U.S. patent application number 11/478170 was filed with the patent office on 2007-02-01 for derivatives and analogs of galanthamine.
This patent application is currently assigned to Sanochemia Pharmazeutika Aktiengesellschaft. Invention is credited to Laszlo Czollner, Johannes Frohlich, Manfred Hirnschall, Ulrich Jordis, Beate Kalz, Matthias Treu, Stefan Welzig.
Application Number | 20070027138 11/478170 |
Document ID | / |
Family ID | 25608130 |
Filed Date | 2007-02-01 |
United States Patent
Application |
20070027138 |
Kind Code |
A1 |
Jordis; Ulrich ; et
al. |
February 1, 2007 |
Derivatives and analogs of galanthamine
Abstract
New compounds of general formula I ##STR1##
Inventors: |
Jordis; Ulrich; (Wien,
AT) ; Frohlich; Johannes; (Dornbach im Wienerwald,
AT) ; Treu; Matthias; (Wien, AT) ; Hirnschall;
Manfred; (Wien, AT) ; Czollner; Laszlo;
(Ebenfurth, AT) ; Kalz; Beate; (Steinbrunn,
AT) ; Welzig; Stefan; (Wien, AT) |
Correspondence
Address: |
POPOVICH, WILES & O'CONNELL, PA;650 THIRD AVENUE SOUTH
SUITE 600
MINNEAPOLIS
MN
55402
US
|
Assignee: |
Sanochemia Pharmazeutika
Aktiengesellschaft
|
Family ID: |
25608130 |
Appl. No.: |
11/478170 |
Filed: |
June 28, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09980025 |
Mar 18, 2002 |
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PCT/AT01/00082 |
Mar 22, 2001 |
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11478170 |
Jun 28, 2006 |
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Current U.S.
Class: |
514/214.03 ;
514/217; 514/224.8; 514/229.8; 514/291; 514/296; 514/411; 540/476;
540/579; 540/588; 544/102; 544/42; 546/98; 548/444 |
Current CPC
Class: |
A61P 25/14 20180101;
A61P 25/08 20180101; A61P 25/16 20180101; A61P 9/10 20180101; A61P
3/10 20180101; C07D 491/10 20130101; A61P 43/00 20180101; A61P
25/28 20180101; C07D 307/94 20130101; A61P 25/00 20180101 |
Class at
Publication: |
514/214.03 ;
514/217; 514/224.8; 514/229.8; 514/291; 514/411; 514/296; 540/579;
540/588; 540/476; 546/098; 548/444; 544/042; 544/102 |
International
Class: |
C07D 471/06 20060101
C07D471/06; A61K 31/55 20060101 A61K031/55; A61K 31/541 20060101
A61K031/541; A61K 31/538 20060101 A61K031/538; A61K 31/473 20060101
A61K031/473 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 31, 2000 |
AT |
A 546/2000 |
Feb 15, 2001 |
AT |
A 238/2001 |
Claims
1. Compounds of general formula I ##STR402## in which the
substituents have the meanings that are explained below: R.sub.1
and R.sub.2 are the same or different and mean: a) hydrogen, F, Cl,
Br, I, CN, NC, OH, SH, NO.sub.2, SO.sub.3H, PO.sub.3H, NH.sub.2,
CF.sub.3, OSO.sub.2 (CH.sub.2).sub.nCF.sub.3, in which n is equal
to 0, 1 or 2, --OSO.sub.2-aryl, --OSO-vinyl or --OSO.sub.2-ethinyl;
b) a low (C.sub.2-C.sub.6), optionally branched, optionally
substituted (Ar)alkyl, (Ar)alkoxy, cycloalkyl or cycloalkoxy group;
c) an amino group, which optionally is substituted by one or two
identical or different low (C.sub.1-C.sub.6), optionally branched,
optionally substituted (Ar)alkyl or (Ar)alkylcarbonyl or
(Ar)alkoxycarbonyl groups or by a group that is selected from an
optionally substituted pyrrolidine, piperidine, morpholine,
thiomorpholine, piperazine, or homopiperazine radical; d) a --COOH,
--COO(Ar)alkyl, --CO-amino group, which optionally is substituted
as indicated under c), or a COH(Ar)alkyl group; e) a --(CH.sub.2)nX
(in which X.dbd.Br, Cl, F or I), --(CH.sub.2).sub.nOH,
--(CH.sub.2).sub.nCHO, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.nCN, --(CH.sub.2).sub.nNC, --(CH).sub.nCOalkyl, or
--(CH.sub.2).sub.nCOaryl group, in which n is 1-4; f) a
--(CH.sub.2).sub.nvinyl, --(CH.sub.2).sub.nethinyl, or
--(CH.sub.2).sub.ncycloalkyl group in which n is 0, 1 or 2, whereby
cycloalkyl is an aliphatic ring with 3 to 7 C atoms; g) a
C.sub.3-C.sub.6-substituted alkenyl group (optionally substituted
with H, F, Br, Cl, CN, CO.sub.2alkyl, COalkyl, COaryl); h) a
C.sub.3-C.sub.6-substituted alkinyl group (optionally substituted
with H, F, Br, Cl, CN, CO.sub.2alkyl, COalkyl, COaryl); or i)
R.sub.1 and R.sup.2 together mean --CH.dbd.CH--CH.dbd.CH--,
--O(CH.sub.2).sub.nO-- (n=1 to 3), --CH.dbd.CHA.sub.1-(A.sub.1 is
NH, O or S), or --CH.sub.2CH.sub.2-A.sub.1 (A.sub.1 is NH, O or S);
R.sub.3 has the same meaning as R], especially OH and OCH.sub.3, or
R.sub.2 and R.sub.3 together mean -A.sub.2(CH.sub.2).sub.nA.sub.2-,
in which n is 1 to 3 and substituents A.sub.2 are the same or
different and mean NH, O or S; R.sub.4 and R.sub.5 are either a)
both hydrogen, or b) one of R.sub.4 and R.sub.5 is hydrogen, an
(Ar)alkyl, (Ar)alkenyl or (Ar)alkinyl group, and the other of
R.sub.4 and R.sub.5 is i) OR.sub.6, in which R.sub.6 means
hydrogen, a low (C.sub.2-C.sub.10, optionally branched or
substituted) alkyl group or cycloalkyl group, a C.sub.3-C.sub.10
substituted silyl group (for example, triethylsilyl,
trimethylsilyl, t-butyldimethylsilyl or dimethylphenylsilyl), a
C.sub.2-C.sub.10 alpha-alkoxyalkyl group, for example
tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl, ethoxymethyl,
2-methoxypropyl, ethoxyethyl, phenoxymethyl or 1-phenoxyethyl; ii)
O--CS--NHR.sub.6 (thiourethane), in which R.sub.6 has the meanings
indicated above under i); iii) O--CO--NHR.sub.7 with the meaning
below: ##STR403## iv) O--CO--HR.sub.6, in which R.sub.6 has the
meanings indicated above under i), especially ester with the
substitution pattern of amino acids (both enantiomers), such as
##STR404## v) NR.sub.7R.sub.7, in which two substituents R.sub.7
are the same or different and mean hydrogen, a low
(C.sub.1-C.sub.4), optionally branched, alkyl group or cycloalkyl
group, or substituents R.sub.7 together are --(CH.sub.2).sub.n--,
in which n is 3 to 5; vi) NH--COR.sub.6 (amide), in which R.sub.6
has the meanings indicated above under i); vii) S--R.sub.6, in
which R.sub.6 has the meaning indicated above under i); viii)
SO.sub.nR.sub.8, in which n is 0, 1 or 2, and in which R.sub.8 is a
(C.sub.1-C.sub.10), optionally branched or cyclic, optionally
substituted (Ar)alkyl group; G.sub.1: --(CH.sub.2).sub.n--, in
which x is 1 or 2; G.sub.2: --(CH.sub.2).sub.y, in which y is 0 to
2; G.sub.3: --(CH.sub.2).sub.n--, in which z is 0 to 3, provided
that the sum of x+y+z is at least 2 and at most 4, or in which
G.sub.3 is carbonyl or thiocarbonyl, --CH(OH)-- or --C(OH).dbd.; W
is: a) CR.sub.13R.sub.14, in which R.sub.13 means hydrogen and
R.sub.14 means --(CH.sub.2).sub.nNR.sub.7R.sub.7,
--CO--NR.sub.7R.sub.7 or --COOR.sub.7, in which n is 0 to 2 and
R.sub.7 has the above-mentioned meanings, or R.sub.7 and R.sub.7
form a ring via --(CH.sub.2).sub.n--, in which n is 3 to 5, whereby
substituents R.sub.13 and R.sub.14 can be exchanged; b) N-Phenyl
(optionally substituted with fluorine, bromine, chlorine,
(C.sub.1-C.sub.4) alkyl, CO.sub.2 alkyl, CN, CONH.sub.2, or alkoxy)
means N-thien-2 or 3-yl, or N-fur-2 or 3-yl or an
N-1,3,5-triazinyl, whereby the triazine radical can then be
substituted with Cl, OR.sub.6 or NR.sub.7R.sub.7, and R.sub.6 or
R.sub.7 has the meaning indicated above; c) One of the substituents
that is presented below ##STR405## in which I means no bond or
--(CH.sub.2).sub.n--, whereby n=0 to 3, carbonyl, thiocarbonyl, O,
S, --SO-- or SO.sub.2, R.sub.6 has the meanings that are indicated
above, and in which, Q is --(CH.sub.2).sub.n-M*-(CH.sub.2).sub.m,
whereby n=0 to 4 and m=0 to 4 and M* means alkinyl, alkenyl,
disubstituted phenyl, disubstituted thiophene, disubstituted furan,
disubstituted pyrazine, disubstituted pyridazine, a spacer of one
of the formulas presented below, a peptide spacer L or a
heterocyclic spacer HS of the formulas below, ##STR406## in which
R.sub.15 means the side chain of D-, L-, D,L-aminoacids or
unnatural amino acids, and for the case of n>1, R.sub.15 in the
individual radicals in each case means the same or a different side
chain of D-, L-, D,L-amino acids or unnatural amino acids, provided
that atom N in addition to Q is connected in each case to groups G2
and G3 of formula I; d) a tricyclic substituent (Tr) that is
optionally substituted at least in one place with at least one
heterocyclic ring as a ring component and a binding site to a
carbon atom of an anellated benzene ring thereof, which is
connected via a spacer Q and the nitrogen atom that is adjacent to
Q in each case with G.sub.2 and G.sub.3 of the compound of formula
I, whereby Q has the meaning that is indicated above under c); or
e) --NH--, --O--, --S--, --SO-- or --SO.sub.2--.
2. Compounds of general formula II ##STR407## in which D means
N--H, N-alkyl, N-acyl, oxygen or sulfur, and in which substituents
R.sub.1 to R.sub.5, G.sub.1 to G.sub.3 and W have the meanings that
are indicated in general formula I.
3. Compounds of general formula III ##STR408## in which X--R.sub.16
is a substituent, in which X is oxygen or sulfur and R.sub.16 is
hydrogen or a low (C.sub.1-C.sub.10), optionally branched,
optionally substituted (Ar) alkyl group, and in which substituents
R.sub.1 to R.sub.5, G.sub.1 to G.sub.3 and W have the meanings that
are indicated in general formula I.
4. Compounds of general formula IV ##STR409## in which R.sub.18 and
R.sub.19 mean hydrogen, alkyl, aryl or aralkyl, and in which the C
atoms that carry substituents R.sub.18 and R.sub.19 are linked to
one another via a single bond or a double bond, and in which
substituents R.sub.1 to R.sub.5 and G.sub.1 and G.sub.3 have the
meanings that are indicated in general formula I, whereby W means
CH or N.
5. Compound according to claim 1, in which substituent R.sub.6
means a triethylsilyl, trimethylsilyl, t-butyldimethylsilyl or
dimethylphenylsilyl.
6. Compound according to claim 1, in which substituent R.sub.6
means tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl,
ethoxymethyl, (2-methoxypropyl), ethoxyethyl, phenoxymethyl or
(1-phenoxyethyl).
7. Compound according to claim 1, in which R.sub.4 is hydrogen, and
R.sub.5 is OH, CN, CO.sub.2-alkyl, CONR.sub.aR.sub.b, in which Ra
is hydrogen, a low (C.sub.1-C.sub.6), optionally branched, cyclic,
substituted alkyl group, and R.sub.b is hydrogen, a low
(C.sub.1-C.sub.6), optionally branched or substituted alkyl group,
or R.sub.a+R.sub.b together are --(CH.sub.2).sub.n--, in which n
means 2 to 6, or --(CH.sub.2).sub.nE(CH.sub.2).sub.n--, in which E
is the same as NH, N-alkyl, O, or S, and n is 0 to 5, aryl (phenyl
or naphthyl), or a 6-heterocycle.
8. Compound according to claim 7, in which the 6-heterocycle is
imidazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl,
oxadiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl and
substituted variants thereof, imidazolinyl, thiazolinyl or
oxazolinyl.
9. Compound according to claim 1, in which R.sub.5 has a meaning
other than hydrogen, and R.sub.4 is OH.
10. Compound according to claim 1, in which R.sub.4 and R.sub.5
together are carbonyl (.dbd.O), hydrazone (.dbd.N--NH--R.sub.9,
.dbd.N--NR.sub.9R.sub.10) or oxime (.dbd.N--OR.sub.10), in which
R.sub.9 is hydrogen, a low (C.sub.1-C.sub.6), optionally branched
or cyclic, optionally substituted (Ar)alkyl- or (Ar)alkylcarbonyl-,
(Ar)alkylcarbonyloxy group or a sulfonic acid group, such as tosyl
or mesyl, and R.sub.10 is hydrogen, a low (C.sub.1-C.sub.6),
optionally branched or cyclic, optionally substituted (Ar)alkyl- or
(Ar)alkylcarbonyl group, a sulfonic acid group, such as a tosyl
group or mesyl group.
11. Compound according to claim 1, in which R.sub.4 and R.sub.5
together are substituents of the type ##STR410## in which Y.sub.1,
Y.sub.2 are the same or different and mean O, S, NH or N--R.sub.9
(free valences are in any case hydrogen), in which R.sub.9 is
hydrogen, a low (C.sub.1-C.sub.6), optionally branched or cyclic,
optionally substituted (Ar)alkyl- or (Ar) alkylcarbonyl-,
(Ar)alkylcarbonyloxy group or a sulfonic acid group, such as tosyl
or mesyl.
12. Compound according to claim 11, in which Y.sub.1 is NH and
Y.sub.2 is N--R.sub.9, and in which R.sub.4 and R.sub.5 are
connected by --(CH.sub.2).sub.n-- (n=2, 3, or 4).
13. Compound according to claim 1, in which G.sub.1 and G.sub.2
together or separately mean: --C(R.sub.11R.sub.12)--, in which
R.sub.11 and R.sub.12 mean hydrogen, OH, a low, optionally branched
or cyclic, optionally substituted (Ar)alkyl, aryl, (Ar)alkyloxy or
aryloxy group or together an alkylspiro group (C.sub.3-C.sub.7
spiro ring).
14. Compound according to claim 1, in which G.sub.1 and G.sub.2
together mean ##STR411## in which m is 1 to 7.
15. Compound according to claim 1, in which tricyclic substituent
Tr is a condensed benzene ring of general formula ##STR412##
16. Compound according to claim 15, in which ring A is a
substituted benzene ring.
17. Compound according to claim 15, in which one of rings B and C
is an optionally substituted heterocyclic ring and the other is a
substituted ring that can contain one or more heteroatoms in the
ring.
18. Compound according to claim 15, in which the benzene ring is
substituted in at least one place, whereby these substituents are
halogens, such as fluorine and chlorine, halo-C.sub.1-C.sub.3 alkyl
groups, such as trifluoromethyl, C.sub.1-C.sub.3 alkyl groups, such
as methyl, C.sub.1-C.sub.3 alkoxy groups, such as methoxy, and the
hydroxy group, especially a halogen, such as fluorine.
19. Compound according to claim 15, in which the optionally
substituted heterocyclic ring B or C is a 4- to 14-membered ring,
preferably a 5- to 7-membered ring, especially a 5- to 7-membered,
nonaromatic ring, which contains one or two identical or different
heteroatoms.
20. Compound according to claim 19, in which at least one
heteroatom of the heterocyclic ring (1 to 3 heteroatoms are
possible) is nitrogen, oxygen, or sulfur.
21. Compound according to claim 20, in which heterocyclic ring B or
C is pyridine, pyrazine, pyrimidine, imidazole, furan, thiophene,
pyrrolidine, piperidine, hexamethylenimine, tetrahydrofuran,
piperazine, morpholine or thiomorpholine.
22. Compound according to claim 15, in which the 5- to 8-membered
ring B or C is a 5- to 8-membered heterocyclic or alicyclic ring,
or a carbon ring that is substituted at least in one place.
23. Compound according to claim 22, in which the 5- to 8-membered
carbon ring is a benzene ring or a saturated or unsaturated ring,
for example, benzene, cyclopentane, cyclopentene, cyclohexane,
cyclohexene, cyclohexadiene, cycloheptane, cycloheptene and
cycloheptadiene.
24. Compound according to claim 1, in which tricyclic substituent
Tr is a group from one of the formulas that is presented below
##STR413##
25. Compound according to claim 1, in which tricyclic substituent
Tr is a group from one of the formulas that is presented below
##STR414##
26. Compound according to one of claims 1 to 25 claim 1, in which
Tr is a cyclic or bicyclic hydrocarbon.
27. Compound according to claim 26, in which Tr has one of the
formulas below: ##STR415##
28. Compound according to claim 1, in which substituent Tr is
substituted at least in one place with R.sub.1, and R.sub.1 has the
meanings indicated in claim 1.
29. Compound according to claim 1, in which substituent W is
nitrogen and/or substituent G.sub.1 is --(CH.sub.2).sub.x--, in
which x is equal to 1 or 2 and G.sub.2 means (CH.sub.2).sub.y--, in
which y is equal to 0 to 2, provided that x+y together mean at
least 2 and at most 4.
30. Compound according to claim 1, in which substituents G.sub.1
and G.sub.2 together or separately have the meaning of
--CR.sub.11R.sub.12--, in which R.sub.11 and R.sub.12 mean
hydrogen, hydroxy, a low, optionally branched or cyclic, optionally
substituted (Ar)alkyl, aryl, (Ar)alkoxy or aryloxy group.
31. Compound according to claim 1, in which G.sub.1 and G.sub.2
together are an alkylspiro group (C.sub.3-C.sub.7 spiro ring).
32. Process for the production of the compounds of claim 1,
characterized in that the combinatory or parallel-synthesis
technology is used, whereby the basic molecule is immobilized by a
functional group (linker) in a solid phase, which implements the
synthesis of the target compound and then this target compound is
separated from the solid phase.
33. Process according to claim 32, wherein the basic molecule is
immobilized in the solid phase via a carbon center, a nitrogen
center or an oxygen center.
34. Process according to claim 32, wherein --X(CH.sub.2).sub.nCO
(X.dbd.CH.sub.2, CO, O, S, NH), --X(CH.sub.2).sub.nOCO
(X.dbd.CH.sub.2, CO, O, S, NH), --XC.sub.6H.sub.4CH.sub.2--
(.dbd.CH.sub.2, CO, O, S, NH), THP, or
--X(CH.sub.2).sub.nSi(alkyl).sub.2 is used as a functional group
(linker).
35. Process according to claim 32, wherein
--X(CH.sub.2).sub.nCO(X.dbd.CH.sub.2, O, NH, So.sub.0-2),
--X(CH.sub.2).sub.nCS (X.dbd.CH.sub.2, O, NH, SO.sub.0-2),
X(CH.sub.2).sub.nJCO (X.dbd.CH.sub.2, O, NH, So.sub.0-2; J=NH, O,
S), or XC.sub.6H.sub.4CH.sub.2 (X.dbd.CH.sub.2, O, S) is used as a
functional group (linker).
36. Process according to claim 32 or 33, wherein
--(CH.sub.2).sub.nSi(alkyl).sub.2-,
--C.sub.6H.sub.4Si(alkyl).sub.2-,
--(CH.sub.2).sub.nSn(alkyl).sub.2-,
--C.sub.6H.sub.4Sn(alkyl).sub.2, --(CH.sub.2).sub.nS, or
--C.sub.6H.sub.4S is used as a functional group (linker).
37. A pharmaceutical composition comprising at least one of the
compounds of general formulas I, II, III or IV, or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable vehicle.
38. (canceled)
39. Process for the production of pharmaceutical agents, in which
at least one of the compounds of general formulas I, II, III or IV
is mixed with a pharmaceutically acceptable vehicle and/or
formulation adjuvant.
Description
[0001] This application is a continuation of U.S. Ser. No.
09/980,025, filed Mar. 18, 2002, the contents of which are hereby
incorporated by reference.
[0002] This invention relates to new substituted benzofuran
derivatives, process for their production, their salts as well as
the use for [0003] a) Treatment of Alzheimer's disease, [0004] b)
treatment of Parkinson's disease, [0005] c) treatment of
Huntington's disease (chorea), [0006] d) treatment of multiple
sclerosis, [0007] e) treatment of amyotrophic lateral sclerosis,
[0008] f) treatment of epilepsy, [0009] g) treatment of the
sequelae of stroke, [0010] h) treatment of the sequelae of
cranio-cerebral trauma, [0011] i) treatment and prophylaxis of the
sequelae of diffuse oxygen and nutrient deficiency in the brain, as
they are observed after hypoxia, anoxia, asphyxia, cardiac arrest,
poisonings, as well as in the case of complications in difficult
deliveries of infants or in the case of anesthesia, [0012] j)
especially also prophylactic treatment of apoptotic degeneration in
neurons that were or are damaged by local radiotherapy or
chemotherapy of brain tumors, and [0013] k) treatment of bacterial
meningitis and [0014] l) treatment of diseases with apoptotic
components, especially in the wake of an amyloid-associated cell
degeneration, [0015] m) treatment of diabetes mellitus, especially
if the disease is accompanied by amyloid degeneration of islet
cells.
[0016] The new derivatives and analogs of galanthamine according to
the invention increase the muscular power and the perseverance of
Alzheimer patients.
[0017] The new compounds according to the invention are those of
general formula I ##STR2## in which the substituents have the
meanings that are explained below:
[0018] R.sub.1 and R.sub.2 are the same or different and mean:
[0019] a) hydrogen, F, Cl, Br, I, CN, NC, OH, SH, NO.sub.2,
SO.sub.3H, PO.sub.3H, NH.sub.2, CF.sub.3, OSO.sub.2(CH.sub.2)
CF.sub.3, in which n is equal to 0, 1 or 2), OSO.sub.2-aryl,
OSO.sub.2-vinyl or OSO.sub.2-ethinyl;
[0020] b) a low (C.sub.1-C.sub.6), optionally branched, optionally
substituted (Ar)alkyl, (Ar)alkoxy group, cycloalkyl or
cycloalkyloxy group;
[0021] c) an amino group, which optionally is substituted by one or
two identical or different low (C.sub.1-C.sub.6), optionally
branched, optionally substituted (Ar)alkyl or (Ar)alkylcarbonyl or
(Ar)alkoxycarbonyl groups or an amino group which exhibits a cyclic
substitution in the form of a pyrrolidine, piperidine, morpholine,
thiomorpholine, piperazine, homopiperazine radical that is
substituted in any case,
[0022] d) a COOH, COO(Ar)alkyl, CO-amino, with the definition of
the amino group as in the last paragraph under c) or a
CHOH(Ar)alkyl group;
[0023] e) a --(CH.sub.2)nX (in which X.dbd.Br, Cl, F or I),
--(CH.sub.2).sub.nOH, --(CH.sub.2) CHO, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.nCN, --(CH.sub.2).sub.nNC,
--(CH.sub.2).sub.nCOalkyl, --(CH.sub.2).sub.nCOaryl group, in which
n means 1-4;
[0024] f) a --(CH.sub.2) vinyl, (CH.sub.2).sub.nethinyl group, or
(CH.sub.2).sub.ncycloalkyl group in which n describes 0, 1 or 2,
and cycloalkyl describes an aliphatic ring of the ring size of
3-7;
[0025] g) a C.sub.3-C.sub.6-substituted alkenyl group (optionally
substituted with H, F, Br, Cl, CN, CO.sub.2alkyl, COalkyl,
COaryl);
[0026] h) a C.sub.3-C.sub.6-substituted alkinyl group (optionally
substituted with H, F, Br, Cl, CN, CO.sub.2alkyl, COalkyl, COaryl);
or
[0027] i) R.sup.1 and R.sup.2 together mean
--CH.dbd.CH--CH.dbd.CH--, --O(CH.sub.2).sub.nO-- (n=1 to 3),
--CH.dbd.CH-A1 or --CH2--CH2-A1, whereby NH, O or S can stand for
Al;
[0028] R.sub.3 has the same meaning as R.sub.1, especially OH and
OCH.sub.3 and in addition
[0029] R.sub.2 and R.sub.3 together mean
-A.sub.2(CH.sub.2).sub.nA.sub.2, in which n is 1 to 3 and A.sub.2
means two identical or different radicals that are selected from
NH, O or S;
[0030] R.sub.4 and R.sub.5 are either
[0031] a) both hydrogen, or
[0032] b) a combination of hydrogen or an (Ar)alkyl, (Ar)alkenyl or
(Ar)alkinyl group with [0033] i) OR.sub.6, in which R.sub.6 means
hydrogen, a low (C.sub.1-C.sub.10, optionally branched or
substituted) alkyl group or cycloalkyl group, a C.sub.3-C.sub.10
substituted silyl group (for example, triethylsilyl,
trimethylsilyl, t-butyldimethylsilyl or dimethylphenylsilyl), a
C.sub.2-C.sub.10 .alpha.-alkoxyalkyl group, for example
tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl, ethoxymethyl,
(2-methoxypropyl), ethoxyethyl, phenoxymethyl or (1-phenoxyethyl);
[0034] ii) O--CS--NHR.sub.6 (thiourethane), in which R.sub.6 has
the above-mentioned meaning [0035] iii) O--CO--NHR.sub.7 with the
meaning below: ##STR3## [0036] iv) O--CO--HR.sub.6, in which
R.sub.6 has the above-mentioned meaning, especially ester with the
substitution pattern of amino acids (both enantiomers), such as
##STR4## [0037] v) NR.sub.7R.sub.7, in which two substituents
R.sub.7 are the same or different and mean hydrogen, a low
(C.sub.1-C.sub.4), optionally branched or cyclic alkyl group, or
the two substituents R.sub.7 together are --(CH.sub.2).sub.n-, in
which n is 3 to 5; [0038] vi) NH--COR.sub.6 (amide), in which
R.sub.6 has the above-mentioned meaning; [0039] vii) S--R.sub.6, in
which R.sub.6 is hydrogen or a low (C.sub.1-C.sub.10), optionally
branched, optionally substituted (Ar)alkyl group, and in which
R.sub.6 has the above-mentioned meaning; [0040] viii)
SO.sub.nR.sub.8, in which n is 0, 1 or 2, in which R.sub.8 is a
(C.sub.1-C.sub.10), optionally branched or cyclic, optionally
substituted (Ar)alkyl group.
[0041] If R.sub.4 is hydrogen, R.sub.5 can be OH, CN,
CO.sub.2-alkyl, CONR.sub.aR.sub.b, in which R.sub.a is hydrogen, a
low (C.sub.1-C.sub.6), optionally branched, cyclic alkyl group that
is substituted in any case, and R.sub.b is hydrogen, a low
(C.sub.1-C.sub.6), optionally branched or substituted alkyl group,
or R.sub.a+R.sub.b together are --(CH.sub.2).sub.n--, in which n
means 2 to 6, or --(CH.sub.2).sub.nE(CH.sub.2).sub.n--, in which E
is the same as NH, N-alkyl, O, or S, and n is 0 to 5, aryl (phenyl
or naphthyl), 6-.pi. heterocycle, (such as, for example,
imidazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl,
oxadiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl and
substituted variants thereof), or imidazolinyl, thiazolinyl or
oxazolinyl.
[0042] For the case that R.sub.5 is not hydrogen, R.sub.4 can also
be OH.
[0043] R.sub.4 and R.sub.5 together can be carbonyl (.dbd.O),
hydrazone (.dbd.N--NH--R.sub.9, .dbd.N--NR.sub.9R.sub.10 or oxime
(.dbd.N--OR.sub.10), in which R.sub.9 is hydrogen, a low
(C.sub.1-C.sub.6), optionally branched or cyclic, optionally
substituted (Ar)alkyl- or (Ar)alkylcarbonyl-, (Ar)alkylcarbonyloxy
group or a sulfonic acid group, such as tosyl or mesyl, and
R.sub.10 is hydrogen, a low (C.sub.1-C.sub.6), optionally branched
or cyclic, optionally substituted (Ar)alkyl- or (Ar)alkylcarbonyl
group, a sulfonic acid group, such as a tosyl group or mesyl
group.
[0044] R.sub.4 and R.sub.5 together can be substituents of the type
##STR5## in which Y.sub.1, Y.sub.2 are the same or different and
mean O, S, NH or N--R.sub.9 (free valences are in any case
hydrogen), or for the case that Y.sub.1 is NH and Y.sub.2 is
N--R.sub.9, R.sub.4 and R.sub.5 can be connected by --(CH
2).sub.n-- (n=2, 3, or 4).
[0045] G.sub.1: --(CH.sub.2).sub.x--, in which x is 1 or 2;
[0046] G.sub.2: --(CH.sub.2).sub.y--, in which y is 0 to 2;
[0047] G.sub.3: --(CH.sub.2).sub.z--, in which z is 0 to 3, is
carbonyl or thiocarbonyl, provided that x+y+z together are at least
2 and at most 4 or in which G.sub.3 means --CH(OH)-- or
--C(OH).dbd..
[0048] G.sub.1 and G.sub.2 together or separately can also
mean:
[0049] --C(R.sub.11R.sub.12)--, in which R.sub.11 and R.sub.12 mean
hydrogen, OH, a low, optionally branched or cyclic, optionally
substituted (Ar)alkyl, aryl, (Ar)alkyloxy or aryloxy group or
together an alkylspiro group (C.sub.3-C.sub.7 spiro ring) or
G.sub.1 and G.sub.2 together mean ##STR6##
[0050] in which m is 1 to 7.
[0051] W can have the following meanings: [0052] a)
CR.sub.13R.sub.14, in which R.sub.13 means hydrogen and R.sub.14
means the radicals --(CH.sub.2).sub.nNR.sub.7R.sub.7 or
--CO--NR.sub.7R.sub.7 or --COOR.sub.7, whereby n can assume the
values 0 to 2 and R.sub.7 is as defined above, or R.sub.7R.sub.7
form a ring by --(CH.sub.2).sub.n (in which n is 3 to 5), whereby
substituents R.sub.13 and R.sub.14 can be exchanged. [0053] b)
N-Phenyl (whereby the phenyl radical optionally is substituted with
fluorine, bromine, chlorine, (C.sub.1-C.sub.4) alkyl, CO.sub.2
alkyl, CN, CONH.sub.2, or alkoxy) or N-thien-2 or 3-yl, or N-fur-2
or 3-yl or N-1,3,5-triazinyl, whereby the triazine radical can then
be substituted with C.sub.1, OR.sub.6 or NR.sub.7R.sub.7, and
R.sub.6 or R.sub.7 have the meaning indicated above; [0054] c) One
of the substituents that is presented below ##STR7## in which I
means no bond or --(CH.sub.2).sub.n--, with n=0 to 3, carbonyl,
thiocarbonyl O, S, --SO-- or SO.sub.2, R.sub.6 has the meaning that
is indicated above, and in addition, Q is defined as
--(CH2)n-M.sup.+-(CH2)m, whereby n=0 to 4 and m=0 to 4 and M.sup.+
represents alkinyl, alkenyl, disubstituted phenyl, disubstituted
thiophene, disubstituted furan, disubstituted pyrazine,
disubstituted pyridazine, a peptide spacer L or a heterocyclic
spacer HS, whereby this definition of the spacer is defined in
addition by the following graphic formulas ##STR8## in which
R.sub.15 means the side chain of D-, L-, D, L-aminoacids or
unnatural amino acids, and for the case of n>1, R.sub.15 in the
individual radicals in each case means the same or a different side
chain of D-, L-, D, L-amino acids or unnatural amino acids, whereby
these formulas are defined such that atom N in addition to Q is
connected in each case to G2 and G3 of formula I;
[0055] d) W can also be connected to a tricyclic substituent (Tr)
via spacer Q, whereby the tricyclic substituents are defined by the
following graphic formulas, ##STR9## and these formulas are defined
such that atom N in addition to Q is connected in each case with G2
and G3 of formula I, and Q and Z have the meaning indicated under
c).
[0056] The tricyclic substituent (Tr) means a tricyclic ring
system, with at least one heterocyclic ring as a ring component and
a binding site to a carbon atom of an anellated benzene ring
thereof, whereby Tr optionally is substituted at least in one
place, in which ring A is an optionally substituted benzene ring
and one of rings B and C is an optionally substituted heterocyclic
ring and the other can contain a substituted 4- to 14-membered,
preferably a 5- to 7-membered ring, which can contain one or more
heteroatoms in the ring. The benzene ring is optionally further
substituted in at least one place, whereby these substituents can
be halogens, such as fluorine and chlorine, halo-C.sub.1-C.sub.3
alkyl groups, such as trifluoromethyl, C.sub.1-C.sub.3alkyl groups,
such as methyl, C.sub.1-C.sub.3 alkoxy groups, such as methoxy, and
the hydroxy group, whereby halogens, such as fluorine, are
preferred.
[0057] Heterocyclic ring B or C that is optionally substituted is,
for example, a 4- to 14-membered ring, preferably a 5- to
7-membered ring. At least one heteroatom of the heterocyclic ring
(1 to 3 heteroatoms are possible) can be nitrogen, oxygen, sulfur.
In particular, rings B and C are pyridine, pyrazine, pyrimidine,
imidazole, furan, thiophene, pyrrolidine, piperidine,
hexamethylethylenimine, tetrahydrofuran, piperazine, morpholine and
thiomorpholine, whereby 5- to 7-membered nonaromatic rings, which
can have one or two heteroatoms that are the same or different, are
preferred.
[0058] Ring B or C can also be a non-aromatic, heterocyclic ring
that contains 1-3 heteroatoms, such as nitrogen, oxygen or sulfur,
and nonaromatic heterocyclic rings with a nitrogen atom, and
another heteroatom, which is nitrogen, oxygen or sulfur.
[0059] "5- to 8-membered rings B or C" are 5- to 8-membered
heterocyclic or alicyclic rings or carbon rings, which are
substituted at least in one place. These 5- to 8-membered carbon
rings can be a benzene ring or a saturated or unsaturated ring, for
example, benzene, cyclopentane, cyclopentene, cyclohexane,
cyclohexene, cyclohexadiene, cycloheptane, cycloheptene and
cycloheptadiene.
[0060] If rings B or C contain at least one heteroatom (e.g., 1-3
heteroatoms, such as nitrogen, oxygen, sulfur, etc.), i.e., if ring
B or C is a heterocyclic ring, it may or may not be aromatic. Such
aromatic heterocyclic rings are, for example, pyridine, furan,
thiophene. Preferred nonaromatic, heterocyclic rings are the
above-indicated examples of rings B or C.
[0061] Accordingly, tricyclic substituent Tr can be a condensed
benzene ring of general formula ##STR10## Examples in this respect
are:
[0062] Carbazole, [0063] 1,2,3,4-4a,9a-hexahydrocarbazole, [0064]
9,10-dihydroacridine, [0065] 1,2,3,4-tetrahydroacridine, [0066]
10,11-dihydro-5H-dibenz[b,f]azepine, [0067]
5,6,11,12-tetrahydrodibenz[b,g]azocine, [0068]
6,11-dihydro-5H-dibenz[b,e,]azepine, [0069]
6,7-dihydro-5H-dibenz[c,e]azepine, [0070]
5,6,11,12-tetrahydrodibenz[b,f]azocine, [0071] dibenzofuran, [0072]
9H-xanthene, [0073] 1-O-11-dihydrobenz[b,f]oxepin, [0074]
6,11-dihydrobenz[b,e]oxepin, [0075]
6,7-dihydro-5H-dibenz[b,g]oxacine, [0076] dibenzothiophene, [0077]
9H-thioxanthene, [0078] 10,11-dihydrodibenzo[b,f]thiepin, [0079]
6,11-dihydrodibenzo[b,e]thiepin, [0080]
6,7-dihydro-5H-dibenzo[b,g]thiocin, [0081] 10H-phenothiazine,
[0082] 10H-phenoxazine, [0083] 5,10-dihydrophenazine, [0084]
10,11-dibenzo[b,f]-[1,4]thiazepine, [0085]
2,3,5,6,11,11a-hexahydro-1H-pyrrolo[2,1-b][3]benzazepine, [0086]
1-O,11-dihydro-5H-dibenzo[b,e][1,4]diazepine, [0087]
5,11-dihdyrodibenz[b,e][1,4]oxazepine, [0088]
5,11-dihydrodibenzo[b,f][1,4]thiazepine, [0089]
10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine, [0090]
1,2,3,3a,8,8a-hexahydropyrrolo[2,3b]indole.
