
(3H, br s), 3.01 (1H, d, J 4), 3.21 (2H, br s), 3.49 (2H, br s),
6.47 (1H, d, J 4), 7.24-7.48 (7H, m), 7.55-7.58 (1H, m), 7.78-7.87
(2H, m), 7.98-8.01 (1H, m);
[0272] II. Preparation of
(.+-.)4-((.alpha.-Chloro)-1-naphtylmethyl)-N,N-d- iethylbenzamide
(Compound 53)
[0273] The compound 53 was prepared by following the synthesis
procedure as described for compound 2.
[0274] Used for the next step without further purification.
Example 30
[0275] Preparation of
(.+-.)4-((.alpha.-(1-piperazinyl))-1-naphtylmethyl)--
N,N-diethylbenzamide (Compound 54)
[0276] The compound of this Example was prepared by following the
synthesis procedure as described for compound 3.
[0277] v.sub.max (KBr)/cm.sup.-1 3307, 3050, 2966, 2814, 1625,
1431, 1287, 1098, 843, 797; .delta..sub.H (400 MHz, CDCl.sub.3)
1.04 (3H, br s), 1.17 (3H, br s), 2.14 (1H, br s), 2.40 (2H, br s),
2.46 (2H, br s), 2.83-2.95 (4H, m), 3.17 (2H, br s), 3.48 (2H, br
s), 5.05 (1H, s), 7.22-7.28 (2H, m), 7.40-7.54 (5H, m), 7.70-7.94
(3H, m), 8.40-8.43 (1H, m);
[0278] Piperazine Ring Modifications: General Experimental and
Examples
[0279] The compounds according to Examples 31-42 were synthesized
as shown in Scheme 13 below.
[0280] M.
[0281] I. Preparation of 2-Dimethyl-S-methyl-piperazine-3,5-dione
(Compound 55)
[0282] N-t-Butoxycarbonyl-2-aminoisobutyric acid (5.0 g, 25 mmol)
and D,L-alanine methylester hydrochloride (3.5 g, 25 mmol) was
dissolved in dry dichloromethane (50 mL) and cooled to 0.degree. C.
Triethylamine (3.5 mL, 25 mmol) and then
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (4.8
g, 25 mmol) was added and the mixture was stirred at 0.degree. C.
until lumps dissolved. The reaction mixture was then left in the
freezer 4 d at -20.degree. C. The organic solution was washed with
water, 1M citric acid (aq.), water, dried (Na.sub.2SO.sub.4) and
evaporated in vacuo to give 6.0 g (83.degree. C.) of coupling
product. Most of the coupling product (5 g) was dissolved in formic
acid (50 mL) and stirred 12 h at 25.degree. C. The acid was removed
in vacuo and the residue dissolved in 2-butanol and heated at
reflux for 4 h. The solution was cooled to 0.degree. C. and the
crystals filtered off and dried in vacuo at 100.degree. C. Yield
2.6 g of pure compound 55 (82%) which could be recrystallized from
methanol, mp: >300.degree. C. IR (Kbr) (cm-1): 3000 (br), 1680
(s) (C.dbd.O). .sup.1H NMR (D.sub.2O): .delta.=4.75 (s, 2H, NH).
4.21 (q, 1H, CHMe), 1.50-1.42 (m, 9H, 3Me).
C.sub.7H.sub.12N.sub.2O.sub.2 requires C, 53.83; H, 7.74; N, 17.94.
Found C, 53.89; H, 7.90; N, 17.79.
[0283] II. Preparation of 2-Dimethyl-5-methyl-piperazine
Dihydrochloride (Compound 56)
[0284] Compound 55 (2.2 g, 14 mmol) was dissolved on dry THF (120
mL). Lithium aluminum hydride (42 mL, 1M in THF) was added in small
portions. When addition complete, the solution was heated at reflux
over night The solution was allowed to cool then excess hydride was
destroyed by dropwise addition of water (1.6 mL), NaOH (1.6 mL, 15%
solution) and water (4.8 mL). The granular precipitate was filtered
off and solvent evaporated in vacuo. The residue was dissolved in
dichloromethane, dried (K.sub.2CO.sub.3) and evaporation of solvent
in vacuo gave 1.5 g (84%). Treatment with excess HCl in ether gave
the dihydrochloride compound 56 which could be recrystallized from
methanol/ether mp: >300.degree. C. IR (cm-1), KBr: 2760, 1570
(R.sub.2NH.sub.2+). MS (amine):128, 113, 84, 71, 58. .sup.1H NMR
(D.sub.2O+DSS): .delta.=2.70-2.50 (m, 5H, CH.sub.2--N, CH--N), 1.14
(s, 3H, 1 Me), 1.00-0.94 (s+d, 6H, 2 Me).
C.sub.7H.sub.16N.sub.2.times.2HCl requires C, 41.80; H, 9.02; N,
13.93. Found C, 42.03; H, 9.24; N, 14.00.
Example 31
[0285] Preparation of
4-(4-(2-Dimethyl-5-methyl-piperazinyl)-3-methoxybenz-
yl)-N,N-diethylbenzamide Dihdrocloride (Compound 57)
[0286] 4-(Chloro-(3-methoxyphenyl)methyl)-N,N-diethylbenzamide
(0.61 g, 2.0 mmol) and compound 56 (0.50 g, 3.9 mmol) was dissolved
in dry acetonitrile (5 mL). Potassium carbonate (0.26 g, 2.0 mmol)
was added and the mixture heated at reflux for 2 d. The solvent was
removed in vacuo and the residue purified by flash chromatography
on silica (CH.sub.2Cl.sub.2/MeOH/NH.sub.3(aq.)), 98:1:1 to 95:5:1
to yield 0.65 g (79%). Treatment with excess of HCl in ether.
filtering and drying crystals in vacuo over KOH gave the
dihydrochloride compound 57, mp: 134-36.degree. C. IR (HCl salt,
KBr) (cm-1): 3400 (br, OH), 2900 (br, R.sub.2NH.sub.2+), 1600 (s,
C.dbd.O or R.sub.2NH.sub.2+), 1283, 1038 (C--O). MS (amine) 3
peaks: 423, 353, 325, 296, 127. .sup.1H NMR: (amine, CDCl.sub.3):
.delta.=7.40-6.60 (m, 8H, Ar--H), 5.26, 5.25, 4.61 (3s, 1H,
CHAr.sub.2), 3.70 (s, 3H, MeO), 3.4, 3.2 (2 br. s, 4H, MeCH.sub.2),
3.1-2.0 (m, 5H, piperazine-H), 1.3-0.9 (m, 15H, 5Me).
C.sub.26H.sub.37N.sub.3O.sub.2.times.2HCl requires C, 62.89; H,
7.92; N, 8.46. Found C, 63.41; H, 8.38; N, 8.56.
Example 32
[0287] Preparation of
4-(4-(1-Allyl-2-dimethyl-5-methyl-piperazinyl)-3-met-
hoxybenzyl)-N,N-diethylbenzamide Dihydrochloride (Compound 58)
[0288] Compound 57 (0.39 g, 0.92 mmol) was dissolved in dry
acetonitrile (5 mL). Potassium carbonate (0.13 g, 0.92 mmol) and
allyl bromide (90 .mu.L, 1.02 mmol) was added. After 3 h at
25.degree. C. the solvent was evaporated and the residue purified
by flash chromatography on silica (CH.sub.2Cl.sub.2/MeOH), 98:2 to
95:5 to give a total of 0.39 g (92%). Treatment with excess of HCl
in ether, filtering and drying crystals in vacuo over KOH gave the
dihydrochloride, compound 58, mp: 105-21.degree. C. IR (HCl salt,
Kbr) (cm-1): 3400 (br, OH), 2500 (br, R.sub.2NH.sub.2+), 16200 (s)
(C.dbd.O or R.sub.2NH.sub.2+), 1285, 1043 (C--O). .sup.1H NMR:
(amine, CDCl.sub.3): .delta.=7.50-6.60 (m, 8H, Ar--H), 5.70 (m, 1H,
allyl-H), 5.00 (m, 2H, allyl-H), 4.70 (s, 1H, CHAr.sub.2), 3.70 (s,
3H, MeO), 3.5+3.3 (2 br. s, 4H, MeCH.sub.2), 3.0-1.9 (m, 7H,
piperazine-H), 1.2-0.8 (m, 15H, 5Me).
C.sub.29H.sub.41N.sub.3O.sub.2.times.2HCl requires C, 64.91; H,
8.08; N, 7.83. Found C, 65.70; H, 8.60; N, 8.29.
[0289] N.
[0290] I. Preparation of 4-Allyl-2-dimethyl-5-methyl-piperazine
(Compound 59)
[0291] Compound 56 (0.14 g, 0.91 mmol) was dissolved in
acetonitrile and allyl bromide (80 .mu.L, 0.91 mmol) was added at
0.degree. C. After 1 h another portion of allyl bromide was added.