[0091] Tricyclic substituent Tr can be a condensed benzene ring of
general formula ##STR11## and can mean, for example: [0092]
1H,3H-Naphth[1,8-cd][1,2]oxazine, [0093]
naphth[1,8-de]-1,3-oxazine, [0094] naphth[1,8-de]-1,2-oxazine,
[0095] 1,2,2a,3,4,5-hexahydrobenz[cd]indole, [0096]
2,3,3a,4,5,6-hexahydro-1H-benzo[de]quinoline, [0097]
4H-pyrrolo[3,2,1-ij]quinoline, [0098]
1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline, [0099]
5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline, [0100]
1H,5H-benzo[ij]quinolizine, [0101]
2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine, [0102]
azepino[3,2,1-hi]indole, [0103]
1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole, [0104]
1H-pyrido[3,2,1-jk][1]benzazepine, [0105]
5,6,7,8-tetrahydro-1H-pyrido[3,2,1-jk][1]benzazepine, [0106]
1,2,56,7,8-hexahydro-5H-pyrido[3,2,1-jk][1]benzazepine, [0107]
2,3-dihydro-1H-benz[de]isoquinoline, [0108]
1,2,3,4,4a,5,6,7-octahydronaphth[1,8-bc]azepine, [0109]
2,3,5,6,7,8-hexahydro-1H-pyrido[3,2,1-jk][1]benzazepine.
[0110] Tricyclic substituent Tr can be a condensed benzene ring of
general formula ##STR12## Examples of these compounds are: [0111]
1,2,3,5,6,7-Hexahydrobenzo[1,2-b:4,5b']dipyrrole, [0112]
1,2,3,5,6,7-hexahydrocyclopent[f]indole, [0113]
1,2,3,6,7,8-hexahydrocyclopentan[e]indole or [0114]
2,3,4,7,8-hexahydro-1H-cyclopenta[f]quinoline.
[0115] Tricyclic substituent Tr can be a condensed benzene ring of
general formula ##STR13## Examples of this are: [0116]
1,2,3,6,7,8-Hexahydrocyclopent[e]indole or [0117]
2,3,4,7,8,9-hexahydro-1H-cyclopenta[f]quinoline.
[0118] Additional examples of tricyclic substituents Tr are
condensed benzene rings of the following formulas, whereby the
binding site to Q can take up the space of any hydrogen atom:
##STR14##
[0119] In addition, Tr can be a cyclic or bicyclic hydrocarbon
which is referred to by the following formula: ##STR15##
[0120] In addition, each substituent Tr can be substituted by one
or more substituents R.sub.1, whereby the definition of substituent
R.sub.1 is the same as in formula I.
[0121] e) In addition, W can mean --NH--, --S--, --SO-- or
--SO.sub.2--.
[0122] In addition, the invention relates to compounds of general
formula II ##STR16## in which D stands for NH, N-alkyl, N-acyl,
oxygen or sulfur, and in which substituents R.sub.1 to R.sub.1,
G.sub.1 to G.sub.3 and W can have the meanings that are indicated
above in general formula I.
[0123] In addition, the invention relates to compounds of general
formula III ##STR17## in which X--R.sub.16 is a substituent in
which X is oxygen or sulfur and R.sub.16 is hydrogen or a low
(C.sub.1-C.sub.10), optionally branched or cyclic, optionally
substituted (Ar)alkyl group, and in which substituents R.sub.1 to
R.sub.5, G.sub.1 to G.sub.3 and W can have the meanings that are
indicated above in general formula I.
[0124] The invention extends to compounds of general formula IV
##STR18## in which W represents CH or N, and R.sub.18 and R.sub.19
mean hydrogen, alkyl, aryl or aralkyl, and in which the C atoms
that carry substituents R.sub.18 and R.sub.19 are linked to one
another via a single bond or a double bond and in which
substituents R.sub.1 to R.sub.5 as well as G.sub.1 and G.sub.3 have
the meanings that are indicated above in general formula I.
[0125] It is preferred if in the compound of general formula IV
substituent W is nitrogen and/or substituent C.sub.1 is
--(CH.sub.2).sub.x--, in which x is equal to 1 or 2 and C means
--(CH.sub.2).sub.y--, in which y is equal to 0 to 2, provided that
x+y together mean at least 2 and at most 4.
Separation of Optical Isomers from rac. Norgalanthamine:
[0126] In addition, the invention includes a process for chiral
separation of
(6R)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH[1]benzofuro[3a,3,2-ef][2benza-
zepin-6-ol (norgalanthamine) (4)
[0127] The separation of (+) and (-) isomers is carried out by
fractionated crystallization in such a way that [0128] a solution
or suspension of the optical isomer mixture in which 3 to 50.times.
the amount is added to or introduced into [0129] a solvent, such as
water, methanol, ethanol, propanol, isopropanol, acetone or
mixtures of this solvent, mainly methanol [0130] with the equimolar
amount or excess chiral acid (unsubstituted, (+) or (-) tartaric
acid, citric acid, lactic acid, preferably (+)--O,O-di-p-toluoyl
tartaric acid that is substituted in one or more places and that is
dissolved in one of the above-mentioned solvents--and the solution
or suspension of the optical isomer mixture is added, [0131] that
the solution is inoculated with crystals produced from the natural
(-) galanthamine derivatives and chiral organic acids, such as
(+)--O,O-di-p-toluoyl tartaric acid, [0132] and is allowed to stand
at -40 to +20 degrees, preferably 0 degrees for 2-24 hours or
longer, [0133] that the formed crystals are filtered and dried,
[0134] then mixed with excess NH.sub.4OH and extracted with an
organic solvent, such as chloroform, methylene chloride, ethyl
acetate, butyl acetate, diethyl ether, t-butylmethyl ether, dibutyl
ether, petroleum ether, xylene, benzene, toluene or similar
solvents, and the corresponding (-) norgalanthamine is isolated by
distillation of the solvent.
[0135] In this process, concentration by evaporation of the mother
liquor, uptake of excess NH.sub.4OH, extraction with an organic
solvent (as indicated above) and concentration by evaporation yield
additional fractions of norgalanthamine, from which in the same way
as above, the (+) norgalanthamine can be produced with chiral
organic acids, such as (-)--O,O-di-p-toluoyl tartaric acid.
[0136] The products that are obtained according to the invention
can be purified by a suitable process, for example, sublimation,
fractionated crystallization or chromatography.
[0137] Among the compounds according to the invention, especially
the compounds that are mentioned below are considered:
[0138] In the survey below, "AchE" means acetylcholinesterase,
"BchE" means butyrylcholinesterase, "hr" means human recombinant,
"mE" means pre-incubation of the enzyme with inhibitor, and
"IC.sub.50" means concentration, in which 50% inhibition takes
place. TABLE-US-00001 IC50 IC50 Patent (AChE, (BChE, Example
Substance mE, hr) mE, hr) Laboratory Number Code IC50 IC50 Code
Patent Substanz- Structure (AChE, (BChE, Labor- Beispiel- Code
Struktur mE, hr) mE, hr) Code Nummer SPH-1118 ##STR19## 100 200 Ro
22 77 SPH-1146 ##STR20## 1,2 3,6 TK 66/1 136 / SPH-1149 ##STR21##
0,2 0,21 HM 104 137 SPH-1162 ##STR22## 200 Cl 2-1, CB 19 138
SPH-1184 ##STR23## 0,2 0,6 LCz 225/1 139 SPH-1191 ##STR24## 0,35
4,4 LCz 205 140 SPH-1196 ##STR25## 5,2 5 TK 36-2 30 SPH-1163
##STR26## 200 0,47 MH 7-1-1 35 SPH-1199 ##STR27## 200 2,3 MH 25-1
102 SPH-1200 ##STR28## 200 17 MH 30-1 88 SPH-1201 ##STR29## 46 0,6
MH-29-1 105 SPH-1202 ##STR30## 200 5,2 MH-28-1 104 SPH-1203
##STR31## MH-26-1 103 SPH-1204 ##STR32## 200 200 MH 31-2 89
SPH-1205 ##STR33## 70 2,4 MH 33 90 SPH-1206 ##STR34## 78 2,5 MH
38-1 91 SPH-1207 ##STR35## 47 0,7 MH 39-1 92 SPH-1208 ##STR36## 200
25 CB 2 141 SPH-1209 ##STR37## 31 20 CB 5 142 SPH-1210 ##STR38##
200 43 CB 4 143 SPH-1211 ##STR39## 23 30 CB 13, CB 29 27 SPH-1213
##STR40## 6 10 TK 96/3 71 SPH-1214 ##STR41## 4,2 200 CB 34, CB 34-2
19 SPH-1215 ##STR42## 70 200 CB 33 23 SPH-1217 ##STR43## 9,5 17 CB
28 40 SPH-1218 ##STR44## 25 0,54 CB 30 8 SPH-1219 ##STR45## 28,5
200 CB 36 31 SPH-1220 ##STR46## 7,2 21 CB 41 45 SPH-1221 ##STR47##
4,8 200 CB 45 20 SPH-1222 ##STR48## 6,7 200 CB 46 22 SPH-1227
##STR49## 40 6 HM 38 144 SPH-1228 ##STR50## 200 200 CB 43 15
SPH-1229 ##STR51## 38 30 CB 52 9 SPH-1230 ##STR52## CB 53 13
SPH-1231 ##STR53## 33 200 CB 49 21 SPH-1232 ##STR54## 36 200 CB 50
26 SPH-1233 ##STR55## 200 200 CB 51 16 SPH-1234 ##STR56## 66 200 CB
56 10 SPH-1235 ##STR57## 3,4 11 CB 42 46 SPH-1236 ##STR58## 21 200
CB 48 28 SPH-1237 ##STR59## 24 200 CB 47 24 SPH-1242 ##STR60## 70
40 CB 55 17 SPH-1243 ##STR61## 40 200 0358 14 SPH-1244 ##STR62##
7,6 36 CB 57 12 SPH-1245 ##STR63## 25 200 CB 59 11 SPH-1246
##STR64## 17,5 20 MR 16 18 SPH-1247 ##STR65## 2,4 4 MR 17 48-Stufel
SPH-1248 ##STR66## 40 90 MR 7 34 SPH-1249 ##STR67## 45 26 MR 13 43
SPH-1250 ##STR68## 200 95 MH-66 94 SPH-1251 ##STR69## 59 45 MH-71
95 SPH-1252 ##STR70## 200 52 MH-72 96 SPH-1253 ##STR71## 60 5,4
MH-75 97 SPH-1254 ##STR72## 200 3 MH-76 98 SPH-1255 ##STR73## 200
200 MH-81 99 SPH-1256 ##STR74## 200 14 MH-83 93 SPH-1259 ##STR75##
140 80 HM 60 29 SPH-1262 ##STR76## 54,5 36 MR 14 42 SPH-1263
##STR77## 200 200 Ap 74 1 SPH-1264 ##STR78## 50 200 HM 58 33
SPH-1266 ##STR79## 30 200 CB 75 59 SPH-1267 ##STR80## 30 200 CB 73
25 SPH-1268 ##STR81## 44 200 CB 78 55 SPH-1269 ##STR82## 2,6 10 CB
85 57 SPH-1270 ##STR83## 2,5 7 CB 86 58 SPH-1271 ##STR84## 15 4 CB
87 69 SPH-1272 ##STR85## 6,7 30 CB 81 60 SPH-1273 ##STR86## 21 3,4
CB 99, BK 10 145 SPH-1276 ##STR87## 42 40 CB 89 68 SPH-1277
##STR88## 33 7,3 HM 57 41 SPH-1278 ##STR89## 100 32 HM 60 32
SPH-1280 ##STR90## 0,5 0,24 CB 98 48 SPH-1282 ##STR91## 4 0,54 CB
100, BK 11 49 SPH-1283 ##STR92## 93 100 DD 9 76 SPH-1284 ##STR93##
8 90 DD 10 75 SPH-1286 ##STR94## 0,3 15 BK-32-1-3, AH B 72 SPH-1287
##STR95## 18,5 63 HM 109 56 SPH-1288 ##STR96## 6,3 60 HM 112, DD 13
146 SPH-1289 ##STR97## 0,7 1,2 HM 117 61 SPH-1290 ##STR98## 1,2 100
MH 123-3, AH 11 110 SPH-1291 ##STR99## 0,8 200 MH 123-3, TT 33 110b
SPH-1292 ##STR100## 40 100 CB 112 53 SPH-1293 ##STR101## 4,2 25 MH
122-3, Pi-4 114 SPH-1295 ##STR102## 15 32 BM 1 63 SPH-1296
##STR103## 46 200 CB 147, DD 16 51 SPH-1298 ##STR104## 200 70
MH-117 106 SPH-1302 ##STR105## 23 200 HM 203 147 SPH-1309
##STR106## 200 200 MT 176 128d SPH-1310 ##STR107## 5,3 200 MT 141
83 SPH-1311 ##STR108## 1,3 2,1 BM 4 65 SPH-1312 ##STR109## 3 2,4 DD
24 73 SPH-1314 ##STR110## 8,4 2,4 DD 18 64 SPH-1315 ##STR111## 2,8
5 70 SPH-1317 ##STR112## 80 200 PI 12 111 SPH-1318 ##STR113## 200
200 PI 14 112 SPH-1319 ##STR114## 200 200 PI 19 23 SPH-1320
##STR115## 83 30 PI 21 116 SPH-1326 ##STR116## 8,4 2,6 CB 171 54
SPH-1327 ##STR117## 24 3 WO 2 50 SPH-1328 ##STR118## 7,2 200 CB 161
52 SPH-1329 ##STR119## 2,9 0,85 DD 26 67 SPH-1330 ##STR120## 64 67
RMA 15 78 SPH-1331 ##STR121## 50 200 MH 142 119 SPH-1332 ##STR122##
200 200 MH 145 120 SPH-1333 ##STR123## 9 23 RMA 14, DD 7 79
SPH-1335 ##STR124## 0,02 0,8 CB 177, BK 6 6-Stufe 3 SPJ-1339
##STR125## 0,3 1,5 HM 264-1 149 SPH-1340 ##STR126## 32 30 HM 265-1
150 SPH-1345 ##STR127## 200 200 MH 143 1.19 ##STR128## SPH 1346
##STR129## 200 200 MH 146 121 ##STR130## SPH-1357 ##STR131## 0,022
0,8 MF 8 151 SPH-1359 ##STR132## 0,0052 0,24 MF 19 7-Stufe3
SPH-1362 ##STR133## 3 200 MF-3, CK-21-3 181 SPH-1363 ##STR134## 3,6
20 MF-17, CK-24-2 180 SPH-1369 ##STR135## 0,022 1,5 MT 273 3
SPH-1371 ##STR136## 0,36 BK-32-2, BK-32-1-3 170 SPH-1372 ##STR137##
0,022 UJ-1682-2 4
SPH-1373 ##STR138## 0,043 UJ-1685 5 SPH-1374 ##STR139## 0,027
UJ-1686 3 SPH-1375 ##STR140## 0,023 UJ-1683 7 SPH-1376 ##STR141##
0,02 UJ-1684 6 SPH-1377 ##STR142## 0,024 BK-34-2 155 SPH-1490
##STR143## MB-8 171 SPH-1491 ##STR144## MB-1 172 SPH-1492
##STR145## MB-7 173 SPH-1493 ##STR146## MB-10 174 SPH-1494
##STR147## MB-15 175 SPH-1515 ##STR148## ML-7 157 SPH-1521
##STR149## 176 SPH-1522 ##STR150## CK-52-6 158 SPH-1523 ##STR151##
CK-58-2 159 SPH-1524 ##STR152## CK-65-1 160 SPH-1525 ##STR153##
CK-63 161 SPH-1526 ##STR154## CK-63 162 SPH-1528 ##STR155##
CK-49-1-IPP-3-1 163 SPH-1529 ##STR156## CK-59-AcPP-3-1 164 SPH-1530
##STR157## CK-59-ISS-4-1 165 SPH-1531 ##STR158## CK-59-IPP-2-1 166
SPH-1532 ##STR159## CK-59-MSS-5-1 167 SPH-1534 ##STR160## CK-9-2
182 SPH-1535 ##STR161## CK-10 183 SPH-1536 ##STR162## CK-32 184
SPH-1537 ##STR163## CK-17 185 SPH-1538 ##STR164## CK-17-1 186
SPH-1539 ##STR165## CK-36 187 SPH-1540 ##STR166## CK-41 188
SPH-1541 ##STR167## CK-48 189 SPH-1542 ##STR168## CK-43-5 190 SPH
Number Structure IC50 AChE .mu.M IC50 BChE .mu.M SPH-Nummer
Struktur IC50 AChE .mu.M IC50 BChE .mu.M SPH-1193 ##STR169## 1,5
0,8
[0139] Within the scope of the invention, i.a., the compound
(6R)-3-methoxy-5,6,9,10,11,12-hexahydro-4a[H1]benzofuro[3a,3,2-ef][2]benz-
azepin-6-ol (norgalanthamine), specifically racemic
norgalanthamine, (-) norgalanthamine and (+) norgalanthamine, is
especially to be considered. Both racemic norgalanthamine and its
(+)- and (-)-isomers can be used in pharmaceutical agents for
treatment of the diseases mentioned above under a) to m) as active
ingredients per se or in combination with other active
ingredients.
[0140] The compounds according to the invention can be synthesized
with proper use of the process and modes of operation for the
production of galanthamine and galanthamine derivatives described
in WO 96/12692 and WO 97/40049.
[0141] An addition to the above-mentioned synthesis methods, some
of the compounds according to the invention can be produced with
use of the combinatory (or parallel) synthesis technology. With
this synthesis method, the skeleton of interest (or nuclear
molecule) is immobilized in a solid phase (e.g., glass pellets,
polymer pellets or another inert vehicle), which facilitates the
separation of excess reactants from a modified skeleton. The solid
phase that is used in each case depends on the concentration
capacity, the reactants that are used and the reaction solvents. In
particular, polymer pellets, such as, for example, Merriefield
resin, Wang resin or TentaGel (Rapp) resin, are considered.
[0142] The immobilization of the skeleton is carried out by a
functional group that can be recovered in the last step of the
synthesis under suitable reaction conditions. The last step
consists in the cleavage of the desired product from the solid
phase. The selection of the linker unit, which couples the basic
molecule to the solid phase, depends on the combination and/or the
series of reactants and the reaction conditions that are necessary
to obtain maximum yields and/or purity. Moreover, with different
linkers, the products can be cleaved off from the same solid phase
under different conditions. This technology allows a quick
synthesis including automated syntheses of compounds according to
the invention.
[0143] Relative to the combinatory and/or parallel synthesis,
reference is made to the bibliographic references below, in which
general process descriptions are included: [0144] 1) Abelson, J.
N., Combinatorial Chemistry. Academic Press, San Diego (1996).
[0145] 2) Epton, R., Innovation and Perspectives in Solid Phase
Synthesis and Combinatorial Libraries, Mayflower Scientific
Limited, Birmingham (1996). [0146] 3) Wilson, S. R. and Czarnik, A.
W., Combinatorial Chemistry. Synthesis and Applications. John Wiley
& Sons, Inc., New York (1997). [0147] 4) Gordon, E. M. and
Kerwin, J. F. J., Combinatorial Chemistry and Molecular Diversity
in Drug Discovery. John Wiley and Sons, Inc., New York (1998).
[0148] 5) Thompson, L. A., Ellman, J. A. Chem. Rev. 96, 555 (1996).
[0149] 6) Special Issue on Combinatorial Chemistry, cf., Acc. Chem.
Res., 29, 111 (1996). [0150] 7) Fruchtel, J. S.; Jung, G. Angew.
Chem. [Applied Chemistry] Int. Ed. Engl. 35, 17 (1996). [0151] 8)
Cheng, S.; Comer, D. D.; Williams, J. P.; Myers, P. L.; Boger, D.
L. J. Am. Chem. Soc., 118, 2567 (1996). [0152] 9) For additional
information regarding this quickly developing field, see: A Dynamic
Database of References in Molecular Diversity at http://www.5z.com.
[0153] 10) Bayer, E.; Angew Chem. Int. Ed., 30, 113-129 (1991).
[0154] 11) Mayer, J. P.; Zhang, J.; Bjergarde, K.; Lentz, D. M.;
Gaudino, J. J.; Tetrahedron Letters, 37, 8081 (1996). [0155] 12)
Bayer, E.; Angew. Chem. Int. Ed., 30, 113-129 (1991). [0156] 13) DE
19745628 A1.
[0157] In the example of a norgalanthamine skeleton
(G.sub.1=G.sub.2 G.sub.3=methylene; W.dbd.NH) or "homogalanthamine
(G.sub.1=G.sub.2=G.sub.3=methylene; W.dbd.CH--NH.sub.2), a bond
between the molecule and the solid phase can be obtained either via
a carbon center (C-linked), a nitrogen center (N-linked) or an
oxygen center (O-linked). The linkage points depend on the type of
structural modification desired. In the reaction diagrams mentioned
below by way of example, various transformations of skeletons
linked by linkers to various solid phases are depicted.
##STR170##
[0158] O-Linker Transformations of Skeletons of the
Norganlanthamine Type and the "Homogalanthamine" Type ##STR171##
N-Linker Transformations of a Molecule Skeleton of the
Norgalanthamine Type ##STR172## C-Linker Transformations of a
Skeleton of the Norgalanthamine Type ##STR173## C-Linker
Transformations of the "Homogalanthamine Skeleton"
[0159] The compounds according to the invention, as well as
pharmaceutically acceptable acid addition salts thereof can be used
as active ingredients in pharmaceutical agents, for example for
treating diseases with apoptotic components.
[0160] Neurodegenerative diseases of the human nervous system
belong to the syndromes for which few or no causal treatment
methods are now available. Neurological diseases of this type with
chronic course are primarily defined as follows: [0161] Primary
degenerative dementias (primarily Alzheimer's disease), [0162]
Cerebral and spinal paralysis (amyotrophic lateral sclerosis,
multiple sclerosis), [0163] Centrally induced motor disturbances
(Parkinson's disease and Huntington's disease) and [0164] Diseases
of the epileptic group.
[0165] Neurodegeneration, however, also plays a role in the
immediate wake of acute neurological cases, among which primarily
the following can be mentioned: [0166] Ischemic stroke (obstruction
of an artery supplying the brain), [0167] hemorrhagic stroke
(internal cerebral hemorrhage), [0168] cranio-cerebral trauma, and
[0169] brain damage after cardiac failure or respiratory arrest
(hypoxia/anoxia).
[0170] The compounds of the invention as well as pharmaceutically
acceptable acid addition salts thereof can use active ingredients
of pharmaceutical agents for treatment of neurodegenerative
processes, whereby the primary aim is not to bring about an
improvement of the acute symptoms and signs but rather a slowing
and modification of the associated processes.
[0171] Within the framework of diabetes mellitus type II, there is
increasing evidence of a role of amyloid fragments in the cell
degeneration of the insulin-producing Langerhans' islet cells. The
cell degeneration can be aggravated by a non-controlled calcium
inflow. .sup.1,2,3
[0172] The compounds according to the invention as well as
pharmaceutically acceptable acid addition salts thereof can be used
as active ingredients in pharmaceutical agents, for example for
treating degenerative diseases of the islet cells (such as, e.g.,
diabetes mellitus type II).
[0173] The compounds of the invention can be used as active
ingredients in pharmaceutical agents that can be used as follows:
[0174] a) for treatment of Alzheimer's disease, [0175] b) for
treatment of Parkinson's disease, [0176] c) for treatment of
Huntington's disease (chorea), [0177] d) for treatment of multiple
sclerosis, [0178] e) for treatment of amyotrophic lateral
sclerosis, [0179] f) for treatment of epilepsy, [0180] g) for
treatment of the sequelae of stroke, [0181] h) for treatment of the
sequelae of cranio-cerebral trauma, [0182] i) for treatment and
prophylaxis of the sequelae of diffuse oxygen and nutrient
deficiency in the brain, as they are observed after hypoxia,
anoxia, asphyxia, cardiac arrest, poisonings, as well as in the
case of complications in difficult deliveries of infants or in the
case of anesthesia, [0183] j) especially also for prophylactic
treatment of apoptotic degeneration in neurons that were or are
damaged by local radiotherapy or chemotherapy of brain tumors, and
[0184] k) for treatment of bacterial meningitis and [0185] l) for
treatment of diseases with apoptotic components, especially in the
wake of an amyloid-associated cell degeneration, [0186] m) for
treatment of diabetes mellitus, especially if it is accompanied by
amyloid degeneration of islet cells.
[0187] The compounds according to the invention or their
pharmaceutically acceptable acid addition salts, e.g.,
hydrobromide, hydrochloride, methyl sulfate, methiodide, tartrate,
fumarate, oxalate, etc. (see table below) can be administered to
patients orally, rectally or by subcutaneous, intramuscular,
intravenous or intrathecal injection or infusion, or
intracerebroventricularly, e.g., using an implanted container.
TABLE-US-00002 English Acid Salt Sulfamic Sulfamic acid --
Amidosulfonic acid Amidosulfonate 1,2- 1,2- 1,2- ethanedisulfonic
ethanedisulfonic ethanedisulfonate acid 2-ethylsuccinic
1,2-ethylsuccinic 2-ethylsuccinate acid 2-hydroxyethanesulfonic =
isethionic 2-hydroxyethanesulfonic 2-hydroxyethanesulfonate acid
3-hydroxynaphthoic 3-hydroxynaphthoic 3-hydroxynaphthoate acid
acetic acetic acid acetate benzoic benzoic acid benzoate
benzenesulfonic benzenesulfonic benzenesulfonate acid calcium
calcium dihydrogen calcium dihydrogenedetic ethylenediamine
ethylenediamine tetraacetic acid tetraacetate camphorsulfonic
camphorsulfonic camphorsulfonate acid carbonic carbonic acid
carbonate citric citric acid citrate dodecylsulfonic
dodecylsulfonic dodecylsulfonate acid ethanesulfonic ethanesulfonic
acid ethanesulfonate edetic ethylenediamine ethylenediamine
tetraacetic acid tetraacetate fumaric fumaric acid fumarate
glubionic glubionic acid glubionate glucoheptonic glucoheptonic
acid glucoheptonate gluconic gluconic acid gluconate glutamic
glutamic acid glutamate hexylresorcinic hexylresorcylic
hexylresorcylate acid HBr hydrobromic acid hydrobromide HCl
hydrochloric acid hydrochloride bicarbonic carbonic acid
bicarbonate bitartaric tartaric acid hydrogen tartrate hydriodic
hydriodic acid hydriodide lactic lactic acid lactate lactobionic
lactobionic acid lactobionate laevulinic laevulinic acid
laevulinate estolic laurylsulfuric acid laurylsulfate
(laurylsulfuric) LIPOIC-(ALPHA) ACID lipoic acid liponate malic
malic acid malate maleic maleic acid maleinate malonic malonic acid
malonate methanesulfonic methanesulfonic methanesulfonate acid
naphthalenesulfonic napththalene- naphthalene sulfonic acid
sulfonate nitric nitric acid nitrate pantothenic pantothenic acid
pantothenate phosphoric phosphoric acid phosphate polygalacturonic
polygalacturonic polygalacturonate acid pectic acid propionic
propionic acid propionate salicylic salicylic acid salicylate
succinic succinic acid succinate sulfuric sulfuric acid sulfate
tartaric tartaric acid tartrate
[0188] Typical dosage rates in administration of these active
ingredients depend on the nature of the compound that is used and
in intravenous administration are in the range of 0.01 to 2.0 mg
per day and per kilogram of body weight based on the physical
condition and other medications of the patient.
[0189] The following specific formulations can be used:
[0190] Tablets and capsules that contain 0.5 to 50 mg
[0191] Solution for parenteral administration that contains 0.1 to
30 mg of active ingredient/ml
[0192] Liquid formulations for oral administration at a
concentration of 0.1 to 15 mg/ml
[0193] Liquid formulations for intracerebroventricular
administration, at a concentration of 1 or 5 mg of active
ingredient/ml.
[0194] The compounds according to the invention can also be a
transdermal system, in which 0.1 to 10 mg/day is released.
[0195] A transdermal dosage system consists of a storage layer that
contains 0.1 to 30 mg of the active substance as a free base or
salt in any case together with a penetration accelerator, e.g.,
dimethyl sulfoxide, or a carboxylic acid, e.g., octanoic acid, and
a realistic-looking polyacrylate, e.g., hexylacrylate/vinyl
acetate/acrylic acid copolymer including softeners, e.g.,
isopropylmyristat. As a covering, an active ingredient-impermeable
outside layer, e.g., a metal-coated, siliconized polyethylene patch
with a thickness of, for example, 0.35 mm, is used. To produce an
adhesive layer, e.g., a dimethylaminomethacrylate/methacrylate
copolymer in an organic solvent is used.
[0196] The invention also relates to pharmaceutical compositions
that in a pharmaceutically acceptable adjuvant contains a
therapeutically effective amount of at least one of the compounds
that are proposed according to the invention.
[0197] The invention also extends to the use of these compounds for
the production of pharmaceutical agents and processes for the
production of such compounds.
[0198] In particular, the compounds according to the invention,
which in many cases show a cholinesterase-inhibiting action, are
suitable as therapeutic and/or prophylactic active ingredients for
senile dementia, Alzheimer's disease, etc. The compounds that are
proposed according to the invention are new tetracyclic, condensed,
heterocyclic compounds.
[0199] In addition to the therapeutic and/or prophylactic
properties, the compounds and compositions according to the
invention can also be used in the diagnosis of disease conditions
of the above-mentioned type.
LITERATURE
[0200] 1) Kawahara, M.; Kuroda, Y.; Arispe, N.; Rojas, E.;
"Alzheimer's Beta-Amyloid, Human Islet Amylin, and Prion Protein
Fragment Evoke Intracellular Free Calcium Elevations by a Common
Mechanism in a Hypothalamic BnRH Neuronal Cell Line." J Biol Chem
2000 May 12; 275 (19): 14077-83 [0201] 2) Ma, Z.: Westermark, P.;
Westermark, G T; "Amyloid in Human Islets of Langerhans:
Immunologic Evidence that Islet Amyloid Polypeptide is Modified in
Amyloidogenesis." Pancreas 2000 August; 21(2): 212-8 [0202] 3)
Rhoades, E.; Agarwal, J.; Gafni, A.; "Aggregation of an
Amyloidogenic Fragment of Human Islet Amyloid Polypeptide." Biotin
Biophys Acta 2000 Feb. 9; 1476(2): 230-8
[0203] Below, operating instructions and examples for the
production of compounds according to the invention are
indicated.
General Remarks
[0204] "Concentration" refers to the removal of solvents under
reduced pressure by means of a rotary evaporator.
[0205] "MPLC" refers to a chromatographic purification on silica
gel 20-60 .mu.m with use of Buchi chromatography columns, a
Shimadzu LC-8A pump and a Shimadzu 6AV UV detector.
EXAMPLE 1
Step 1: 4-Bromo-2-methoxy-5-(2-nitroethenyl)-phenol
[0206] ##STR174##
[0207] 40.0 g (173 mmol) of 2-bromo-5-hydroxy-4-methoxybenzaldehyde
and 13.3 g (173 mmol) of ammonium acetate are refluxed in 400 ml of
nitromethane for 15 minutes. The reaction mixture is evaporated to
the dry state, the residue is digested in about 70 ml of methanol
and then suctioned off. To obtain a second fraction of the product,
the methanol solution is concentrated by evaporation to about 30 ml
and then poured onto 500 ml of water. The precipitated solid is
filtered off by suction, washed with about 100 ml of water and
dried together with the first fraction at 50.degree. C./50 mbar, by
which a total of 43.6 g (92% of theory) of yellow crystals is
obtained on 4-bromo-2-methoxy-5-(2-nitroethenyl)-phenol with a
melting point of 152-154.degree. C.
[0208] TLC: CH.sub.2Cl.sub.2: MeOH=9:1
[0209] .sup.1H-NMR (CDCl.sub.3; .delta. (ppm): 3.85 (s, 3H,
OCH.sub.3); 7.30 (s, 1H, H-6); 7.38 (s, 1H, H-3); 8.03 (d,
.sup.3J.sub.HH=13.41 Hz, 1H, ArCH.dbd.); 8.16 (d,
.sup.3J.sub.HH=13.41 Hz, 1H, .dbd.CHNO.sub.2)
[0210] .sup.13C-NMR (CDCl.sub.3; .delta. (ppm) 56.3 (q, OCH.sub.3);
114.7 (d, C-6); 116.1 (d, C-3); 116.6 (s, C-2); 121.4 (s, C-1);
136.8 (d, ArCH.dbd.); 137.6 (d, .dbd.CHNO.sub.2); 146.5 (s, C-5)
152.2 (s, C-4)
Step 2: 4-Bromo-2-methoxy-5-(2-aminoethyl)-phenol
[0211] ##STR175## Method A:
[0212] 7.2 g (74 mmol) of concentrated sulfuric acid is added in
drops at 0.degree. C. under nitrogen atmosphere to 168 ml (148
mmol) of a 0.88N lithium aluminum hydride solution in diethyl
ether. 10.0 g (36.5 mmol) of
4-bromo-2-methoxy-5-(2-nitroethenyl)-phenol is partially dissolved
in one liter of absolute diethyl ether in boiling heat, and then
the supernatant solution is added with a transfer needle and dry
nitrogen to the aluminum hydride solution at room temperature.
After the addition is completed, 700 ml of diethyl ether from the
reaction mixture is distilled in undissolved
4-bromo-2-methoxy-5-(2-nitroethenyl)-phenol in the receiving flask.
By heating to reflux, a saturated solution is produced that is fed
to the reaction mixture as above. This process is repeated (three
to four times) until the addition of
4-bromo-2-methoxy-5-(2-nitroethenyl)-phenol is completed. Then, it
is hydrolyzed with water at 0.degree. C., and the ethereal phase is
extracted twice with 300 ml each of 4N hydrochloric acid. The acid
solution is mixed with 22.2 g (148 mmol) of L-(+)-tartaric acid,
made basic with concentrated aqueous ammonia and exhaustively
extracted with chloroform. The combined organic phases are washed
with saturated aqueous sodium chloride solution, dried
(Na.sub.2SO.sub.4), filtered and concentrated by evaporation, by
which 2.20 g (24% of theory) of colorless crystals is obtained on
4-bromo-2-methoxy-5-(2-aminoethyl)-phenyl with a melting point of
170-172.degree. C.
Method B:
[0213] A solution of 18.0 g (65.7 mmol) of
4-bromo-2-methoxy-5-(2-nitroethenyl)-phenol in 200 ml of absolute
tetrahydrofuran is added in drops over the course of 2 hours under
nitrogen to a reflux-heated solution of 15.0 g (394.2 mmol) of
lithium aluminum hydride in 1 l of absolute tetrahydrofuran. Then,
while being cooled with ice, the reaction mixture is hydrolyzed
with about 20 ml of water and evaporated to the dry state. The
residue is taken up in 500 ml of 2N hydrochloric acid and washed
with 500 ml of ethyl acetate. The washing phase is shaken back with
200 ml of 2N hydrochloric acid, the combined aqueous phases are
mixed with 70 g (467 mmol) of L-(+)-tartaric acid, made basic with
concentrated aqueous ammonia and extracted three times with 800 ml
of chloroform each. The combined organic phases are dried on sodium
sulfate, filtered and concentrated by evaporation, by which 9.92 g
(61% of theory) of colorless crystals is obtained on
4-bromo-2-methoxy-5-(2-aminoethyl)-phenol with a melting point of
170-172.degree. C.
Step 3:
4-Bromo-5-{N-[(4-hydroxyphenyl)methyl]-2-aminoethyl}-2-methoxyphen-
ol
[0214] ##STR176##
[0215] 6.4 g (26.0 mmol) of
4-bromo-2-methoxy-5-(2-aminoethyl)-phenol and 3.2 g (26.0 mmol) of
p-hydroxy-benzaldehyde are refluxed for 2 hours in 150 ml of
absolute ethanol. Then, while being cooled with ice, 5.0 g (132.0
mmol) of sodium borohydride is added and refluxed for another half
hour, the excess sodium borohydride is destroyed by adding
approximately 1 ml of glacial acetic acid as well as 50 ml of water
while being cooled with ice, and the solution is concentrated by
evaporation. The residue is acidified with 2N hydrochloric acid and
washed with 50 ml of chloroform. During hydrolysis, optionally
larger solid fragments can form, which must be ground before
extraction since they include large amounts of product. The washing
phase is shaken back with 30 ml of 2N hydrochloric acid, the
combined aqueous phases are made basic with concentrated aqueous
ammonia and extracted three times with 80 ml each of ethyl acetate.
The organic phases are combined, dried on sodium sulfate, filtered
and concentrated by evaporation, by which 8.9 g (97% of theory) of
colorless crystals is obtained on
4-bromo-5-{N-[(4-hydroxyphenyl)methyl]-2-aminoethyl}-2-methoxyphenol
with a melting point of 69-72.degree. C.