After 2 h the solvent was evaporated and the residue purified by
flash chromatography on silica (CH.sub.2Cl.sub.2/MeOH), 95:5 to
80:20 to give the monoallyl compound 59, 116 mg (69%).
Example 33
[0292] Preparation of
4-(1-(4-Allyl-2-dimethyl-5-methyl-piperazinyl)-3-met-
hoxybenzyl)-N,N-diethylbenzamide Dihydrochloride (Compound 60)
[0293] The compound of this Example was prepared by following the
synthesis procedure as described for Example 3.
[0294] Mp: 125-30.degree. C. IR (2HCl, KBr) (cm-1): 3430(br), 2978,
2480(br.), 1607, 1436, 1285. MS(free amine):366, 296, 167. .sup.1H
NMR: (D.sub.2O+DSS): .delta.=7.60-6.90 (m, 9H, Ar--H), 6.0-5.5 (m,
4H, allyl-H+Ar.sub.2CH), 3.80 (2s, 3H, MeO), 4.0-3.7 (m, 11H,
allyl-H, piperazine-H, amide-CH.sub.2), 1.3-1.0 (m, 15H,
piperazine-Me, amide-Me). Anal. calc. for
C.sub.29H.sub.41N.sub.3O.sub.2.times.2HCl.times.2.9H.sub.- 2O: C,
59.15; H, 8.35; N, 7.14. Found: C, 59.05; H, 8.00; N, 7.22.
Example 34
[0295] Preparation of
4-(1-(2-dimethyl-5-methyl-piperazinyl)-3-methoxybenz-
yl)-N,N-diethylbenzamide Dihydrochloride (Compound 61)
[0296] 56 (42 mg, 0.33 mmol) and potassium carbonate (46 mg, 0.33
mmol) was dissolved in water (2 mL) and di-t-butyl dicarbonate (79
mg, 0.36 mmol) was added. After stirring 1 h the solvent was
evaporated in vacuo and the residue purified by chromatography on
silica (CH.sub.2Cl.sub.2/MeOH), 90:10 to give 43 mg of the
mono-N-Boc protected 55 which was dissolved in dry acetonitrile
together with potassium carbonate (26 mg, 0.19 mmol) and 4
(Chloro-(3-methoxyphenyl)methyl)-N,N-d- iethylbenzamide (63 mg,
0.19 mmol). After heating 4 days at reflux, the solvent was removed
in vacuo and residue purified by chromatography on silica
(CH.sub.2C.sub.2/MeOH), 100:0, 95:5. Treatment with formic acid (5
mL) for 3 h, evaporation of solvent in vacuo and extraction of the
residue with CH.sub.2Cl.sub.2/1M NaOH, drying of the organic phase
(K.sub.2CO.sub.3) and evaporation of solvent in vacuo gave 27 mg
(33%) of the free amine. Treatment with excess HCl in ether gave
the dihydrochloride which was dissolved in water and freeze-dried.,
mp: 145-50.degree. C. IR (2HCl, KBr) (cm-1): 3500-3400(br), 1601,
1442, 1285. MS(free amine): 423, 296, 325, 127. .sup.1H NMR:
(CDCl.sub.3): .delta.=7.4-6.6 (m, 8H, Ar--H), 5.39, 5.36 (2s, 1H,
Ar.sub.2CH), 3.75 (s, 3H, MeO), 3.5, 3.25 (2 br. s, 4H, amide-Me),
2.80, 2.50, 2.05 (3m, 5H, piperazine-H), 1.5 (br.s, 1H, N--H),
1.25-1.0 (br. m, 6H, amide-Me), 1.15 (s, 3H, Me), 0.90 (d, 3H, Me),
0.85 (s, 3H, Me). Calc. for
C.sub.26H.sub.37N.sub.302.times.2HCl.times.7.4H.sub.2O: C, 49.58;
H, 8.61; N, 6.67. Found: C, 49.61; H, 7.73; N, 6.56.
[0297] O.
[0298] I. Preparation of
4-(Phenyl-hydroxymethyl)-N,N-diethylbenzamide (Compound 62)
[0299] The compound 62 was prepared by following the synthesis
procedure as described for compound 1.
[0300] MS: 282, 211, 165, 105. .sup.1H NMR: (CDCl.sub.3):
.delta.=7.38-7.20 (m, 9H), 5.80 (d, J=3.5 Hz, 1H), 3.5, 3.2 (2br.s,
4H), 1.2, 1.05 (2br. s, 6H).
[0301] II. Preparation of
4-(Chloro-phenyl-methyl)-N,N-diethylbenzamide (Compound 63
[0302] The compound 63 was prepared by following the synthesis
procedure as described for compound 2.
[0303] GC-MS (2 peaks):296, 225, 165, 121. and 300, 266, 229, 195,
165. .sup.1H NMR: (CDCl.sub.3): .delta.=7.45-7.20 (m, 9H), 6.09 (s,
1H), 3.4 (br. m, 4H), 1.1 (br. m, 6H).
Example 35
[0304] Preparation of
4-((1-piperazinyl)-benzyl)-N,N-diethylbenzamide Dihydrochloride
(Compound 64)
[0305] The compound of this Example was prepared by following the
synthesis procedure as described for compound 3.
[0306] Mp: 157-69.degree. C. IR (amine, CDCl.sub.3 in KBr cell)
(cm-1): 3690, 3630, 1613, 1435, 1265. MS (free amine): 351, 306,
295, 266, 194, 165. .sup.1H NMR: (free amine, CDCl.sub.3):
.delta.=7.46-7.16 (m, 9H, Ar--H), 4.24 (s, 1H, CHAr.sub.2), 3.5+3.2
(2 br. s, 4H, MeCH.sub.2), 2.89 (m, 4H, piperazine-H), 2.36 (br. s,
4H, piperazine-H), 1.94 (br s, 1H, NH), 1.2+1.1 (2 br. s, 6H, 2Me).
Anal. calc. for C.sub.22H.sub.29N.sub.3O-
.times.2HCl.times.1.90H.sub.2O, C, 57.61; H, 7.65; N, 9.16. Found
C, 57.59; H, 7.66; N, 8.92.
Example 36
[0307] Preparation of
4-((4-Allyl-1-piperazinyl)-benzyl)-N,N-diethylbenzam- ide
Dihydrochloride (Compound 65)
[0308] The compound of this Example was prepared by following the
synthesis procedure as described for Examples 2 and 3.
[0309] Mp: 175-205.degree. C. IR (amine, CDCl.sub.3 in KBr cell)
(cm-1): 3689, 1613, 1455, 1434, 1290, 1143. MS (free amine): 391,
165, 125. .sup.1H NMR: (free amine, CDCl.sub.3): .delta.=7.42-7.12
(m. 9H, Ar--H), 5.81 (m, 1H, allyl-H), 5.10 (m, 2H, allyl-H), 4.23
(s, 1H, CHAr.sub.2), 3.5+3.2 (2 br. s, 4H, MeCH.sub.2), 3.00 (m,
2H, allyl-H), 2.6-2.4 (br. s, 8H, piperazine-H), 1.1 (2 br. s, 6H,
2Me). Anal. calc. for
C.sub.25H.sub.35N.sub.3O.times.2HCl.times.1.0H.sub.2O, C, 62.23; H,
7.73; N, 8.71. Found C, 62.22; H, 7.49; N, 8.42.
[0310] P.
[0311] I. Preparation of
2-Hydroxymethyl-5-methyl-piperazine-3,5-dione (Compound 66)
[0312] (D,L)-N-t-Butoxycarbonyl-alanine (5.0 g, 26 mmol) was
dissolved in methylene chloride (50 mL) with triethyl amine (8.1
mL), dried with 4 A molecular sieves and transfered to dry flask
under nitrogen. i-Butyl chloroformate (3.8 mL, 29 mmol) was added
at -10.degree. C. The Solution was stirred 15 min, then D,L-serine
methylester hydrochloride (4.1 g, 26 mmol) was added and the
solution was allowed to reach 25.degree. C. and stirred 12 h.
Washing the solution with brine, drying (MgSO.sub.4) and
evaporating solvent in vacuo gave a solid which was treated with
formic acid for 1 h. The acid was removed in vacuo and the residue
dissolved in anhydrous 2-butanol (5 mL) and heated at reflux 2
days. The solvent was removed and the residue crystallized when
treated with acetone to give 1 g of compound 66 (24%).
[0313] II. Preparation of 2-Hydroxymethyl-5-methyl-piperazine
(Compound 67)
[0314] The compound 67 was prepared by following the synthesis
procedure as described for compound 55.
[0315] II. Preparation of
2-(t-Butyldiphenylsilyloxy)methyl-5-methyl-piper- azine (Compound
68)
[0316] Compound 67 (0.41 g, 3.1 mmol) was dissolved in dry DMF (5
mL). Chloro-t-butyldiphenylsilane (0.95 g, 3.4 mmol) and immidazole
(0.47 g, 6.9 mmol) was added and stirring was continued 12 h. The
product was extracted by adding ethyl acetate, brine and 1M NaOH
and shaking. The organic phase was dried and evaporated in vacuo.
Chromatography of the residue on silica (CH.sub.2Cl.sub.2/MeOH,
100:0, 95:5, 90:10 and 80:20) gave 0.39 g (34%) pure compound
68.
Example 37
[0317] Preparation of
4-(4-(2-Hydroxymethyl-5-methyl)piperazinyl-benzyl)-N-
,N-diethylbenzamide Dihydrochloride (Compound 69)
[0318] The compound of this Example was prepared by following the
synthesis procedure as described for compound 3.
[0319] Mp: 145-50.degree. C. IR (2HCl, KBr) (cm-1): 3300(br),
2700(br), 1612, 1446, 1382, 1296, 1080. MS(free amine):381, 218,
181, 91. .sup.1H NMR: (free amine, CDCl.sub.3): .delta.=7.44-7.18
(m, 9H, Ar--H), 5.17, 5.14 (2s, 1H, ArCH.sub.2), 3.75-2.60 (m, 12H,
piperazine-H, amide-CH.sub.2), 2.02 (m, 1H, piperazine-H),
1.30-1.05 (m, 9H, piperazine-Me+amide-Me). Anal. calc. for
C.sub.24H.sub.33N.sub.3O.sub.2.t- imes.2HCl.times.1.8H.sub.2O: C,
57.55; H, 7.77; N, 8.39. Found: C, 57.05; H, 7.67; N, 8.19.
Example 38
[0320] Preparation of
4-((4-(2-Hydroxymethyl-5-methyl)piperazinyl)-3-metho-
xybenzyl)-N,N-diethylbenzamide Dihydrochloride (Compound 70)
[0321] The compound of this Example was prepared by following the
synthesis procedure as described for compound 3.
[0322] Mp: 185-90.degree. C. IR (2HCl, KBr) (cm-1): 3500-2500(br),
1596, 1440, 1045. .sup.1H NMR: (free amine, CDCl.sub.3):
.delta.=7.40-6.60 (m, 8H, Ar--H), 5.05, 5.10 (2s, 1H, Ar.sub.2CH).
3.70 (s, 3H, MeO), 3.8-2.5 (m, 12H, piperazine, amide CH.sub.2)
1.2-1.0 (br. s, 9H, amide-Me, piperazine-Me).
Example 39
[0323] Preparation of
4-((4-(1-Allyl-2-hydroxymethyl-5-methyl)piperazinyl)-
-3-methoxybenzyl)-N,N-diethylbenzamide Dihydrochloride (Compound
71)
[0324] The compound of this Example was prepared by following the
synthesis procedure as described for Examples 2 and 3.
[0325] Mp: 125-30.degree. C. IR (2HCl, KBr) (cm-1): 3400(br), 1603,
1445, 1285. MS(free amine): two, peaks: 310, 239, 135 and 312, 241,
135. .sup.1H NMR: (free amine, CDCl.sub.3): .delta.=7.50-6.70 (m,
8H, Ar--H), 5.80, 5.20, 5.00 (3m, 3H, allyl-H), 4.0-2.3 (m, 14H,
piperazine-H,allyl-H, amide-CH.sub.2) 3.80 (s, 3H, MeO), 1.2 (br.
s, 6H, amide-Me). Anal.calc. for
C.sub.25H.sub.35N.sub.3O.sub.3.times.2HCl.times- .3.7H.sub.2O: C,
55.57; H, 8.06; N, 6.94. Found: C, 55.53; H, 7.82; N, 7.16.
[0326] Q.
[0327] I. Preparation of Methyl 3-(hydroxy-(2-naphtyl)methyl)phenyl
Ether (Compound 72)
[0328] The compound 72 was prepared by following the synthesis
procedure as described for compound 1.
[0329] MS: 264, 155, 135, 128, 109, 101. .sup.1H NMR: (CDCl.sub.3):
.delta.=7.90-6.78 (m, 1H, Ar--H), 5.98 (d, J=3.5 Hz, 1H,
Ar.sub.2H), 3.78 (s, 3H, MeO), 2.32 (d, J=3.5 Hz, 1H, OH).
[0330] II. Preparation of Methyl 3-(chloro-(2-naphtyl)methyl)phenyl
Ether (Compound 73)
[0331] The compound 73 was prepared by following the synthesis
procedure as described for compound 2.
[0332] GC-MS (2 peaks): 278, 247, 215, 171, 155, 135 and 282, 248,
247, 231, 215. .sup.1H NMR: (CDCl.sub.3): .delta.=7.86-6.81 (m,
11H, Ar--H), 6.25 (s, 1H, Ar.sub.2H), 3.76 (s, 3H, MeO).
[0333] III. Preparation of 4-Allyl-2-methylpiperazine (Compound
74)
[0334] 2-Methylpiperazine (0.4 g, 4 mmol) was dissolved in
acetonitrile (5 mL) and allyl bromide (86 .mu.L, 1 mmol) was added
at 0.degree. C. Stirring was continued at 0.degree. C. for 1 h,
then at 25.degree. C. for 6 h. Evaporation of solvent in vacuo and
chromatography on silica (CH.sub.2O.sub.2/MeOH, 80:20) gave 80 mg
(57%) pure compound 74.
Example 40
[0335] Preparation of Methyl
3-((2-naphtyl)-(3-methyl-piperazinyl)methyl)p- henyl Ether
Dihydrochloride (Compound 75)
[0336] The compound of this Example was prepared by following the
synthesis procedure as described for compound 3.
[0337] Mp: 170-74.degree. C. IR (KBr) (cm-1): 3461, 2458, 1600,
1439, 1263, 1043. MS (amine): 386, 247, 215, 139, 112. .sup.1H NMR:
(amine, CDCl.sub.3): .delta.=7.84-6.66 (m, 11H, Ar--H), 4.33 (s,
1H, CHAr.sub.2). 3.74, 3.73 (2s, 3H, MeO), 3.00-2.70 (m. 6H,
piperazine-H). 1.95, 1.65 (2m, 2H, piperazine-H), 0.98-0.92 (2d,
J=6.4 Hz, 3H, piperazine-Me). Anal. calc. for
C.sub.23H.sub.26N.sub.20.times.2HCl.times.1.8H.sub.2O, C, 61.14; H,
7.05; N, 6.20. Found, C, 61.05; H, 6.48; N, 6.07.
Example 41
[0338] Preparation of Methyl
3-((2-naphtyl)-(4-allyl-2-methyl-piperazinyl)- methyl)phenyl Ether
Dihydrochloride (Compound 76)
[0339] The compound of this Example was prepared by following the
synthesis procedure as described for Example 3.
[0340] Mp: 173-82.degree. C. IR (KBr) (cm-1): 3430, 2500, 2355,
1601, 1436, 1265, 1047. MS (amine): 386, 274, 247, 215, 139, 125.
.sup.1H NMR: (amine, CDCl.sub.3): =7.86-6.66 (m, 11H, Ar--H), 5.82
(m, 1H, allyl-H), 5.12 (m, 2H, allyl-H), 4.95 (br. s, 1H,
CHAr.sub.2), 3.76, 3.75 (2s, 3H, MeO), 3.04-2.32 (m, 9H,
piperazine-H), 1.15-1.11 (2d, 3H, Me). Anal. calc. for
C.sub.26H.sub.32N.sub.2O.times.2HCl.times.0.4H.sub.2O, C, 66.92; H,
7.08; N, 6.00. Found C, 67.03; H, 7.09; N, 5.88.
Example 42
[0341] Preparation of
4-((4-Acetyl-1-piperazinyl)benzyl)-N,N-diethylbenzam- ide
Hydrochloride (Compound 77)
[0342] The free amine of compound 64 (100 mg, 0.28 mmol) was
dissolved in methylene chloride (5 ml), cooled to 0.degree. C.
Triethyl amine (43 mL 0.31 mmol) was added and then acetyl chloride
(22 .mu.l, 0.31 mmol) was added dropwise. After 10 min, the
solution was washed with potassium carbonate (10%), dried
(K.sub.2CO.sub.3) and evaporated in vacuo. The residue was purified
by chromatography on silica (CH.sub.2Cl.sub.2/MeOH/N- H.sub.3,
95:5:0.5) to give 116 mg of compound 77 (-100%).