[0216] TLC: CHCl.sub.3:MeOH=9:1+2% NH.sub.3
[0217] .sup.1H-NMR (DMSO; .delta. (ppm)): 2.55-2.78 (m, 4H,
ArCH.sub.2CH.sub.2NH); 3.58 (s, 2H, NHCH.sub.2Ph); 3.73 (s, 3H,
OCH.sub.3); 6.60-6.76, 7.02-7.14 (2*m, 6H, 2* Ph)
[0218] .sup.13C-NMR (DMSO; .delta. (ppm)): 35.2 (t, ArCH.sub.2);
48.7 (t, CH.sub.2CH.sub.2NH); 52.2 (t, NHCH.sub.2Ph); 55.9 (q,
OCH.sub.3); 111.3 (s, C-4); 114.8 (d, C-3'); 115.9 (d, C-6); 117.3
(d, C-3); 129.1 (d, C-2'); 130.7 (s, C-5); 131.4 (s, C-1'); 146.0
(s, C-2); 146.8 (s, C-1); 156.0 (s, C-4')
Step 4:
N-[2-(2-Bromo-5-hydroxy-4-methoxyphenyl)ethyl]-N-[(4-hydroxyphenyl-
)methyl]formamide
[0219] ##STR177##
[0220] 8.5 g (24.1 mmol) of
4-bromo-5-{N-[(4-hydroxyphenyl)methyl]-2-aminoethyl}-2-methoxyphenol
and 10 ml (123.8 mmol) of ethyl formate are refluxed with 2.5 ml of
formic acid, 10 ml of N,N-dimethylformamide and a spatula-tip full
of dimethylaminopyridine in 150 ml of absolute dioxane for 24
hours. Toward the end of the reaction, the initially white
suspension turns clear, and the mixture is mixed with 50 ml of
water. The dioxane is distilled off, the white precipitate that is
produced is filtered off by suction and washed with water, by which
the first fraction product is obtained. The filtrate is extracted
three times with 50 ml each of ethyl acetate, the combined organic
phases are dried on sodium sulfate, filtered and concentrated by
evaporation. By subsequent column chromatography (50 g of silica
gel, mobile solvent: CHCl.sub.3:MeOH=97:3), another fraction is
obtained. Both fractions are dried at 50.degree. C./50 mbar until a
constant weight is reached, by which a total of 6.6 g (72% of
theory) of colorless crystals is obtained on
N-[2-(2-bromo-5-hydroxy-4-methoxyphenyl)ethyl]-N-[(4-hydroxyphenyl)methyl-
]-formamide with a melting point of 104-106.degree. C.
[0221] TLC: CHCl.sub.3:MeOH=9:1
[0222] .sup.1H-NMR (DMSO; .delta. (ppm)): 2.56-2.78 (m, 2H,
ArCH.sub.2); 3.43-3.53 (m, 2H, CH.sub.2N); 3.72 (s, 3H, OCH.sub.3);
4.14 (dd, 2H, NCH.sub.2Ph); 6.67-6.80, 7.00-7.11 (2*m, 6H, Ar, Ph);
9.30, 9.48 (2* s, 1H, CHO)
[0223] .sup.13C-NMR (DMSO; .delta. (ppm)): 32.6, 34.2 (2* t,
ArCH.sub.2); 41.5, 44.3 (2* t, CH.sub.2N); 46.1, 50.4 (2* t,
NCH.sub.2Ph); 56.1 (q, OCH.sub.3); 111.4, 111.6 (2* s, C-4); 115.1,
115.2 (2* d, C-6); 115.6, 115.7 (2* d, C-3') 117.7, 118.0 (2* d,
C-3); 126.8, 127.0 (2* s, C-5); 129.4 (d, C-2'); 130.0 (s, C-1');
146.5, 146.6 (2* s, C-2); 147.5, 147.6 (2* s, C-1); 157.1, 157.5
(2* s, C-4'); 162.7, 163.0 (2* d, CHO)
Step 5:
(4a.alpha.,8a.alpha.)-4a,5,9,10,11-Hexahydro-1-bromo-3-methoxy-6-o-
xo-6H-benzofuro[3a,3,2-ef]-[3]benzazepine-10-carboxyaldedyde
[0224] ##STR178##
[0225] A mixture of 13 g (39.5 mmol) of potassium hexacyanoferrate
(III), 300 ml of chloroform and 50 ml of aqueous 10% potassium
carbonate solution is heated to 60.degree. C., mixed with 3 g (7.9
mmol) of
N-[2-(2-bromo-5-hydroxy-4-methoxyphenyl)ethyl]-N-[(4-hydroyphenylyl)methy-
l]-formamide while being stirred vigorously and then mechanically
stirred vigorously for another 10 minutes. Then, the brown solid
that is produced is filtered off on Hyflo, rewashed three times
with 30 ml each of chloroform and pressed out solid. The filtrate
is then washed with about 150 ml of water, the washing phase is
shaken back with 150 ml of chloroform, the combined organic phases
are dried on magnesium sulfate, filtered and concentrated by
evaporation. By purification on column chromatography (15 g of
silica gel, mobile solvent: CHCl.sub.3:MeOH=97:3), 580 mg (19% of
theory) of colorless crystals with a melting point of
218-220.degree. C. is obtained.
[0226] TLC: CHCl.sub.3:MeOH=9:1
[0227] .sup.1H-NMR (CDCl.sub.3; .delta. (ppm)): 2.58-4.27 (m, 8H,
H-5/5'/9/9'/11/11'/12/12'); 3.80 (s, 3H, OCH.sub.3); 4.85 (dd, 1H,
H-4a); 6.09 (dd, 1H, H-8); 6.53 (dd, 1H, H-7); 7.01 (s, 1H, H-2);
8.10, 8.30 (2* s, 1H, CHO.sub.Conf. A/B)
[0228] .sup.13C-NMR (CDCl.sub.3; .delta. (ppm)): 33.4, 35.3 (2*t,
C-9.sub.Conf. A/B); 37.2, 37.4 (2*t, C-5.sub.Conf. A/B); 43.7 (t,
C-11); 48.7, 49.0 (2*t, C-12.sub.Conf. A/B); 50.9, 51.4 (2*s,
C-8a.sub.Conf. A/B) 56.2 (q, OCH.sub.3); 83.8, 84.3 (2*s,
C-4a.sub.Conf. A/B); 115.3, 115.7 (2*s, C-1.sub.Conf. A/B); 116.8,
117.0 (2*d, C-8.sub.Conf. A/B); 127.6, 128.9 (2*s, C-12a.sub.Conf.
A/B); 128.0, 128.8 (2*d, C-7.sub.Conf. A/B) 129.8, 130.8 (2*s,
C-12b.sub.Conf. A/B); 141.5, 141.7 (2*d, C-2 Conf. A/B); 143.8,
144.0 (2*s, C-3a.sub.Conf. A/B); 146.8 (s, C-3); 161.7, 162.3 (2*d,
CHO); 193.0, 193.4 (2*s, C-6)
[0229] C.sub.17H.sub.16BrNO.sub.4 (JOS 1526) 378.23 g/mol
TABLE-US-00003 Cld.: C 53.99 H 4.26 N 3.70 Fnd.: C 53.70 H 4.47 N
3.41
Step 6:
(4a.alpha.,8a.alpha.-4a,5,9,10,11-Hexahydro-1-bromo-3-methoxy-6H-b-
enzofuro[3a,3,2-ef]-[3]benzazepin-6-ol
[0230] ##STR179##
[0231] 4 ml (4.00 mmol) of 1N L-selectride solution is added in
drops at -12.degree. C. under nitrogen to a solution of 500 mg
(1.32 mmol) of
(4aa,8aa)-4a,5,9,10,11-hexahydro-1-bromo-3-methoxy-6-oxo-6H-benzofuro[3a,-
3,2-ef][3]benzazepine-10-carboxaldehyde in 12 ml of absolute
tetrahydrofuran, and the reaction mixture is then stirred for one
hour at -10.degree. C. Then, it is hydrolyzed with 3 ml of
methanol, the solution is evaporated to the dry state, taken up in
50 ml of 2N hydrochloric acid and stirred vigorously for another
hour. The aqueous solution is washed with 50 ml of ethyl acetate,
the washing phase is shaken back with 20 ml of 2N hydrochloric
acid, the combined aqueous phases are made basic with concentrated
aqueous ammonia and extracted three times with 50 ml each of ethyl
acetate. The combined organic phases are dried on magnesium
sulfate, filtered and concentrated by evaporation, by which 380 mg
(82% of theory) of light yellow crystals is obtained on
(4a.alpha.,8a.alpha.)-4a,5,9,10,11-hexahydro-1-bromo-3-methoxy-6H-benzofu-
ro[3a,3,2-ef][3][benzazepin-6-ol with a melting point of
132-136.degree. C.
[0232] TLC: CHCl.sub.3:MeOH=9:1
[0233] .sup.1H-NMR (CDCl.sub.3; .delta. (ppm)) 1.87 (ddd, 1H,
H-5'); 2.62 (ddd, 1H, H-5'); 2.68 (ddd, 1H, H-11); 2.78 (d, 1H,
H-9, .sup.2J.sub.9/9'=12.6 Hz); 2.85 (ddd, 1H, H-11'); 2.98 (d, 1H,
H-9', .sup.2J.sub.9/9'=12.6 Hz); 3.30 (ddd, 1H, H-12); 3.37 (ddd,
1H, H-12'); 3.80 (s, 3H, OCH.sub.3); 4.08 (ddd, 1H, H-6); 4.50 (dd,
1H, H-4a); 6.08 (dd, 1H, H-8, .sup.3J.sub.7/8=10.2 Hz); 6.15 (d,
1H, H-7, .sup.3J.sub.7/8=10.2 Hz); 6.96 (s, 1H, H-2)
[0234] .sup.13C-NMR (CDCl.sub.3; .delta. (ppm)): 30.2 (t, C-5);
36.7 (t, C-9); 49.7 (t, C-11); 51.6 (s, C-8a); 56.0 (q, OCH.sub.3);
57.3 (t, C-12); 62.0 (d, C-6); 85.5 (d, C-4a); 114.9 (s, C-1);
115.7 (d, C-8); 127.3 (d, C-2); 127.7 (d, C-7); 130.5 (s, C-12a);
134.2 (s, C-12b); 143.5 (s, C-3a); 145.4 (s, C-3)
Step 7:
(4a.alpha.,8a.alpha.)-4a,5,9,10,11-Hexahydro-1-bromo-3-methoxy-10--
methyl-6H-benzofuro[3a,3,2-ef]-[3]benzazepin-6-ol
[0235] ##STR180##
[0236] In succession, 1 ml of 35% aqueous formaldehyde solution
and, in portions, 165 mg (2.63 mmol) of sodium cyanoborohydride are
added while being stirred vigorously to a solution of 370 mg (1.05
mmol) of
(4a.alpha.,8a.alpha.)-4a,5,9,10,11-hexahydro-1-bromo-3-methoxy-6H-benzofu-
ro[3a,3,2-ef][3]benzazepin-6-ol in 12 ml of acetonitrile, and the
reaction mixture is stirred vigorously at room temperature for one
hour. The solution is then acidified with 2N hydrochloric acid,
washed with 15 ml of dichloromethane, and the washing phase is
shaken back with 15 ml of 2N hydrochloric acid. The combined
organic phases are made basic with concentrated aqueous ammonia and
extracted three times with 30 ml of dichloromethane each. The
combined organic phases are dried on magnesium sulfate, filtered
and concentrated by evaporation, by which 355 mg (92% of theory) of
yellow crystals is obtained on
(4a.alpha.,8a.alpha.)-4a,5,9,10,11-hexahydro-1-bromo-3-methoxy-10-methyl--
6H-benzofuro[3a,3,2-ef][3]benzazepin-6-ol with a melting point of
158-161.degree. C.
[0237] TLC: CHCl.sub.3:MeOH=9:1
[0238] .sup.1H-NMR (CDCl.sub.3; .delta. (ppm)): 1.91-2.04 (m, 1H,
H-5); 2.27-2.48 (m, 2H, H-5'/11); 2.41 (s, 3H, NCH.sub.3);
2.60-2.81 (m, 2H, H-9/11'); 2.92-3.16 (m, 2H, 9'/12); 3.34 (dd,
.sup.3J.sub.11/12'=6.37 Hz, .sup.2J.sub.12/12', =16.48 Hz, 1H,
H-12'); 4.13-4.25 (m, 1H, H-6); 4.58 (b, 1H, H-4a); 6.02 (dd,
.sup.3J.sub.7/8=10.17 Hz, .sup.4J.sub.6/8=5.08 Hz, 1H, H-8); 6.18
(d, .sup.3J.sub.7/8=10.17 Hz, 1H, H-7); 6.92 (s, 1H, H-2)
Step 8:
(4a.alpha.,8a.alpha.)-4a,5,9,10,11-Hexahydro-3-methoxy-10-methyl-6-
H-benzofuro[3a,3,2-ef]-[3]benzazepin-6-ol
[0239] ##STR181##
[0240] A mixture that consists of 340 mg (0.93 mmol) of
(4a.alpha.,8a.alpha.)-4a,5,9,10,11-hexahydro-1-bromo-3-methoxy-10-methyl--
6H-benzofuro[3a,3,2-ef][3]benzazepin-6-ol and 722 mg (6.51 mmol) of
calcium chloride in 40 ml of 50% ethanol is mixed with 1.4 g (22.32
mmol) of freshly activated zinc powder.sup.1 and refluxed for 5
hours. Then, the zinc is filtered out, it is rewashed with
methanol, and the residual solution is concentrated by evaporation.
The residue is taken up in 50 ml of 1N hydrochloric acid, washed
with 30 ml of ethyl acetate, and the washing phase is shaken back
with 20 ml of hydrochloric acid. The combined aqueous phases are
made basic with concentrated aqueous ammonia and extracted three
times with 50 ml each of ethyl acetate. The combined organic phases
are dried on magnesium sulfate, filtered and concentrated by
evaporation, by which 230 mg (86% of theory) of yellow crystals is
obtained on
(4a.alpha.,8a.alpha.)-4a,5,9,10,11-hexahydro-3-methoxy-10-methyl-6H-benzo-
furo[3a,3,2-ef][3]benzazepin-6-ol with a melting point of
152-155.degree. C. .sup.1Zinc powder (Aldrich Company) mixed with
2N hydrochloric acid, thoroughly mixed, filtered off and first
washed neutral with distilled water, then thoroughly rewashed with
methanol
[0241] TLC: EE:EtOH=9:1 (visible by oxidation in the iodine
chamber)
[0242] .sup.1H-NMR (CDCl.sub.3; .delta. (ppm)): 1.90-2.04 (m, 1H,
H-5); 2.26-2.46 (m, 2H, H-11/11'); 2.42 (s, 3H, NCH.sub.3);
2.62-2.80 (m, 3H, H-5'/9/9'); 3.01-3.12 (m, 1H, H-12); 3.12-3.29
(m, 1H, H-12'); 3.83 (s, 3H, OCH.sub.3); 4.12-4.22 (m, 1H, H-6);
4.57 (b, 1H, H-4a); 6.01 (ddd, .sup.3J.sub.7/8=10.16 Hz,
.sup.4J.sub.6/8=5.18 Hz, .sup.5J.sub.5/8=0.95 Hz; 1H, H-8); 6.22
(dd, .sup.3J.sub.7/8=10.16 Hz, .sup.4J.sub.5/7=1.09 Hz, 1H, H-7);
6.61 (d, .sup.3J.sub.1/2=8.21 Hz, 1H, H-2) 6.66 (d,
.sup.3J.sub.1/2=8.21 Hz, 1H, H-1)
[0243] .sup.13C-NMR (CDCl.sub.3; .delta. (ppm)): 30.0 (t, C-5);
34.5 (t, C-9); 48.9 (s, C-8a); 49.3 (q, NCH.sub.3); 55.6 (q,
OCH.sub.3); 59.1 (t, C-11); 62.0 (d, C-6); 66.3 (t, C-12); 85.6 (d,
C-4a); 111.1 (d, C-1); 121.5 (d, C-8); 126.5 (d, C-2); 128.3 (d,
C-7); 130.9 (s, C-12a); 132.7 (s, C-12b); 142.9 (s, C-3a); 145.3
(s, C-3b);
EXAMPLE 2
(4a.alpha.,8a.alpha.)-4a,5,9,10,11-Hexahydro-1-bromo-6-[(4-bromophenyl)met-
hyl]-3-methoxy-6H-benzofuro[3a,3,2-ef][3]benzazepin-6-ol
[0244] ##STR182##
[0245] A mixture of 23 mg (0.068 mmol) of
(4a.alpha.,8a.alpha.)-4a,5,9,10,11-hexahydro-1-bromo-3-methoxy-6H-benzofu-
ro[3a,3,2-ef][3]benzazepin-6-ol, 19 mg (0.136 mmol) of potassium
carbonate and 12 mg (0.082 mol) of sodium iodide is mixed in 20 ml
of absolute acetone with 21 mg (0.082 mmol) of 4-bromobenzyl
bromide and refluxed. After one hour, the reaction mixture is
concentrated by evaporation, the residue is taken up in 10 ml of 2N
hydrochloric acid, washed with ethyl acetate, made basic with
concentrated aqueous ammonia and extracted three times with 5 ml
each of ethyl acetate. The combined organic phases are washed once
with saturated aqueous sodium chloride solution, dried
(Na.sub.2SO.sub.4, activated carbon), filtered and concentrated by
evaporation. Further purification is carried out via flash
chromatography (15 g of silica gel; mobile solvent:
CHCl.sub.3.dbd.CHCl.sub.3:MeOH=95:5), by which 10 mg (29% of
theory) of oily substance on
(4a.alpha.,8a.alpha.)-4a,5,9,10,11-hexahydro-1-bromo-6-[(4-bromophenyl)me-
thyl]-3-methoxy-6H-benzofuro[3a,3,2-ef][3]benzazepin-6-ol is
obtained.
[0246] TLC: CHCl.sub.3:MeOH=9:1
[0247] .sup.1H-NMR (CDCl.sub.3; .delta. (ppm)): 1.78 (ddd, 1H,
H-5); 1.98-2.31 (m, 4H, H-5'/9/11/11'); 2.70 (ddd, 1H, H-9'); 3.57
(ddd, 1H, H-12); 3.82 (s, 3H, OCH.sub.3); 3.86 (ddd, 1H, H-12');
4.15 (b, 1H, H-6); 4.42 (d, 1H, NCH.sub.2); 4.65 (b, 1H, H-4a);
5.00 (d, 1H, NCH.sub.2'); 5.91 (d, 1H, H-7); 6.06 (dd, 1H, H-8);
6.92 (s, 1H, H-2); 7.28 (d, 2H, Ph-2/6); 7.43 (d, 2H, Ph-3/5)
##STR183##
EXAMPLE 2
EXAMPLE 3
2-[4-[(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-benzof-
uro[3a,3,2-e,f][2]benzazepine-11-yl]butyl]-1,2-benzoisothiazol-3(2H)-one,
1,1-dioxide tartrate, dihydrate (SPH-1374)
[0248] ##STR184##
[0249] 2-(6-Bromohexyl)-1,2-benzisothiazol-3(2H)-one-1,1-dioxide
(2.33 g, 7.32 mmol), produced according to Hamor, G. H.; Rubessa,
F.; Farmaco Ed. Sci. 1970, 25, 36-39, Norgalanthamine (2.00 g, 7.32
mmol) and N-ethyldiisopropylamine (2.84 g, 22.0 mmol) in absolute
chloroform (20 ml) are stirred at boiling temperature for 24
hours.
[0250] The solvent is drawn off, and the residue is purified by
column chromatography (150 g of silica gel,
chloroform:methanol:ammonia:96.5:3:0.5), by which the product is
obtained as a colorless foam (2.67 g, 5.23 mmol, 71.4%).
[0251] TLC: Chloroform:methanol:ammonia=89:10:1; Rf=0.5
[0252] .sup.1H-NMR (CDCl.sub.3): .delta. 8.05-7.72 (m, 4H),
6.63-6.55 (m, 2H), 6.10-5.90 (m, 2H), 4.56 (b, 1H), 4.15-4.01 (m,
2H), 3.84-3.70 (m, 6H), 3.42-3.04 (m, 2H), 2.71-2.35 (m, 4H),
2.10-1.72 (m, 4H) 1.65-1.40 (m, 2H);
[0253] .sup.13C-NMR (CDCl.sub.3) .delta. 158.8 (s), 145.7 (s),
143.9 s), 137.5 (s) 134.6 (d), 134.1 (d), 133.0 (s), 129.4 (s),
127.4 (d), 127.2 (s) 126.8 (d), 124.9 (d), 121.8 (d), 120.7 (d),
111.0 (d), 88.5 (d), 61.9 (d), 57.5 (t), 55.7 (q), 51.4 (t), 50.5
(t), 48.3 (S), 39.1 (t), 32.9 (t), 29.8 (t), 26.0 (t), 24.5 (t)
[0254] The base (SPH-1369, 2.50 g, 4.90 mmol) and (+)-tartaric acid
(0.80 g, 5.33 mmol, 1.09 equivalents) is heated in EtOH (95%, about
10 ml) until the solution turns clear (about 50.degree. C.), and
this solution is added still hot drop by drop within 5 minutes to
absolute ether (about 200 ml) that is stirred with a magnet,
whereby a white precipitate is produced. After standing overnight
at room temperature, the crystals that are obtained are filtered
off by suction and washed with absolute ether (3.times.50 ml), and
the product is dried in a vacuum desiccator at room temperature/50
mbar on calcium chloride, whereby the tartrate dihydrate is
obtained in the form of a colorless powder (3.184 g, 93.3% of
theory). A sample quantity is dried at 2 mbar and 40.degree. C. for
8 hours on phosphorus pentoxide.
[0255]
C.sub.27H.sub.30N.sub.2O.sub.6S.C.sub.4H.sub.4O.sub.4.2H.sub.2O
(JOS 1659) (697.7) TABLE-US-00004 Fnd. C 56.18 H 5.78 N 4.23 Cld.
a) C 55.74 H 5.81 N 4.15 b) C 55.76 H 5.79 N 4.26
EXAMPLE 4
2-[5-[(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-benzof-
uro[3a,3,2-e,f][2]benzazepine-11-yl]pentyl]-1,2-benzoisothiazol-3(2H)-one,
1,1-dioxide (SPH-1372)
[0256] ##STR185##
[0257] 2-(5-Bromopentyl)-1,2-benzisothiazol-3(2H)-one-1,1-dioxide
(1.66 g, 5.00 mmol), norgalanthamine (1.37 g, 5.00 mmol) and
N-ethyldiisopropylamine (1.94 g, 15.0 mmol) in absolute chloroform
(15 ml) are stirred for 24 hours at boiling temperature.
[0258] The solvent is drawn off, and the residue is purified by
column chromatography (150 g of silica gel,
chloroform:methanol:ammonia:96.5:3:0.5), by which the product is
obtained as a colorless foam (2.09 g, 3.99 mmol, 79.7%).
[0259] TLC: Chloroform:methanol:ammonia=89:10:1; Rf=0.5
[0260] .sup.1H-NMR (CDCl.sub.3): .delta. 8.05-7.70 (m, 4H),
6.63-6.50 (m, 2H), 6.09-5.85 (m, 2H), 4.55 (b, 1H), 4.15-3.99 (m,
2H), 3.82-3.60 (m, 5H), 3.41-2.92 (m, 2H), 2.70-2.32 (m, 3H),
2.09-1.70 (m, 4H), 1.58-1.23 (m, 6H);
[0261] .sup.13C-NMR (CDCl.sub.3): .delta. 158.7 (s), 145.6 (s),
143.8 (s), 137.5 (s), 134.5 (d), 134.1 (d), 133.0 (q), 129.4 (s),
127.3 (d), 127.2 (s), 126.8 (d), 124.8 (d), 121.8 (d), 120.7 (d),
111.0 (d), 88.5 (d), 61.8 (d), 57.5 (t), 55.7 (q), 51.4 (t), 51.0
(t), 48.2 (S), 39.1 (t), 32.8 (t), 29.8 (t), 28.1 (t), 26.6 (t),
24.3 (t), 20.3 (d)
Production of Fumarate (UJ-1682)
[0262] A hot (about 50.degree. C.) solution of the base (1.686 g,
3.21 mmol) in EtOH (95%, 10 ml) is combined with saturated fumaric
acid solution (10 ml, about 0.5 M in 95% ethanol), heated at about
60.degree. C. until a clear solution is obtained, and this solution
that is still hot is fed in drops within 5 minutes to absolute
ether (about 200 ml) that is stirred with a magnet, whereby a white
precipitate is produced. After standing overnight at room
temperature, the crystals that are obtained are filtered off by
suction and washed with absolute ether (3.times.50 ml), and the
product is dried in a vacuum desiccator at room temperature/50 mbar
on calcium chloride, whereby the fumarate is obtained in the form
of a colorless powder (1.394 g, 67.7% of theory). A sample quantity
is dried at 2 mbar and at 40.degree. C. for 8 hours on phosphorus
pentoxide. A second fraction is obtained from the mother liquor
(=UJ-1682-1-2).
[0263]
C.sub.28H.sub.32N.sub.2O.sub.6S.C.sub.4H.sub.4O.sub.4.1/2C.sub.4H.-
sub.10O (JOS 1657) (677.8) TABLE-US-00005 Cld. C 59.54 H 6.21 N
4.21 Fnd. C 59.49 H 6.18 N 4.20
EXAMPLE 5
2-[6-[(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-benzof-
uro[3a,3,2-e,f][2]benzazepine-11-yl]hexyl]-1,2-benzoisothiazol-3(2H)-one,
1,1-dioxide fumarate (SPH-1373)
[0264] ##STR186##
[0265] 2-(6-Bromohexyl)-1,2-benzisothiazol-3(2H)-one-1,1-dioxide
(1.50 g, 4.33 mmol), produced according to Kim, Sung-Kyu; Cho,
Su-Dong; Moon, Jung-Kyen; Yoon, Yong-Jin. J. Heterocycl. Chem.
(1996), 33(3), 615-618, norgalanthamine (1.18 g, 4.33 mmol) and
N-ethyldiisopropylamine (1.68 g, 13.0 mmol) in absolute chloroform
(15 ml) is stirred for 24 hours at boiling temperature. The solvent
is drawn off, and the residue is purified by column chromatography
(150 g of silica gel, chloroform:methanol:ammonia:96.5:3:0.5), by
which the base is obtained as a colorless foam (1.91 g, 3.52 mmol,
81.4%).
[0266] TLC: Chloroform:methanol:ammonia=89:10:1; Rf=0.5
[0267] .sup.1H NMR (CDCl.sub.3) .delta. 8.08-7.72 (m, 4H),
6.68-6.55 (m, 2H), 6.12-5.90 (m, 2H), 4.57 (b, 1H), 4.16-4.01 (m,
2H), 3.82-3.65 (m, 6H), 3.52-3.03 (m, 2H), 2.71-2.28 (m, 3H),
2.10-1.71 (m, 4H), 1.55-1.25 (m, 7H);
[0268] 158.8 (s), 145.7 (S), 143.9 (s), 137.6 (s), 134.6 (d), 134.2
(d), 133.1 (s), 129.5 (s), 127.4 (d), 127.3 (s), 126.9 (d), 125.0
(d), 121.9 (d), 120.8 (d), 111.1 (d), 88.6 (d), 62.0 (d), 57.6 (t),
55.8 (q), 51.5 (t), 48.3 (t), 39.3 (t), 32.9 (t), 29.9 (t) 28.2
(t), 27.1 (t), 26.7 (t) 26.6 (t)
Production of Fumarate
[0269] A clear solution that is obtained by heating the base (1.33
g, 2.47 mmol) in fumaric acid solution (8 ml, saturated solution in
95% ethanol) to about 60.degree. C. is added drop by drop within 5
minutes to absolute ether that is stirred with a magnet, whereby a
white precipitate is produced. After standing overnight at room
temperature, the crystals that are obtained are filtered off by
suction and washed with absolute ether (3.times.50 ml), and the
product is dried in a vacuum desiccator at room temperature/50 mbar
on calcium chloride, whereby the fumarate is obtained in the form
of a colorless powder (1.170 g, 72% of theory). A sample quantity
is dried at 2 mbar and 40.degree. C. for 8 hours on phosphorus
pentoxide.
[0270] C.sub.29H.sub.34N.sub.2O.sub.6S.C.sub.4H.sub.4O.sub.4 (JOS
1658) TABLE-US-00006 Cld.: C 60.54, H 5.85, N 4.28 Fnd.: C 60.49, H
5.97, N 4.22
EXAMPLE 6
Step 1: 2-(4-Bromobutyl)-5,6-dimethoxy-1-oxoindane-2-carboxylic
acid methyl ester
[0271] ##STR187##
[0272] 5,6-Dimethoxy-1-oxoindane-2-carboxylic acid methyl ester
(4.0 g, 16.0 mmol), produced according to Fukushi, Hideto; Mabuchi,
Hiroshi; Itoh, Katsumi; Terashita, Zen-ichi; Nishikawa, Kohei;
Sugihara, Hirosada; Chem. Pharm. Bull. 1994, 42(3), 541-550, is
added in substance at room temperature to a suspension of sodium
hydride (0.84 g, 17.6 mmol, 50% in white oil, released from white
oil by digestion with absolute petroleum ether (3.times.50 ml) in
absolute DMF, and the solution is stirred for 45 minutes at room
temperature. Then, it is mixed with 1,4-dibromobutane (24.2 g,
112.0 mmol) and stirred for 18 hours at room temperature. It is
dispersed between water and ether, the aqueous phase is extracted
quantitatively with ether, the combined organic phases are washed
with water (5.times.), saturated common salt solution (1.times.)
and dried (sodium sulfate/activated carbon). Excess dibromoalkane
under high vacuum is separated by bulb tube distillation
(100.degree. C./0.05 mbar) from the residue that is obtained after
concentration by evaporation, and the residue that is obtained is
recrystallized from boiling tert-butylmethyl ether (25 ml), by
which the product is obtained in the form of colorless crystals
(5.02 g, 13.0 mmol, 81.6%).
[0273] TLC: Petroleum ether:ethyl acetate=3:1; Rf=0.15
[0274] Melting point: 92-93.degree. C.
[0275] .sup.1H NMR (CDCl.sub.3): .delta. 7.13 (s, 1H), 6.88 (s,
1H), 3.94 (s, 3H) 3.87 (s, 3H), 3.65 (s, 3H), 3.58 (d, J=18.3 Hz,
1H), 3.33 (t, J=6.7 Hz, 2H), 2.97 (d, J=17.2 Hz, 1H), 2.20-1.99 (m,
1H), 1.95-1.73 (m, 3H), 1.53-1.26 (m, 2H);
[0276] .sup.13C NMR (CDCl.sub.3): .delta. 200.7 (s), 171.6 (s),
156.1 (s), 149.7 (s), 148.5 (s), 127.7 (s), 107.1 (d), 104.8 (d),
60.6 (s), 56.2 (q), 56.0 (q), 52.6 (q), 36.3 (t), 33.6 (t), 33.2
(t), 32.6 (t) 23.1 (t)
[0277] Number, chemical displacement and multiplicity of the peaks
found confirm the postulated structure
Step 2
2-(4-Bromobutyl)-5,6-dimethoxyindan-1-one
[0278] ##STR188##
[0279] 2-(4-Bromobutyl)-5,6-dimethoxy-1-oxoindane-2-carboxylic acid
methyl ester (3.0 g, 7.79 mmol) is stirred in concentrated
hydrochloric acid (10 ml) and acetic acid (30 ml) for 12 hours at
60.degree. C. It is mixed with saturated sodium carbonate solution,
neutralized with sodium carbonate and extracted quantitatively with
ether, the combined organic phases are washed with saturated sodium
carbonate solution (3.times.), water (1.times.), saturated common
salt solution (1.times.), dried (sodium sulfate/activated carbon)
and the residue that is obtained after concentration by evaporation
is crystallized from tert-butylmethyl ether (10 ml). In this way,
the product is obtained in the form of colorless crystals (1.85 g,
5.65 mmol, 72.5%).
[0280] TLC: Petroleum ether:ethyl acetate=3:1; Rf=0.2
[0281] Melting point: 72-73.degree. C.
[0282] .sup.1H NMR (CDCl.sub.3): .delta. 7.15 (s, 1H), 6.85 (s,
1H), 3.95 (s, 3H) 3.88 (s, 3H), 3.40 (t, J=6.8 Hz, 1H), 3.23 (dd,
J=18.0 Hz, J=8.0 Hz, 1H), 2.78-2.57 (m, 2H), 2.00-1.72 (m, 3H),
1.65-1.35 (m, 3H); .sup.13C NMR (CDCl.sub.3): .delta. 207.1 (s),
155.5 (s), 149.4 (s), 148.8 (s), 129.3 (s), 107.3 (d), 104.3 (d),
56.1 (t), 56.0 (t), 47.4 (d), 33.5 (t), 32.6 (t), 32.5 (t), 30.6
(t), 25.8 (t)
Step 3
2-(4-[(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-benzof-
uro[3a,3,2-e,f][2]benzazepine-11-yl]butyl]-5,6-dimethoxyindan-1-one
[0283] ##STR189##
[0284] 2-(4-Bromobutyl)-5,6-dimethoxyindan-1-one (1.0 g, 3.01
mmol), norgalanthamine (919 mg, 3.36 mmol) and potassium carbonate
(1.26 g, 9.09 mmol, anhydrous, finely ground) are stirred at
boiling temperature for 24 hours as in absolute acetonitrile (10
ml).
[0285] The reaction mixture is filtered, the solvent is drawn off,
and the residue is purified by column chromatography (150 g of
silica gel, chloroform:methanol:ammonia:96.5:3:0.5), by which the
product is obtained as a colorless foam (1.21 g, 2.32 mmol,
77.6%).
[0286] TLC: Chloroform:methanol:ammonia:8.95:10:0.5, Rf=0.65
[0287] .sup.1H-NMR (CDCl.sub.3): .delta. 7.14 (s, 1H), 6.83 (s,
1H), 6.67-6.52 (m, 2H), 6.12-5.90 (m, 2H), 4.57 (b, 1H), 4.02-4.18
(m, 2H), 3.93 (s, 3H), 3.87 (s, 3H), 3.80 (s, 3H), 3.75 (d, J=13.7
Hz, 1H), 3.43-3.06 (m, 3H), 2.75-2.35 (m, 5H), 2.11-1.83 (m, 3H),
1.59-1.29 (m, 6H);
[0288] .sup.13C NMR (CDCl.sub.3): .delta. 207.5 (s), 155.4 (s),
149.3 (s), 148.9 (s), 145.7 (s), 144.0 (s), 133.1 (s), 129.4 (s),
127.5 (d), 126.9 (d), 121.9 (d), 111.1 (d), 107.3 (d), 104.2 (d),
88.6 (d), 62.0 (d), 57.7 (t), 56.1 (q), 56.0 (q), 55.8 (q) 51.5
(t), 51.2 (t) 48.3 (t), 47.5 (d), 32.8 (t), 32.5 (t), 31.5 (t),
29.9 (t), 27.4 (t), 25.1 (t)
EXAMPLE 7
Step 1: 2-(5-Bromopentyl)-5,6-dimethoxy-1-oxoindane-2-carboxylic
acid methyl ester
[0289] ##STR190##
[0290] 5,6-Dimethoxy-1-oxoindane-2-carboxylic acid methyl ester
(3.0 g, 12.0 mmol) is added in substance at room temperature to a
suspension of sodium hydride (0.62 g, 13.2.mmol, 50% in white oil,
released from white oil by digestion with absolute petroleum ether
(3.times.50 ml)) in absolute DMF, and the solution is stirred for
45 minutes at room temperature. Then, it is mixed with
1,5-dibromopentane (19.3 g, 84.0 mmol) and stirred for 18 hours at
room temperature. It is dispersed between water and ether, the
aqueous phase is extracted quantitatively with ether, the combined
organic phases are washed with water (5.times.), saturated common
salt solution (1.times.) and dried (sodium sulfate/activated
carbon). Excess dibromoalkane is separated under high vacuum by
bulb tube distillation (100.degree. C./0.05 mbar) from the residue
that is obtained after concentration by evaporation, and the
residue that is obtained is recrystallized from boiling
tert-butylmethyl ether (20 ml), by which the product is obtained in
the form of colorless crystals (3.75 g, 9.4 mmol, 78.3%).
[0291] TLC: Petroleum ether:ethyl acetate=3:1; Rf=0.15
[0292] Melting point: 108.5-100.degree. C.
[0293] .sup.1H NMR (CDCl.sub.3): .delta. 7.15 (s, 1H), 6.89 (s,
1H), 3.96 (s, 3H) 3.89 (s, 3H), 3.67 (s, 3H), 3.60 (d, J=19.1 Hz,
1H), 3.35 (t, J=7.0 Hz, 2H), 2.96 (d, J=19.1 Hz, 1H), 2.20-1.15 (m,
8H)
[0294] .sup.13C NMR (CDCl.sub.3): .delta. 200.9 (s), 171.8 (s),
156.1 (s), 149.7 (s), 148.4 (s), 127.9 (s), 107.1 (d), 104.9 (d),
60.8 (s), 56.2 (q), 56.1 (q), 52.6 (q), 36.4 (t), 34.5 (t), 33.5
(t), 32.3 (t) 28.3 (t), 26.9 (d), 23.7 (t)
Step 2
2-(5-Bromopentyl)-5,6-dimethoxyindan-1-one
[0295] ##STR191##
[0296] 2-(5-Bromopentyl)-5,6-dimethoxy-1-oxoindane-2-carboxylic
acid methyl ester (3.0 g, 7.51 mmol) is stirred in concentrated
hydrochloric acid (10 ml) and acetic acid (30 ml) for 12 hours at
60.degree. C. It is mixed with saturated sodium carbonate solution,
neutralized with sodium carbonate and extracted quantitatively with
ether, the combined organic phases are washed with saturated sodium
carbonate solution (3.times.), water (1.times.), saturated common
salt solution (1.times.), dried (sodium sulfate/activated carbon),
and the residue that is obtained after concentration by evaporation
is crystallized from tert-butylmethyl ether (10 ml). In this way,
the product is obtained in the form of colorless crystals (1.78 g,
5.22 mmol, 69.5%).