[0343] Mp: 140-50.degree. C. IR (KBr) (cm-1): 3480(br), 2987,
2500(br), 1623, 1429, 1285, 1245. MS (free amine): 393, 267, 165,
127. .sup.1H NMR: (free amine, CDCl.sub.3): .delta.=7.46-7.18 (m,
9H, Ar--H), 4.25 (s, 1H, CHAr.sub.2), 3.70-3.15 (m, 8H,
amide-CH.sub.2, piperazine-H), 2.36 (m, 4H, piperazine-H), 2.05 (s,
3H, MeCO), 1.15 (br. m, 6H, amide-Me). Anal. calc. for
C.sub.24H.sub.31N.sub.3O.sub.2.times.1HCl.times.0.80H.sub.2O, C,
64.87. H, 7.62; N, 9.46. Found C, 65.01; H, 7.76; N, 9.42.
22232425
[0344] Diethylbenzamide Replacements Etch
[0345] The compounds according to Examples 43-48 were prepared as
shown in Scheme 14 below.
[0346] R.
[0347] I. Preparation of
4-((4-t-Butoxycarbonyl-1-piperazinyl)-benzyl)-ben- zoic Acid
(Compound 78)
[0348] Compound 64 (6.0 g, 17 mmol) was dissolved in 6N
hydrochloric acid and heated at 120.degree. C. for 3 days. The
solution was then neutralized with aquous NaOH (-12 g). The
solution was concentrated to 100 mL, mixed with THF (100 mL) and
di-t-butyl dicarbonate (3.7 g, 17 mmol) added dissolved in THF (50
mL). After stirring 1 h at 25.degree. C., the aquous phase was
acidified with 1M citric acid and extracted two times with ethyl
acetate. The organic phase was dried (K.sub.2CO.sub.3) and
evaporated, and the residue purified by chromatography on silica
(EtOAc/heptane/AcOH, 10:90:0 to 66:33:1) to give a total of 3.85 g
(57%) of compound 78.
Example 43
[0349] Preparation of 4-((1-piperazinyl)-benzyl)-benzoic Acid
Dihydrochloride (Compound 79)
[0350] Compound 78 (150 mg, 0.38 mmol) was treated with excess HCl
in acetic acid 1 h. Acid removed in vacuo and residue dissolved in
methanol and precipitated by addition of ether. The precipitate was
dried in vacuum at 100.degree. C. Mp: 172-80.degree. C. IR (KBr)
(cm-1): 3000(br), 1700, 1606, 1454. .sup.1H NMR: (DMSO-d.sub.6):
.delta.=12.85 (s, 1H, CO.sub.2H), 8.95 (s, 2H, NH), 7.92-7.20 (m,
9H, Ar--H), 4.56 (s, 1H, Ar.sub.2CH), 3.33 (s, 8H, piperazine-H).
Anal. calc. for C.sub.18H.sub.20N.sub.2O.sub.2.times.2HCl, C,
58.54; H, 6.00; N, 7.59. Found: C, 59.9; H, 6.47; N, 7.88.
Example 44 and 45
[0351] Preparation of Methyl
4-((4-t-butoxycarbonyl-1-piperazinyl)-benzyl)- benzoate (Compound
80) and Methyl 4-((1-piperazinyl)-benzyl)benzoate Dihydrochloride
(Compound 81)
[0352] Compound 78 (0.15 g, 0.38 mmol) and cesium carbonate (0.25
g, 0.76 mmol) was mixed in DMF (2 mL) and methyl iodide (72 .mu.L,
1.1 mmol) was added. After 2 h at 25.degree. C., potassium
carbonate (10%, aq.) and the solution was extracted with ethyl
acetate. After evaporation of solvent in vacuo, the residue was
purified by chromatography on silica (EtOAc/heptane, 30:70) to
yield 0.13 g (87%) of the methyl ether, compound 80.
Boc-deprotection was acheived by treatment with excess HCl in
methanol at 50.degree. C. The solvent was removed and the residue
was purified again on silica The dihydrochloride, compound 81 (35
mg), was prepared according to previous methodology. Mp:
185-95.degree. C. IR (KBr) (cm-1): 3400(br), 270((br), 1720, 1612,
1430, 1285, 1190, 1112. MS (EI, free amine): 310, 265, 225, 206,
165. .sup.1H NMR: (D.sub.2O/CD.sub.3OD+DSS): .delta.=8.20-7.34 (m,
9H, Ar--H), 5.03 (s, 1H, CHAr.sub.2), 3.89 (s, 3H, MeO), 3.42 (m,
4H, piperazine-H), 3.08 (m, 4H, piperazine-H). Anal. calc. for
C.sub.19H.sub.22N.sub.2O.sub.2.times.2HCl.- times.1H.sub.2O. C,
56.86; H, 6.53; N, 6.98. Found C, 56.82; H, 6.54; N, 7.00.
[0353] S.
[0354] I. Preparation of 4-((1-[)piperazinyl)-benzyl)benzamide
Dihydrochloride (Compound 83)
[0355] Compound 78 (0.11 g, 0.28 mmol) was dissolved in dry
methylene chloride/THF, 1:1 (5 mL) and cooled to -20.degree. C.
Triethylamine (78 .mu.L, 0.56 mmol) was added and then i-butyl
chloroformate (37 .mu.L, 028 mmol). After 10 min, ammonia in
methylene chloride (0.51 mL, 1.1M, 0.56 mmol) was added and the
temperature was allowed to rise slowly to 25.degree. C. After 3 h,
the solvent was removed in vacuo and the residue was purified by
chromatography on silica (CH.sub.2Cl.sub.2/MeOH/NH.sub.3, 95:5:1
and 90:10:1) to give 70 mg (62%). Treatment with HCl in methanol 3
h at 50.degree. C., removal of solvent in vacuo and chromatography
on silica (CH.sub.2Cl.sub.2/MeOH/NH.sub.3, 90:10:1 and 80:20:1)
gave the free amine which was converted to the dihydrochloride salt
82. Mp: 192-200.degree. C. IR (KBr) (cm-1): 3939(br), 3184(br),
2700(br), 1665, 1610, 1565, 1426. MS (amine): 295, 250, 210, 165,
152. .sup.1H NMR: (amine, CD.sub.3OD): .delta.=7.96-7.22 (m, 9H,
Ar--H), 4.93 (s, 2H, NH), 4.40 (s, 1H, Ar.sub.2CH), 2.94+2.46 (2m,
8H, piperazine-H). Anal. calc. for
C.sub.181H.sub.21N.sub.3O.times.2HCl.times.1.1H.sub.2O, C, 55.70;
H, 6.54; N, 10.83. Found C, 55.83; H, 6.76, N, 10.75.
Example 46
[0356] Preparation of 4-((1-piperazinyl)-benzyl)-N-ethylbenzamide
Hydrochloride (Compound 83)
[0357] The compound of this Example was prepared by following the
synthesis procedure as described for compound 82, but substituting
ammonia for ethylamine.
[0358] Mp: 180-85.degree. C. IR (KBr) (cm-1): 3331(br), 2700(br),
1640, 1545, 1440, 1308. MS: (EI, amine) 323, 278, 267, 238, 195,
165. .sup.1H NMR: (amine, CD.sub.3OD): .delta.=7.84-7.14 (m, 9H,
Ar--H), 4.9 (br. s, NH), 4.45 (s, 1H, Ar.sub.2CH), 3.40 (m, 2H,
ethyl-CH.sub.2), 3.25, 2.65 (2m, 8H, piperazine-H), 1.20 (m, 3H,
ethyl-Me).
Example 47
[0359] Preparation of 4-(1-piperazinyl-benzyl)-benzonitrile
Dihydrochloride (Compound 84)
[0360] Compound 82 (45 mg, 0.11 mol) was dissolved in dry THF (2
mL) and cooled to 0.degree. C. Pyridine (36 .mu.L, 0.44 mg) and
trifluoroacetic anhydride (3 mL, 0.22 mmol) was added and stirring
was continued for 1 h at 25.degree. C. Water was added and the
solution was extracted with ethyl acetate. The organic phase was
washed with dilute NaHCO.sub.3 (aq), dried (K.sub.2CO.sub.3) and
evaporated in vacuo. The residue was treated with HCl in methanol 3
h at 50.degree. C. Removal of solvent in vacuo and chromatography
on silica (CH.sub.2Cl.sub.2/MeOH/NH.sub.3, 90:10:1) of residue gave
15 mg (49%). Treatment with excess HCl in ether/methanol gave the
dihydrochloride compound 84 which was precipitated, dissolved in
water and freeze-dried. Mp: 141-45.degree. C. IR (KBr) (cm-1):
3400(br), 2700(br), 2230, 1434. MS (free amine): 277, 232, 192,
165. .sup.1H NMR: (free amine, CDCl.sub.3): .delta.=7.58-7.18 (m,
9H, Ar--H), 4.27 (s, 1H, CHAr.sub.2) 2.89, 2.35 (2m, 8H,
piperazine-H), 1.70 (s, NH). Anal. calc. for
C.sub.18H.sub.19N.sub.3.times.2HCl.times.1H.sub.2O, C, 58.70; H,
6.29; N, 11.41. Found C, 58.88; H, 6.46; N, 11.24.
Example 48
[0361] Preparation of 4-(1-piperazinyl-benzyl)-acetophenone
Dihydrochloride (Compound 85)
[0362] Compound 78 (0.20 g, 0.50 mmol) was dissolved in dry THF (5
mL) and cooled to 0.degree. C. under nitrogen. Methyl lithium (3.1
mL, 0.8M in ether, 2.5 mmol) was added during 1 min and stirring
was continued for 2 h. Chlorotrimethylsilane (0.63 mL, 5.0 mmol)
was added and the temperature was allowed to reach 25.degree. C.,
then ammonium chloride (aq) was added. The organic phase was
decanted off, evaporated and the residue purified by chromatography
on silica (CH.sub.2Cl.sub.2/MeOH/NH.su- b.3, 95:5:1) to give 0.11 g
(75%) of ketone without Boc-group. The dihydrochloride salt,
compound 85 was prepared by treatment with excess HCl in ether. Mp:
175-85.degree. C. IR (KBr) (cm-1): 3400(br), 2700(br), 1680, 1607,
1424, 1269. MS (EI, free amine): 294, 249, 209, 165. .sup.1H NMR:
(free amine, CDCl.sub.3): =7.77-7.04 (m, 9H, Ar--H), 4.22 (s, 1H,
CHAr.sub.2), 2.92 (m, 4H, piperazine-H), 2.43 (s, 3H, MeCO), 2.40
(m, 4H, piperazine-H).
[0363] Anal. calc. for
C.sub.19H.sub.22N.sub.2O.times.2HCl.times.1.6H.sub.- 2O, C, 57.61;
H, 6.92; N, 7.07. Found C, 57.54; H, 6.75; N, 6.91. 26 27
[0364] The compounds according to Example 49 were synthesized as
shown in Scheme 15 above.
[0365] T.
[0366] I. Preparation of 4-benzoyl-N-t-butoxylcarbonylpiperidine
(Compound 86)
[0367] A mixture of 4-benzoylpiperidine hydrochloride (6.77 g, 30.0
mmol), di-tert-butyldicarbonate (7.2 g, 33.0 mmol) and KHCO.sub.3
(6.0 g, 60 mmol) in H.sub.2O-THF (50/20 mL) was refluxed for 1 h.
The reaction mixture was ex d with ethyl acetate (2.times.100 mL).
The combined organic layers were washed with brine, dried over
MgSO.sub.4. Removal of solvents gave
4-benzoyl-N-t-butoxylcarbonyl-piperidine (8.54 g, 98%);
.delta..sub.H (400 MHz, CDCl.sub.3) 1.47 (s, 9H), 1.70 (m, 2H),
1.83 (m, 2H), 2.91 (m, 2H), 3.42 (m, 2H), 4.18 (brs, 2H), 7.46 (m,
2H), 7.56 (m, 1H), 7.93 (m, 2H).
[0368] II. Preparation
4-(.alpha.-Hydroxy-.alpha.-(4-N-t-butoxycarbonylpip-
eridinyl)-benzyl)-N,N-diethylbenzamide (Compound 87)
[0369] To a solution of 4-iodo-N,N-diethylbenzamide (3.03 g, 10.0
mmol) and TMEDA (1.28 g, 11.0 mmol) in dry THF (30 mL) was added
t-butylithium (10.0 mL, 1.7 M, 17.0 mmol) at -78.degree. C. After
10 min, 4-benzoyl-N-t-butoxylcarbonylpiperidine (2.89 g, 10.0 mmol)
in THF (5 mL) was dropwise added. The reaction mixture was warned
to r.t. and then quenched with aqueous NH.sub.4Cl solution and
extracted with ethyl acetate (2.times.100 mL). The combined organic
layers were washed with ne, dried over MgSO.sub.4. Removal of
solvents gave a crude product, which was purified by silica gel
column eluting with MeOH--CH.sub.2Cl.sub.2 (0:100.fwdarw.2:98) to
provide
4-(.alpha.-hydroxy-.alpha.-(4-N-t-butoxycarbonylpiperidinyl)benzyl)-N,N-d-
iethylbenzamide (MTL 0327, 2.60 g, 56%): m.p.: 100-103.degree. C.
(CH.sub.2Cl.sub.2): v.sub.max (KBr) cm.sup.-1 3426, 2973, 1687,
1618, 1428, 1289, 1168; .delta..sub.H (400 z, CDCl.sub.3) 1.08
(brs, 3H), 1.20 (brs, 3H), 1.30 (m, 4H), 1.41 (s, 9H), 2.50 (t,
J=11.2 Hz, 1H), 2.66 (m, 2H), 2.86 (s, OH), 3.22 (brs, 2H), 3.50
(brs, 2H), 4.09 (brs, 2H), 7.18 (m, 1H), 7.26 (m, 4H), 7.45 (m,
4H); .delta..sub.C-13 (100 MHz, CDCl.sub.3) 12.8, 14.1, 26.2, 28.3,
39.1, 43.2, 44.3, 53.3, 79.2, 79.4, 125.75, 125.79, 126.2, 126.6,
128.1, 135.1, 145.3, 146.8, 154.6, 1710.0.
Example 49
[0370] Preparation
4-((.alpha.-4-piperidinyl)-benzyl)-N,N-diethylbenzamide (Compound
88)
[0371] To a solution of 4-(.alpha.-hydroxy-x
4-N-t-butoxylcarbonylpiperidi- nyl)benzyl)-N,N-diethylbenzamide
(466 mg, 1.0 mmol) and triethylsilane (232 mg, 2.0 mmol) in dry
dichloromethane (10 mL) was added trifluoroacetic acid (10.0 mL) at
r.t. After 30 min at r.t., more triethylsilane (232 mg, 2.0 mmol)
was added. The reaction mixture was stirred for 14 h at r.t, and
then condensed. The residue was dissolved in AcOEt (100 ml). The
resulting solution was washed with 1 N NaOH solution, aqueous
NH.sub.4Cl solution and brine, dried over MgSO.sub.4. Removal of
solvents gave a crude product, which was purified by silica gel
column eluting with NH.sub.4OH (1 N)-MeOH--CH.sub.2Cl.sub.2
(2.5:15:82.5) to provide
4-((.alpha.-4-piperidinyl)benzyl)-N,N-diethylbenzamide (245 mg,
70%): m.p.: 160-162.degree. C. (CH.sub.2Cl.sub.2); v.sub.max (KBr)
cm.sup.-1 3325, 2937, 1613, 1461, 1283, 1095; .delta..sub.H (400
MHz, CDCl.sub.3) 1.05 (brs, 3H), 1.07 (m, 2H), 1.19 (brs, 3H), 1.53
(m, 2H), 2.04 (brs, NH), 2.20 (m, 1H), 2.55 (t, J=11.6 Hz, 2H),
3.01 (m, 2H), 3.23 (brs, 2H), 3.51 (d, J=10.4 Hz, 1H), 3.52 (brs,
2H), 7.15 (m, 1H), 7.27 (m, 8H); .delta..sub.C-13 (100 MHz,
CDCl.sub.3) 12.8, 14.1, 32.2, 39.0, 39.9, 43.1, 46.5, 59.0, 126.1,
126.5, 127.9, 128.0, 128.3, 134.8, 143.0, 144.7, 171.0.
Example 50
[0372] Preparation of N
N-Diethyl-4-(3-methoxybenzyl-1-piperazinyl)-benzam- ide
[0373] Procedure as for
N,N-Diethyl-4-[(2,5,5-trimethyl-1-piperazinyl)-3-m-
ethoxybenzyl]-benzamide.
N,N-Diethyl-4-(chloro-3-methoxybenzyl)-benzamide (1.6 g, 4.8 mmol)
was reacted with piperazine (1.6 g, 19 mmol) in acetonitrile (20
mL) for 4 h at 80.degree. C. to give a total of 1.1 g product (63%)
which was converted into the dihydrochloride salt. Mp:
165-82.degree. C. IR (amine, CDCl.sub.3 in KBr cell) (cm-1): 3688,
1611, 1458, 1436, 1285. MS(free amine): 381, 336, 296, 224, 196,
165, 152, 112. .sup.1H NMR: (amine, CDCl.sub.3): .delta.=1.05, 1.15
(2 br. s, 6H, 2Me), 2.51, 3.02 (2br. s, 8H, piperazine-H), 3.2,
3.45 (2 br. s, 4H, MeCH.sub.2) 3.72, 3.73 (2s, 3H, MeO), 4.21 (s,
1H, CHAr.sub.2), 4.5 (br. s, 1H, NH), 6.60-7.40 (m, 8H, Ar--H).
C.sub.23H.sub.31N.sub.3O.sub.2.time- s.2HCl.times.0.80H.sub.2O
requires: C, 58.92; H, 7.44; N, 8.96. Found: C, 58.98; H, 7.76; N,
8.86.