[0297] TLC: Petroleum ether:ethyl acetate=3:1; Rf=0.2
[0298] Melting point: 67.5-68.5.degree. C.
[0299] .sup.1H NMR (CDCl.sub.3): .delta. 7.15 (s, 1H), 6.85 (s,
1H), 3.95 (s, 3H), 3.89 (s, 3H), 3.50 (t, J=7.0 Hz, 2H), 3.20 (dd,
J=6.4 Hz, J=9.5 Hz, 1H), 2.72 (d, J=3.2 Hz, 1H), 2.60 (d, J=3.2 Hz,
1H), 2.00-1.65 (m, 3H), 1.55-1.35 (m, 5H);
[0300] .sup.13C NMR (CDCl.sub.3): .delta. 207.4 (s), 155.5 (s),
149.4 (s), 148.8 (s), 129.4 (s), 107.4 (d), 104.3 (d), 56.2 (q),
56.0 (q), 47.5 (d), 44.9 (t), 32.5 (t), 32.3 (t), 31.4 (t), 26.8
(t), 26.5 (t)
Step 3
2-[5-[(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-benzof-
uro[3a,3,2-e,f][2]benzazepine-11-yl]pentyl]-5,6-dimethoxyindan-1-one
(SPH-1359)
[0301] ##STR192##
[0302] 2-(4-Bromopentyl)-5,6-dimethoxyindan-1-one (1.66 g, 4.86
mmol), norgalanthanamine (1.46 g, 5.35 mmol) and potassium
carbonate (2.01 g, 14.6 mmol, anhydrous, finely ground) are stirred
for 24 hours at boiling temperature as in absolute acetonitrile (10
ml).
[0303] The reaction mixture is filtered, the solvent is drawn off,
and the residue is purified by column chromatography (150 g of
silica gel, chloroform:methanol:ammonia:96.5:3:0.5), by which the
product is obtained as a colorless foam (1.84 g, 2.32 mmol,
70.9%)
[0304] TLC: Chloroform:methanol:ammonia:89.5:10:0.5, Rf=0.65
[0305] .sup.1H NMR (CDCl.sub.3): .delta. 7.11 (s, 1H), 6.82 (s,
1H), 6.63-6.54 (m, H), 6.10-5.88 (m, 2H), 4.55 (b, 1H), 4.17-4.00
(m, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.78 (s, 3H), 3.73 (d, J=13.7
Hz, 1H), 3.40-3.01 (m, 3H), 2.72-2.25 (m, 5H), 2.10-1.75 (m, 3H),
1.65-1.19 (m, 8H);
[0306] .sup.13C NMR (CDCl.sub.3): .delta. 207.4 (s), 155.3 (s),
149.2 (s), 148.8 (s), 145.6 (s), 143.8 (s), 133.0 (s), 129.4 (s),
129.3 (s), 127.4 (d), 126.9 (d), 121.8 (d), 111.0 (d), 107.2 (d),
104.2 (d), 88.5 (d), 77.2 (d), 61.9 (d), 57.6 (t), 56.0 (q), 55.9
(q), 55.7 (q), 51.4 (t), 48.2 (s), 47.5 (d), 32.9 (t), 32.4 (t),
31.5 (t), 29.8 (t), 27.2 (t), 27.1 (t)
Production of Fumarate
[0307] A solution of the base (1.00, 1.8.74 mmol) in saturated
fumaric acid solution (6 ml, about 0.5 M in 95% ethanol) is heated
at about 60.degree. C. until a clear solution is obtained, and this
solution that is still hot is added drop by drop within 5 minutes
to absolute ether (about 150 ml) that is stirred with a magnet,
whereby a white precipitate is produced. After standing overnight
at room temperature, the crystals that are obtained are filtered
off by suction and washed with absolute ether (3.times.50 ml), and
the product is dried in a vacuum desiccator at room temperature/50
mbar on calcium chloride, whereby the fumarate is obtained in the
form of a colorless powder (0.694, 57.0% of theory). A sample
quantity is dried at 2 mbar and 40.degree. C. for 8 hours on
phosphorus pentoxide. A second fraction is obtained from the mother
liquor.
[0308] C.sub.32H.sub.39NO.sub.6.C.sub.4H.sub.4O.sub.4.1/2H.sub.2O
(658.7) TABLE-US-00007 Cld. C 65.64 H 6.73 N 2.13 Fnd.: C 65.83 H
6.72 N 2.10
[0309] Formulas and Table for Examples 8-79 TABLE-US-00008
##STR193## ##STR194## ##STR195## ##STR196## ##STR197## BATCH
Beispiel Nr. SPH LABCODE R1 8 3bi SPH-1218 CB 30 --C(SMe).dbd.NCN 9
4a SPH-1229 CB 52 -pyrimidine-(2-A) 10 4b SPH-1234 CB 56
-2-Cl-pyrimidine-(4-yl) 11 4c SPH-1245 CB 59
-2-NEt2-pyrimidine-(4yl) 12 4d SPH-1244 CB 57
-2-O(CH2)3NMe2-pyrimidine-(4-yl) 13 4e SPH-1230 CB 53
-4,6-Cl-1,3,5-triazine-(2-yl) 14 4f SPH-1243 CB 58
4,6-di(NEt2)2-1,3,5-triazine-(2-yl) 15 4g SPH-1228 CB 43
-4,6-OPh-1,3,5-triazine-(2-yl) 16 4h SPH-1233 CB 51
-4,6-di(O(CH2)2NH2-1,3,5-triazine(2-yl) 17 4i SPH-1242 CB 55
4,6-di(O(CH2)3NMe2-1,3,5-triazine-(2-yl) 18 4j SPH-1246 MR 16
--CO--CH2Cl 19 4l SPH-1214 CB 34 --CO--NHCH(Me)2 20 4m SPh-1221 CS
45 --CO--NHC(Me)3 21 4n SPH-1231 CB 49 --CONHEt 22 4o SPH-1222 CS
46 --CONH-cyclohexane 23 4p SPH-1215 CB 33 --CONHPh 24 4q SPH-1237
CB 47 --CONH--Ph(4-Cl) 25 4r SPH-1267 CB 73 --CO--NH--CH(Me)Ph,
S-(-) 26 4s SPH-1232 CB 50 --CONH-2-naphthaline 27 4t SPH-1211 CB
13 --CSNHMe 28 4u SPH-1236 CB 48 --CSNHCH.sub.2CH.dbd.CH.sub.2 29
4v SPH-1259 HM 59 --C(COOMe)CHCOOMe 30 SPH1196 TK 36-2
--(CH2)3-(2-(4-F-phenyl)-2,5- diazabicyclo[2.2.1]heptane)-5-yl) 31
4x SPH-1219 CB 36 --CH.dbd.C(CN)2 32 4y SPH-1278 HM 60
CH.dbd.C(COOMe)2 33 4z SPH-1264 HM 58 --CHCHCOCH.sub.2OEt 34 4ac
SPH-1248 MR 7 --CH.sub.2--COOEt 37 4af SPH-1116 Ja 6-2
--(CH2)2--NH2 40 4ai SPH-1217 CB 28 --(CH2)2--COOEt 41 4aj SPH-1277
HM 57 --(CH2)2--COOC(Me)3 42 4ak SPH-1262 MR 14 --(CH2)2--CONHCHMe2
43 4ab SPH-1102 TK 72/5 --CH.sub.2--CH.dbd.CH.sub.2 43 4al SPH-1249
MR 13 --(CH2)2--CONHCMe3 44 4am SPH-1216 CB 35 --(CH2)2--CN 45 4an
SPH-1220 CB 41 --(CH2)3--OH 46 4aa SPH-1103 TK 74/3 --Bn 46 4ao
SPH-1235 CB 42 --(CH2)3--NH2 47 4ap SPH-1107 TK 94/3
--(CH2)3--N-piperidine 48 8a SPH-1280 CB 98 --Ph 49 8b SPH-1282 CB
100 -thiophene-2yl 50 8c SPH-1327 WO2 -(N-benzoyl)-4-piperidine 51
8e SPH-1296 CB 147 --COOPh 52 8f SPH-1328 CB 161 --C(.dbd.S)OPh 53
8g SPH-1292 CB 112 -Fmoc 54 8h SPH-1326 CB 171
--CO--(CH2)2--CH.dbd.CH.sub.2 55 8i SPH-1268 CB 78 --CONH2 56 8j
SPH-1287 HM 109 --CSNHMe 57 8k SPH-1269 CB 85 --CO--NHCH(Me)2 58 8l
SPH-1270 CB 86 --CO--NHC(Me)3 59 8m SPH-1266 CB 75
--CONH--Ph(2-CF3) 60 8n SPH-1272 CB 81 --C(SMe)NCN 61 8o SPH-1289
HM 117 --CH2-cyclopropane 63 8r SPH-1295 BM 1 --CH.sub.2--CN 64 8s
SPH-1314 DD 18 --CH2--CO--(2-phenyl-2,5-
diazabicyclo[2.2.1]heptane)-5-yl) 65 8t SPH-1311 BM4 --(CH2)2--NH2
66 8u SPH-1117 Ro21 CB 120 --(CH2)2--N-morpholine 67 8v SPH-1329 DD
26 --(CH2)2-(2-phenyl-2,5- diazabicyclo[2.2.1]heptane)-5-yl) 68 8w
SPH-1276 CS 89 --(CH2)2--COOH 69 4ae SPH-1096 TK 81/3 --(CH2)2--OH
69 8x SPH-1271 CB 87 --(CH2)2--COOC(Me)3 70 8z SPH-1315
--(CH2)3--OH 71 8aa SPH-1213 TK 96/3 --(CH2)3--NMe2 72 4k SPH-1104
Ro 20 --CO(CH2)14Me 72 8ab SPH-1286 HM 113 --(CH2)3--N-piperidine
73 4ad SPH-1099 TK 80-3 --CH.sub.2--CN 73 8ac SPH-1312 DD 24
--(CH2)3-(2-(4-F-phenyl)-2,5- diazabicyclo[2.2.1]heptane)-5-yl) 74
4ag SPH-1098 Ro 11 --(CH2)2--N-morpholine 75 9a SPH-1284 DD 10
--CO--NHCH(Me)2 76 9b SPH-1283 DD 9 --CO--NHC(Me)3 77 9c SPH-1118
Ro 22 --(CH2)2--N-morpholine 78 9d SPH-1330 RMA-15 --(CH2)3--NMe2
79 9e SPH-1333 RMA 14 --(CH2)3--N-piperidine [Key:] Galanthamin
Derivate = galanthamine derivatives [Key:] Beispiel = Example
--CONH-2-naphthaline = --CONH-2-naphthalene
EXAMPLE 8
Step 1
(6R)-1-Bromo-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef-
[2]benzazepin-6-one (2a)
[0310] Water (660 ml) and concentrated hydrochloric acid (400 ml)
were added to a stirred solution of
(6R)-5,6,9,10,11,12,1-bromo-3-methoxy-6-oxo-4aH-hexahydro-benzofuro[3a,3,-
2-ef][2]benzazepine-11(12H)-carboxaldehyde (2) (100.0 g, 0.26 mol)
in toluene (2.6 l). The reaction mixture was refluxed for 48 hours
while being stirred. The precipitate was filtered off and washed
with water (3.times.500 ml). The phases of the hydrate were
separated, and the organic phase was extracted with water
(3.times.500 ml). The precipitate was heated with the combined,
aqueous solutions of the hydrate and hot-filtered. The solution was
set at pH=12 with 30% sodium hydroxide. The precipitate was
filtered and dried (50.degree. C./50 mbar) to obtain 64.5 g (70%)
of title compound (2a) at about a melting point of 228-231.degree.
C. .sup.1H-NMR (CDCl.sub.6 .delta. 6.94 (dd, J.sub.1=10.3, 1.9 Hz,
1H), 6.62 (s, 1H), 6.00 (d, J=10.5 Hz, 1H), 4.69 (m, 1H), 4.04 (d,
J=15.9 Hz, 1H), 3.83 (d, J=15.9 Hz, 1H), 3.80 (s, 3H), 3.29 (m,
2H), 3.07 (d, J=1.9 Hz, 1H), 2.70 (dd, J.sub.1=17.8 Hz, J.sub.2=3.7
Hz, 1H), 2.16 (m, 1H), 1.80 (dt, J.sub.1=14.0 Hz, J.sub.2=2.9 Hz,
1H); .sup.13C-NMR (CDCl.sub.3) .delta. 194.3 (s), 146.9 (s), 143.8
(s), 135.3 (d), 130.6 (s), 129.3 (s), 126.9 (d), 121.9 (d), 111.8
(s), 87.9 (d), 56.3 (t), 55.9 (q), 51.8 (t), 49.0 (s), 37.2 (t),
33.0 (t). Anal. (C.sub.16H.sub.16BrNO.sub.3.O.4H.sub.2O) C, H,
N.
Step 2
(6R)-1-Bromo-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef-
[2]benzazepin-6-ol (3)
[0311] An L-selectride solution (1 M, 276 ml, 0.276 mol) was added
at -10.degree. C. to a solution of
(6R)-1-bromo-3-methoxy-5,6,9,10,11,12-hexahydro-4aH[1]benzofuro[3a,3,2-ef-
][2]benzazepin-6-one (2a) (64.5 g, 0.184 mol) in dry THF (1.3 l).
After 30 minutes of stirring at -10 to -5.degree. C., the reaction
mixture was hydrolyzed with MeOH (80 ml) and concentrated by
evaporation. The residue that was obtained was dissolved in 2N
hydrochloric acid and stirred for 18 hours at room temperature. The
solution was set at pH=9 with concentrated ammonia and extracted
with EtOAc (3.times.500 ml), the combined, organic layers were
washed with brine and dried (Na.sub.2SO.sub.4) to produce 55.9 g
(90.6%) of the product. .sup.1H-NMR (CDCl.sub.3) .delta. 6.85 (s,
1H), 6.05 (m, 2H), 4.56 (b, 1H), 4.48 (d, J=14.7 Hz, 1H), 4.10 (m,
1H), 3.85 (d, J=14.7 Hz, 1H), 3.80 (s, 3H), 3.35-3.05 (m, 2H), 2.62
(m, 1H), 2.25 (m, 1H), 1.98 (d, J=13.2 Hz, 1H), 1.85-1.65 (m, 2H);
.sup.13C-NMR (CDCl.sub.3) .delta. 145.8 (s), 144.0 (s), 134.1 (s),
131.6 (s), 127.9 (d), 126.8 (d), 115.5 (d), 113.0 (s), 88.4 (d),
61.7 (d), 56.0 (q), 52.7 (t), 49.3 (s), 46.6 (t), 29.7 (t).
Step 3
(6R)-3-Methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benz-
azepin-6-ol (=(+/-)norgalanthamine) (4)
[0312] Activated zinc (89.0 g, 1.36 mol) and calcium chloride (44.0
g, 0.40 mol) were added to a solution of
(6R)-1-bromo-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-e-
f][2]benzazepin-6-ol (3) (20.0 g, 56.8 mmol) in 50% EtOH (1000 ml).
The reaction mixture was refluxed for 18 hours and filtered on
Celite. The filtrate was concentrated by evaporation, the residue
was diluted with 2N hydrochloric acid (500 ml) and extracted with
EtOAc (3.times.400 ml). The pH of the aqueous phase was set at
above 8.5 with concentrated ammonia and extracted with
CH.sub.2Cl.sub.2 (3.times.100 ml) and with
CH.sub.2Cl.sub.2:MeOH=9:1 (3.times.100 ml). The combined organic
extracts were washed with brine (200 ml), dried (Na.sub.2SO.sub.4)
and concentrated by evaporation to produce 12.3 g (79.0% of
compound 4: .sup.1H-NMR (CDCl.sub.3) .delta. 6.62 (b, 2H), 6.02 (m,
2H), 4.61 (b, 1H), 4.14 (t, J=4.3 Hz, 1H), 3.98 (d, J=5.0 Hz, 2H),
3.83 (s, 3H), 3.30 (m, 1H), 2.69 (t, J=15.7, 1H), 2.10-1.63 (m,
4H); .sup.13C-NMR (CDCl.sub.3) .delta. 146.2 (s), 144.1 (s), 133.1
(s), 131.7 (s), 127.8 (d), 126.8 (d), 120.8 (d), 111.1 (d), 88.4
(d), 61.9 (d), 55.9 (q), 53.3 (t), 48.5 (s), 46.7 (t), 39.4 (t),
29.9 (t).
[0313] Anal. (C.sub.20H.sub.26N.sub.2O.sub.4) C, H, N.
Step 4
Methyl(6R)-1-bromo-N.sup.11-cyano-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro--
4aH[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)carboximidothioate
(3bi)
[0314] 0.21 g, 1.4 mmol) of N-cyanodithiocarbonimidic acid dimethyl
ester (0.21 g, 1.4 mmol) was added to a solution of
(+/-)-norgalanthamine (0.5 g, 1.4 mmol) in EtOH:DMF=4:1 (20 ml).
The reaction mixture was refluxed for 4 days and concentrated by
evaporation. The residue was crystallized in EtOH to produce 0.25 g
(41.7%) of compound 3bi: .sup.1H-NMR (CDCl.sub.3): .delta. 6.90 (s,
1H) 6.05 (dd, J.sub.1=10.3 Hz, J.sub.2=5.0 Hz, 1H), 5.86 (d, J=10.3
Hz, 1H), 5.62 (d, J=16.5 Hz, 1H), 4.62 (b, 1H), 4.36 (d, J=16.5,
1H), 4.14 (m, 1H), 3.83 (s, 3H), 3.79 (m, 1H), 2.96 (d, J=15.3 Hz,
1H), 2.77 (s, 3H), 2.68 (m, 1H), 1.92 (m, 3H); .sup.13C-NMR
(CDCl.sub.3): .delta. 146.3 (s), 145.0 (s), 132.7 (s), 129.0 (s),
125.4 (d) 125.2 (d), 125.2 (s), 116.0 (d), 114.3 (d), 88.0 (d),
61.3 (d), 56.1 (q), 55.0 (t), 49.6 (t), 48.6 (s), 29.4 (t), 16.1
(q).
[0315] Anal. (C.sub.19H.sub.20BrN.sub.3O.sub.3S.0.85 EtOH) C, H,
N.
EXAMPLE 9
(6R)-3-Methoxy-11-(2-pyrimidinyl)-5,6,9,10,11,12-hexahydro-4aH[1]benzofuro-
[3a,3,2-ef[2]benzazepin-6-ol (4a)
[0316] 0.21 g, 1.8 mmol) of 2-chloropyrimidine and sodium
bicarbonate (0.61 g, 7.2 mmol) were added to a solution of
(+/-)-norgalanthamine (0.5 g 1.8 mmol) in EtOH (30 ml). The
reaction mixture was refluxed for 2 days and concentrated. The
residue was diluted with water (30 ml), and EtOAc (3.times.20 ml)
was extracted. The combined, organic extracts were washed with
common salt solution (20 ml), dried (Na.sub.2SO.sub.4) and
concentrated by evaporation to produce 0.51 g (80.8%) of 4a:
.sup.1H-NMR (DMSO-d) .delta. 7.82 (d, J=4.0 Hz, 2H), 6.42 (d,
J=12.0 Hz 1H), 6.23 (d, J=12.0 Hz, 1H), 6.03 (t, J=4.0 Hz, 1H),
5.83 (d, J=8.0 Hz, 1H), 5.54 (dd, J.sub.1=8.0 Hz, J.sub.2=3.0 Hz,
1H), 4.98 (d, J=14.0 Hz, 1H), 428 (d, J=16.0, 1H), 4.09 (b, 1H),
3.94 (d, J=14.0 Hz, 1H), 3.72 (m, 1H), 3.38 (s, 3H), 3.21 (t,
J=14.0 Hz, 1H), 2.54 (d, J=12.0 Hz, 1H), 2.15 (m, 1H), 1.55 (m,
3H), .sup.13C-NMR (DMSO-d) .delta. 159.5 (s), 156.7 (2), 145.5 (s),
142.8 (s), 131.6 (s), 128.9 (s), 126.8 (d), 126.1 (d), 120.8 (d),
109.9 (d), 108.8 (d), 86.8 (d), 61.3 (d), 54.8 (q), 50.2 (t), 47.3
(s), 47.4 (t), 34.6 (t) 29.2 (t). Anal.
(C.sub.20H.sub.21N.sub.3O.15 EtOH) C, H, N.
EXAMPLE 10
[0317]
(6R)-11-(2-Chloro-4-pyrimidinyl)-3-methoxy-5,6,9,10,11,12-hexahydr-
o-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol (4b) was produced
analogously to Example 9. Reaction time 40 hours, yield 0.62 g
(88.6%). .sup.1H-NMR (CDCl.sub.3) .delta. 7.84 (d, J=4.0 Hz, 1H),
6.88 (d, J=12.0 Hz, 1H), 6.69 (d, J=12.0 Hz, 1H), 6.05 (b, 2H),
5.90 (d, J=4.0 Hz, 1H), 5.58 (b, 1H), 4.34 (m, 2H), 4.18 (b, 1H),
3.80 (s, 3H), 3.60 (t, J=16.0 Hz, 1H), 2.73 (d, J=16.0 Hz, 1H),
2.39 (m, 1H), 2.04 (d, J=18 Hz, 1H), 1.87 (m, 2H); .sup.13C-NMR
(CDCl.sub.3) .delta. 160.5 (s), 158.4 (s), 157.0 (s), 145.0 (s)
144.1 (s), 132.2 (s), 128.2 (d), 127.8 (s), 126.6 (d), 126.1 (d),
111.0 (d), 107.1 (d), 88.1 (d), 61.6 (d), 55.8 (q), 53.8 (t) 48.3
(s), 46.0 (t), 34.9 (t), 29.6 (t).
EXAMPLE 11
(6R)-11-(2-Diethylamino)-4-pyrimidinyl)-3-methoxy-5,6,9,10,11,12-hexahydro-
-4aH-[1]benzofuro]3a,3,2-ef][2]benzazepin-6-ol (4c)
[0318] 0.1 g (1.30 mmol) of potassium hydroxide was added to a
solution of compound 4b (0.5 g, 1.30 mmol) in diethylamine (6 ml,
57.6 mmol). The reaction mixture was refluxed for 22 hours and
concentrated by evaporation. The residue was diluted with saturated
solution of potassium carbonate (30 ml) and extracted with EtOAc
(3.times.20 ml). The combined, organic phases were washed with
common salt solution (20 ml), dried (Na.sub.2SO.sub.4) and
concentrated by evaporation. Flash chromatography yielded 0.21 g
(38.5%) of 4c. Below, only the different NMR signals are described:
.sup.1H-NMR (CDCl.sub.3) .delta. 2.97 (d, J=16.0 Hz, 4H), 1.34 (m,
6H); .sup.13C-NMR (CDCl.sub.3) .delta. 36.3 (t), 14.0 (q)
EXAMPLE 12
[0319]
(6R)-11-(2-(3-(Dimethylamino)propoxy)-4-pyrimidinyl)-3-methoxy-5,6-
,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol
(4d): The production was carried out analogously to Example 11.
Reaction time 2 hours, yield 0.16 g (41.0%). Only the different NMR
signals are described: .sup.1H-NMR (CDCl.sub.3) .delta. 4.34 (m,
2H), 2.28 (s, 6H), 2.00 (m, 4H); .sup.13C-NMR (CDCl.sub.3)
.delta.5.0 (t), 56.3 (t), 45.2 (q), 27.0 (t).
EXAMPLE 13
[0320]
(6R)-11-(4,6-Dichloro-1,3,5-triazine-2-yl)-3-methoxy-5,6,9,10,11,1-
2-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol (4e): A
solution of 2,4,6-trichloro-1,3,5-triazine (0.66 g, 3.7 mmol) in
acetone (16 ml) was poured onto ice water (35 ml) and added in
small portions at 0.degree. C. to (+/-)-norgalanthamine (1.0 g, 3.7
mmol). After the addition of 2N-sodium hydroxide (2 ml), the
reaction mixture was refluxed for 40 hours. The aqueous phase was
extracted with EtOAc (3.times.30 ml). The combined, organic phases
were washed with common salt solution (30 ml), dried
(Na.sub.2SO.sub.4) and concentrated by evaporation, to produce 0.90
g (59.5%) of compound 4e: .sup.1H-NMR (CDCl.sub.3) .delta. 6.82 (d,
J=10.0 Hz, 1H), 6.63 (d, J=10.0 Hz, 1H), 6.02 (b, 2H), 5.30 (d,
J=11.0 Hz, 1H), 4.75 (d, J=16.0, 1H), 4.50 (b, 1H) 4.22 (d, J=11.0
Hz, 1H), 4.11 (b, 1H), 3.78 (s, 3H), 3.59 (m, 1H), 3.06 (m, 1H),
2.61 (d, J=16.0 Hz, 1H), 1.90 (m, 3H); .sup.13C-NMR (CDCl.sub.3)
.delta. 207.0 (s) 171.2 (s), 163.7 (s), 146.2 (s), 143.9 (s), 132.2
(d), 129.5 (s), 127.6 (s), 126.7 (d), 121.5 (d), 110.8 (d), 88.0
(d), 61.7 (d), 55.7 (q), 51.8 (t), 48.2 (s), 43.4 (t), 35.9 (t),
29.7 (t).
[0321] Compounds 4f-4i contain the basic galanthamine skeleton,
such as 4e, but are different in the nitrogen substituent. Since
the proton and carbon signal of the galanthamine core are not
significantly different, the NMR signals of the nitrogen
substituent are relayed below.
EXAMPLE 14
[0322]
(6R)-11-(4,6-Bis-(diethylamino-1,3,5-triazine-2-yl)-3-methoxy-5,6,-
9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol
(4f): A solution of compound 4e (0.30 g, 0.71 mmol) in 40 ml of
acetone was poured onto 100 ml of ice water, and at 0.degree. C., a
solution of diethylamine (5.7 ml, 54.7 mmol) in acetone (10 ml) was
added. The reaction mixture was refluxed for 2 hours and then
poured onto 200 ml of ice water. The aqueous phase was extracted
with 3.times.100 ml of EtOAc. The combined organic phases were
washed with common salt solution (100 ml), dried on sodium sulfate
and concentrated by evaporation. Flash chromatography yielded 0.17
g (47.8%) of compound 4f: .sup.1H-NMR (CDCl.sub.3) .delta. 3.54 (m,
8H), 1.18 (m, 12H); .sup.13C-NMR (CDCl.sub.3) .delta. 41.7 (t),
13.4 (q)
EXAMPLE 15
[0323]
(6R)-11-(4,6-Diphenoxy-1,3,5-triazine-2-yl)-3-methoxy-5,6,9,10,11,-
12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol (4 g):
6.5 g (18.3 mmol) of 2,4,6-triphenoxy-1,3,5-triazine was added to a
solution of (+/-)-norgalanthamine (1.0 g, 3.74 mmol) in dioxane (60
ml). The reaction mixture was refluxed for 20 hours. The
precipitate was filtered off and washed with dioxane. The filtrate
was concentrated by evaporation, and flash chromatography yielded
0.91 g (45.9%) of compound 4 g: .sup.1H-NMR (CDCl.sub.3) .delta.
7.42-7.03 (m, 10H); .sup.13C-NMR (CDCl.sub.3) .delta. 172.1 and
162.3 (s), 138.3 and 138.1 (d), 134.6 (d), 131.3 and 130.8 (d).
EXAMPLE 16
[0324]
(6R)-11-(4,6-Bis-(2aminoethoxy)-1,3,5-triazine-2-yl)-3-methoxy-5,6-
,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol
(4H): The compound was produced according to the procedure
indicated in Example 11, whereby the reaction time was 3 hours.
0.15 g (67.9%) of compound 4H was obtained. .sup.1H-NMR
(CDCl.sub.3) .delta. 3.64 (m, 4H), 3.42 (m, 4H); .sup.13C-NMR
(CDCl.sub.3) .delta. 61.3 (t), 42.1 (t).
EXAMPLE 17
[0325]
(6R)-11-(4,6-Bis-(2-(dimethylamino)ethoxy)-1,3,5-triazine-2-yl)-3--
methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin--
6-ol (4i). According to the procedure indicated in Example 11,
compound 4i was obtained at a reaction time of 3 hours in a yield
of 0.16 g (59.5%): .sup.1H-NMR (CDCl.sub.3) .delta. 4.12 (q, J=6.0
Hz, 4H), 2.29 (d, J=4.0 Hz, 12H), 1.29 (m, 8H); .sup.13C-NMR
(CDCl.sub.3) .delta. 65.6 (t), 56.0 (t), 45.2 (q), 29.2 (t).
EXAMPLE 18
[0326]
2-Chloro-1-((6R)-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]be-
nzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)-1-ethanone (4j): 0.82
g of chloroacetyl chloride (7.3 mmol) and 0.81 g (8.0 mmol) of
triethylamine were added to a solution of (+/-)-norgalanthamine
(2.0 g, 7.3 mmol) in dry TRF (100 ml). The reaction mixture was
refluxed for 3 hours and concentrated by evaporation. The residue
was diluted with 2N hydrochloric acid (100 ml) and extracted with
EtOAc (3.times.75 ml). The aqueous phase was set at pH>8.5 with
concentrated ammonia and extracted with 3.times.75 ml of
CH.sub.2Cl.sub.2. The combined, organic phases were washed with
common salt solution, dried on sodium sulfate and concentrated by
evaporation. Flash chromatography yielded 0.20 g (7.7% of compound
4j): .sup.1H-NMR (CDCl.sub.3) .delta. 6.78 (b, 1H), 6.12 (m, 2H),
5.30 (d, J=11.0 Hz, 1H), 4.65 (m, 2H), 4.32-4.01 (m, 3H), 3.78 (s,
3H), 3.59 (m, 1H), 3.06 (m, 1H), 2.61 (d, J=16.0 Hz, 1H), 1.90 (m,
3H), .sup.13C-NMR (CDCl.sub.3) .delta. 166.0 (s) 146.2 (s), 144.9
(s), 132.3 (d), 128.3 (s), 127.3 (s), 126.0 (d), 120.2 (d), 111.2
(d), 88.2 (d), 61.7 (d), 55.8 (q), 52.8 (t), 48.1 (S), 45.5 (t)
41.4 (t), 35.4 (t), 29.6 (t).
EXAMPLE 19
(6R)-6-Hydroxy-N.sup.11-isopropyl-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]ben-
zofuro[3a,3,2-ef[2]benzazepine-11(12H)carboxamide (4l)
[0327] According to the procedure that is indicated in Example 11,
0.50 g of compound 4H was obtained at a reaction time of 4 hours
with a melting point of 106-108.degree. C.: .sup.1H-NMR
(CDCl.sub.3) .delta. 6.68 (dd, J=10.3; 8.3 Hz, 2H), 6.00 (m, 2H),
4.59 (b, 1H), 4.47 (d, J=16.4 Hz, 1H), 4.31 (d, J=16.4, 1H), 4.16
(m, 1H), 3.86 (m, 1H), 3.83 (s, 3H), 3.36 (dt, J=12.6; 2.0 Hz, 1H),
2.69 (dd, J 15.7; 3.4 Hz, 1H), 2.28 (d, J=11.3 Hz, 1H), 2.02 (m,
1H), 1.88 (dd, J=12.3; 3.4 Hz, 1H), 1.77 m, 1H), 1.07 (dd, J=21.8;
6.4 Hz, 6H); .sup.13C-NMR (CDCl.sub.3) .delta. 156.4 (s), 146.8
(s), 144.5 (s), 132.4 (s), 129.0 (s), 127.9 (d), 126.4 (d), 120.1
(d), 111.0 (d), 88.3 (d), 61.7 (d), 55.8 (q), 51.5 (t), 48.3 (s),
45.4 (t), 42.4 (d), 36.4 (t), 29.7 (t), 23.3 (q), 23.1 (q). Anal.
(C.sub.20H.sub.26N.sub.2O.sub.4), C, H, N.
[0328] Compounds 4m-4s contain the galanthamine skeleton such as
41, but are different with respect to the nitrogen substituent.
Since the proton and carbon signals of the galanthamine core do not
differ from one another significantly, only the signals of the
nitrogen substituent are relayed below.
EXAMPLE 20
(6R)--N.sup.11-t-Butyl-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benz-
ofuro[3a,3,2-ef[2]benzazepine-11(12H)-carboxamide (4m)
[0329] Process according to Example 11, reaction time 3 hours,
yield 0.57 g (85%); melting point 204-205.degree. C.; .sup.1H-NMR
(CDCl.sub.3) .delta. 1.24 (s, 9H); .sup.13C-NMR (CDCl.sub.3) 156.4
(s), 50.7 (s), 29.3 (q) Anal. (C.sub.21H.sub.28N.sub.2O.sub.4) C,
H, N.
EXAMPLE 21
(6R)--N.sup.11-Ethyl-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzof-
uro[3a,3,2-ef[2]benzazepine-11(12H)-carboxamide (4n)
[0330] Process according to Example 11, reaction time 3 hours,
yield 0.61 g (98%); melting point 137-139.degree. C.; .sup.1H-NMR
(CDCl.sub.3) .delta. 3.14 (q, J=4.0 Hz, 2H), 1.04 (t, J=10 Hz, 3H);
.sup.13C-NMR (CDCl.sub.3) .delta. 157.0 (s), 35.6 (t), 15.3
(q).
EXAMPLE 22
(6R)--N.sup.11-Cyclohexyl-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[[1]-
benzofuro[3a,3,2-ef][2]benzazepine-11-(12H)-carboxamide (4o)
[0331] Process according to Example 11, reaction time 5 hours,
yield 0.56 g (79%); melting point 225-228.degree. C.; .sup.1H-NMR
(CDCl.sub.3) .delta. 1.24 (s, 9H); .sup.13C-NMR (CDCl.sub.3)
.delta. 48.8 (d), 33.4 (t), 33.2 (t), 25.5 (t), 24.8 (t), 24.6
(t).
EXAMPLE 23
(6R)-6-Hydroxy-3-methoxy-N.sup.11-phenyl-5,6,9,10-tetrahydro-4aH-[1]benzof-
uro[3a,3,2-ef][2]benzazepine-11-(12H)-carboxamide (4p)
[0332] Process according to Example 11, reaction time 4 hours,
yield 0.34 g (47%); melting point 198-199.degree. C.; .sup.1H-NMR
(CDCl.sub.3) .delta. 7.24 (m, 4H), 6.99 (q, J=4.2 Hz, 1H);
.sup.13C-NMR (CDCl.sub.3) .delta. 154.5 (s), 138.7 (s), 128.7 (d),
122.9 (d), 119.7 (d), Anal. (C.sub.23H.sub.24N.sub.2O.sub.4,
H.sub.2O) C, H, N.
EXAMPLE 24
[0333]
(6R)--N.sup.11-4-Chlorophenyl-6-hydroxy-3-methoxy-5,6,9,10-tetrahy-
dro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11-(12H)-carboxamide
(4q): Process according to Example 11, reaction time 5 hours, yield
0.16 g (21%); .sup.1H-NMR (CDCl.sub.3) .delta. 17.49-6.94 (m, 4H);
.sup.13C-NMR .delta. (CDCl.sub.3) 154.1 (s), 139.1 (s), 123.4 (s),
122.9 (d), 119.7 (d).
EXAMPLE 25
[0334]
(6R)-6-Hydroxy-3-methoxy-N.sup.11-(S)-(-).alpha.-methylbenzyl-5,6,-
9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11-(12H)-carboxa-
mide (4r): Process according to Example 11, reaction time 6 hours,
yield 0.66 g (58%); .sup.1H-NMR (CDCl.sub.3) .delta. 7.21 (d, J=6.0
Hz, 4H), 7.17 (m, 1H), 4.91 (m, 1H), 1.41 (dd, J=20.0; 12 Hz, 3H);
.sup.13C-NMR (CDCl.sub.3) .delta. 156.6 and 165.4 (s), 144.5 (s),
128.3 and 128.1 (d), 126.5 and 126.4 (d), 125.9 and 125.5 (d), 46.1
(d), 22.9 and 22.6 (q).
EXAMPLE 26
[0335]
(6R)-6-Hydroxy-3-methoxy-N.sup.1''-(s)-(-).alpha.-methylbenzyl-5,6-
,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11-(12H)-carbox-
amide (4s): Process according to Example 11, reaction time 6 hours,
yield 0.66 g (58%); .sup.1H-NMR (CDCl.sub.3) .delta. 7.82 (d, J=8.0
Hz, 1H), 7.61 (d, J=6.0 Hz, 2H), 7.43 (m, 4H); .sup.13C-NMR
(CDCl.sub.3) .delta. 155.4 (s), 134.0 (s), 133.6 (s), 132.5 (s),
128.6 (d), 127.9 (d), 125.9 (d), 125.7 (d), 125.6 (d), 125.6 (d),
121.1 (d).