Example 51
[0374] Preparation of
N,N-Diethyl-4-[(4-ally-1-piperazinyl)-3-methoxybenzy-
l]-benzamide
[0375] Procedure as for
N,N-Diethyl-4-[(4-allyl-2,5,5-triethyl-1-piperazin-
yl)-3-methoxybenzyl]-benzamide.
[0376] N,N-Diethyl-4-(3-methoxybenzyl-1-piperazinyl)-benzamide
(0.16 g, 0.42 mmol) gave 30 mg product (20%) which was converted to
dihydrochloride salt. Mp: 151-76.degree. C. IR (amine, CDCl.sub.3
in KBr cell) (cm-1): 3688, 1611, 1457, 1435, 1288. MS(free amine):
421, 125. .sup.1H NMR: (amine, CDCl.sub.3): .delta.=1.1 (2 br. s,
6H, 2Me), 2.3-2.6 (br. s, 8H, piperazine-H), 3.00 (m, 2H, allyl-H),
3.2-3.5 (2 br. s, 4H, MeCH.sub.2), 3.78 (s, 3H, MeO), 4.20 (s, 1H,
CHAr.sub.2), 5.14 (m, 2H, allyl-H), 5.85 (m, 1H, alkyl-H),
6.70-7.46 (m, 8H, Ar--H).
C.sub.26H.sub.35N.sub.3O.sub.2.times.2HCl.times.1.4H.sub.2O
requires: C, 60.09; H, 7.72; N, 8.08. Found C, 60.12; H, 7.59; N,
7.88. 28
[0377] The compounds of Examples 52-55 were synthesized as shown in
Scheme 16 above.
[0378] U.
[0379] Compound I: 4-(.alpha.-hydroxybenzyl)-nitrobenzene
[0380] 4-nitrobenzoin (4.55 g, 20.1 mmol) was dissolved in 70 ml of
anhydrous methanol cooled down to 0.degree. C. in an ice bath, NaBH
(0.915 g, 24.2 mmol) was then added under N.sub.2, the mixture was
stirred at r.t., for overnight, quenched with NH.sub.4Cl sat'd
aqueous solution, MeOH was evaporated and EtOAc was added, the
mixture was washed with water, the organic layer was dried over
MgSO.sub.4 and concentrated to give a solid as the desired product
(-4.58 g, .about.100% yield).
[0381] .sup.1H NMR (CDCl.sub.3, TMS):.delta.(ppm): 2.40 (s, br, 1H,
OH); 5.92 (d, J=3.2 Hz, 1H, Ar--CH--OH); 7.30-7.40 (m, 5H, Ar);
7.58 (d, J=8.6, 2H, Ar--NO.sub.2); 8.18 (d, J=8.6 Hz, 2H,
Ar--Ne).
[0382] Compound II: 4-(.alpha.-chlorobenzyl)-nitrobenzene
[0383] Compound I (4.58 g, 20 mmol) was dissolved in anhydrous
CH.sub.2Cl.sub.2, thionyl chloride (4.68 g, 39.4 mmol) was then
added to the mixture under N.sub.2, the reaction mixture was
refluxed for 5 hr and was cooled down to r.t., the solvent and
excess of thionyl chloride were evaporated under vacuum to give a
yellowish solid as the desired product (-100% yield).
[0384] .sup.1H NMR (CDCl.sub.3, TMS):.delta.(ppm): 6.16 (s, 1H,
--CH--Cl); 7.30-7.40 (m, 5H, Ar); 7.59 (d, J=8.6 Hz, 2H,
Ar--NO.sub.2); 8.20 (d, J=8.6 Hz, 2H, Ar--NO.sub.2).
[0385] Compound III:
4-(N-benzyl-1-piperazinyl)benzyl]-nitrobenzene
[0386] To compound II (11.0 g, 4.1 mmol) and N-benzylpiperazine
(1.45 g, 8.2 mmol) dissolved in anhydrous acetonitrile, catalytic
amount of potassium carbonate was added and the reaction mixture
was then refluxed overnight. After cooling down to r.t, the mixture
was washed with brine, the organic layer was concentrated under
vacuum to give an oil, it was then purified by MPLC using
CH.sub.2Cl.sub.2/MeO NH.sub.4OH=95/5/1 as the eluent to give the
pure desired product (1.2 g, 76% yield).
[0387] .sup.1H NMR(CDCl.sub.3, TMS):.delta.: 2.41-2.48 (8H, br,
piperazin ring), 3.51 (2H, s, Ph-CH.sub.2), 4.34 (1H, s,
Ar--CH--Ar), 7.20-8.12 (14H, Ar)ppm.
[0388] .sup.13C NMR(CDCl.sub.3, TMS): .delta.: 51.7, 53.1, 62.9,
75.5, 123.8, 127.0, 128.1, 128.5, 128.7, 129.2, 137.9, 140.9,
146.8, 150.6 ppm.
Example 52
[0389] Preparation of 4-[(N-benzyl-piperazinyl)-benzyl]-aniline
(Compound 91)
[0390] To compound III (900 mg, 2.33 mmol) dissolved in 10 ml of
MeOH, Ra--Ni (150 mg) was added and the temperature was increased
to 35.degree. C., hydrazine (380 mg, 11.63 mmol) was then added
slowly via a syringe while it was stirring, the temperature of the
mixture was increased to 70.degree. C., until the evolution of the
gas seized, the reaction mixture was cooled down to r.t., filtered
over celite and concentrated to give an oil, which was purified by
MPLC using CH.sub.2Cl.sub.2/MeOH=99/1-- 99/5 as the eluent to give
a yellowish solid as the desired product (660 mg, .about.80%
yield).
[0391] Elemental Analysis Calcd.for:
C.sub.24H.sub.2N.sub.3.0.2H.sub.2O: C, 79.64; H, 7.43; N, 11.55.
Found: C, 79.83; H, 7.65; N, 11.64.
[0392] IR(NaCl Film): v=2807, 1620, 1513, 1451, 1282, 1137
cm.sup.-1.
[0393] .sup.1H NMR(CDCl.sub.3, TMS):.delta.: 2.3-2.48 (8H, br,
piperazine ring), 3.45 (2H, s, br, --NH.sub.2), 3.48 (2H, s,
Ph--CH.sub.2), 4.10 (1H, s, Ar--CH--Ar), 6.51 (2H, m, Ar),
7.11-7.37 (12H, m, Ar)ppm.
Example 53
[0394] Preparation of
4-[(N-benzyl-1-piperazinyl)-benzyl]-acetanilide (Compound 92)
[0395] To 4-[(N-benzyl-1-piperazinyl)benzyl]-aniline (compound 91)
(50 mg, 0.14 mmol) and anhydrous pyridine (excess) were dissolved
in anhydrous dichloromethane, followed by the addition of acetic
anhydride (4 eq.). The reaction mixture was stirred at r.t., for 30
min. and quenched by H.sub.2O, then washed with sat'd NaHCO.sub.3
aqueous solution and brine, the organic layer was dried over
anhydrous MgSO.sub.4, filtered and concentrated to give an oil as
the product (44 mg, 80% yield).
[0396] .sup.1H NMR: (CDCl.sub.3, TMS) .delta.: 2.1(3H, s,
--CH.sub.3), 2.3-2.48 (8H, br, pipyrazin ring), 3.48 (2H, s,
Ph--CH.sub.2), 4.16 (1H, s, Ar--CH--Ar), 7.20-8.12 (14H,
Ar)ppm.
[0397] Elemental Analysis Calcd.for:
C.sub.26H.sub.29N.sub.3O.2.1HCl.0.3H.- sub.2O: C, 64.83; H, 6.64;
N, 8.40. Found: C, 64.86; H, 6.64; N, 8.73
Example 54
[0398] Preparation of
4-[(N-benzyl-1-piperazinyl)-benzyl]-methanesulfonami- de
[0399] To 4-[(N-benzyl-1-piperazinyl)-benzyl]-aniline (compound 91)
(100 mg, 0.28 mmol) and pyridine (excess) were dissolved in
anhydrous dichloromethane (5 ml) followed by the addition of
methanesufonic anhydride (97.55 mg, 0.56 mmol), the reaction
mixture was stirred at rt. for 20 min. followed by TLC, then it was
quenched by adding drop of water, 10 ml of EtOAc was added, the
mixture was washed with saturated NH.sub.4Cl aqueous solution and
brine, the organic layer was dried over MgSO.sub.4, concentrated
and purified by MPLC using CH.sub.2Cl.sub.2/MeOH=99/1-95/5 as the
solvent to give the pure product as a white solid (.about.90 mg,
.about.70% yield).
[0400] Melting point: 195-200.degree. C.(dcp.)
[0401] .sup.1H NMR: (CDCl.sub.3, TMS) o: 2.3-2.48 (8H, br,
pipyrazin ring), 2.96 (3H, s, CH.sub.2SO.sub.2), 3.51 (2H, s,
Ph--CH.sub.2), 4.21 (1H, s, Ar--CH--Ar), 6.25 (1H, br, S--NH--),
7.10-7.41 (14H, m, Ar)ppm.
[0402] .sup.13C NMR:(CDCl.sub.3) .delta.: 142.4, 140.2, 137.9,
135.3, 129.2, 129.1, 1285, 128.1, 127.9, 127.0, 121.0, 75.5, 63.0,
53.2, 51.8, 39.3 ppm.
[0403] Elemental analysis: Calcd.for:
C.sub.25H.sub.29N.sub.3O.sub.2S. 0.9H.sub.2O: C, 66.46; H, 6.87; N,
9.30. Found: C, 66.53; H, 6.61; N, 9.23.
Example 55
[0404] Preparation of
Methyl-N-4-[(N-benzyl-1-piperazinyl)-benzyl]-2-methy- lacetate
[0405] To 4-[N-benzyl-1-piperazinyl)-benzyl]-aniline (compound 91)
(100 mg, 0.28 mmol), Lithium hydride (2.5 mg, 0.3 mmol) and
1-bromomethylacetate (44.16 mg, 0.28 mmol) were mixed in anhydrous
THF, the reaction mixture were refluxed for 2 hr. and cooled down
to rt., then quenched with drops of water, washed with brine twice,
dried over anhydrous MgSO.sub.4 and concentrated to an oil,
purified by MPLC using CH.sub.2Cl.sub.2/MeOH=98/2 as the solvent to
give an oil as the product (-23 mg, 20% c).
[0406] IR (NaCl Film): HCl salt
[0407] v=3404(br), 2922(br), 1745, 1610, 1517, 1439, 1207
cm.sup.-1
[0408] .sup.1H NMR: (CDCl.sub.3) .delta.: 2.40 (8H, br, piperazine
ring), 3.50 (2H, s, Ph--CH.sub.2), 3.75 (3H, s, --O--CH.sub.3),
3.85 (2H, d, J=5.2 Hz, N--CH.sub.2), 4.12 (1H, s, Ar--CH--Ar), 4.18
(1H, t, J=5.2 Hz, Ar--N--CH.sub.2), 6.49 (2H, d, J=9.4 Hz,
--N--Ar), 7.14-7.38 (12H, m, Ar)ppm.
[0409] Anal.Calcd.for: C.sub.27H.sub.31N.sub.3O.sub.2.3HCl: C,
60.17; H, 6.36; N, 7.80. Found: C, 59.97; H, 6.61; N, 7.46.
[0410] Compound IV:
4-(3-fluoro-(.alpha.-hydroxybenzyl)-acetonitrile
[0411] To 1-Fluoro-3-iodo-benzene (7.53 g, 33.9 mmol) was dissolved
in anhydrous THF and was cooled down to -78.degree. C.,
n-Butyllithium (2.5M in THF, 33.9 mmol) was added slowly into the
reaction mixture via a syringe, the mixture was stirred for 10 min.
followed by the addition of the solution of 4-Acetamidobenzaldehyde
(1.84 g, 11.3 mmol) in 5 ml of dry DME, the reaction mixture was
then stirred at -78.degree. C. for 30 min. before quenched with
NH.sub.4Cl aqueous solution. The organic layer was washed with
brine and dried over anhydrous MgSO.sub.4, filtered and
concentrated to an oil, purified by MPLC using 10% heptane in
CH.sub.2O.sub.2 and 100% CH.sub.2Cl.sub.2 to give the pure product
(1.65 g, 56% yield).
[0412] .sup.1H NMR: (CDCl.sub.3) .delta.: 2.14 (3H, s, OCCH.sub.3),
2.55 (1H, s, br. OH), 5.76 (1H, d, J=3.2 Hz, Ar--CH--Ar), 7.35 (1H,
s, CONH), 6.90-7.50 (8H, m, Ar)ppm.
[0413] Compound V:
4-(3-fluoro-.alpha.-chlorobenzyl)-acetonitrile
[0414] This was prepared using the same method as described for the
preparation of compound (II) but using compound (IV). It was used
directly for the next step reaction without purification.
[0415] .sup.1H NMR: (CDCl.sub.3) .delta.: 2.15 (3H, s, OCCH.sub.3),
6.10 (1H, s, Ar--CH--Ar), 7.84 (1H, s, CONH), 6.9.about.7.6 (8H, m,
Ar), 7.84 (1H, s, CONH)ppm
Example 56
[0416] Preparation of
4-[(N-benzyl-1-piperazinyl)-3-fluorobenzyl]-acetanil- ide (Compound
95)
[0417] This was prepared using the same method as described for the
preparation of compound (III) but using compound (V).
[0418] .sup.1H NMR: (CDCl.sub.3) .delta.: 2.14 (3H, s, OCCH.sub.3),
2.40 (8H, br, piperazine), 3.51 (2H, s, Ph--CH.sub.2), 4.19 (1H, s,
Ar--CH--Ar), 6.80-7.40 (13H, m, Ar)ppm.
[0419] Analysis:
[0420] Anal.Calcd.for:
C.sub.26H.sub.28FN.sub.3O.2HCl.1.6CH.sub.2Cl.sub.2.- 2H.sub.2O: C,
56.24; H, 6.02; N, 7.13. Found: C, 56.29; H, 6.10; N, 6.88.
[0421] Pharmaceutical Compositions
[0422] The novel compounds according to the present invention may
be administered per orally, intramuscularly, subcutaneously,
intraperitoneally, intrathoracially, intravenously, intrathecally
and intracerebroventricularly.
[0423] The dosage will depend on the route of administration, the
severity of the disease, age and weight of the patient and other
factors normally considered by the attending physician, when
determining the individual regimen and dosage level at the most
appropriate for a particular patient.
[0424] For preparing pharmaceutical compositions from the compounds
of this invention, inert, pharmaceutically acceptable carriers can
be either solid or liquid. Solid form preparations include powders,
tablets, dispersible granules, capsules, cachets, and
suppositories.
[0425] A solid carrier can be one or more substances which may also
act as diluents, flavoring agents, solubilizers, lubricants,
suspending agents, binders, or tablet disintegrating agents; it can
also be an encapsulating material.
[0426] In powders, the carrier is a finely divided solid which is
in a mixture with the finely divided active component. In tablets,
the active component is mixed with the carrier having the necessary
binding properties in suitable proportions and compacted in the
shape and size desired.
[0427] For preparing suppository compositions, a low-melting wax
such as a mixture of fatty acid glycerides and cocoa butter is
first melted and the active ingredient is dispersed therein by, for
example, stirring. The molten homogeneous mixture is then poured
into convenient sized molds and allowed to cool and solidify.
[0428] Suitable carriers are magnesium carbonate, magnesium
stearate, talc, lactose, sugar, pectin, dextrin, starch,
tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a
low-melting wax, cocoa butter, and the like.
[0429] Pharmaceutically acceptable salts are acetate,
benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide,
calcium acetate, camsylate, carbonate, chloride, cetrate,
dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,
glucaptate, gluconate, glutamate, glycollylarsanilate,
hexytresorcinate, hydrabamine, hydrobromide, hydrochloride,
hydroxynaphthoate, iodide, isethionate, lactate, lactobionate,
malate, maleate, mandelate mesylate, methylbromide, methylnitrate,
methylsulfate, mucate, napsylate, nitrate, pamoate (embonate),
pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,
stearate, subacetate, succinate, sulfate, tannata, tartrate,
teoclate, triethiodide, benzathine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine, procaine, aluminium,
calcium, lithium, magnesium, potassium, sodium, and zinc.
[0430] Preferred pharmaceutically acceptable salts are the
hydrochlorides and citrates.
[0431] The term composition is intended to include the formulation
of the active component with encapsulating material as a carrier
providing a capsule in which the active component (with or without
other carriers) is surrounded by a carrier which is thus in
association with it. Similarly, cachets are included.
[0432] Tablets, powders, cachets, and capsules can be used as solid
dosage forms suitable for oral administration.
[0433] Liquid from compositions include solutions, suspensions, and
emulsions. Sterile water or water-propylene glycol solutions of the
active compounds may be mentioned as an example of liquid
preparations suitable for parenteral administration. Liquid
compositions can also be formulated in solution in aqueous
polyethylene glycol solution.
[0434] Aqueous solutions for oral administration can be prepared by
dissolving the active component in water and adding suitable
colorants, flavoring agents, stabilizers, and thickening agents as
desired. Aqueous suspensions for oral use can be made by dispersing
the finely divided active component in water together with a
viscous material such as natural synthetic gums, resins, methyl
cellulose, sodium carboxymethyl cellulose, and other suspending
agents known to the pharmaceutical formulation art.