EXAMPLE 27
(6R)-6-Hydroxy-3-methoxy-N.sup.11-methyl-5,6,9,10-tetrahydro-4aH-[1]benzof-
uro[3a,3,2-ef][2]benzazepine-11-(12H)-carboxamide (4t)
[0336] Process according to Example 11, reaction time 3 hours,
yield 0.57 g (99%); melting point 219-221.degree. C.; .sup.1H-NMR
(CDCl.sub.3) .delta. 6.81 (d, J=8.3 Hz, 1H), 6.71 (d, J=8.1 Hz,
1H), 6.12 (d, J=10.3 Hz, 1H), 5.81 (dd, J=10.2; 4.4 Hz), 1H), 5.21
(d, J=15.8 Hz, 1H), 4.44 (s, 1H), 4.25 (d, J=5.5, 1H), 4.07 (b,
1H), 3.72 (s, 3H), 3.66 (m, 1H), 2.84 (d, J=3.4 Hz, 3H); 2.28 (d,
J=11.2 Hz, 1H), 2.04 (d, J=20.1 Hz, 1H), 1.88 (d, J=12.1 Hz, 1H),
1.65 (d, J=13.9 Hz, 1H); .sup.13C-NMR (CDCl.sub.3) .delta. 182.2
(s), 147.2 (b), 144.9 (s), 132.4 (s), 128.2 (d), 126.6 (s), 126.2
(d), 120.5 (d), 111.3 (d), 88.3 (d), 61.7 (d), 55.9 (q), 53.7 (t),
50.5 (t), 48.2 (s), 35.6 (t), 32.9 (q) 29.7 (t). Anal.
(C.sub.18H.sub.22N.sub.2O.sub.3S.O.05 CH.sub.3C.sub.6H.sub.5) C, H,
N.
EXAMPLE 28
[0337]
(6R)-6-Hydroxy-3-methoxy-N.sup.11-allyl-5,6,9,10-tetrahydro-4aH-[1-
]benzofuro[3a,3,2-ef][2]benzazepine-11-(12H)-carbothioamide (4u):
Process according to Example 11, reaction time 5 hours, yield 0.47
g (70%); melting point 192-194.degree. C.; same skeleton as 47,
only the different NMR signals are relayed: .sup.1H-NMR
(CDCl.sub.3) .delta. 6.85 (m, 1H), 5.13 (m, 2H), 4.14 (m, 2H);
.sup.13C-NMR (CDCl.sub.3) .delta. 181.2 (s), 133.7 (d), 116.6 (t),
48.3 (t). Anal. (C.sub.20H.sub.24N.sub.2O.sub.3S) C, H, N.
EXAMPLE 29
[0338]
((6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,-
3,2-ef](2]benzazepine-11-(12H)-yl-fumaric acid dimethyl ester (4v):
Process according to Example 11. 0.37 g (2.61 mmol) of
but-2-enedionic acid dimethyl ester was added to a solution of
(+/-)-norgalanthamine (0.5 g, 1.74 mmol) in 40 ml of
CH.sub.2Cl.sub.2, and it was stirred for 20 hours. The solvent was
removed to obtain an oily product, whose flash chromatography
yielded 0.28 g (39.1%) of 4v.
[0339] Melting point 112-115.degree. C., .sup.1H-NMR (CDCl.sub.3)
.delta. 6.63 (dd, J.sub.1=12.6 Hz, J.sub.2=8.1 Hz, 2H), 6.02 (dd,
J.sub.1=15.9 Hz, J.sub.2=11.5 Hz, 2H), 4.77 (b, 1H), 4.59 (b, 1H),
4.22 (d, J=15.9, 1H), 4.13 (b, 1H), 3.92 (s, 3H), 3.83 (s, 3H),
3.72 (d, J=15.9 Hz, 1H), 3.59 (s, 3H); 3.46 (m, 1H), 3.19 (dt,
J.sub.1=15.1 Hz, J.sub.2=3.1 Hz, 3H), 2.68 (dd, J.sub.1=15.8 Hz,
J.sub.2=2.2 Hz, 1H), 2.00 (m, 1H), 1.54 (m, 1H); .sup.13C-NMR
(CDCl.sub.3) .delta. 167.6 and 165.7 (s), 153.0 (s), 146.0 (s),
144.3 (s), 132.9 (s), 128.5 (s), 127.8 (d), 126.4 (d), 121.8 (d),
111.2 (d), 88.6 (d), 86.6 (d), 61.9 (d), 56.9 (t), 55.8 (q), 55.0
(q) 50.2 (q), 48.3 (s), 33.0 (t), 29.3 (t). Anal.
(C.sub.22H.sub.25NO.sub.7) C, H, N.
EXAMPLE 30
[0340]
(6R)-11-(3-2-(4-Fluoro)phenyl-2,5-diazabicyclo[2.2.1]heptane-5-yl--
propyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]b-
enzazepin-6-ol (4w): Process according to Example 11, reaction time
4 days, yield 0.14 g (63.0%); .sup.1H-NMR (CDCl.sub.3) .delta. 7.21
(m, 2H); 6.68 (m, 3H), 5.0 (s, 1H), 4.47 (d, J=14.0 Hz, 1H), 3.90
(m, 1H), 3.63 (m, 3H), 3.24 (m, 1H), 2.04 (m, 3H); .sup.13C-NMR
(CDCl.sub.3) 168.0 and 167.6 (s), 146.4 (d), 144.1 (s), 127.7 and
127.5 (d), 112.5 and 112.4 (d), 67.0 (t), 57.0 and 56.8 (d), 56.8
and 56.6 (t), 51.8 and 51.6 (t), 36.6 (t); 33.7 and 33.6 (t).
EXAMPLE 31
[0341]
2-((6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3-
a,3,2-ef][2]benzazepine-11(12H)-ylmethylene)-malononitrile
(4.times.): Process according to Example 11, reaction time 6 hours,
yield 0.41 g (64.8%); .sup.1H-NMR (CDCl.sub.3) .delta. 7.12 (m,
1H), 6.63 (dd, J.sub.1=12.6 Hz, J.sub.2=8.1 Hz, 2H), 6.02 (dd,
J.sub.1=15.9 Hz, J.sub.2=11.5 Hz, 2H), 4.59 (b, 1H), 4.22 (d,
J=15.9, 1H), 4.13 (b, 1H), 3.83 (s, 3H), 3.72 (d, J=15.9 Hz, 1H),
3.46 (m, 1H), 3.19 (dt, J.sub.1=15.1 Hz, J.sub.2=3.1 Hz, 3H), 2.68
(dd, J.sub.1=15.8 Hz, J.sub.2=2.2 Hz, 1H), 2.00 (m, 1H), 1.54 (m,
1H); .sup.13C-NMR (CDCl.sub.3) .delta. 157.2 and 156.8 (d), 146.0
(s), 144.3 (s), 132.9 (s), 128.5 (s), 127.8 (d), 126.4 (d), 124.2
(s), 121.8 (d), 116.8 and 116.5 (s), 115.0 and 114.7 (s), 111.2
(d), 88.6 (d), 61.9 (d), 56.9 (t) 55.8 (q), 48.3 (s), 33.0 (t),
29.8 (t).
EXAMPLE 32
[0342]
2-((6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[[1]benzofuro[-
3a,3,2-ef][2]benzazepine-11(12H)-ylmethylene)-malonic acid diethyl
ester (4y): Process according to Example 11, reaction time 21
hours, yield 0.46 g (63.3%), melting point 145-146.degree. C., same
skeleton as compound 4v, only the different NMR signals are
described: .sup.1H-NMR (CDCl.sub.3) .delta. 6.83 (s, 1H), 3.43 (m,
6H); .sup.13C-NMR (CDCl.sub.3) .delta. 181.2 (s), 133.7 (d), 116.6
(t), 48.3 (t). Anal. (C.sub.22H.sub.25NO.sub.70.25
C.sub.6H.sub.14O) C, H, N.
EXAMPLE 33
[0343]
3-((6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3-
a,3,2-ef][2]benzazepine-11(12H)-yl-acrylic acid ethyl ester (4z):
Process according to Example 11, reaction time 20 hours, yield 0.30
g (46.2%), melting point 121-122.degree. C., same skeleton as
compound 4v, only the different NMR signals are described:
.sup.1H-NMR (CDCl.sub.3) .delta. 7.40 (dd, J.sub.1=16.0 Hz,
J.sub.2=2.0 Hz, 1H), 4.68 (d, J=16.0 Hz, 1H), 4.10 (m, 2H), 1.28 8
m, 3H); .sup.13C-NMR (CDCl.sub.3) .delta. 169.3 and 167.8 (s),
161.1 (d), 97.5 (d), 59.0 (t), 14.5 and 14.3 (q).
[0344] Process E: A solution (+/-)-norgalanthamine (0.5 g, 1.83
mmol), 0.51 g (3.66 mmol) of potassium carbonate, (2.20 mmol) of
sodium iodide and alkyl halide (2.20 mmol) in acetone (20 ml) were
refluxed for 12 hours and concentrated by evaporation. The residue
was dissolved in 30 ml of 2N hydrochloric acid and extracted with
1.times.20 ml of AcOEt. The aqueous solution was set at pH>8.5
with concentrated ammonia and extracted with AcOEt (3.times.20 ml).
The combined, organic extracts were washed with common salt
solution, dried (Na.sub.2SO.sub.4), concentrated by evaporation and
purified by MPLC.
[0345] Compounds 4ab-4ah and 4an-4aq contain the basic galanthamine
skeleton such as 4aa, but are different with respect to the
nitrogen substituent. Since the proton and carbon signals of the
galanthamine core are not essentially different from one another,
only the NMR signals of the nitrogen substituent are relayed
below.
EXAMPLE 34
Ethyl-2-((6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,-
3,2-ef][2]benzazepine-11(12H)-yl)acetate (4ac)
[0346] According to process e with use of ethyl chloroacetate and a
reaction time of 1 hour, 0.48 g of the compound (73%) was obtained;
.sup.1H-NMR (CDCl.sub.3) .delta. 4.10 (m, 2H), 3.32 (s, 2H), 1.21
(t, J=7.3 Hz, 3H); .sup.13C-NMR (CDCl.sub.3) .delta. 170.7 (s),
60.4 (t), 58.0 (t), 14.1 (q).
EXAMPLE 35
Instructions:
Substitution in Position 1
Direct Introduction of New Substituents
3.2.1.1 [4aS-(4.alpha.a,
6.beta.,8aR*)]-4a,5,9,10,11,12-Hexahydro-1-(N,N-dimethylamino)-3-methoxy--
11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,
1-(N,N-dimethylamino)-galanthamine (MH-7)
[0347] TABLE-US-00009 ##STR198## ##STR199## 320 mg (1.06 mmol)
1-aminogalanthamine (4) 0.50 ml formic acid in 2 ml of water 0.25
ml formaldehyde (37%)
[0348] While being stirred with a magnet, all reactants, dissolved
in 10 ml of water, were heated together to 70.degree. C. After 4.5
hours, it was made basic with concentrated aqueous ammonia, whereby
a white precipitate in yellow solution precipitated. The reaction
mixture was exhaustively extracted with ethyl acetate, the combined
organic phases were dried on sodium sulfate, filtered, and the
solvent was drawn off.
[0349] The resulting substance mixture was separated on a silica
gel column (CHCL.sub.3:MeOH=1:1) and then distilled under high
vacuum by means of a bulb tube.
[0350] Yield: 0.17 g (0.52 mmol=49% of theory) of a light yellow
oil
[0351] C.sub.19H.sub.26N.sub.2O.sub.3 [330.43]
[0352] TLC: R.sub.f=0.49 (CHCl.sub.3:MeOH=1:1)
[0353] Boiling point: 180.degree. C./0.01 Torr
[0354] .alpha.D.sup.20 [c=0.1, CHCl.sub.3]=-156.36.degree.
[0355] FID Numbers:
[0356] .sup.1H: MHEMOF.016, .sup.13C: MHEM1F.002, DEPT:
MHEM2F.002
[0357] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 6.57 (s, 1H),
6.08 (dd, J=10.3, 1.0 Hz, 1H), 5.97 (dd, J=10.3, 4.8 Hz, 1H), 4.56
(bs, 1H), 4.45 (d, J=15.1 Hz, 1H), 4.12 (bs, 1H), 3.83 (s, 3H),
3.55 (d, J=15.1 Hz, 1H), 3.12 (td, J=13.1, 1.7 Hz, 1H), 2.97 (dt,
J=14.1, 3.5 Hz, 1H), 2.72-2.53 (m, 1H), 2.58 (s, 6H), 2.44 (s, 3H),
2.12-1.98 (m, 2H), 1.62 (ddd, J=13.6, 3.8, 2.1 Hz, 1H);
.sup.13C-NMR (50 MHz, CDCl.sub.3): .delta. 147.1 (s), 143.2 (s),
142.0 (s), 133.7 (s), 127.3 (d), 127.2 (d), 124.2 (s), 103.9 (d),
88.3 (d), 62.0 (d), 55.9 (q), 54.4 (t), 54.1 (t), 48.4 (s), 45.7
(q), 44.2 (q), 34.8 (t), 29.8 (t)
EXAMPLE 37
[0358]
(4aS,6R,8aS)-11-(3-Aminoethyl)-3-methoxy-5,6,9,10,11,12-hexahydro--
4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol (4af), Process F,
reactant compound 4ad, reaction time 1 hour; yield 0.31 g (59.2%);
melting point 47-51.degree. C.; .sup.1H-NMR (CDCl.sub.3) .delta.
2.69 (m, 2H), 1.92 (b, 2H); .sup.13C-NMR (CDCl.sub.3) .delta. 51.9
(s), 38.0 (t).
EXAMPLE 40
[0359]
Ethyl-3-((6R)-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzo-
furo[3a,3,2-ef][2]benzazepine-11(12H)-yl)propanoate (4ai): Process
B, reaction time 4 hours; yield 0.64 g (47.5%); .sup.1H-NMR
(CDCl.sub.3) .delta. 4.15 (q, J=6.0 Hz, 2H), 2.81 (t, 7.0 Hz, 2H),
2.47 (t, J=7.0 Hz, 2H), 1.23 (t, J=6 Hz, 3H); .sup.13C-NMR
(CDCl.sub.3) .delta. 172.4 (s), 60.3 (t), 57.3 (t), 32.9 (t), 14.1
(q).
EXAMPLE 41
[0360]
t-Butyl-3-((6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]ben-
zofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)propanoate (4aj):
Process B, reaction time 5 hours; yield 0.83 g (60.0%); .sup.1H-NMR
(CDCl.sub.3) .delta. 2.82 (t, J=7.0 Hz, 2H), 2.40 (t, J=7.0 Hz,
2H), 1.43 (S, 9H); .sup.13C-NMR (CDCl.sub.3) .delta. 172.0 (s),
80.5 (s), 57.7 (t), 34.2 (t), 28.0 (q). Anal.
(C.sub.24H.sub.33NO.sub.5) C, H, N.
EXAMPLE 42
[0361]
3-((6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3-
a,2,2-ef][2]benzazepine-11(12H)-yl)-N.sup.11-isopropylpropanamide
(4ak): Process B, reaction time 18 hours; yield 0.55 g (78.7%);
.sup.1H-NMR (CDCl.sub.3) .delta. 3.81 (m, 1H), 2.79 (t, J=6 Hz,
2H), 2.32 (t, J=6.0 Hz, 2H), 1.10 (t, J=12.0 Hz, 6H); .sup.13C-NMR
(CDCl.sub.3) .delta. 171.4 (s), 56.9 (t), 40.7 (d), 33.2 (t), 22.7
(q).
EXAMPLE 43
[0362]
3-((6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3-
a,3,2-ef][2]benzazepine-11(12H)-yl)-N1-t-butylpropanamide (4al):
Process B, reaction time 24 hours; yield 0.37 g (51.2%);
.sup.1H--NMR (CDCl.sub.3) .delta. 2.76 (t, 6.0 Hz, 2H), 2.29 (m,
2H), 1.28 (s, 9H); .sup.13C-NMR (CDCl.sub.3) .delta. 171.4 (s),
51.4 (t), 50.3 (s), 33.5 (t) 28.7 (q).
EXAMPLE 44
[0363]
3-((6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3-
a,3,2-ef][2]benzazepine-11(12H)-yl)propanitrile (4 am): Process B,
reaction time 4 hours; yield 0.53 g (90.6%); .sup.1H-NMR
(CDCl.sub.3) .delta. 2.82 (t, J=7.1 Hz, 2H), 2.47 (t, J=6.8 Hz,
2H); .sup.13C-NMR (CDCl.sub.3) .delta. 118.7 (s), 51.6 (t), 46.6
(t), 16.7 (t).
EXAMPLE 45
[0364]
(6R)-11-(3-Hydroxypropyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[-
1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol (4an): Process F, reactant
compound 4ai, reaction time 7 hours; yield 0.21 g (47.7%);
.sup.1H-NMR (CDCl.sub.3) .delta. 3.77 (m, 2H), 2.72 (m, 2H), 2.02
(m, 2H); .sup.13C-NMR (CDCl.sub.3) .delta. 63.9 (t), 57.3 (t), 29.8
(t).
EXAMPLE 46
[0365]
(6R)-11-(3-Aminopropyl)-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzo-
furo[3a,3,2-ef][2]benzazepin-6-ol (4ao): Process F, reactant
compound 4 am, reaction time 1 hour; yield 78 mg (52.8%);
.sup.1H-NMR (CDCl.sub.3) .delta. 3.22 (m, 2H), 2.68 (m, 2H), 1.72
(m, 2H); .sup.13C-NMR (CDCl.sub.3) .delta. 51.3 (t), 37.8 (t), 29.3
(t).
EXAMPLE 47
[0366]
(6R)-11-(3-Piperidine-1-yl-propyl)-3-methoxy-5,6,9,10-hexahydro-4a-
H-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol (4ap): Process e,
reaction time 3 days; yield 0.36 g (53.2%); .sup.1H-NMR
(CDCl.sub.3) .delta. 2.68 (m, 8H), 1.77 (m, 6H), 1.50 (m, 2H);
.sup.13C-NMR (CDCl.sub.3) .delta. 57.4 (t) 44.1 (t), 49.2 (t), 24.7
(t), 23.4 (t), 23.3 (t).
EXAMPLE 48
Step 1
(4a,S,6R8aS)-3-Methoxy-5,6,9,10,11,12-hexahydro-4aH[1]benzofuro[3a,3,2-ef[-
2]benzazepin-6-ol, (-)-norgalanthamine (8)
Method 1:
[0367] A solution of 7.72 g (20.0 mmol) of (+)-O,O-di-p-toluoyl
tartaric acid in 15 ml of methanol is added in drops to a solution
of 10.92 g (40.0 mmol) of rac.norgalanthamine (4) in 40 ml of
methanol, and it is then rewashed with 1 ml of methanol. The
solution is mixed with a seed crystal (without a seed crystal,
crystal formation can take several weeks), and it is allowed to
stand for two days at 4.degree. C. Then, it is thoroughly ground
with a glass rod and allowed to stand for another two to five days
at 4.degree. C., whereby it is always thoroughly ground again with
a glass rod. Then, the precipitated salt is suctioned off, rewashed
three times with ice-cold methanol and taken up in 100 ml of water.
The aqueous phase is made basic with concentrated aqueous ammonia
and extracted three times with 60 ml each of ethyl acetate. The
combined organic phases are washed once with saturated aqueous
sodium chloride solution, dried (Na.sub.2SO.sub.4, activated
carbon), filtered and concentrated by evaporation, by which 2.9 g
(37.5% of theory) of colorless crystals is obtained on
(-)-norgalanthamine (8).
Method 2:
[0368] m-CPBA (peroxide content 76%, 15.6 g 70 mmol) was added to a
solution of galanthamine (1) (20.0 g, 70 mmol) in CH.sub.2Cl.sub.2
(350 ml), and the clear solution was stirred for 40 minutes at room
temperature. In this stage, the conversion into the N-oxide was
quantitative, as was found by HPLC. Then, a solution of
FeSO.sub.4.7H.sub.2O (9.7 g 35 mmol) in MeOH (100 ml) was added.
The mixture was stirred for 20 minutes, mixed with 2N hydrochloric
acid (200 ml), the volatile portions (CH.sub.2Cl.sub.2 and MeOH)
were evaporated at reduced pressure and then washed with ether
(3.times.100 ml). The aqueous solution was set at pH>8.5 with
concentrated ammonia and extracted with CH.sub.2Cl.sub.2
(3.times.100 ml) and with CH.sub.2Cl.sub.2:MeOH=9:1 (3.times.100
ml). The combined, organic extracts were washed with common salt
solution (200 ml), dried on Na.sub.2SO.sub.4 and concentrated by
evaporation to produce a crystalline product (18.2 g, 96%), which
consisted of a 92:8 mixture of norgalanthamine and galanthamine.
MPLC (CHCl.sub.3:MeOH:Et.sub.3N=98:1.25:0.5), 16.1 g (84.7%) of
norgalanthamine (8): .sup.1H-NMR (CDCl.sub.3) .delta. 6.62 (b, 2H),
6.02 (m, 2H), 4.61 (b, 1H), 4.14 (t, J=4.3 Hz, 1H), 3.98 (d, J=5.0
Hz, 2H), 3.83 (s, 3H), 3.30 (m, 1H), 2.69 (d, J=15.7, 1H),
2.10-1.63 (m, 4H); .sup.13C-NMR (CDCl.sub.3 .delta. 146.2 (s),
144.1 (s), 133.1 (s), 131.7 (s), 127.8 (d), 126.8 (d), 120.8 (d),
111.1 (d), 88.4 (d), 61.9 (d), 55.9 (q), 53.3 (t), 48.5 (s), 46.7
(t), 39.4 (t), 29.9 (t).
Step 2
[0369]
(4a,S,6R.sub.8aS)-3-Methoxy-11-phenyl-5,6,9,10,11,12-hexahydro-4aH-
[1]benzofuro[3a,3,2-ef[2]benzazepin-6-ol (8a). 0.28 g of
phenylboric acid (7.2 mmol), 0.6 ml of pyridine (7.2 mmol), 0.67 g
of copper acetate (3.6 mmol) and one molecular sieve (1.0 g) were
added to a solution of 1.0 g of compound 8 (-)-norgalanthamine in
50 ml of CH.sub.2Cl.sub.2. The reaction mixture was stirred at room
temperature for 3 days. The precipitate was filtered off and washed
with 3.times.10 ml of CH.sub.2Cl.sub.2. The filtrate was extracted
3.times. with 50 ml of dilute ammonia solution. The combined,
aqueous phases were extracted with 3.times.50 ml of
CH.sub.2Cl.sub.2, the organic phases were washed with common salt
solution, dried on sodium sulfate and concentrated by evaporation.
MPLC yielded 0.33 g (26.4%) of compound 8a. Melting point
178-180.degree. C.;
[0370] .sup.1H-NMR (CDCl.sub.3) .delta. 7.18 (m, 2H), 6.82 (m, 3H),
6.67 (dd, J.sub.1=33.8 Hz, J.sub.2=7.6 Hz, 2H), 6.05 (b, 2H), 4.66
(b, 1H), 4.53 (m, 1H), 4.19 (d, J=15.3 Hz, 1H), 3.85 (s, 3H), 3.81
(d, J=15.3 Hz, 1H), 3.33 (m, 1H), 2.68 (m, 1H), 2.07 (m, 3H), 1.62
(m, 1H); .sup.13C-NMR (CDCl.sub.3 .delta. 158.2 (s), 145.9 (s),
144.5 (s), 133.0 (s), 129.4 (s), 128.9 (d), 128.1 (d), 126.9 (d),
126.1 (d), 121.1 (d), 116.0 (d), 111.4 (d), 88.6 (d), 61.9 (d),
57.0 (t), 55.9 (q), 50.6 (t) 48.2 (s), 32.8 (t), 29.9 (t). Anal.
(C.sub.22H.sub.23NO.sub.3.0.75 H.sub.2O) C, H, N.
EXAMPLE 49
[0371]
(4a,S,6R,8aS)-3-Methoxy-11-thiophenyl-5,6,9,10,11,12-hexahydro-4aH-
-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol (8b). The compound was
produced as in compound 8a, and the reaction time was 3 days, yield
0.14 g (28.0%). Only the NMR signals that are different from 8a are
described: 1H-NMR (CDCl.sub.3) 7.23 (m, 1H), 6.92 (t, J=3.0 Hz,
1H), 6.83 (d, J=2.7 Hz, 1H); .sup.13C-NMR (CDCl.sub.3 .delta. 145.7
(s), 127.6 (d), 126.2 (d), 125.0 (d). Anal.
(C.sub.20H.sub.21NO.sub.3S) C, H, N.
EXAMPLE 50
[0372]
(4a,S,6R,8aS)-11-Benzoyl-piperidine-4-yl)-3-methoxy-5,6,9,10,11,12-
-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol (8c).
1-Benzoyl-piperidin-4-one (0.34 g, 1.7 mmol), 0.47 g of titanium
isopropylate (1.7 mmol) and 3.6 g (1.3 mmol) of compound 8 were
melted for 30 minutes at 110.degree. C. After cooling at room
temperature, a solution of sodium cyanoborohydride (65 mg, 0.9
mmol) in dry EtOH (10 ml) was added, and the reaction mixture was
stirred at room temperature for 24 hours. After 2 ml of water was
added, the precipitate was filtered off, the filtrate was
concentrated by evaporation, and the residue was diluted with 20 ml
of EtOAc and filtered again. The clear solution was concentrated by
evaporation. MPLC yielded 0.24 g (38.8%) of compound 8c.
.sup.1H-NMR (CDCl.sub.3) .delta. 7.52-7.31 (m, 5H), 6.65 (b, 2H),
6.08 (m, 2H), 4.64 (b, 1H), 4.22-3.90 (m, 4H), 3.82 (s, 3H), 3.37
(m, 2H), 3.01-2.62 (m, 5H), 2.10-1.82 (m, 5H), 1.67-1.42 (m, 2H);
.sup.13C-NMR (CDCl.sub.3) 170.1 (s), 145.8 (s), 144.0 (s), 136.0
(s), 133.1 (s), 129.4 (d), 128.8 (d), 128.4 (d), 128.3 (d), 127.6
(d), 126.7 (d), 121.6 (d), 111.2 (d), 88.6 (d), 61.9 (d), 55.8 (q),
55.6 (t), 48.3 (t), 30.8 (t), 29.8 (t).
EXAMPLE 51
[0373]
(4a,S,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzo-
furo[3a,3,2-ef][2]benzazepine-11(12H)-carboxylic acid phenyl ester
(8e): 2.5 g of sodium bicarbonate (29.8 mmol) and 1.84 ml of phenyl
chloroformate (14.6 mol) were added to a solution of 0.50 g of
compound 8 (1.74 mmol) in 50 ml of CHCl.sub.3. The mixture was
vigorously stirred and refluxed for two hours and then diluted with
water (30 ml). The phases were separated. The aqueous phase was
extracted with 2.times.30 ml of CH.sub.2 Cl.sub.2, and the combined
organic phases were washed with 1N hydrochloric acid (30 ml), dried
on sodium sulfate and concentrated by evaporation under reduced
pressure to produce the crude product. MPLC
(CH.sub.2Cl.sub.2:MeOH=99:1) yielded 0.58 g (84.2%) of compound 8e:
1H-NMR (CDCl.sub.3) .delta. 7.51-7.04 (m, 5H), 6.82 (dd,
J.sub.1=24.0 Hz, J.sub.2=6.0 Hz, 2H), 6.04 (b, 2H), 4.91 (b, 1H),
4.69 (d, J=6.0 Hz, 2H), 4.20 (b, 1H), 3.83 (s, 3H), 3.42 (m, 1H),
3.19 (m, 1H), 2.43-1.90 (m, 4H); .sup.13C-NMR (CDCl.sub.3) .delta.
151.3 (s), 146.6 (s), 145.7 (s), 130.5 (s), 130.1 (s), 129.4 (d),
129.3 (d), 125.9 (d), 125.3 (d), 125.0 (d), 121.6 (d), 111.9 (d),
88.3 (d), 62.8 (d), 57.7 (t), 55.9 (q), 53.4 (t), 49.3 (s), 43.3
(t), 32.7 (t).
EXAMPLE 52
[0374]
(4a,S,6R,8aS)-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzo-
furo[3a,3,2-ef][2]benzazepine-11(12H)-carbothionic acid-O-phenyl
ester (8f): 0.24 ml of chlorothionoformate (1.74 mmol) was added to
a solution of 0.50 g of compound 8 (1.74 mmol) in 25 ml of
CHCl.sub.3, and the reaction mixture was stirred for 1 hour under
nitrogen. The solvent was separated to produce a colorless oil that
was flash-chromatographed to produce 0.50 g (71.2%) of compound 8a:
.sup.1H-NMR (CDCl.sub.3) .delta. 7.48-7.12 (m, 3H), 7.02 (d, J=6.0
Hz, 2H), 6.83 (m, 2H), 6.04 (b, 2H), 5.08 (m, 1H), 4.71 (d, J=26.0
Hz, 2H), 4.28 (m, 1H), 3.88 (s, 3H), 3.41 (m, 2H), 2.51-2.09 (m,
4H); .sup.13C-NMR (CDCl.sub.3) .delta. 187.5 and 187.4 (s), 153.8
and 153.7 (s), 146.7 and 146.6 (s), 145.8 and 145.7 (s), 131.3 and
130.6 (s), 130.2 and 129.5 (s), 129.2 and 129.1 (d), 126.0 and
125.9 (d), 125.0 and 124.9 (d), 122.7 and 122.6 (d), 121.6 and
120.4 (d), 115.3 (d), 112.0 (d), 84.4 and 84.2 (d), 63.1 and 62.9
(d), 55.9 (q), 51.5 (t), 49.5 and 49.3 (s), 47.8 (t), 36.9 (t),
33.1 (t).
EXAMPLE 53
[0375]
(4a,S,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzo-
furo[3a,3,2-ef][2]benzazepine-11(12H)-carboxylic
acid-9-H-fluor-9-ylmethyl ester (8 g): 0.5 g of
9-fluorenylmethyloxycarbonyl chloride (20 mmol) was added to a
solution of 0.5 g of compound 8 (1.8 mmol) and 2.5 ml of
triethylamine (1.8 mmol) in 20 ml of CH.sub.2Cl.sub.2, and it was
stirred for 30 minutes at room temperature. The reaction mixture
was concentrated by evaporation, the residue was diluted with 80 ml
of 2N hydrochloric acid and extracted with 5.times.50 ml of
CH.sub.2Cl.sub.2. The organic phases were combined, washed with
common salt solution, dried on sodium sulfate and concentrated by
evaporation to produce 0.88 g (99.2%) of compound 8 g. Melting
point 76-79.degree. C.; .alpha..sub.D=-33.0.degree.; .sup.1H-NMR
(CDCl.sub.3) .delta. 1.72 (dd, J=13.5; 5.0 Hz, 1H), 1.80-2.10 (m,
2H), 2.69 (dd, J=13.5; 5.0 Hz, 1H), 3.20-3.45 (m, 2H), 3.85 (s,
3H), 3.95-4.35 (m, 3H), 4.40-4.52 (m, 2H), 5.78-6.05 (m, 2H),
6.22-6.82 (m, 2H), 7.19-7.82 (m, 8H); .sup.13C-NMR (CDCl.sub.3)
.delta. 155.1 (s), 144.4 (s), 144.0 (S), 141.4 (s), 134.0 (s) 129.1
(s), 128.1 (s), 128.0 (d), 127.6 (d), 126.4 (d), 124.9 (d), 124.7
(d), 121.0 (d), 119.9 (d), 111.1 (d), 88.3 (d), 66.9 (t), 61.9 (d),
56.0 (q), 51.5 (t), 48.3 (S), 47.3 (d), 45.9 (t), 36.4 (t), 29.7
(t).
EXAMPLE 54
[0376]
1-((4a,S,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]be-
nzofuro[3a,3,2-ef](2]benzazepine-11(12H)-yl)pent-4-en-1-one (8 h):
0.97 ml (5.1 mmol) of pent-4-enoic anhydride was added at 0.degree.
C. to a solution of 1.0 g of compound 8 (3.7 mmol) and 0.51 ml (3.7
mmol) of triethylamine in 40 ml of CH.sub.2Cl.sub.2MeOH=5:2, and it
was stirred for 20 minutes. The reaction mixture was diluted with
20 ml of CH.sub.2Cl.sub.2, extracted with 2.times.20 ml of
saturated sodium bicarbonate solution. The combined aqueous phases
were extracted with 2.times.40 ml of CH.sub.2Cl.sub.2, the combined
organic phases were washed with common salt solution, dried on
sodium sulfate and concentrated by evaporation to produce 1.24 g
(95.3%) of compound 8 h: .sup.1H-NMR (CDCl.sub.3) .delta. 6.66 (b,
2H), 5.98 (m, 2H), 5.78 (m, 1H), 4.98 (m, 2H), 4.66 (d, J=12.8 Hz,
1H), 4.55 (s, 1H), 4.41 (d, J=16.5 Hz, 1H), 4.11 (b, 1H), 3.93 (m,
1H), 3.81 (s, 3H), 3.17 (t, J=17.7 Hz, 1H), 2.76-2.15 (m, 5H), 1.92
(m, 3H); .sup.13C-NMR (CDCl.sub.3) .delta. 171.7 (s), 146.8 (s),
144.6 (s), 137.3 (d), 132.4 (s), 128.1 (s), 128.0 (d), 126.3 (d),
120.3 (d), 114.9 (d), 111.0 (d), 88.2 (d), 61.7 (d), 55.8 (q), 52.7
(t), 48.2 (s), 44.6 (t), 35.7 (t), 33.2 (t), 29.7 (t), 28.8 (t)
EXAMPLE 55
[0377]
1-((4a,S,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]be-
nzofuro[3a,3,2-ef][2)benzazepine-11(12H)-carboxamide (8i): the pH
was set at 3 with 2N hydrochloric acid in a suspension of 0.5 g of
compound 8 (1.8 mmol) in 25 ml of water, and 0.23 g (3.6 mmol) of
sodium cyanide was added. The reaction mixture was stirred for 25
hours at room temperature, and then the pH was set at above 8.5
with concentrated ammonia and finally extracted with 3.times.20 ml
of CH.sub.2Cl.sub.2. The combined, aqueous phases were extracted
with common salt solution, dried on sodium sulfate and concentrated
by evaporation. MPLC (CHCl.sub.3:MeOH(NH.sub.3)=95:5) yielded 0.38
g (66%) of compound 8i: .sup.1H-NMR (CDCl.sub.3) .delta. 6.67 (dd,
J=12.8; 8.1 Hz, 2H), 6.00 (dd, J=15.1; 10.4 Hz, 2H), 4.68 (b, 1H),
4.51 (d, J=16.8 Hz, 1H), 4.31 (d, J=1.6.8 Hz, 1H), 4.11 (m, 1H),
3.81 (s, 3H), 3.35 (t, J=12.8 Hz, 1H), 2.67 (d, J=15.3 Hz, 1H),
2.41 (b, 1H), 1.97 (m, 2H), 1.72 (d, J=13.8 Hz, 1H); .sup.13C-NMR
(CDCl.sub.3) .delta. 158.1 (s), 146.8 (s), 144.5 (s), 132.3 (s),
128.6 (s), 128.0 (d), 126.2 (d), 120.3 (d), 111.1 (d), 88.1 (d),
61.6 (d), 55.8 (q), 51.9 (t), 48.3 (s), 45.6 (t), 36.3 (t), 29.7
(t).
EXAMPLE 56
[0378]
(4a,S,6R,8aS)-6-Hydroxy-3-methoxy-N.sup.11-methyl-5,6,9,10-tetrahy-
dro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carbothioamide
(8j): Process according to Example . . . , reaction time 4 hours,
yield 1.02 g (88%); melting point 229-230.degree. C., .sup.1H-NMR
and .sup.13C-NMR were identical to compound 4t. Anal.
C.sub.18H.sub.22N.sub.2O.sub.3S.O.2 CH.sub.3C.sub.6H.sub.5C, H,
N.
EXAMPLE 57
[0379]
(4a,S,6R,8aS)-6-Hydroxy-N.sup.11-isopropyl-3-methoxy-5,6,9,10-tetr-
ahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboxamide
(8k): Process A, reaction time 3 hours, yield 1.86 g (71%);
.sup.1H-NMR and .sup.13C-NMR were identical to compound 4i.
EXAMPLE 58
[0380]
(4a,S,6R,8aS)--N.sup.11-t-Butyl-6-hydroxy-3-methoxy-5,6,9,10-tetra-
hydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboxamide
(8l): Process A, reaction time 3 hours, yield 1.63 g (60%); melting
point 106-108.degree. C.; .sup.1H-NMR and .sup.13C-NMR were
identical to compound 4 m.
EXAMPLE 59
[0381]
(4a,S,6R,8aS)-6-Hydroxy-3-methyl-N.sup.11-2-trifluoromethyl-5,6,9,-
10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboxamid-
e (8m): Process A, reaction time 5 hours, yield 0.60 g (59%);
[0382] .sup.1H-NMR (CDCl.sub.3) .delta. 8.20 (t, J=8.0 Hz, 1H),
7.24 (m, 2H), 7.02 (m, 1H); .sup.13C-NMR (CDCl.sub.3) .delta. 153.6
(s), 137.6 (s), 127.6 (d) 126.1 (d), 123.0 and 117.8 (s), 122.3
(d), 119.8 (s), 111.3 (d)
EXAMPLE 60
[0383]
Methyl-(4a,S,6R,8aS)--N.sup.11-Cyano-6-hydroxy-=3-methoxy-5,6,9,10-
-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboximidot-
hioate (8n). The compound was produced as described for compound
3bi. Reaction time 3 days, yield 0.90 g (33.2%); .sup.1H-NMR
(CDCl.sub.3) .delta. 6.72 (m, 2H), 5.98 (d, J=10.2 Hz, 2H), 4.62
(m, 2H), 4.14 (b, 1H), 3.92 (d, J=11.8 Hz, 1H), 3.84 (s, 3H), 3.44
(m, 2H), 2.74 (s, 3H), 2.68 (m, 1H), 1.99 (m, 3H); .sup.13C-NMR
(CDCl.sub.3) .delta. 146.2 (s), 144.9 (s), 131.7 (s), 128.7 (d),
125.8 (s), 125.5 (d), 121.8 (d), 111.2 (d), 88.1 (d), 61.6 (d),
55.8 (q), 51.2 (t), 49.7 (t), 47.9 (s), 29.6 (t), 16.1 (q).