[0435] Preferably the pharmaceutical compositions is in unit dosage
form. In such form, the composition is divided into unit doses
containing appropriate quantities of the active component. The unit
dosage form can be a packaged preparation, the package containing
discrete quantities of the preparations, for example, packaged
tablets, capsules, and powders in vials or ampoules. The unit
dosage form can also be a capsule, cachet, or tablet itself, or it
can be the appropriate number of any of these packaged forms.
[0436] Biological Evaluation
[0437] A) In Vitro Model
[0438] Cell Culture
[0439] Human 293S cells expressing cloned human .mu., .delta., and
.kappa. receptors and neomycin resistance were grown in suspension
at 37.degree. C. and 5% CO.sub.2 in shaker flasks containing
calcium-free DMEM 10% FBS, 5% BCS, 0.1% Pluronic F-68, and 600
.mu.g/ml geneticin.
[0440] Membrane Preparation
[0441] Cells were pelleted and resuspended in lysis buffer (50 mM
Tris, pH 7.0, 2.5 mM EDTA, with PMSF added just prior to use to 0.1
mM from a 0.1 M stock in ethanol), incubated on ice for 15 min,
then homogenized with a polytron for 30 sec. The suspension was
spun at 1000 g (max) for 10 min at 4.degree. C. The supernatant was
saved on ice and the pellets resuspended and spun as before. The
supernatants from both spins were combined and spun at 46,000 g
(max) for 30 min. The pellets were resuspended in cold Tris buffer
(50 mM Tris/Cl, pH 7.0) and spun again. The final pellets were
resuspended in membrane buffer (50 mM Tris, 0.32 M sucrose, pH
7.0). Aliquots (1 ml) in polypropylene tubes were frozen in dry
ice/ethanol and stored at -70.degree. C. until use. The protein
concentrations were determined by a modified Lowry assay with
SDS.
[0442] Binding Assays
[0443] Membranes were thawed at 37.degree. C., cooled on ice,
passed 3 times through a 25-gauge needle, and diluted into binding
buffer (50 mM Tris, 3 mM MgCl.sub.2, 1 mg/ml BSA (Sigma A-7888), pH
7.4, which was stored at 4.degree. C. after filtration through a
0.22 m filter, and to which had been freshly added 5 .mu.g/ml
aprotinin, 10 .mu.M bestatin, 10 .mu.M diprotin A, no DTT).
Aliquots of 100 .mu.l (for .mu.g protein, see Table 1) were added
to iced 12.times.75 mm polypropylene tubes containing 100 .mu.l of
the appropriate radioligand (see Table 1) and 100 .mu.l of test
peptides at various concentrations. Total (TB) and nonspecific (NS)
binding were determined in the absence and presence of 10 .mu.M
naloxone respectively. The tubes were vortexed and incubated at
25.degree. C. for 60-75 min, after which time the contents are
rapidly vacuum-filtered and washed with about 12 ml/tube iced wash
buffer (50 mM Tris, pH 7.0, 3 mM MgCl.sub.2) through GF/B filters
(Whatman) presoaked for at least 2 h in 0.1% polyethyleneimine. The
radioactivity (dpm) retained on the filters was measured with a
beta counter after soaking the filters for at least 12 h in
minivials containing 6-7 ml scintillation fluid. If the assay is
set up in 96-place deep well plates, the filtration is over
96-place PEI-soaked unifilters, which were washed with 3.times.1 ml
wash buffer, and dried in an oven at 55.degree. C. for 2 h. Th e
filter plates were counted in a TopCount Packard) after adding 50
.mu.l MS-20 scintillation fluid/well.
[0444] Data Analysis
[0445] The specific binding (SB) was calculated as TB-NS, and the
SB in the presence of various test peptides was expressed as
percentage of control SB. Values of IC.sub.50 and Hill coefficient
(n.sub.H) for ligands in displacing specifically bound radioligand
were calculated from logit plots or curve fitting programs such as
Ligand, GraphPad Prism, SigmaPlot, or ReceptorFit. Values of
K.sub.i were calculated from the Cheng-Prussoff equation.
Mean.+-.S.E.M. values of IC.sub.50, K.sub.i and n.sub.H were
reported for ligands tested in at least three displacement
curves.
[0446] Receptor Saturation Experiments
[0447] Radioligand K.sub..delta. values were determined by
performing the binding assays on cell membranes with the
appropriate radioligands at concentrations ranging from 0.2 to 5
times the estimated K.sub..delta. (up to 10 times if amounts of
radioligand required are feasable). The specific radioligand
binding was expressed as pmole/mg n protein. Values of K and
B.sub.max from individual experiments were obtained from nonlinear
fits of specifically bound (B) vs. nM free (F) radioligand from
individual according to a one-site model.
[0448] B) Biological Model (In Vivo Model)
[0449] Freund's Complete Adjuvant (FCA), and Sciatic Nerve Cuff
Induced Mechano-Allodynia in Rat
[0450] Animals
[0451] Male Sprague-Dawley rats (Charles River, St-Constant,
Canada) weighing 175-200 g at the time of surgery were used. They
were housed in groups of three in rooms thermostatically maintained
at 20.degree. C. with a 12:12 hr light/dark cycle, and with free
access to food and water. After arrival, the animals were allowed
to acclimatize for at least 2 days before surgery. The experiments
were approved by the appropriate Medical Ethical Committee for
animal studies.
[0452] Experimental Procedure
[0453] Freund's Complete Adjuvant
[0454] The rats were first anesthetized in a Halothane chamber
after which 10 .mu.l of FCA was injected s.c. into the dorsal
region of the left foot, between the second and third external
digits. The animals were then allowed to recover from anesthesia
under observation in their home cage.
[0455] Sciatic Nerve CF
[0456] The animals were prepared according to the method described
by Mosconi and Kruger (1996). Rats were anesthetized with a mixture
of Ketamine/Xylazine i.p. (2 ml/g) and placed on their right side
and an incision made over, and along the axis of, the lateral
aspect of the left femur. The muscles of the upper quadriceps were
teased apart to reveal the sciatic nerve on which a plastic cuff
(PE-60 tubing, 2 mm long) was placed around. Mme wound was then
closed in two layers with 3-0 vicryl and silk suture
[0457] Determination of Mechano-Allodynia Using Von Frey
Testing
[0458] Testing was performed between 08:00 and 16:00 h using the
method described by Chaplan et al. (1994). Rats were placed in
Plexiglas cages on top of a wire mesh bottom which allowed access
to the paw, and were left to habituate for 10-15 min. The area
tested was the mid-plantar left hind paw, avoiding the less
sensitive foot pads. The paw was touched with a series of 8 Von
Frey hairs with logarithmically incremental stiffness (0.41, 0.69,
1.20, 2.04, 3.63, 5.50, 8.51, and 15.14 grams; Stoelting, Ill.,
USA). The von Frey hair was applied from underneath the mesh floor
perpendicular to the plantar surface with sufficient force to cause
a slight buckling against the paw, and held for approximately 6-8
seconds. A positive response was noted if the paw was sharply
withdrawn. Flinching immediately upon removal of the hair was also
considered a positive response. Ambulation was considered an
ambiguous response, and in such cases the stimulus was
repeated.
[0459] Testing Protocol
[0460] The animals were tested on postoperative day 1 for the
FCA-treated group and on post-operative day 7 for the Sciatic Nerve
Cuff group. The 50% withdrawal threshold was determined using the
up-down method of Dixon (1980). Testing was started with the 2.04 g
hair, in the middle of the series. Stimuli were always presented in
a consecutive way, whether ascending or descending. In the absence
of a paw withdrawal response to the initially selected hair, a
stronger stimulus was presented; in the event of paw withdrawal,
the next weaker stimulus was chosen. Optimal threshold calculation
by this method requires 6 responses in the immediate vicinity of
the 50% threshold, and counting of these 6 responses began when the
first change in response occurred, e.g. the threshold was first
crossed. In cases where thresholds fell outside the range of
stimuli, values of 15.14 (normal sensitivity) or 0.41 (maximally
allodynic) were respectively assigned. The resulting pattern of
positive and negative responses was tabulated using the convention,
X=no withdrawal; O=withdrawal, and the 50% withdrawal threshold was
interpolated using the formula:
50% g threshold=10.sup.(Xf+*k.delta.)/10,000
[0461] where Xf=value of the last von Frey hair used (log units);
k=tabular value (from Chaplan et al. (1994)) for the pattern of
positive/negative responses; and .delta.=mean difference between
stimuli (log units). Here .delta.=0.224.
[0462] Von Frey thresholds were converted to percent of maximum
possible effect (% MPE), according to Chaplan et al. 1994. The
following equation was used to compute % MPE:
% MPE=Drug treated threshold (g)-allodynia threshold (g).times.100
Control threshold (g)-allodynia threshold (g)
[0463] Administration of Test Substance
[0464] Rats were injected (subcutaneously, intraperitoneally, or
orally) with a test substance prior to von Frey testing, the time
between administration of test compound and the von Frey test
varied depending upon the nature of the test compound.
* * * * *