EXAMPLE 61
(4a,S,6R,8aS)-11-(Cyclopropylmethyl)-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]-
benzofuro[3a,3,2-ef][2]benzazepin-6-ol (8o)
[0384] Process according to Example E, reaction time 36 hours,
yield 0.12 g (29.0%); same skeleton as 4aa, only the different NMR
signals are described.
[0385] .sup.1H-NMR (CDCl.sub.3) .delta. 3.48 (t, J=8.0 Hz, 2H),
0.91 (m, 1H) 0.53 (d, J=12 Hz, 2H), 0.11 (d, J=6 Hz, 2H);
.sup.13C-NMR (CDCl.sub.3) .delta. 57.2 (t), 9.8 (d), 4.7 (t), 4.1
(t).
EXAMPLE 63
[0386]
3-((4a,S,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]be-
nzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)ethanonitrile (8r):
Process as in Example E, reaction time 2 hours, yield 1.67 g
(61.1%); melting point 169-171.degree. C.; .sup.1H-NMR and
.sup.13C-NMR were identical to compound 4ad. Anal.
(C.sub.18H.sub.20N.sub.2O.sub.3.O.67H.sub.2O) C, H, N.
EXAMPLE 64
[0387]
1-(2-Phenyl-2,5-diazabicyclo[2.2.1]heptane-5-yl)-2-((4a,S,6R,8aS)--
6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benz-
azepine-11(12H)-yl)-1-ethanone (8s): Process as in Example E,
reaction time 3 days, yield 0.68 g (37.8%); melting point
85-89.degree. C.; .alpha..sub.D=-169.3.degree., same skeleton as
4aa, only different NMR signals are described: .sup.1H-NMR
(CDCl.sub.3) .delta. 7.21 (m, 2H); 6.68 (m, 3H), 5.0 (s, 1H), 4.47
(d, J=14.0 Hz, 1H), 3.90 (m, 1H), 3.63 (m, 3H), 3.24 (m, 1H), 2.04
(m, 3H); .sup.13C-NMR (CDCl.sub.3) .delta. 168.0 and 167.6 (s),
146.4 (d), 144.1 (s), 127.7 (d), 127.5 (d), 112.5 (d), 112.4 (d),
67.0 (t), 57.0 and 56.8 (d), 56.8 and 56.6 (t), 51.8 and 51.6 (t),
36.6 (t); 33.7 and 33.6 (t). Anal.
(C.sub.29H.sub.33N.sub.3O.sub.4.O.33H.sub.2O) C, H, N.
EXAMPLE 65
(4a,S,6R,8aS)-11-(3-Aminoethyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]-
benzofuro[3a,3,2-ef][2]benzazepin-6-ol (8t)
[0388] Process according to Example F, reactant compound 8r;
reaction time 18 hours, yield 1.01 g (66.1%); melting point
72-75.degree. C.; .alpha..sub.D=-71.58.degree., .sup.1H-NMR and
.sup.13C-NMR were identical to compound 4af. Anal.
(C.sub.18H.sub.24N.sub.2O.sub.3.0.65 EtOH.0.05 CH.sub.2Cl.sub.2))
C, H, N.
EXAMPLE 66
[0389]
(4a,S,6R,8aS)-11-(2-Morpholine-4-yl-ethyl)-3-methoxy-5,6,9,10,11,1-
2-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol (8u):
Process according to Example E, reaction time 2 days, yield 1.77 g
(63.6%); melting point 101-104.degree. C.;
.alpha..sup.D.sub.20=-110.9.degree., .sup.1H-NMR and .sup.13C-NMR
were identical to compound 4ag. Anal.
(C.sub.22H.sub.30N.sub.2O.sub.4O.15 CH.sub.2Cl.sub.2) C, H, N.
EXAMPLE 67
[0390]
(4a,S,6R,8aS)-11-(2-Phenyl-2,5-diazabicylo[2.2.1]heptane-5-yl-ethy-
l)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzaz-
epin-6-ol (8v): Process according to Example F, reactant compound
8s, reaction time 30 minutes, yield 0.26 g (50.8%); melting point
72-75.degree. C.; .alpha..sup.D.sub.20-131.6.degree., .sup.1H-NMR
and .sup.13C-NMR were identical to compound 4ah. Anal.
(C.sub.29H.sub.35N.sub.3O.sub.3.0.35 CH.sub.2Cl.sub.2.0.5
Et.sub.3N) C, H, N.
EXAMPLE 68
[0391]
3-((4a,S,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]be-
nzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)propanoic acid (8w): A
solution of 8w (0.5 g, 1.25 mmol) was added to CH.sub.2Cl.sub.2 (20
ml) in trifluoroacetic acid (5 ml). The reaction mixture was
stirred at room temperature for 2 hours and yielded a concentrate
of 0.37 g (64.5%) of 8w: same skeleton as 4aa, only different NMR
signals are described: .sup.1H-NMR (CDCl.sub.3) 8.95 (b, 1H), 2.82
(m, 2H), 2.25 (m, 2H).
EXAMPLE 69
[0392]
t-Butyl-3-((4a,S,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4-
aH-[1]benzofuro[3a,3,2-ef](2]benzazepine-11(12H)-propanoate
(8.times.): Process B, reaction time 6 hours, yield 0.74 g (53.2%);
.sup.1H-NMR and .sup.13C-NMR were identical to compound 4aj.
EXAMPLE 70
[0393]
(4a,S,6R,8aS)-11-(3-Hydroxypropyl)-3-methoxy-5,6,9,10,11,12-hexahy-
dro-4aH-[1]benzofuro[3a,3,2-ef](2]benzazepin-6-ol (8z); Process E,
reaction time 4 days, yield 0.32 g (56.7%);
.alpha..sub.D=90.0.degree.; .sup.1H-NMR and .sup.13C-NMR were
identical to compound 4an.
EXAMPLE 71
[0394]
(4a,S,6R,8aS)-11-((3-Dimethylamino)propyl-3-methoxy-5,6,9,10,11,12-
-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol
(8a.alpha.): Process E, reaction time 24 hours, yield 0.45 g
(51.6%); same skeleton as 4aa, only the different NMR signals are
described.
[0395] .sup.1H-NMR (CDCl.sub.3) .delta. 2.50 (m, 2H), 2.30 (m, 2H),
2.22 (s, 3H), 2.18 (s, 3H), 1.82 (m, 2H); .sup.13C-NMR (CDCl.sub.3)
.delta. 55.6 (t), 53.4 (t), 45.0 (q); 25.3 (t).
EXAMPLE 72
[0396]
(4a,S,6R,8aS)-3-Methoxy-11-(3-piperidine-1-yl-propyl)-5,6,9,10,11,-
12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol (8ab):
Process E, reaction time 3 days, yield 1.77 g (54.7%); melting
point 84-92.degree. C.; .alpha..sup.D.sub.20=-50.64; .sup.1H-NMR
and .sup.13C-NMR were identical to compound 4an. Anal.
(C.sub.24H.sub.34N.sub.2O.sub.3.3C.sub.4H.sub.6O.sub.6) C, H,
N.
EXAMPLE 73
(4a,S,6R,8aS)-11-(3-2-(4-Fluoro)phenyl-2,5-diazabicyclo[2.2.1]heptane-5-yl-
-propyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]-
benzazepin-6-ol (8ac)
[0397] Process E, reaction time 4 days, yield 1.77 g (59.3%);
melting point 84-92.degree. C.; .alpha..sup.D.sub.20=-50.64;
.sup.1H-NMR and .sup.13C-NMR were identical to compound 4aq. Anal.
(C.sub.30H.sub.36FN.sub.3O.sub.3.2CH.sub.2Cl.sub.2.2 Et.sub.3N) C,
H, N.
EXAMPLE 74
[0398]
(4a,R,6S,8aR)-3-Methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[-
3a,3,2-ef][2]benzazepin-6-ol, (+) norgalanthamine (9) was prepared
and described for 8: yield 5.35 g (74.2%); .sup.1H-NMR and
.sup.13C-NMR were identical to compound 8.
EXAMPLE 75
[0399]
(4a,R,6S,8aR)-6-Hydroxy-N.sup.11-isopropyl-3-methoxy-5,6,9,10-tetr-
ahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboxamide
(9a): Process A, reaction time 3 hours; yield 1.03 g (79%);
.sup.1H-NMR and .sup.13C-NMR were identical to compound 41.
EXAMPLE 76
[0400]
(4a,R,6S,8aR)--N.sup.11-t-Butyl-6-hydroxy-3-methoxy-5,6,9,10-tetra-
hydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboxamide
(9b): Process A, reaction time 3 hours; yield 0.85 g (63%);
.sup.1H-NMR and .sup.13C-NMR were identical to compound 4m.
EXAMPLE 77
[0401]
(4a,R,6S,8aR)-3-Methoxy-11-(2-morpholine-4-yl-ethyl)-5,6,9,10,11,1-
2-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol (9c):
Process E, reaction time 2 days; yield 0.12 g (53.2%); .sup.1H-NMR
and .sup.13C-NMR were identical to compound 4ag.
EXAMPLE 78
[0402]
(4a,R,6S,8aR)-1-((3-Dimethylamino)propyl)-3-methoxy-5,6,9,10,11,12-
-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol (9d):
Process E, reaction time 22 hours; yield 0.19 g (44.6%);
.sup.1H-NMR and .sup.13C-NMR were identical to compound 8aa.
EXAMPLE 79
[0403]
(4a,R,6S,8aR)-11-(3-Piperidine-1-yl-propyl)-3-methoxy-5,6,9,10,11,-
12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol (9e):
Process E, reaction time 20 hours; yield 0.33 g (75.0%);
.sup.1H-NMR and .sup.13C-NMR were identical to compound 4ap.
EXAMPLE 80
Step 1
2-Bromo-4-methoxy-5-(1-methylethoxy)benzaldehyde
[0404] TABLE-US-00010 ##STR200## ##STR201##
[0405] 2-Bromo-5-hydroxy-4-methoxybenzaldehyde (100.0 g, 433 mmol),
2-bromopropane (160.0 g, 1.30 mol) and potassium carbonate (300 g,
2.16 mol, anhydrous, freshly ground) are stirred in acetonitrile
(1200 ml) for 48 hours at 60.degree. C.
[0406] The reaction mixture is filtered, the solvent is distilled
off in a rotary evaporator, and the residue is dispersed between
water (800 ml) and ether (800 ml). The aqueous phase is extracted
with ether (2.times.300 ml), the combined organic phases are washed
with water (2.times.500 ml) and saturated common salt solution
(1.times.500 ml), dried (sodium sulfate/activated carbon),
filtered, and the residue that is obtained after the solvent was
distilled off is recrystallized from methanol (500 ml). In this
way, the product is obtained in the form of pale rose-colored
crystals (98.1 g, 83%).
[0407] Melting point: 75-76.degree. C.
[0408] TLC: Petroleum ether:ethyl acetate=3:1, Rf=0.75
[0409] .sup.1H NMR (CDCl.sub.3): .delta. 10.13 (s, 1H), 7.40 (s,
1H), 7.03 (s, 1H), 4.61 (septet, J=6.4 Hz, 1H), 3.92 (s, 3H), 1.38
(d, J=6.4 Hz 6H);
[0410] .sup.13C NMR (CDCl.sub.3): .delta. 190.8 (d), 15.6 (s),
147.1 (s), 126.4 (s), 120.0 (s), 115.8 (d), 113.7 (d), 71.5 (d),
56.4 (q), 21.8 (q)
Step 2
2-Bromo-4-methoxy-5-(1-methylethoxy)benzenemethanol
[0411] ##STR202##
[0412] 2-Bromo-4-methoxy-5-(1-methylethoxy)benzaldehyde (6.0 g,
22.0 mmol) is added in substance at 15.degree. C. within 15 minutes
to a suspension of sodium borohydride (1.67 g, 44.1 mmol) in
anhydrous ethanol (60 ml), and the mixture is stirred for one hour
at room temperature.
[0413] The residue that remains after the solvent is distilled off
is dispersed between saturated sodium bicarbonate solution (60 ml)
and ether (100 ml). The aqueous phase is extracted with ether
(3.times.40 ml), the combined organic phases are washed with
saturated sodium bicarbonate solution (1.times.100 ml), water
(1.times.100 ml) and saturated common salt solution (1.times.100
ml), dried (sodium sulfate/activated carbon) and filtered. After
the solvent is distilled off in a rotary evaporator, the product is
obtained in the form of colorless crystals (5.575 g, 95).
[0414] Melting point: 67-69.degree. C.
[0415] TLC: Petroleum ether:ethyl acetate=4:1, Rf=0.25
[0416] .sup.1H NMR (CDCl.sub.3): .delta. 7.00 (s, 2H), 4.64 (s,
2H), 4.50 (septet, J=6.4 Hz, 1H), 3.85 (s, 3H), 2.05 (s, 1H), 1.34
(d, J=6.4 Hz, 6H);
[0417] .sup.13C NMR (CDCl.sub.3): .delta. 150.1 (s), 146.5 (s),
131.8 (s), 116.1 (s), 115.9 (d), 112.6 (s), 71.7 (t), 64.3 (d),
56.0 (q), 21.8 (q)
[0418] MT-44 JOS 1693
[0419] C.sub.11H.sub.15BrO.sub.3 TABLE-US-00011 Cld.: C, 48.02; H,
5.50 Fnd.: C, 48.11; H, 5.29
Step 3
1-Bromo-2-(chloromethyl)-5-methoxy-4-(1-methylethoxy)-benzene
[0420] ##STR203##
[0421] Thionyl chloride (20 ml) in absolute CH.sub.2Cl.sub.2 (10
ml) is added in drops within 10 minutes to
2-bromo-4-methoxy-5-(1-methylethoxy)benzenemethanol (5.63 g, 20.5
mmol) in absolute CH.sub.2Cl.sub.2 (60 ml), and it is stirred for
90 minutes at room temperature.
[0422] The residue that is obtained after solvent is removed in a
rotary evaporator is dispersed between ether (100 ml) and saturated
sodium bicarbonate solution (100 ml), the combined organic phases
are washed with saturated sodium bicarbonate solution (2.times.100
ml), water (1.times.100 ml) and saturated common salt solution
(1.times.100 ml), dried (sodium sulfate/activated carbon),
filtered, and the solvent is distilled off in a rotary evaporator.
In this way, the product is obtained in the form of colorless
crystals (5.72 g, 95%).
[0423] Melting point: 68-70.degree. C.
[0424] TLC: Petroleum ether:ethyl acetate=3:1, Rf=0.9
[0425] .sup.1H NMR (CDCl.sub.3): .delta. 7.05 (s, 1H), 6.97 (s,
1H), 4.66 (s, 2H), 4.51 (septet, J=6.4 Hz, 1H), 3.85 (s, 3H), 1.37
(d, J=6.4 Hz, 6H);
[0426] .sup.13C NMR (CDCl.sub.3): .delta. 151.2 (s), 146.8 (s),
128.5 (s), 117.7 (s), 116.1 (d), 114.8 (s), 71.9 (t), 56.2 (d),
64.4 (q), 21.9 (q)
[0427] MT-45 JOS 1760
[0428] C.sub.14H.sub.20O.sub.3 TABLE-US-00012 Cld.: C, 71.16; H,
8.53 Fnd.: C, 70.90; H, 8.28
Step 4
1-[4-(1-Methylethoxy)phenyl]ethanone
[0429] ##STR204##
[0430] 1-(4-Hydroxyphenyl)ethanone (12.7 g, 93.2 mmol),
2-bromopropane (57.3 g, 466 mmol) and potassium carbonate (62.2 g,
466 mmol, anhydrous, freshly ground) are stirred in absolute
acetonitrile (150 ml) for 24 hours at 60.degree. C.
[0431] The reaction mixture is filtered, the solvent is distilled
off in a rotary evaporator, and the residue is dispersed between
water (200 ml) and ether (200 ml). The aqueous phase is extracted
with ether (2.times.80 ml), the combined organic phases are washed
with water (2.times.100 ml) and saturated common salt solution
(1.times.100 ml), dried (sodium sulfate/activated carbon) and
filtered. In this way, after the solvent is distilled off, the
product is obtained in the form of colorless crystals (16.8 g,
99%).
[0432] Melting point: 36-80.degree. C.
[0433] TLC: Petroleum ether:ethyl acetate=4:1, Rf=0.5
[0434] .sup.1H NMR (CDCl.sub.3) .delta. 7.82 (d, J=9.5 Hz, 2H),
6.88 (d, J=9.5 Hz, 2H), 4.63 (septet, J=6.4 Hz, 1H), 2.52 (s, 3H),
1.33 (d, J=6.4 Hz, 6H);
[0435] .sup.13C NMR (CDCl.sub.3): .delta. 196.7 (s), 161.9 (s),
130.5 (d), 129.8 (s), 115.0 (d), 70.0 (d), 26.2 (q), 21.8 (q)
Step 5
2-Bromo-1-[4-(1-methylethoxy)phenyl]ethanone
[0436] ##STR205##
[0437] Bromine (11.7 g, 73.5 mmol) in absolute dioxane (70
ml)/absolute ether (100 ml) is added in drops within one hour to a
solution of 1-[(4-(1-methylethoxy)phenyl]ethanone (10.0 g, 56.0
mmol) in absolute dioxane (100 ml), and it is stirred for 2 hours
at room temperature. The reaction mixture is mixed with sodium
sulfite (5.0 g) in water (100 ml), the phases are separated, and
the aqueous phase is extracted with ether (3.times.100 ml), the
combined organic phases are washed with water (2.times.100 ml),
saturated sodium bicarbonate solution (2.times.150 ml) and
saturated common salt solution (1.times.200 ml), dried (sodium
sulfate/activated carbon), filtered, and the residue that is
obtained after the solvent is distilled off is crystallized under a
mixture that consists of petroleum ether (25 ml) and cyclohexane
(25 ml) at -20.degree. C. In this way, the product is obtained in
the form of colorless crystals that rapidly become dark in color
(8.80 g, 59%).
[0438] Melting point: 36-37.degree. C.
[0439] TLC: Petroleum ether:ethyl acetate=4:1, Rf=0.7
[0440] .sup.1H NMR (CDCl.sub.3): .delta. 7.93 (d, J=9.5 Hz, 2H),
6.92 (d, J=9.5 Hz, 2H), 4.63 (septet, J=6.4 Hz, 1H), 4.40 (s, 2H),
1.35 (d, J=6.4 Hz, 6H);
[0441] .sup.13C NMR (CDCl.sub.3) .delta. 189.8 (s), 162.7 (s),
131.4 (d), 126.4 (s), 115.3 (d), 70.3 (d), 30.7 (t), 21.9 (q)
Step 6
1-(2-Bromoethyl)-4-(1-methylethoxy)benzene
[0442] ##STR206##
[0443] Tert-butylamine-borane complex (7.45 g, 85.0 mmol, pellets
or powder) is added at 5.degree. C. to a suspension of anhydrous
aluminum chloride (5.70 g, 43.0 mmol) in absolute CH.sub.2Cl.sub.2
(100 ml). After 15 minutes,
2-bromo-1-[4-(1-methylethoxy)phenyl]-ethanone (7.30 g, 28.4 mmol)
in anhydrous CH.sub.2Cl.sub.2 (50 ml) is added in drops within 30
minutes.
[0444] The mixture is stirred for three hours at room temperature,
mixed with 0.1N hydrochloric acid (100 ml), and the aqueous phase
is extracted with CH.sub.2Cl.sub.2 (2.times.30 ml). The combined
organic phases are washed with 0.1N hydrochloric acid (2.times.50
ml), saturated sodium bicarbonate solution (2.times.50 ml) and
saturated common salt solution (1.times.100 ml), dried (sodium
sulfate/activated carbon), and the residue that is obtained after
the solvent is concentrated by evaporation is purified by bulb tube
distillation (0.05 mbar/80.degree. C.), whereby the product is
obtained as a colorless oil (5.81 g, 83%).
[0445] TLC: Petroleum ether, Rf=0.35
[0446] .sup.1H NMR (CDCl.sub.3): .delta. 7.18 (d, J=9.5 Hz, 2H),
6.87 (d, J=9.5 Hz, 2H), 4.53 (septet, J=6.4 Hz, 1H), 3.53 (t, J=6.9
Hz, 2H), 3.08 (t, J=6.9 Hz, 2H), 1.33 (d, J=6.4 Hz, 6H);
[0447] .sup.13C NMR (CDCl.sub.3) .delta. 156.7 (s), 130.7 (s),
129.5 (d), 115.8 (d), 69.8 (d), 38.5 (t), 33.2 (t), 21.9 (q)
[0448] MT-35 JOS 1760
[0449] C.sub.11H.sub.15BrO TABLE-US-00013 Cld.: C, 54.34; H, 6.22
Fnd.: C, 54.34; H, 6.09
Step 7
2-[2-[4-(1-Methylethoxy)phenyl]ethyl]propanedioic acid dimethyl
ester
[0450] ##STR207##
[0451] 1-(2-Bromoethyl)-4-(1-methylethoxy)benzene (19.0 g, 78.1
mmol), malonic acid dimethyl ester (40.0 g, 300 mmol) and potassium
carbonate (42.0 g, 300 mmol, anhydrous, freshly ground) in absolute
DMF (400 ml) are stirred for 10 hours at 70.degree. C.
[0452] The solvent is removed in a rotary evaporator, and the
residue is dispersed between water (250 ml) and ether (250 ml). The
aqueous phase is extracted with ether (1.times.100 ml), the
combined organic phases are washed with water (3.times.200 ml) and
saturated common salt solution (1.times.150 ml), dried (sodium
sulfate/activated carbon) and excess malonic acid dimethyl ester is
distilled off from the residue that is obtained after the solvent
is removed from the rotary evaporator (160.degree. C./15 mbar).
[0453] The crude product is purified by means of bulb tube
distillation (140.degree. C./0.001 mbar), by which the product is
obtained as a colorless oil (18.9 g, 82%).
[0454] TLC: Petroleum ether:ethyl acetate=9:1, Rf=0.4
[0455] .sup.1H NMR (CDCl.sub.3): .delta. 7.08 (d, J=10 Hz, 2H),
6.81 (d, J=10 Hz, 2H), 4.50 (septet, J=6.5 Hz, 1H), 3.71 (s, 6H),
3.32 (t, J=75 Hz, 1H), 2.58 (t, J=7.5 Hz, 2H), 2.19 (q, J=7.5 Hz,
2H), 2.65-2.47 (m, 2H), 2.26-2.06 (m, 2H), 1.31 (d, J=6 Hz,
6H);
[0456] .sup.13C NMR (CDCl.sub.3): .delta. 169.8 (s), 156.3 (s),
132.3 (s), 129.4 (d), 115.9 (d), 69.9 (d), 52.5 (q), 50.8 (d), 32.4
(t), 30.6 (t), 22.1 (q)
Step 8
2-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]methyl-2-[2-[4-(1-methyletho-
xy)phenyl]ethyl]propane-dioic acid methyl ester
[0457] ##STR208##
[0458] 2-[2[4-(1-Methylethoxy)phenyl]ethyl]propanedioic acid
dimethyl ester (18.9 g, 64.2 mmol),
1-bromo-2-(chloromethyl)-4-(1-methylethoxy)-5-methoxybenzene (18.9
g, 64.2 mmol) and potassium carbonate (45.0 g, 32 l mmol,
anhydrous, freshly ground) in absolute DMF (300 ml) are stirred for
12 hours at 60.degree. C.
[0459] The residue that remains after the solvent is removed is
dispersed between water (250 ml) and ether (250 ml). The aqueous
phase is extracted with ether (1.times.100 ml), the combined
organic phases are washed with water (3.times.200 ml) and saturated
common salt solution (150 ml), dried (sodium sulfate/activated
carbon), filtered, and the solvent is removed in a rotary
evaporator.
[0460] After drying under high vacuum, the product is obtained as a
colorless oil (33.7 g, 95%).
[0461] TLC: Petroleum ether:ethyl acetate=9:1, Rf=0.5
[0462] .sup.1H NMR (CDCl.sub.3): .delta. 7.04 (s, 1H), 7.01 (d,
J=10 Hz, 2H), 6.79 (d, J=10 Hz, 2H), 6.73 (s, 1H); 4.47 (septet,
J=6.5 Hz, 1H), 4.36 (septet, J=6.5 Hz, 1H), 3.80 (s, 3H), 3.72 (s,
6H) 3.48 (s, 2H), 2.65-2.47 (m, 2H), 2.26-2.06 (m, 2H), 1.31 (d,
J=6.5 Hz, 12H);
[0463] .sup.13C NMR (CDCl.sub.3): .delta. 171.4 (s), 156.1 (s),
149.8 (s), 146.2 (s), 133.0 (s), 129.3 (s), 129.1 (d), 118.2 (s),
116.2 (d), 116.0 (d), 115.8 (d), 69.7 (d), 58.7 (s), 55.9 (q), 52.3
(q), 37.4 (t), 34.5 (t), 29.9 (t), 21.95 (q), 21.9 (q)
[0464] MT-54 JOS 1698
[0465] C.sub.27H.sub.35BrO.sub.7 TABLE-US-00014 Cld.: C, 58.81; H,
6.40 Fnd.: C, 59.00; H, 6.26
Step 9
Alpha-[[2-bromo-4-methoxy-5-(1-methylethoxy)phenyl]methyl]-4-(1-methyletho-
xy)benzenebutanoic acid
[0466] ##STR209##
[0467]
2-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]methyl-2-(2-[4-(1-me-
thylethoxy)-phenyl]ethyl]propanedioic acid dimethyl ester (33.7 g,
61.1 mmol) and potassium hydroxide (17.5 g, 312 mmol) are stirred
in ethanol (150 ml)/water (30 ml) for 12 hours at boiling
temperature.
[0468] The reaction mixture is acidified with concentrated
hydrochloric acid up to a pH of 1 and kept under reflux for one
hour.
[0469] The residue that remains after the solvent is removed is
dispersed between water (250 ml) and ether (250 ml). The aqueous
phase is extracted with ether (2.times.100 ml), the combined
organic phases are washed neutral with water, washed with saturated
common salt solution (150 ml), dried (sodium sulfate/activated
carbon) and filtered. The residue that remains after the solvent is
removed is decarboxylated in a bulb tube for 30 minutes at
140.degree. C. and then distilled at 150.degree. C./0.005 mbar. In
this way, the product is obtained in the form of colorless crystals
(27.5 g, 94%).
[0470] Melting point: 114-116.degree. C.
[0471] TLC: Chloroform:methanol=9:1, Rf=0.65
[0472] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.09, (s, 1H), 7.01 (d,
J=7.3 Hz, 2H), 6.80 (s, 1H), 6.78 (d, J=7.3 Hz, 2H), 4.69-4.37 (m,
2H), 372 (s, 3H), 3.00-2.33 (m, 5H), 1.99-1.58 (m, 2II), 1.18 (d,
J=6.4 Hz, 12H);
[0473] .sup.13C NMR (DMSO.sub.6) 176.0 (s), 155.6 (s), 149.3 (s),
145.8 (s), 133.1 (s), 130.3 (s), 129.1 (d), 118.1 (d), 116.0 (d),
115.5 (s), 114.1 (d), 70.6 (d), 69.0 (d), 55.8 (q), 44.9 (d), 33.5
(t), 31.9 (t), 21.85 (q), 21.8 (q)
[0474] MT-100 JOS 1592
[0475] C.sub.24H.sub.31BrO.sub.5 TABLE-US-00015 Cld.: C, 60.13; H,
6.52 Fnd.: C, 60.38; H, 6.55
Step 10
Alpha
[[2-bromo-4-methoxy-5-(1-methylethoxy)phenyl]methyl]-4-(1-methyletho-
xy)benzenebutanoic acid amide
[0476] ##STR210##
[0477] Thionyl chloride (50 ml) is added in drops at 0.degree. C.
within 15 minutes to
alpha[[2-bromo-4-methoxy-5-(1-methylethoxy)phenyl]methyl]-4-(1-methyletho-
xy)-benzenebutanoic acid (10.0 g, 20.8 mmol) in CH.sub.2Cl.sub.2
(100 ml), and the mixture is stirred for two hours at this
temperature.
[0478] The solvent is removed in a rotary evaporator, the residue
is taken up in absolute formamide (15 ml) and mixed at 0.degree. C.
with ammonia in formamide (100 ml of a solution that is saturated
at this temperature). The mixture is stirred for one hour at
0.degree. C. and poured onto water (1500 ml).
[0479] The precipitated crystals are filtered off and digested with
water (4.times.400 ml). In this way, the product is obtained in the
form of colorless crystals (9.21 g, 92%).
[0480] Melting point: 154-156.degree. C.
[0481] TLC: CH.sub.2Cl.sub.2:methanol=9:1, Rf=0.7
[0482] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.32 (s, 1H), 7.08 (s,
1H), 7.02 (d, J=7.3 Hz, 2H), 6.83 (s, 1H), 6.80 (s, 1H), 6.78 (d,
J=7.3 Hz, 2H), 4.68-4.32 (m, 2H), 3.77 (s, 3H), 3.39 (s, 3H),
3.00-2.62 (m, 2H), 2.00-1.58 (m, 2H), 1.18 (d, J=6.4 Hz, 12H);
[0483] .sup.13C NMR (DMSO-d.sub.6): 175.8 (s), 155.5 (s), 149.1
(s), 145.8 (s), 133.5 (s), 130.9 (s), 129.9 (d), 118.1 (d), 115.8
(d), 115.5 (s), 114.1 (d), 70.9 (d), 69.0 (d), 55.8 (q), 45.9 (d),
34.2 (t), 32.1 (t), 21.85 (q), 21.8 (q)
[0484] MT-112 JOS 1591
[0485] C.sub.24H.sub.32BrNO.sub.4 TABLE-US-00016 Cld.: C, 60.25; H,
6.74; N, 2.93 Fnd.: C, 59.99; H, 6.56; N, 2.82
Step 11
Production of
alpha[[2-bromo-5-hydroxy-4-methoxyphenyl]methyl]-4-hydroxybenzenebutanoic
acid amide
[0486] ##STR211##
[0487] Boron trichloride (40 ml, 1.6 M in CH.sub.2Cl.sub.2) is
added in drops at -78.degree. C. to a solution of
alpha[[2-bromo-5-hydroxy-4-methoxyphenyl]methyl]-4-hydroxybenzenebutanoic
acid amide (9.30 g, 19.4 mmol) in absolute CH.sub.2Cl.sub.2 (150
ml), and it is stirred for one hour at this temperature. Then, the
mixture is heated to room temperature and stirred for two
hours.
[0488] It is mixed with water (300 ml), and the organic solvent is
distilled off in a rotary evaporator, whereby the crude product
precipitates as crystals, the latter is filtered off and is
digested with water (6.times.200 ml) and diisopropyl ether
(2.times.40 ml). In this case, the product is obtained in the form
of colorless crystals (6.76 g, 88%).
[0489] Melting point: 177-179.degree. C.
[0490] TLC: CH.sub.2Cl.sub.2:methanol=9:1, Rf=0.4
[0491] .sup.1H NMR (DMSO-d.sub.6): .delta. 9.18 (s, 2H), 7.18 (S,
III), 7.04 (s, 1H), 6.97 (d, J=7.3 Hz, 2H), 6.72 (s, 1H), 6.65 (s,
1H), 6.66 (d, J=7.3 Hz, 2H), 3.77 (s, 3H), 3.48 (s, 3H), 2.92-2.38
(m, 4H);
[0492] .sup.13C NMR (DMSO-d.sub.6): .delta. 175.6 (s), 155.5 (s),
147.0 (s), 145.8 (s), 131.3 (s), 129.9 (s), 129.8 (d), 117.9 (s),
115.8 (d), 115.0 (d), 11.9 (d), 56.0 (q), 48.1 (d), 37.6 (t), 37.0
(t)
[0493] MT-114 JOS 1692
[0494] C.sub.18H.sub.20BrO.sub.4 TABLE-US-00017 Cld.: C, 54.84; H,
5.11; N, 3.55 Fnd.: C, 54.55; H, 4.90; N, 3.28
Step 12
1-Bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-oxa-6H-benzo[a]cyclohepta[hi-
]benzofuran-11-carboxylic acid amide
[0495] ##STR212##
[0496]
.alpha.-[[2-Bromo-5-hydroxy-4-methoxyphenyl]methyl]-4-hydroxybenze-
nebutanoic acid amide (3.00 g, 7.61 mmol) is suspended in
chloroform (300 ml) and mixed with a solution of potassium
hexacyanoferrate (III) (13.2 g, 40.0 mmol) in potassium carbonate
solution (75 ml, ten percent).
[0497] The mixture is stirred vigorously at room temperature for 40
minutes and filtered on Hyflo. The aqueous phase is extracted with
chloroform (3.times.50 ml), the combined organic phases are washed
with water (2.times.200 ml) and saturated common salt solution
(1.times.150 ml), dried (sodium sulfate/silica gel), filtered, and
the crude product that is obtained after the solvent is
concentrated by evaporation is purified by column chromatography
(50 g of silica gel, ethyl acetate). In this way, the product is
obtained in the form of colorless crystals (0.36 g, 12%).
[0498] TLC: Chloroform:methanol 9:1, Rf=0.4 and 0.5
[0499] .sup.1H NMR (CDCl.sub.3): .delta. 7.00 (s, 1H); 6.86 (dd,
J=12 Hz, J=1 Hz, 1H), 6.06 (d, J=1 Hz, 1H), 5.02 (bs, 2H), 4.70 (s,
1H), 3.82 (s, 3H), 3.62 (d, J=16 Hz, 1H), 3.23 (dd, J=16 Hz, J=3
Hz, 1H), 3.08-2.89 (m, 1H), 2.77 (dd, J=16 Hz, J=6 Hz, 1H),
2.62-1.70 (m, 5H)
[0500] .sup.13C NMR (DMSO-d.sub.6): .delta. 202.5 (s), 184.9 and
179.1 (s), 146.5 and 146.1 (d), 145.0 and 145.9 (s), 143.3 and
142.0 (s), 132.0 and 131.8 (s), 128.9 and 128.0 (s), 126.7 and
126.2 (d), 116.3 and 115.0 (s), 114.4 (d), 87.4 and 87.3 (d), 56.0
(q), 49.5 and 49.3 (s), 45.3 (d), 37.3 and 37.0 (t), 35.4 (t), 34.4
(t), 30.4 (t)
Deeper-Running Diastereomer
[0501] .sup.1H NMR (CDCl.sub.3) .delta. 6.70-6.85 (m, 2H),
6.07-5.91 (m, 2H), 4.54 (s, 1H), 4.12 (s, 1H), 3.82 (s, 3H), 2.99
(s, 1H), 2.86 (t, J=15 Hz, 1H), 2.72 (d, J=16 Hz, 1H), 2.63 (dd,
J=16 Hz, J=3 Hz, 1H), 2.30-1.60 (m, 9H);
[0502] .sup.13C NMR (CDCl.sub.3): .delta. 146.4 (s), 143.9 (s),
133.7 (s), 128.5 (s), 128.1 (d), 127.5 (d), 123.3 (d), 111.7 (d),
88.9 (d), 62.4 (d), 56.3 (q), 52.8 (d), 48.3 (s), 45.1 (t), 35.8
(t), 35.6 (t), 30.4 (t)
[0503] MT-115 JOS 1585
[0504] C.sub.18H.sub.18BrNO.sub.4 TABLE-US-00018 Cld.: C, 55.12; H,
4.63; N, 3.57 Fnd.: C, 54.91; H, 4.66; N, 3.41
EXAMPLE 81
1-Bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzo[a]cyclohept-
a[hi]benzofuran-11-carboxylic acid amide
[0505] ##STR213##
[0506] L-Selectride.RTM. (6.6 ml, 6.6 mmol, 1 M in THF) is added at
0.degree. C. within 15 minutes to a suspension of
1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-oxa-6H-benzo[a]cyclohepta[h-
i]benzofuran-11-carboxylic acid amide (860 mg, 2.19 mmol) in
absolute THF (5 ml), and the mixture is stirred for 12 hours at
room temperature. It is hydrolyzed with water (3 ml) and dispersed
between water (10 ml) and ethyl acetate (10 ml), the aqueous phase
is extracted with ethyl acetate (3.times.5 ml), the combined
organic phases are washed with 1N hydrochloric acid (3.times.10
ml), water (2.times.10 ml), saturated sodium bicarbonate solution
(1.times.10 ml) and saturated common salt solution (1.times.10 ml),
dried (sodium sulfate/activated carbon), filtered, and the crude
product that is obtained after the solvent is distilled off is
purified by column chromatography (50 g of silica gel, ethyl
acetate). In this way, the product is obtained in the form of
colorless crystals (741 mg, 86%).
[0507] TLC: Chloroform:methanol=9:1, Rf=0.35 and 0.45
[0508] .sup.1H NMR (CDCl.sub.3): .delta. 6.92 (s, 1H), 6.10-5.89
(m, 2H), 5.82-5.53 (m, 2H), 4.54 (s, 1H), 4.13 (s, 1H), 3.81 (s,
3H), 3.51 (d, J=15 Hz, 1H), 3.05 (dd, J=17 Hz, J=6 Hz, 1H),
2.96-2.84 (m, 1H), 2.65 (d, J=16 Hz, 1H), 2.83 (dd, J=16 Hz, J=6
Hz, 1H), 2.44-1.40 (m, 9H);
[0509] .sup.13C NMR (CDCl.sub.3): .delta.177.7 and 175.2 (s), 145.3
(s), 145.7 (s), 144.2 (s), and 143.9 (s), 133.8 and 134.2 (s),
128.3 and 128.2 (d), 126.5 (d), 116.1 and 115.9 (s), 115.3 and
115.1 (d), 88.5 (d), 61.8 (d), 56.1 (q), 49.1 and 49.0 (s), 46.0
(d), 41.9 (t), 35.9 and 35.7 (t), 29.8 and 29.6 (t), 28.8 and 26.2
(t)
[0510] MT-120
[0511] JOS 1710
[0512] C.sub.18H.sub.20BrNO.sub.4 TABLE-US-00019 Cld.: C, 54.84; H,
5.11; N, 3.55 Fnd.: C, 54.84; H, 5.18; N, 3.43
EXAMPLE 82
11-Amino-1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzo[a]-
cyclohepta[hi]benzo-furan-6-ol (SPH-1459)
[0513] ##STR214##
[0514] Bis(trifluoroacetoxy)iodobenzene (PIFA, 787 mg, 1.78 mmol)
is dissolved in acetonitrile (3.5 ml, HPLC-quality) and mixed with
water (3.5 ml, HPLC-quality). Then,
1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzo[a]cyclohep-
ta[hi]benzofuran-11-carboxylic acid amide is added in substance
within 2 hours, and the mixture is stirred for 24 hours at room
temperature. The solvent is distilled off in a rotary evaporator,
the residue is taken up in chloroform (5 ml), filtered, and
purified by column chromatography (30 g of silica gel,
chloroform:methanol: ammonia=96:3:1). In this way, the product is
obtained in the form of colorless crystals (490 mg, 75%)
[0515] TLC: Chloroform:methanol=9:1, Rf=0.2 and 0.25
[0516] .sup.1H NMR (MeOH-d.sub.4) .delta. 7.07 (s, 1H), 6.12-5.87
(m, 2H), 5.82-5.53 (m, 2H), 4.53 (s, 1H), 4.14 (s, 1H), 3.80 (s,
3H), 3.59 (d, J=20 Hz, 1H), 3.14-2.92 (m, 1H), 2.47 (d, J=17 Hz,
1H), 2.16 (s, 3H), 2.01-2.62 (m, 2H);
[0517] .sup.13C NMR (MeOH-d.sub.4): .delta. 148.3 and 148.2 (s),
146.5 and 146.1 (s), 135.8 (s), 129.9 and 129.3 (s), 128.5 and
127.9 (d), 125.9 and 123.9 (d), 118.4 and 118.1 (s), 116.9 and
116.0 (d), 118.4 and 118.0 (s), 116.8 and 116.0 (d), 89.0 and 88.9
(d), 62.4 and 62.3 (d), 57.2 (q), 50.6 and 50.4 (s), 49.8 (d), 38.5
(t), 36.0 and 33.0 (t), 31.8 and 31.0 (t), 31.4 and 2.8.3 (t)
[0518] JOS 1707
[0519] C.sub.17H.sub.20BrNO.sub.3*1 CHCl.sub.3 TABLE-US-00020 Cld.:
C, 44.52; H, 4.36; N, 2.88 Fnd.: C, 44.90; H, 4.30; N, 2.67
EXAMPLE 83
11-Amino-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzo[[a]cyclohe-
pta[hi]benzofuran-6-ol
[0520] ##STR215## Production of the Copper-Zinc Alloy
[0521] Zinc powder (600 mg) and copper(I) iodide are reacted under
argon in water (4 ml) and ethanol (4 ml) for 45 minutes in an
ultrasonic bath, whereby a dark-black, fine-powder suspension is
produced.
Debromination
[0522]
11-Amino-1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H--
benzo[a]cyclohepta[hi]benzofuran-6-ol (80 mg, 0.22 mmol) and
calcium chloride (300 mg, 2.7 mmol) are added in substance to the
suspension that is produced, and the mixture is stirred for 12
hours at boiling temperature. It is mixed with concentrated aqueous
ammonia solution (1 ml), the solvent is removed in a rotary
evaporator, the residue is taken up in chloroform (15 ml),
filtered, and the residue that is obtained after the filtrate is
concentrated by evaporation in a rotary evaporator is purified by
column chromatography (30 g of silica gel,
chloroform:methanol:ammonia=96:3:1). In this way, the two optical
isomers can be separated (10 mg, 0.04 mmol of isomer A: 26 mg, 0.09
mmol of isomer B; a total of 36 mg, 59%) and obtained as a
colorless foam.
Higher-Running Diastereomer
[0523] .sup.1H NMR (CDCl.sub.3): .delta. 6.73-6.62 (m, 2H), 6.05
(s, 2H), 4.62 (s, 1H), 4.14 (s, 1H), 3.82 (s, 3H), 3.57 (s, 1H),
3.22 (d, J=16 Hz, 1H), 2.83 (dd, J=16 Hz, J=6.5 Hz, 1H), 2.24-1.60
(m, 9H);
[0524] .sup.13C NMR (CDCl.sub.3): .delta. 146.2 (s), 144.3 (s),
133.6 (s), 128.4 (s), 128.1 (d), 127.2 (d), 124.8 (d), 111.9 (d),
89.0 (d), 62.6 (d), 56.3 (q) 49.0 (s), 48.3 (d), 41.8 (t), 32.5
(t), 30.4 (t), 30.4 (t)
Deeper-Running Diastereomer
[0525] .sup.1H NMR (CDCl.sub.3): .delta. 6.70-6.58 (m, 2H),
6.07-591 (m, 2H), 4.54 (s, 1H), 4.12 (s, 1H), 3.82 (s, 3H), 2.99
(s, 1H), 2.86 (t, J=15 Hz, 1H), 2.72 (d, J=16 Hz, 1H), 2.63 (dd,
J=16 Hz, J=3 Hz, 1H), 2.30-1.60 (m, 9H);
[0526] .sup.13C NMR (CDCl.sub.3): .delta. 146.4 (s), 143.9 (s),
133.7 (s), 128.5 (s), 128.1 (d), 127.5 (d), 123.3 (d), 111.7 (d),
88.9 (d), 62.4 (d), 56.3 (q), 52.8 (d), 48.3 (s), 45.1 (t), 35.8
(t), 35.6 (t), 30.4 (t). ##STR216##
EXAMPLE 84
Step 1
Condensation and Reduction: General Operating Instructions
[0527] TABLE-US-00021 ##STR217## ##STR218## 1 equivalent
2-methyl-4-methoxy-5-hydroxybenzaldehyde or
2,4-dimethoxy-5-hydroxybenzaldehyde 1 equivalent tyramine 0.8
equivalent sodium borohydride 10 ml ethanol (96%)/1 g of
aldehyde
[0528] The educt was suspended in ethanol, and the tyramine was
added while being stirred, then the reaction mixture was refluxed
for 8.5 hours. Since the Schiff base (MH-16' or 34') that formed on
the TLC plate breaks back down into the starting materials, the
reaction progress was determined by reduction of a small sample
with sodium borohydride, conventional working-up and application of
the product obtained.
[0529] After 8.5 hours, the reaction mixture was cooled in an ice
bath to 0.degree. C., and the sodium borohydride, dissolved in 4 ml
of water/1 g, was slowly added in drops, then stirred in an ice
bath for 30 minutes. Then, it was poured onto 150 ml of ice/water/1
g of aldehyde while being stirred vigorously, the white precipitate
that was produced was filtered off and dried in a vacuum drying
oven. A second fraction of the product, which was collected and
dried, was precipitated from the mother liquor.
EXAMPLE 84
Step 1a;
5-(N-[2-[4-Hydroxyphenyl]ethyl]aminomethyl)-2-methoxy-4-methylphenol
(MH-16)
[0530] TABLE-US-00022 ##STR219## ##STR220## 27.8 g (168 mmol)
2-methyl-4-methoxy-5- hydroxybenzaldehyde (6) 23.0 g (168 mmol)
tyramine 5.20 g (134 mmol) = sodium borohydride 0.8 equivalents
[0531] Yield: 43.4 g (161 mmol=96% of theory) of a beige powder
C.sub.17H.sub.21NO.sub.3 [287.36]
[0532] TLC: R.sub.f=0.21 (CHCl.sub.3:MeOH=9:1+1% concentrated
NH.sub.4OH)
[0533] Melting point: 122-124.degree. C. TABLE-US-00023 % C % H % N
Cld.: 71.06 7.37 4.87 Fnd.: 71.07 7.41 4.86
[0534] .sup.1H-NMR (200 MHz, DMSO-d.sub.6): .delta. 6.90 (m, 2H),
6.67 (s, 1H), 6.62 (m, 2H), 6.55 (s, 1H); 3.72 (s, 3H); 3.51 (s,
2H); 2.73 (t, J=6.5 Hz, 2H); 2.60 (t, J=6.5 Hz, 2H); 2.10 (s, 3H);
.sup.13C-NMR (50 MHz, DMSO-D.sub.6): .delta. 155.4 (s), 145.8 (s),
143.9 (s), 130.9 (s), 130.4 (s), 129.3 (d), 126.0 (s), 116.2 (d),
115.0 (d), 114.3 (d), 55.7 (q), 51.1 (t), 50.3 (t), 35.0 (t), 17.9
(q)
EXAMPLE 84
Step 1b
5-(N-[2-[4-Hydroxyphenyl]ethyl]aminomethyl)-2,4-dimethoxyphenol
(MH-34)
[0535] TABLE-US-00024 ##STR221## ##STR222## 18.85 g (103.47 mmol)
5-hydroxy-2,4-dimethoxy- benzaldehyde (8) 14.21 g (103.47 mmol)
tyramine 3.13 g (82.74 mmol) = NaBH.sub.4 0.8 equivalent 200 ml
ethanol 96%
[0536] Yield: 28.1 g 92.63 mmol=89.5% of theory
[0537] C.sub.17H.sub.21NO.sub.4 [303.36]
[0538] TLC: R.sub.f=0.14 (CHCl.sub.3:MeOH=9:1+1% concentrated
NH.sub.4OH)
[0539] Melting point: 170-173.degree. C.
[0540] C.sub.17H.sub.21NO.sub.4 [303.36] (contaminated with
aliphatic substance about C.sub.15H.sub.32, Schliffett)
TABLE-US-00025 % C % H % N Cld.: 67.31 6.98 4.62 Fnd.: 68.10 7.04
4.66
[0541] .sup.1H-NMR (200 MHz, DMSO-d.sub.6): .delta. 6.95 (m, 2H),
6.70 (s, 1H) 6.64 (m, 2H), 6.57 (s, 1H), 3.75 (s, 3H), 3.66 (s,
3H), 3.52 (s, 2H), 2.59 (bs, 4H);".sup.3C-NMR (50 MHz,
DMSO-d.sub.6): .delta. 155.3 (s), 149.9 (s), 146.3 (s), 139.7 (s),
130.4 (s), 129.3 (d), 120.4 (s), 116.6 (d), 115.0 (d), 98.4 (d),
56.0 (q+q), 50.6 (t), 47.1 (t), 35.0 (t)
EXAMPLE 84
Step 2
Formylation: General Operating Instructions
[0542] TABLE-US-00026 ##STR223## ##STR224## 1 equivalent amine 2
equivalents formic acid ester (ethyl formate or methyl formate) 10
ml 1,4-dioxane, distilled/1 g of amine 0.2 ml dimethylformamide/1 g
of amine
[0543] Catalytic Amount of Formic Acid
[0544] All reagents were refluxed together (formic acid optionally
was added several times), and the reaction mixture was evaporated
to the dry state in a vacuum after the end of the reaction. The
solid residue was taken up in 10 ml of methanol/1 g of amine, and
50 ml of ice/water/1 g of amine was added in portions while being
stirred, whereby the suspension of the intermediate product was
converted under hydrolysis into the flocculent end product, which
was suctioned off and dried.
EXAMPLE 84
Step 2a
N-((5-Hydroxy-4-methoxy-2-phenylmethyl)-N-(2-[4-hydroxyphenyl]ethyl)]forma-
mide (MH-18)
[0545] TABLE-US-00027 ##STR225## ##STR226## 55.0 g (191 mmol)
5-(N-[2-[4- hydroxyphenyl]ethyl]aminomethyl)-2-
methoxy-4-methylphenol (XVII) 23.5 ml (383 mmol = methyl formate 2
equivalents) 11.0 ml DMF 1.50 ml formic acid 400 ml
1,4-dioxane.
[0546] The working-up is carried out after 7 hours.
[0547] Yield: 49.8 g (158 mmol=82.6% of theory) of a beige
powder
[0548] C.sub.18H.sub.21NO.sub.4 [315.37]
[0549] TLC: R.sub.f=0.35 (CHCl.sub.3:MeOH=9:1+1% concentrated
NH.sub.4OH)
[0550] Melting point: 170-171.degree. C. TABLE-US-00028 % C % H % N
Cld.: 68.55 6.71 4.44 Fnd.: 68.77 6.86 4.14
[0551] .sup.1H-NMR (200 MHz, DMSO-d.sub.6): .delta. 9.20 (s, 1H),
8.74 (d, J=15.3 Hz, 1H), 8.19 (s, 0.5H),7.88 (s, 0.5H), 7.00-6.87
(m, 2H), 6.74 (s, 1H), 6.72-6.56 (m, 2H), 6.59 (s, 1H), 4.31 (s,
1H), 4.23 (s, 1H), 3.73 (s, 3H), 3.21 (dd, J=15.3, 7.6 Hz, 2H),
2.60 (t, J=7.6 Hz, 2H), 2.12 (s, 3H); .sup.13C-NMR (50 MHz,
DMSO-d.sub.6) .delta. 162.7 and 162.3 (d), 155.7 (s), 146.7 and
146.5 (s), 144.4 and 144.2 (s), 129.7 and 129.4 (d), 128.9 and
128.4 (s), 126.5 (s), 126.4 and 126.3 (s), 116.3 and 115.9 (d),
115.1 (d), 114.6 and 114.4 (d), 55.6 (q), 48.0 and 47.4 (t), 43.3
and 41.6 (t), 33.2 and 31.9 (t), 18.1 and 18.0 (q).
EXAMPLE 84
Step 2b
[0552]
N-(2-(4-Hydroxyphenyl)ethyl)-N-((5-hydroxy-2,4-dimethoxyphenyl)met-
hyl)-formamide (MH-35) TABLE-US-00029 ##STR227## ##STR228## 27 g
(89 mmol) 5-(N-[2-[4- hydroxyphenyl]ethyl]aminomethyl)-
2,4-dimethoxyphenol (XXV) 14.4 ml (178 mmol) ethyl formate 200 ml
1,4-dioxane 5.5 ml dimethylformamide 2 ml formic acid
[0553] The working-up was carried out after 24 hours, and the
formic acid was added in 3 portions at intervals of several
hours.
[0554] Yield: 26.13 g (78.85 mmol=88.6% of theory) of a beige
powder
[0555] C.sub.18H.sub.21NO.sub.5 [331.37]
[0556] TLC: R.sub.f=0.53 (CHCl.sub.3:MeOH=9:1+1% concentrated
NH.sub.4OH)
[0557] Melting point: 130-132.degree. C. TABLE-US-00030 % C % H % N
Cld.: 65.24 6.39 4.23 Fnd.: 64.97 6.40 4.18
[0558] .sup.1H-NMR (200 MHz, DMSO-d.sub.6): .delta. 9.18 (bs, 1H),
8.48 (d, J=7.4 Hz, 1H), 8.16 (s, 0.5H), 7.86 (s, 0.5H), 6.98-6.87
(m, 2H), 6.71-6.58 (m, 4H), 4.31 (s, 1H), 4.19 (s, 1H), 3.78 (s,
3H), 3.75 (s, 3H), 3.21 (dd, J=16.4, 7.7 Hz, 2H), 2.69-2.55 (m,
2H); .sup.13C-NMR (50 MHz, DMSO-d.sub.6): .delta. 162.7 and 162.5
(d), 155.7 and 155.6 (s), 150.6 and 150.3 (s), 146.7 and 147.3 (s),
140.1 and 139.9 (s), 129.6 and 129.3 (d), 129.0 and 128.4 (s),
116.8 and 116.4 (d), 116.2 and 115.9 (s), 115.1 (d), 98.5 and 98.4
(d), 56.3 and 56.2 (q), 55.9 (q), 47.9 and 45.2 (t), 43.0 and 38.3
(t), 33.4 and 31.9 (t)
EXAMPLE 84
Step 3
Phenolic Oxidative Coupling: 1-Methylgalanthamine (XV)
[0559]
[(.+-.)-(4a.alpha.,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-me-
thyl-6-oxo-6H-benzofuro[3a,3,2-ef][2]benzazepine-11-carboxaldehyde,
1-Methyl-N-formylnarwedine (MH-19) TABLE-US-00031 ##STR229##
##STR230## 11.4 g (69.8 mmol) N-((5-hydroxy-4-methoxy-2-
phenylmethyl)-N-(2-[4- hydroxyphenyl]ethyl]formamide (XVIII) 47.0 g
(338 mmol) potassium carbonate 47.0 g (142 mmol) potassium
hexacyanoferrate (III) 1.60 l toluene 470 ml water 40.0 g Hyflo
[0560] Potassium carbonate, potassium hexacyanoferrate (III), water
and toluene were heated in a 4 liter-four-neck flask to 80.degree.
C., and then the educt was sprinkled while being mechanically
stirred vigorously. The temperature was kept at 80.degree. C. for 1
hour, then Hyflo was added and stirred for 10 more minutes. The
reaction mixture was suctioned off, and the solid residue was
rewashed 1.times. with water and 3.times. with hot toluene. The
toluene phase was separated from the aqueous phase, and the latter
was extracted with toluene. The organic phases were combined, the
solvent was drawn off, and the product was dried in a vacuum drying
oven.
[0561] Yield: 6.17 g (19.7 mmol=55.0% of theory) of a light yellow
powder
[0562] C.sub.18H.sub.19NO.sub.4 [313.39]
[0563] TLC: R.sub.f=0.48 and 0.42 (2 rotamers)
(CHCl.sub.3:MeOH=9:1+1% concentrated NH.sub.4OH)
[0564] Melting point: Decomposition>215.degree. C.
TABLE-US-00032 % C % H % N Cld.: 69.00 6.11 4.47 Fnd.: 68.78 6.33
4.40
[0565] .sup.1H-NMR (Mixture that consists of 2 rotamers, 200 MHz,
DMSO-d.sub.6): .delta. 8.18 (s, 0.2H), 8.10 (s, 0.8H), 7.25 (dd,
J=10.4, 1.9 Hz, 0.8H), 7.15 (dd, J=10.4, 1.9 Hz, 0.2H), 6.73 (s,
0.2H), 6.69 (s, 0.8H), 5.95 (d, J=10.3 Hz, 0.8H), 5.93 (d, J=10.3
Hz, 0.2H), 5.14 (d, J=15.4 Hz, 0.8H), 4.83 (d, J=15.4 Hz, 0.2H),
4.67 (bs, 1H), 4.51 (d, J=15.4 Hz, 0.2H), 4.07 (d, J=15.4 Hz,
0.8H), 3.97 (bs, 1H), 3.78-3.60 (m, 4H), 3.07 (dd, J=17.4, 3.4 Hz,
1H), 2.78 (dd, J=17.4, 1.9 Hz, 1H), 2.33 (s, 3H), 2.30 (s, 0.8H),
2.22 (s, 0.2H), 1.86 (dt, J=13.5, 3.7 Hz, 1H) .sup.13C-NMR (mixture
that consists of 2 rotamers, 50 MHz, DMSO-d.sub.6): .delta. 194.9
(s), 162.8 and 162.1 (d), 145.2 and 144.8 (d), 145.5 and 145.3 (s),
142.9 and 142.8 (s), 130.6 and 130.3 (s), 128.2 (s), 127.5 and
127.0 (s), 126.4 and 126.2 (d), 114.5 and 114.2 (d), 87.0 and 86.8
(d), 55.6 (q), 49.2 and 49.0 (s), 47.4 and 45.6 (t), 41.8 and 40.1
(t), 37.7 (t), 37.5 (t), 37.4 (t), 34.1 (t), 19.2 and 18.9 (q)
EXAMPLE 85
[(.+-.)-(4a.alpha.,6.beta.,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-me-
thyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,
1-methyl-N-demethylgalanthamine (MH-20)
[0566] TABLE-US-00033 ##STR231## ##STR232## 500 mg (1.60 mmol)
1-Methyl-N-formylnarwedine (XIX) 6.00 ml (6.06 mmol = L-selectride
1 M in THF 3.78 equivalents) 12.0 ml absolute THF
[0567] A suspension of finely ground educt in absolute THF was
cooled to 0.degree. C., and then L-selectride was added in drops,
whereby a temperature increase of 5.degree. C. was to be observed.
At 0.degree. C., it was stirred for 1 hour, whereby a clear
solution formed. After 70 minutes, 5 drops of water and 1 ml of
concentrated aqueous ammonia were added, stirred for 10 minutes,
and then the reaction mixture was concentrated by evaporation by
50% in a vacuum. Then, 10 ml of ammonia were added once more, and
the solution was extracted with methylene chloride. The combined
organic phases were rewashed once with dilute ammonia solution,
dried on sodium sulfate, filtered, and the solvent was drawn off.
The luminous red oil that was produced was purified on a silica gel
column.
[0568] Yield: 440 mg (1.53 mmol=96.0% of theory) of a colorless
oil
[0569] C.sub.17H.sub.21NO.sub.3 [287.36]
[0570] TLC: R.sub.f=0.39 (CHCL.sub.3:MeOH=9:1+1% NH.sub.4OH)
[0571] C.sub.17H.sub.21NO.sub.3.times.0.8 H.sub.2O [301.76]
TABLE-US-00034 % C % H % N Cld.: 67.66 7.55 4.64 Fnd.: 67.60 7.40
4.65
[0572] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 6.51 (s, 1H),
6.06 (d, J=10.2 Hz, 1H), 5.97 (dd, J=10.2, 4.5 Hz, 1H), 4.57 (bs,
1H), 4.27 (d, J=16.0 Hz, 1H), 4.11 (t, J=4.4 Hz, 1H), 3.80 (s, 3H),
3.77 (d, J=16.0 Hz, 1H), 3.40-3.10 (m, 2H), 2.65 (dd, J=15.6, 3.2
Hz, 1H), 2.23 (s, 3H), 1.99 (ddd, J=15.6, 4.9, 2.3 Hz, 1H),
1.89-1.63 (m, 2H); .sup.13C-NMR (50 MHz, CDCl.sub.3): .delta. 144.4
(s), 142.9 (s), 133.4 (S), 130.5 (s), 127.8 (s), 127.5 (d), 127.1
(d), 113.5 (d), 88.1 (d), 61.4 (d), 55.8 (q), 49.0 (s), 48.9 (t),
46.9 (t) 39.7 (t), 29.8 (t), 19.4 (q)
EXAMPLE 86
[(.+-.)-(4a.alpha.,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1,4'-dimethy-
l-spiro[-6H-benzofuro[3a,3,2-ef][2]benzazepine]-6,2'-[1,3]-dioxolane]-11-c-
arboxaldehyde, 1-methyl-N-formyl-narwedine ketal (MH-21)
[0573] TABLE-US-00035 ##STR233## ##STR234## 6.17 g (19.7 mmol)
1-methyl-N-formylnarwedine (XIX) 40.0 ml toluene 375 mg (1.97 mmol)
p-toluenesulfonic acid 11.1 ml (149 mmol) propylene glycol
[0574] In a flask with a water separator, the educt was introduced
into toluene, and 1/3 of the p-toluenesulfonic acid was added to
2/3 of propylene glycol. The reaction mixture was refluxed, and
after 2 hours, the solution of the residual p-toluenesulfonic acid
in propylene glycol was added in portions over 5 hours, then
refluxed for another 6 hours. After the end of the reaction (HPLC
study necessary, since TLC has little informational value), the
toluene phase was separated, and the propylene glycol phase was
exhaustively extracted with toluene. The collected toluene phases
were extracted 2.times. with acetic acid (8% in water), 2.times.
with saturated sodium bicarbonate solution and 2.times. with water,
then the solvent was drawn off.
[0575] Yield: 5.34 g (14.38 mmol=73% of theory) of a beige foam
[0576] C.sub.21H.sub.2NO.sub.5 [371.44]
[0577] TLC: R.sub.f=0.71 (CHCl.sub.3:MeOH=9:1)
[0578] C.sub.21H.sub.25NO.sub.5.times.0.85 H.sub.2O [386.74]
TABLE-US-00036 % C % H % N Cld.: 65.22 6.96 3.62 Fnd.: 65.39 7.19
3.52
[0579] .sup.1H-NMR (mixture that consists of diastereomers and
rotamers, 200 MHz, CDCl.sub.3): .delta. 8.14-8.01 (m, 1H),
7.30-7.09 (m, 2H), 6.51 (s, 1H), 6.22-5.97 (m, 1H), 5.85-5.61 (m,
1H), 5.38 and 4.77 (d, J=15.7 Hz, 1H), 4.49 (bs, 1H), 4.37-4.01 (m,
2H), 3.93-3.74 (m, 5H), 3.71-3.10 (m, 1H), 2.79-2.58 (m, 1H), 2.41
(s, 2H), 2.32 (d, J=10.2 Hz, 3H), 2.25-1.74 (m, 3H); .sup.13C-NMR
(mixture that consists of diastereomers and rotamers, 50 MHz,
CDCl.sub.3): .delta. 162.5 (d), 161.7 (d), 143.7 (s), 143.6 (s),
143.3 (d), 142.7 (d), 129.9 (s), 129.6 (s), 127.8 (d), 127.6 (d),
126.0 (s), 125.7 (s), 114.6 (d), 114.4 (d), 87.5 (d), 87.4 (d),
68.2 (d), 68.0 (t), 56.1 (q), 56.0 (q), 49.2 (s), 49.0 (s), 48.7
(t), 46.7 (t), 43.2 (t), 41.2 (t), 38.7 (t), 37.2 (t), 37.1 (t),
34.8 (t), 19.7 (q), 19.4 (q), 18.9 (q)
EXAMPLE 87
[(.+-.)-(4a.alpha.,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1,11-dimethy-
l-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one, 1-methylnarwedine
(MH-22)
[0580] TABLE-US-00037 ##STR235## ##STR236## 5.34 g (14.4 mmol)
1-methyl-N-formylnarwedine ketal (XX) 25.2 ml (25.2 mmol) = lithium
aluminum hydride 1 M in THF 1.75 equivalents 20 ml absolute THF
[0581] 1-Methyl-N-formylnarwedine (V) was dissolved in absolute
THF, and lithium aluminum hydride was added in portions while being
stirred. After 15 minutes, the reaction mixture was mixed with 10
ml of toluene, then hydrolyzed with 1.5 ml of water, and after 1.5
ml of sodium hydroxide solution (15% in water) was added, it was
stirred for 15 minutes. After 1.5 g of Hyflo was added, it was
refluxed for 1 hour, filtered off, the filter cake was boiled up
3.times. with 10 ml of toluene:THF=1:1 each and in each case
suctioned off. The organic phases were evaporated to the dry state,
taken up with 25 ml of 4N HCl and stirred for 25 minutes at
60.degree. C., then exhaustively extracted with ethyl acetate. The
collected organic phases were backwashed with dilute HCl. The
collected acidic, aqueous phases were released by distillation of
excess ethyl acetate, then made basic with concentrated aqueous
ammonia and exhaustively extracted with chloroform. The collected
chloroform phases were washed with saturated common salt solution,
dried on sodium sulfate, filtered, and the solvent was drawn off.
The purification was carried out by recrystallization from
diisopropyl ether:ethyl acetate=9:1.
[0582] Yield: 4.01 g (13.36 mmol=93% of theory) of light yellow,
very fine needles
[0583] C.sub.18H.sub.21NO.sub.3 [299.37]
[0584] TLC: R.sub.f=0.42 (CHCl.sub.3:MeOH 95:5)
[0585] Melting point: 121-122.degree. C. TABLE-US-00038 % C % H % N
Cld.: 72.22 7.07 4.68 Fnd.: 71.95 7.08 4.57
[0586] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 7.01 (dd, J=10.4,
1.6 Hz, 1H), 6.56 (s, 1H), 5.99 (d, J=10.4 Hz, 1H), 4.68-4.62 (m,
1H), 3.97 (d, J=15.7 Hz, 1H), 3.80 (s, 3H), 3.79 (d, J=15.7 Hz,
1H), 3.22-2.95 (m, 3H), 2.71 (dd, J=17.8, 3.7 Hz, 1H), 2.44 (s,
3H), 2.23 (s, 3H), 2.20-2.01 (m, 1H), 1.87 (dt, J=13.8, 3.4 Hz, 1H)
.sup.13C-NMR (50 MHz, CDCl.sub.3): .delta. 194.4 (s), 145.2 (s),
142.9 (s), 131.0 (s), 128.9 (s), 126.8 (d+d+s), 114.3 (d), 87.7
(d), 55.9 (q), 55.8 (t), 54.1 (t), 48.9 (s), 43.5 (q), 37.1 (t),
33.4 (t), 19.4 (q)
EXAMPLE 88
[(.+-.)-(4a.alpha.,6.beta.,8aR)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1,11--
dimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,
1-methylgalanthamine (MH-30)
[0587] TABLE-US-00039 ##STR237## ##STR238## 170 mg (0.57 mmol)
1-methyl-narwedine (XXI) 0.70 ml (0.68 mmol) = L-Selectride.sup.(R)
1 M in THF 1.2 equivalents 5 ml absolute THF
[0588] The educt was introduced into THF under N.sub.2 atmosphere
and cooled to -25.degree. C., then L-Selectride was slowly added in
drops. It was stirred for 30 minutes at -15.degree. C., whereby the
initial suspension was in a clear solution. Then, the reaction
mixture was brought to room temperature over 1 hour, hydrolyzed
with 5 drops of water, stirred for 30 minutes, 0.5 ml of
concentrated aqueous NH.sub.4OH was added, stirred for another 10
minutes, 2 ml of concentrated NH.sub.4OH was added again and
finally it was extracted with methylene chloride. The combined
organic phases were washed with saturated common salt solution,
dried on sodium sulfate, filtered, and the solvent was drawn off,
whereby 350 mg of crude product was produced. This crude product
was purified on a silica gel column (CHCl.sub.3:MeOH=9:1), whereby
a yellow oil was produced, which solidified by adding ether.
[0589] Yield: 120 mg (0.398 mmol=70% of theory) of a colorless
powder
[0590] C.sub.18H.sub.23NO.sub.3 [301.39]
[0591] TLC: R.sub.f=0.43 (CHCl.sub.3:MeOH=95:5), not to be
separated from educt
[0592] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 6.54 (s, 1H),
6.10 (dd, J=10.2, 1.2 Hz, 1H), 5.98 (dd, J=10.2, 4.7 Hz, 1H), 4.56
(bs, 1H), 4.12 (bs, 1H), 3.99 (d, J=15.6 Hz, 1H), 3.82 (s, 3H),
3.81 (d, J=15.6 Hz, 1H), 3.20 (ddd, J=14.2, 12.1, 2.1 Hz, 1H), 2.96
(dt, J=14.2, 3.4 Hz, 1H), 2.65 (ddd, J=15.7, 3.2, 1.5 Hz, 1H), 2.41
(s, 3H), 2.24 (s, 3H), 1.99 (ddd, J=15.5, 5.0, 2.5 Hz, 2H), 1.60
(ddd, J=13.7, 4.0, 2.4 Hz, 1H);
[0593] .sup.13C-NMR (50 MHz, CDCl.sub.3) .delta. 144.0 (s), 143.0
(s), 133.4 (s), 128.9 (s), 127.4 (d+d), 127.0 (s), 126.6 (s), 113.6
(d), 88.3 (d), 61.9 (d), 55.7 (q), 55.4 (t), 53.8 (t), 48.2 (s),
42.7 (q), 33.8 (t), 29.8 (t), 19.4 (q)
Production of Hyodrobromide:
[0594] The reaction solution is hydrolyzed with ethanol (about half
the reaction volume), stirred for 30 minutes, then brought to
pH.ltoreq.1 with concentrated HBr and stirred overnight. The
precipitate that is produced is suctioned off, washed with ethanol
and dried.
[0595] Melting point: 246-250.degree. C. (hydrobromide)
[0596] C.sub.18H.sub.24NO.sub.3Br.times.0.5H.sub.2O [391.30]
TABLE-US-00040 % C % H % N Cld.: 55.25 6.44 3.58 Fnd.: 55.21 6.39
3.56
EXAMPLE 89
[(.+-.)-(4a.alpha.,6.alpha.,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1,1-
1-dimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,
1-methylepigalanthamine (MH-31)
[0597] TABLE-US-00041 ##STR239## ##STR240## 2.00 g (6.68 mmol)
1-methylnarwedine (XXI) 150 ml methanol 2.50 g (6.68 mmol) cerium
trichloride heptahydrate 0.50 g (13.4 mmol) = NaBH.sub.4 2
equivalents
[0598] The educt was dissolved in methanol with heating and then
cooled to 0.degree. C., CeCl.sub.3.times.7H.sub.2O was added and
stirred at 0.degree. C. for about 30-60 minutes. Then, NaBH.sub.4
was added in portions, it was stirred for another 2 hours at
0-5.degree. C., whereby a precipitate formed. The reaction mixture
was hydrolyzed with 5 ml of 2N HCl, methanol was distilled off in a
vacuum, the residue was taken up with another 150 ml of 2N HCl,
made basic with concentrated NH.sub.4OH (violet precipitate),
extracted with ethyl acetate, the collected organic phases were
washed with saturated common salt solution, dried on sodium
sulfate, filtered, and the solvent was drawn off. As a crude
product, an isomer mixture of 1-methylepigalanthamine and
1-methylgalanthamine at a ratio of about 5:1 was produced, which
could be separated by chromatography (silica gel,
CHCl.sub.3:MeOH=9:1+0.5% NH.sub.4OH).
[0599] Yield: 1.34 g (4.45 mmol=66.6% of theory) of a colorless
oil
[0600] C.sub.18H.sub.23NO.sub.3 [301.39]
[0601] TLC: R.sub.f=0.20 (CHCl.sub.3:MeOH=9:1)
[0602] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 6.51 (s, 1H),
6.10 (d, J=10.2 Hz, 1H), 5.79 (d, J=10.2 Hz, 1H), 4.69-4.56 (m,
1H), 4.55 (bs, 1H), 3.96 (d, J=15.3 Hz, 1H), 3.82 (s, 3H), 3.79 (d,
J=15.3 Hz, 1H), 3.21 (td, J=13.1, 1.7 Hz, 1H), 2.97 (dt, J=14.1,
3.3 Hz, 1H), 2.75 (dddd, J=14.1, 5.3, 4.0, 1.2 Hz, 1H), 2.38 (s,
3H), 2.23 (s, 3H), 2.10 (dd, J=13.1, 3.2 Hz, 1H), 2.03 (bs, 1H),
1.69 (ddd, J=13.6, 10.7, 2.6 Hz, 2H); .sup.13C-NMR (50 MHz,
CDCl.sub.3) .delta. 145.0 (s), 142.9 (s), 133.5 (s), 131.7 (d),
128.5 (s), 126.7 (d), 126.6 (s), 113.5 (d), 88.3 (d), 63.1 (d),
55.8 (q), 55.2 (t), 54.1 (t), 48.3 (s), 42.6 (q), 34.6 (t), 32.4
(t), 19.5 (q)
Production of Hydrobromide:
[0603] The 1-methylepigalanthamine that was obtained was taken up
in ethanol and brought to pH.ltoreq.1 with concentrated HBr. The
hydrobromide was brought to crystallization under cold conditions
and the precipitate that was produced was suctioned off, washed
with cold ethanol and dried.
[0604] Melting point: 254-255.degree. C. (hydrobromide)
[0605] C.sub.18H.sub.24NO.sub.3Br.times.0.5 H.sub.2O [391.30]
TABLE-US-00042 % C % H % N Cld.: 56.25 6.44 3.58 Fnd.: 56.28 6.21
3.57
EXAMPLE 90
[0606]
[(.+-.)-(4a.alpha.,6.alpha.,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-met-
hoxy-1-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,
1-methyl-N-demethylepigalanthamine ##STR241##
[0607] Method A (Epimerization of 1-methyl-N-demethylgalanthamine
(XXII))
Step 1 (Acetylation):
[(.+-.)-(4a.alpha.,6.alpha.,8aR*)]-6-O-Acetyloxy-4a,5,9,10,11,12-hexahydr-
o-3-methoxy-1-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepine
(MH-67)
[0608] TABLE-US-00043 ##STR242## ##STR243## 100 mg (0.35 mmol)
1-methyl-N-demethylgalanthamine (XXII) 0.50 ml (1.74 mmol) =
N,N-dimethylformamide-bis(2,2- 5 equivalents dimethylpropyl)-acetal
0.10 ml (1.74 mmol) = glacial acetic acid 5 equivalents 12 ml
toluene
[0609] The educt was heated in 10 ml of toluene under N.sub.2
atmosphere to 80.degree. C. and over 1 hour, a mixture that
consists of N,N-dimethylformamide-bis-(2,2-dimethylpropyl)acetal
and glacial acetic acid in 2 ml of toluene was added in drops.
After 22 hours at 80.degree. C., the cooled toluene phase was
extracted 1.times. with water, then with 2N hydrochloric acid, the
acidic aqueous phase was made basic with concentrated ammonia
solution, it was extracted with ethyl acetate, the organic phases
were washed with saturated common salt solution, dried on sodium
sulfate, filtered, and the solvent was drawn off. The residue was
purified by column chromatography.
[0610] (CHCl.sub.3:MeOH=95:5).
[0611] Yield: 45 mg (0.14 mmol=39% of theory) of a colorless
oil
[0612] C.sub.19H.sub.23NO.sub.4 [329.40]
[0613] TLC: R.sub.f=0.20 (CHCl.sub.3:MeOH=95:5)
[0614] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 6.50 (s, 1H),
6.14 (d, J=10.2 Hz, 1H), 5.72 (d, J=10.2 Hz, 1H), 5.67-5.58 (m,
1H), 4.57 (bs, 1H), 4.24 (d, J=16.0 Hz, 1H), 3.83 (s, 3H), 3.75 (d,
J=16.0 Hz, 1H), 3.40-3.09 (m, 2H), 2.90-2.70 (m, 1H), 2.23 (s, 3H),
2.07 (s, 3H), 2.01-1.73 (m, 3H); .sup.13C-NMR (50 MHz, CDCl.sub.3):
.delta. 170.2 (s), 145.3 (s), 142.8 (s), 133.0 (s), 130.5 (s),
128.4 (d), 127.2 (d) 127.0 (s), 113.5 (d), 87.3 (d), 66.4 (d), 55.8
(q), 48.8 (s+t) 47.1 (t), 40.4 (t), 28.2 (t), 21.1 (q), 19.4
(q)
Step 2: Ester Hydrolysis (MH-78)
[0615] TABLE-US-00044 ##STR244## ##STR245## 17 mg (0.05 mmol)
6-O-acetyl-1-methyl-N- demethylepigalanthamine (XXIIa) 0.5 ml
methanol 0.1 ml 2N KOH 17 mg (0.12 mmol) = 2.4 equivalents
potassium carbonate
[0616] The reagents were stirred together at room temperature.
After the end of the reaction, it was mixed with 1 ml of water,
methanol was drawn off, it was acidified with 4 ml of 2N
hydrochloric acid, the aqueous phase was washed with ethyl acetate,
then made basic with concentrated aqueous ammonia solution and
extracted with ethyl acetate. The organic phases were washed with
saturated common salt solution, dried on sodium sulfate, filtered,
and the solvent was drawn off.
[0617] C.sub.17H.sub.21NO.sub.3 [287.36]
[0618] TLC: R.sub.f=0.07 (CHCl.sub.3:MeOH=9:1)
Method B (Demethylation of 1-Methylepigalanthamine) (MH-94)
[0619] TABLE-US-00045 ##STR246## ##STR247## 0.80 g (2.65 mmol)
1-methylepigalanthamine (XXIII) 1.50 g (6.63 mmol) = 2.5
equivalents azodicarboxylic acid-bis-(2-methyl- 2-propylester) 80
ml tetrahydrofuran
[0620] The reagents were stirred together at room temperature for
24 hours, then the solvent was drawn off. The residue was taken up
in trifluoroacetic acid in methylene chloride, stirred for 30
minutes, made basic in an ice bath with concentrated aqueous
ammonia solution and extracted with methylene chloride. The organic
phases were washed with saturated common salt solution, dried on
sodium sulfate, filtered, and the solvent was removed. The crude
product was purified by column chromatography (CHCl.sub.3:MeOH
9:1).
[0621] Yield: 400 mg (1.39 mmol=53% of theory) of a colorless
oil
[0622] C.sub.17H.sub.21NO.sub.3 [287.36]
[0623] TLC: R.sub.f=0.10 (CHCl.sub.3:MeOH=9:1)
[0624] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 6.50 (s, 1H),
6.08 (d, J=10.3 Hz, 1H), 5.80 (d, J=10.3 Hz, 1H), 4.70-4.62 (m,
1H), 4.57 (bs, 1H), 4.26 (d, J=15.7 Hz, 1H), 3.83 (s, 3H), 3.75 (d,
J=15.7 Hz, 1H), 3.35-3.20 (m, 1H), 2.85-2.70 (m, 1H), 2.50-2.29 (m,
2H), 2.23 (s, 3H), 2.00-1.64 (m, 2H); .sup.13C-NMR (50 MHz,
CDCl.sub.3): .delta. 145.4 (s), 142.9 (s), 133.5 (s), 131.6 (d),
130.7 (s), 127.2 (d), 126.8 (s), 113.3 (d), 88.2 (d), 63.1 (d),
55.9 (q), 48.9 (t), 48.8 (s), 47.2 (t), 32.2 (t), 28.2 (t), 19.5
(q) General Operating Instructions for Quaternary 1-Methyl- and
1-Methylepi-galanthamine Derivatives (Examples 90-99)
##STR248##
[0625] The educt was dissolved* in very little DMF, added to the
alkyl halide, and the reaction mixture was heated (generally not
above the boiling temperature of the alkyl halide, but at most
70.degree. C.). By means of TLC, the end of the reaction was
determined, then the reaction mixture was slowly added in drops to
ether while being stirred (in many cases easily extrudes oil), the
precipitate was suctioned off and washed with ether. For
purification and for removing residual DMF, the precipitate was
dissolved in ethanol and once more precipitated in ethyl acetate,
then dried in a vacuum drying oven at 50.degree. C.
[0626] TLC: CHCl.sub.3:MeOH=9:1, R.sub.f generally slightly over
the starting value. *With R.dbd.CH.sub.2Cl, methylene chloride
(p.A. 99.5%) is used as a solvent and reagent.
EXAMPLE 90
[(.+-.)-(4a.alpha.,6.beta.,8aR*)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-met-
hoxy-1,11-dimethyl-11-(2-methyl-2-propenyl)-6H-benzofuro[3a,3,2-ef][2]benz-
azepinium, chloride (MH-33)
[0627] TABLE-US-00046 (XLI) ##STR249## 280 mg (0.94 mmol)
1-methylgalanthamine (XV) 0.30 ml (3.08 mmol) =
1-chloro-2-methylprop-2-ene 3 equivalents 5.00 ml
dimethylformamide
[0628] The reaction was performed at 70.degree. C. and worked up
after 2 hours, by the reaction mixture having been added in drops
to 25 ml of diethyl ether.
[0629] Yield: 270 mg (0.69 mmol=73% of theory) of a colorless
powder
[0630] C.sub.22H.sub.30CINO.sub.3 [391.94]
[0631] TLC: R.sub.f=0.10 (CHCl.sub.3:MeOH=9:1)
[0632] Melting point: 239-241.degree. C.
[0633] C.sub.22H.sub.30ClNO.sub.3.times.1.4H.sub.2O [417.14]
TABLE-US-00047 % C % H % N Cld.: 63.34 7.92 3.36 Fnd.: 63.22 7.85
3.59
[0634] .sup.13C-NMR (50 MHz, DMSO-d.sub.6): .delta. 144.6 (s),
134.2 (s), 133.5 (s), 131.1 (s), 130.9 (d), 127.5 (t), 124.9 (d),
115.9 (s), 114.4 (d), 86.3 (d), 73.0 (t), 60.8 (t), 59.4 (d), 55.5
(q), 46.3 (s), 43.0 (q), 31.1 (t), 23.8 (q), 18.9 (q)
EXAMPLE 91
[(.+-.)-(4a.alpha.,6.beta.,8aR*)]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-me-
thoxy-1,11-dimethyl-11-(2-propinyl)-6H-benzofuro[3a,3,2-ef][2]benzazepiniu-
m, bromide (MH-38)
[0635] TABLE-US-00048 (XXIX) ##STR250## 349 mg (1.16 mmol)
1-methylgalanthamine (XV) 0.13 ml (1.16 mmol) 3-bromo-1-propine
(propargyl bromide) 4.00 ml dimethylformamide
[0636] The reaction was performed at 60.degree. C. and worked up
after 19 hours by the reaction mixture having been added in drops
to 80 ml of diethyl ether.
[0637] Yield: 300 mg (0.71 mmol=62% of theory) of a beige
powder
[0638] C.sub.21H.sub.26BrNO.sub.3[420.35]
[0639] TLC: R.sub.f=0.09 (CHCl.sub.3:MeOH=9:1)
[0640] Melting point: 216-218.degree. C.
[0641] C.sub.21H.sub.26BrNO.sub.3.times.0.35H.sub.2O.times.0.25
C.sub.3H.sub.7NO [444.93] TABLE-US-00049 % C % H % N Cld.: 58.72
6.44 3.90 Fnd.: 58.70 6.37 3.94
[0642] .sup.13C-NMR (50 MHz, DMSO-d.sub.6): .delta. 144.8 (s),
144.7 (s), 133.4 (s), 131.0 (s), 125.2 (d), 115.3 (s), 114.5 (d),
86.2 (d), 83.7 (d), 72.6 (t), 60.6 (t), 59.7 (d), 55.6 (q), 46.2
(s), 43.0 (g), 31.0 (t), 18.8 (q)
EXAMPLE 92
[(.+-.)-(4a.alpha.,6,8aR*)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1-
,11-dimethyl-11-phenylmethyl-6H-benzofuro[3a,3,2-ef][2]benzazepinium,
bromide (MH-39)
[0643] TABLE-US-00050 (XL) ##STR251## 242 mg (0.80 mmol)
1-methylgalanthamine (XV) 0.25 ml (1.01 mmol) = 1.4 equivalents
benzyl bromide 4.00 ml dimethylformamide
[0644] The reaction was performed at 60.degree. C. and worked up
after 10 minutes.
[0645] Yield: 262 mg (0.55 mmol=69% of theory) of a beige
powder
[0646] C.sub.25H.sub.30BrNO.sub.3 [472.42]
[0647] TLC: R.sub.f=0.08 (CHCl.sub.3:MeOH 9:1)
[0648] Melting point: 246-248.degree. C. TABLE-US-00051 % C % H % N
Cld.: 63.56 6.40 2.96 Fnd.: 63.35 6.34 2.93
[0649] .sup.13C-NMR (50 MHz, DMSO-d.sub.6): .delta. 144.7 (s),
133.4 (d), 130.7 (s), 130.4 (d), 129.0 (d), 128.1 (s), 114.5 (d),
86.3 (d), 59.7 (t), 59.5 (d), 55.6 (q), 46.2 (s), 18.6 (q)
EXAMPLE 93
[(.+-.)-(4a.alpha.,6.beta.,8aR*)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-met-
hoxy-1,11,11-trimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepinium,
iodide (MH-83)
[0650] TABLE-US-00052 (XLII) ##STR252## 140 mg (0.46 mmol)
1-methylgalanthamine (XV) 198 mg (1.39 mmol) = 3 equivalents methyl
iodide 4.00 ml dimethylformamide
[0651] The reaction was performed at 40.degree. C. and worked up
after 1.5 hours, by the reaction mixtue having been added in drops
to 30 ml of diethyl ether.
[0652] Yield: 146 mg (0.54 mmol=71% of theory) of a light brown
powder
[0653] C.sub.19H.sub.26INO.sub.3 [443.32]
[0654] TLC: R.sub.f=0.05 (CHCl.sub.3:MeOH=9:1)
[0655] Melting point: 278-280.degree. C.
[0656] C.sub.19H.sub.26INO.sub.3.times.0.3H.sub.2O [448.72]
TABLE-US-00053 % C % H % N Cld.: 50.86 5.97 3.12 Fnd.: 50.57 5.85
3.43
[0657] .sup.13C-NMR (50 MHz, DMSO-d.sub.6) .delta. 144.6 (s), 144.1
(s), 132.8 (s), 131.6 (s), 114.2 (d), 86.3 (d), 62.6 (t), 59.5 (d),
55.4 (q), 45.9 (s), 31.0 (t), 18.4 (q)
EXAMPLE 94
[(.+-.)-(4a.alpha.,6.beta.,8aR*))-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-me-
thoxy-1,11-dimethyl-11-(2-methyl-2-propenyl)-6H-benzofuro[3a,3,2-ef][2]ben-
zazepinium, chloride (MH-66)
[0658] TABLE-US-00054 (XLIV) ##STR253## 150 mg (0.50 mmol)
1-methylepigalanthamine (XXIII) 45.0 mg (1.50 mmol) =
1-chloro-2-methylprop-2-ene 3 equivalents 4.00 ml
dimethylformamide
[0659] The reaction was performed at 70.degree. C. and worked up
after 100 minutes, by the reaction mixture having been added in
drops to 50 ml of diethyl ether.
[0660] Yield: 160 mg (0.41 mmol=82% of theory) of a colorless
powder
[0661] C.sub.22H.sub.30ClNO.sub.3 [391.94]
[0662] TLC: R.sub.f=0.09 (CHCl.sub.3:MeOH=9:1)
[0663] Melting point: 162-164.degree. C.
[0664] C.sub.22H.sub.30CINO.sub.3.times.0.7H.sub.2O.times.0.15
C.sub.3H.sub.7O [415.51] TABLE-US-00055 % C % H % N Cld.: 64.90
7.87 3.88 Fnd.: 64.77 7.68 3.95
[0665] .sup.13C-NMR (50 MHz, DMSO-d.sub.6): .delta. 144.7 (s),
134.2 (s), 134.1 (s) 131.1 (d), 127.5 (t), 114.4 (d), 87.3 (d),
73.0 (t), 60.7 (d), 59.4 (t), 55.6 (q), 46.3 (s), 23.8 (q), 18.9
(q)
EXAMPLE 95
[0666]
[(.+-.)-(4a.alpha.,6a.alpha.,8aR*)]-4a,5,9,10,11,12-Hexahydro-6-hy-
droxy-3-methoxy-1,11-dimethyl-11-(2-propinyl)-6H-benzofuro[3a,3,2-ef][2]be-
nzazepinium, bromide (MH-71) TABLE-US-00056 (XLVIII) ##STR254## 150
mg (0.50 mmol) 1-methylepigalanthamine (XXIII) 180 mg (1.50 mmol) =
3-bromo-1-propine (propargyl 3 equivalents bromide) 4.00 ml
dimethylformamide
[0667] The reaction was performed at 70.degree. C. and worked up
after 2.5 hours, by the reaction mixture having been added in drops
to 30 ml of diethyl ether.
[0668] Yield: 167 mg (0.40 mmol=82% of theory) of a light brown
powder
[0669] C.sub.21H.sub.26BrNO.sub.3 [420.35]
[0670] TLC: R.sub.f=0.09 (CHCl.sub.3:MeOH=9:1)
[0671] Melting point: 158-162.degree. C.
[0672] .sup.13C-NMR (50 MHz, DMSO-d.sub.6): .delta. 144.8 (s),
133.9 (s), 131.2 (s), 114.5 (d), 87.2 (d), 83.7 (d), 72.6 (d), 55.6
(q), 46.3 (s), 31.9 (t), 18.8 (q)
EXAMPLE 96
[(.+-.)-(4a.alpha.,6.alpha.,8aR*)]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-m-
ethoxy-1,11-dimethyl-11-(2-propenyl)-6H-benzofuro[3a,3,2-ef][2]benzazepini-
um, bromide (MH-72)
[0673] TABLE-US-00057 (XLIX) ##STR255## 150 mg (0.50 mmol)
1-methylepigalanthamine (XXIII) 0.13 ml (1.50 mmol) =
3-bromo-1-propene (allyl bromide) 3 equivalents 4.00 ml
dimethylformamide
[0674] The reaction was performed at 60.degree. C. and worked up
after 2 hours.
[0675] Yield: 150 mg (0.36 mmol=64% of theory) of a light brown
powder
[0676] C.sub.21H.sub.28BrNO.sub.3 [422.36]
[0677] TLC: R.sub.f=0.11 (CHCl.sub.3:MeOH=9:1)
[0678] Melting point: 140-145.degree. C.
[0679] C.sub.21H.sub.28BrNO.sub.3.times.1H.sub.2O.times.0.25
C.sub.3H.sub.7NO [458.64] TABLE-US-00058 % C % H % N Cld.: 56.96
6.98 3.82 Fnd.: 56.69 6.65 4.05
[0680] .sup.13C-NMR (50 MHz, DMSO-d.sub.6): .delta. 144.7 (s),
134.5 (d), 134.0 (s), 131.1 (s), 128.3 (s), 126.1 (d), 115.3 (d),
114.4 (d), 87.2 (d), 60.7 (d), 59.8 (t), 55.6 (q), 46.3 (s), 31.5
(t), 18.8 (q)
EXAMPLE 97
[(.+-.)-(4a.alpha.,6.alpha.,8aR*)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-me-
thoxy-1,11-dimethyl-11-(4-(trifluoromethyl)phenylmethyl)-6H-benzofuro[3a,3-
,2-ef][2]benzazepinium, bromide (MH-75)
[0681] TABLE-US-00059 (XLVI) ##STR256## 150 mg (0.50 mmol)
1-methylepigalanthamide (XXIII) 357 mg (1.50 mmol) =
4-trifluoromethylbezyl bromide 1.4 equivalents 4.00 ml
dimethylformamide
[0682] The reaction was performed at 70.degree. C. and worked up
after 1 hour.
[0683] Yield: 142 mg (0.26 mmol=53% of theory) of a light yellow
powder
[0684] C.sub.26H.sub.29BrF.sub.3NO.sub.3 [540.42]
[0685] TLC: R.sub.f=0.10 (CHCl.sub.3:MeOH=9:1)
[0686] Melting point: 178-182.degree. C.
[0687] .sup.13C-NMR (50 MHz, DMSO-d.sub.6): .delta. 144.8 (s),
134.4 (d+d), 134.2 (d), 132.6 (s), 131.2 (s), 130.9 (s), 130.3 (s),
126.6 (d), 125.8 (s), 121.2 (d), 114.5 (d), 87.3 (d), 60.8 (d),
55.6 (q), 46.3 (s), 34.3 (t), 18.7 (q)
EXAMPLE 98
[(.+-.)-(4a.alpha.,6.alpha.,8aR*)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-me-
thoxy-1,11-dimethyl-11-(phenylmethyl)-6H-benzofuro[3a,3,2-ef][2]benzazepin-
ium, bromide (MH-76)
[0688] TABLE-US-00060 (XLV) ##STR257## 153 mg (0.51 mmol)
1-methylepigalanthamine (XXIII) 92 mg (0.51 mmol) benzyl bromide
4.00 ml dimethylformamide
[0689] The reaction was performed at 70.degree. C. and worked up
after 3 hours.
[0690] Yield: 150 mg (0.32 mmol 63% of theory) of a light brown
powder
[0691] C.sub.25H.sub.30BrNO.sub.3 [472.421
[0692] TLC: R.sub.f=0.11 (CHCl.sub.3:MeOH=9:1)
[0693] Melting point: 169-175.degree. C.
[0694] .sup.13C-NMR (50 MHz, DMSO-d.sub.6) .delta. 144.6 (s), 134.1
(s), 133.4 (d), 131.0 (s), 130.4 (d), 128.9 (d), 128.1 (S), 114.4
(d), 87.2 (d), 61.8 (d), 59.4 (t), 55.6 (q), 46.3 (s), 31.5 (t),
18.6 (q)
EXAMPLE 99
[(.+-.)-(4a.alpha.,6.alpha.,8aR*)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-me-
thoxy-1,11,11-trimethyl-6H-benzofuro[3a,3,2-ef)[2]benzazepinium,
iodide (MH-81)
[0695] TABLE-US-00061 (XLVII) ##STR258## 210 mg (0.70 mmol)
1-methylepigalanthamine (XXIII) 290 mg (2.10 mmol) = methyl iodide
3 equivalents 4.00 ml dimethylformamide
[0696] The reaction was performed at 70.degree. C. and worked up
after 2 hours, by the reaction mixture having been added in drops
to 30 ml of diethyl ether.
[0697] Yield: 240 mg (0.54 mmol=77% of theory) of a light-brown
powder
[0698] C.sub.19H.sub.26INO.sub.3 [443.32]
[0699] TLC: R.sub.f=0.05 (CHCl.sub.3:MeOH=9:1)
[0700] Melting point: decomposition>280.degree. C.
TABLE-US-00062 % C % H % N Cld.: 51.48 5.91 3.16 Fnd.: 51.25 5.75
3.32
[0701] .sup.13C-NMR (50 MHz, DMSO-d.sub.6): .delta. 144.7 (s),
133.6 (s), 131.1 (s), 114.4 (d), 87.1 (d), 62.2 (t), 60.7 (q), 55.5
(q), 48.4 (d), 46.2 (s), 31.5 (t), 18.9 (q)
General Operating Instructions for the Production of
Galanthamine-N-Oxides
EXAMPLES 100-101
[0702] TABLE-US-00063 1 equivalent galanthamine derivative 1-1.5
equivalents 3-chloroperbenzoic acid 100 ml chloroform/1 g of
galanthamine derivative 0.7 ml H.sub.2O.sub.2 (35%)/1 g of
galanthamine derivative
[0703] The 3-chloroperbenzoic acid is dissolved in 1/3 chloroform,
mixed with hydrogen peroxide and stirred for 2 minutes. Then, this
solution is added to a solution of the galanthamine derivative in
2/3 chloroform, it is stirred for 15 minutes, concentrated by
evaporation and purified by means of column chromatography
(gradient: CHCl.sub.3:MeOH=9:1.fwdarw.MeOH).
EXAMPLE 101
[4aS-(4.alpha.a,6.alpha.,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-met-
hyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol, 11-oxide,
epigalanthamine-N-oxide (Pi-23)
[0704] TABLE-US-00064 ##STR259## ##STR260## 49.7 mg (0.17 mmol)
epigalanthamine (26) 29.9 mg (0.17 mmol) 3-chloroperbenzoic acid
0.03 ml hydrogen peroxide (35%) 5 ml chloroform
[0705] Yield: 37 mg (71% of theory)
[0706] C.sub.17H.sub.21NO.sub.4 [303.36]
[0707] TLC: R.sub.f=0.05 (CHCl.sub.3:MeOH 9:1)
[0708] .sup.1H-NMR (200 MHz, CDCl.sub.3) .delta. 6.67 (s, 2H), 5.96
(bs, 2H), 4.78 (d, J=15.0 Hz, 1H), 4.67-4.50 (m, 2H), 4.26 (d,
J=15.0 Hz, 1H), 3.83 (s, 3H), 3.67-3.41 (m, 2H), 3.41 (s, 2H), 2.96
(s, 3H) 2.77 (dt, J=13.1, 3.7 Hz, 1H), 2.05 (bs, 1H), 1.74 (t,
J=11.3 Hz, 1H)
[0709] .sup.13C-spectra could not be taken up because of the quick
solvate formation and crystallization in chloroform, but the
structural determination was made by x-ray crystallography.
General Operating Instructions for the Production of N-Substituted
1-Methylgalanthamine Derivatives
EXAMPLES 102-106
[0710] TABLE-US-00065 ##STR261## ##STR262## 200 mg (0.70 mmol)
1-methyl-N-demethylgalanthamine (or -epigalanthamine) 192 mg (1.39
mmol) = potassium carbonate 2 equivalents 117 mg (0.78 mmol) =
sodium iodide 1.1 equivalents (0.84 mmol) = 1.2 substituted alkyl
halide equivalents 10 ml acetone, dried on a 4 .ANG. molecular
sieve
[0711] Sodium iodide, potassium carbonate and educt were thoroughly
pulverized in a friction column, the mixture together with some
glass pellets were introduced into the flask and suspended in
absolute acetone. The substituted alkyl halide was added in
measured quantities, and the reaction mixture was refluxed. After
the end of the reaction, the reaction mixture was evaporated to the
dry state in a vacuum, and the residue was taken up with 2N HCl,
the aqueous phase was washed with ethyl acetate, then made basic
with concentrated aqueous ammonia and in turn extracted with ethyl
acetate. The collected organic phases were washed with saturated
common salt solution, dried on sodium sulfate, filtered, and the
solvent was drawn off. The crude product was purified on a silica
gel column (mobile solvent: CHCl.sub.3:MeOH=9:1+1% NH.sub.4OH)
EXAMPLE 102
[(.+-.)-(4a.alpha.,6.beta.,8aR*)-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-met-
hyl-11-(2-propenyl)-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,
1-methyl-N-allylgalanthamine (MH-25)
[0712] TABLE-US-00066 (XXXIII) ##STR263## 200 mg (0.70 mmol)
1-methyl-N-demethylgalanthamine (XXII) 0.07 ml (0.84 mmol) =
1-bromo-2-propene (allyl bromide) 1.2 equivalents
[0713] After 10 hours, the reaction was worked up.
[0714] Yield: 50 mg (0.15 mmol=22% of theory) of a yellow oil
[0715] C.sub.20H.sub.25NO.sub.3 [327.43]
[0716] TLC: R.sub.f=0.17 (CHCl.sub.3:MeOH=9:1+1% NH.sub.4OH)
[0717] C.sub.20H.sub.25NO.sub.3.times.0.8H.sub.2O [341.82]
TABLE-US-00067 % C % H % N Cld.: 70.27 7.84 4.10 Fnd.: 70.18 7.60
4.05
[0718] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 6.52 (s, 1H),
6.12 (d, J=10.3 Hz, 1H), 6.03-5.78 (m, 2H), 5.18 (bs, 1H), 5.11 (d,
J=4.5 Hz, 1H), 4.57 (bs, 1H), 4.12 (bs, 1H), 4.09 (d, J=15.0 Hz,
1H), 3.81 (s, 3H), 3.78 (d, J=15.0 Hz, 1H), 3.32-3.02 (m, 4H),
2.72-2.58 (m, 1H), 2.21 (s, 3H), 2.07-1.89 (m, 2H), 1.57 (ddd,
J=13.7, 3.4, 2.7 Hz, 1H); .sup.13C-NMR (50 MHz, CDCl.sub.3):
.delta. 144.0 (s), 143.0 (s), 136.0 (d), 133.6 (s), 129.1 (s),
127.4 (d), 127.2 (d) 126.9 (s), 117.5 (t), 113.7 (d), 88.4 (d),
62.0 (d), 57.2 (t), 55.8 (q), 52.9 (t), 52.0 (t), 48.4 (s), 33.9
(t), 29.8 (t), 19.4 (q)
EXAMPLE 103
[(.+-.)-(4a.alpha.,6.beta.,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-me-
thyl-11-(phenylmethyl)-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,
1-methyl-N-benzylgalanthamine (MH-26)
[0719] TABLE-US-00068 (XXXVI) ##STR264## 200 mg (0.70 mmol)
1-methyl-N-demethylgalanthamine (XXII) 0.1 ml (0.84 mmol) =
bromomethylbenzene (benzyl bromide) 1.2 equivalents
[0720] After 24 hours, the reaction was worked up.
[0721] Yield: 140 mg (0.37 mmol=53% of theory) of a yellow oil
[0722] C.sub.24H.sub.27NO.sub.3 [377.481
[0723] TLC: R.sub.f=0.36 (CHCl.sub.3:MeOH=9:1+1% NH.sub.4OH)
[0724] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 7.30 (m, 5H),
6.50 (s, 1H), 6.16 (d, J=10.2 Hz, 1H), 5.99 (dd, J=10.2, 4.9 Hz,
1H), 4.61 (bs, 1H), 4.13 (bs, 1H), 4.00 (d, J=15.7 Hz, 1H), 3.82
(s, 3H), 3.81 (d, J=15.7 Hz, 1H), 3.69 (s, 2H), 3.34 (td, J=14.1,
12.4, 1.8 Hz, 1H), 3.13 (td, J=14.1, 3.5 Hz, 1H), 2.74-2.37 (m, 2H)
2.19-1.93 (m, 2H), 1.90 (s, 3H), 1.57 (dt, J=13.7, 3.0 Hz, 1H)
.sup.13C-NMR (50 MHz, CDCl.sub.3): .delta. 143.9 (s), 143.0 (s),
138.9 (s), 133.6 (s), 129.2 (s), 128.7 (d), 128.2 (d), 127.4 (d),
127.3 (d), 127.2 (s), 126.9 (d), 113.7 (d), 88.4 (d), 62.0 (d),
57.4 (t), 55.8 (q), 52.4 (t), 52.2 (t), 48.5 (s), 33.7 (t), 29.8
(t), 19.1 (q)
EXAMPLE 104
[(.+-.)-(4a.alpha.,6.beta.,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-me-
thyl-11-(2-(4-morpholinyl)ethyl)-6H-benzofuro[3a,3,2-ef][12]benzazepin-6-o-
l, 1-methyl-N-morpholinoethyl-galanthamine (MH-28)
[0725] TABLE-US-00069 (XXXV) ##STR265## 200 mg (0.70 mmol)
1-methyl-N-demethylgalanthamine (XXII) 155 mg (0.84 mmol) =
4-(2-chloroethyl)morpholine 1.2 equivalents hydrochloride
[0726] After 24 hours, the reaction was worked up.
[0727] Yield: 210 mg (0.52 mmol=75% of theory) of a yellow oil
[0728] C.sub.23H.sub.32N.sub.2O.sub.4 [400.52]
[0729] TLC: R.sub.f=0.51 (CHCl.sub.3:MeOH=9:1+1% NH.sub.4OH)
[0730] C.sub.23H.sub.32N.sub.2O.sub.4.times.0.9H.sub.2O [416.72]
TABLE-US-00070 % C % H % N Cld.: 66.29 8.17 6.72 Fnd.: 66.28 8.09
6.85
[0731] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 6.52 (s, 1H),
6.10 (d, J=10.3 Hz, 1H), 5.97 (dd, J=10.3, 4.8 Hz, 1H), 4.55 (bs,
1H), 4.13 (bs, 1H), 4.12 (d, J=15.9 Hz, 1H), 2.88 (d, J=15.9 Hz,
1H), 3.81 (s, 3H), 3.75-3.65 (m, 4H), 3.30 (ddd, J=14.3, 12.4, 2.0
Hz, 1H), 3.10 (dt, J=14.3, 3.3 Hz, 1H), 2.76-2.58 (m, 4H),
2.55-2.41 (m, 5H), 2.25 (s, 3H), 2.08-1.90 (m, 2H), 1.55 (dd,
J=13.7, 2.8 Hz, 1H); .sup.13C-NMR (50 MHz, CDCl.sub.3): .delta.
144.1 (s), 143.0 (s), 133.5 (s), 128.9 (s), 127.4 (d), 127.1 (d),
126.9 (s), 113.7 (d), 88.4 (d), 66.7 (t+t), 66.6 (t), 61.9 (d),
57.1 (t), 55.8 (q), 54.0 (t+t), 53.4 (t), 52.0 (t), 48.4 (s), 33.4
(t), 29.8 (t), 19.4 (q)
EXAMPLE 105
[(.+-.)-(4a.alpha.,6.beta.,8aR*)-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-met-
hyl-11-(3-(1-piperidinyl)propyl)-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol-
, 1-methyl-N-piperidinopropyl-galanthamine (MH-29)
[0732] TABLE-US-00071 (XXXIV) ##STR266## 200 mg (0.70 mmol)
1-methyl-N-demethylgalanthamine (XXII) 166 mg (0.84 mmol) =
1-(3-chloropropyl)piperidine 1.2 equivalents hydrochloride
[0733] After 24 hours, the reaction was worked up.
[0734] Yield: 180 mg (0.44 mmol=63% of theory) of a yellow oil
[0735] C.sub.25H.sub.36N.sub.2O.sub.3 [412.581
[0736] TLC: R.sub.f=0.27 (CHCl.sub.3:MeOH=9:1+1% NH.sub.4OH)
[0737] C.sub.25H.sub.36N.sub.2O.sub.3.times.0.50 H.sub.2O [421.58]
TABLE-US-00072 % C % H % N Cld.: 71.23 8.85 6.64 Fnd.: 71.33 8.97
6.60
[0738] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 6.52 (s, 1H),
6.10 (d, J=10.4 Hz, 1H), 5.96 (dd, J=10.4, 4.7 Hz, 1H), 4.55 (bs,
1H), 4.12 (bs, 1H), 4.08 (d, J=15.7 Hz, 1H), 3.83 (d, J=15.7 Hz,
1H), 3.81 (s, 3H), 3.24 (ddd, J=14.2, 12.2, 2.0 Hz, 1H), 3.07 (dt,
J 14.2, 3.5 Hz, 1H), 2.71-2.13 (m, 10H), 2.24 (s, 3H), 2.07-1.88
(m, 2H), 1.77-1.35 (m, 9H); .sup.13C-NMR (50 MHz, CDCl.sub.3):
.delta. 144.0 (s), 142.9 (s), 133.5 (s), 128.9 (s), 127.3 (d+d),
127.2 (s), 113.7 (d), 88.4 (d), 62.0 (d), 57.2 (t), 55.8 (q), 54.5
(t+t+t), 53.3 (t), 51.4 (t), 48.5 (s), 33.4 (t), 29.8 (t), 25.7
(t+t), 25.0 (t), 24.2 (t), 19.5 (q)
EXAMPLE 106
[(.+-.)-(4a.alpha.,6.alpha.,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-m-
ethyl-11-(3-(1-piperidinyl)propyl)-6H-benzofuro[3a,3,2-ef][2]benzazepin-6--
ol, 1-methyl-N-piperidinopropyl-epigalanthamine (MH-117)
[0739] TABLE-US-00073 (XXXVII) ##STR267## 100 mg (0.35 mmol)
1-methylepigalanthamine (XXIV) 83 mg (0.42 mmol) =
(1-(3-chloropropyl)piperidine 1.2 equivalent hydrochloride
[0740] After 28 hours, the reaction was worked up.
[0741] Yield: 60 mg (0.15 mmol=42% of theory) of a light yellow
oil
[0742] C.sub.25H.sub.36N.sub.2O.sub.3 [412.58]
[0743] TLC: R.sub.f=0.12 (CHCl.sub.3:MeOH=9:1)
[0744] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 6.50 (s, 1H),
6.10 (d, J=10.2 Hz, 1H), 5.78 (dd, J=10.2, 1H), 4.70-4.57 (m, 1H),
4.54 (bs, 1H), 4.05 (d, J=15.2 Hz, 1H), 3.82 (d, J=15.2 Hz, 1H),
3.82 (s, 3H), 3.25 (ddd, J=13.5, 12.8, 1.6 Hz, 1H), 3.09 (dt,
J=3.5, 2.5 Hz, 1H), 2.75 (dt, J=13.7, 4.1 Hz, 1H), 2.56-2.27 (m,
H), 2.23 (s, 3H), 2.08 (td, J=13.1, 4.0, 2H), 1.81-1.38 (m, 9H);
.sup.13C-NMR (50 MHz, CDCl.sub.3) .delta. 144.9 (s), 142.7 (s),
133.4 (s) 131.3 (s), 128.3 (d+d), 127.0 (s), 113.2 (d), 88.1 (d),
63.0 (d), 57.2 (t), 55.7 (q), 54.4 (t+t+t), 53.1 (t), 51.6 (t),
48.4 (s), 33.1 (t), 29.5 (t), 25.6 (t+t), 24.8 (t), 24.1 (t), 19.5
(g)
General Operating Instructions for the Production of Galanthaminium
Bromide Derivatives
EXAMPLES 107-109
[0745] TABLE-US-00074 ##STR268## ##STR269## 1 equivalent a
galanthaMine derivative 1 equivalent N-bromosuccinimide 50 ml
methylene chloride or chloroform, distilled via P.sub.2O.sub.5/1 g
of a galanthamine derivative
[0746] The educt is dissolved in a solvent, and N-bromosuccinimide
is added while being stirred. A precipitate is immediately formed
that is suctioned off after an appropriate length of time, washed
and suctioned off in the dry state.
[0747] The products that are thus obtained are generally very pure,
but the large amount of solvent rather than a small amount is
important since otherwise succinimide is pulled into the substances
and the latter are subsequently difficult to purify.
EXAMPLE 107
[4aS-(4a.alpha.,6.beta.,8aR*)-4a,5,9,10-Tetrahydro-6-hydroxy-3-methoxy-11--
methyl-6H-benzofuro[3a,3,2-ef][2]benzazepinium, bromide,
galanthaminium bromide (MH-119)
[0748] TABLE-US-00075 ##STR270## ##STR271## 200 mg (0.7 mmol)
galanthamine (1) 124 mg (0.7 mmol) N-bromosuccinimide 10 ml
methylene chloride or chloroform, distilled via P.sub.2O.sub.5
[0749] The precipitate that was produced was suctioned off after 10
minutes.
[0750] Yield: 230 mg (0.63 mmol=90% of theory) of a light yellow
powder
[0751] C.sub.17H.sub.20BrNO.sub.3 [366.25]
[0752] TLC: R.sub.f=0.58 (CHCl.sub.3:MeOH=9:1+1% NH.sub.4OH)
[0753] Melting point: 216-219.degree. C.
[0754] C.sub.17H.sub.20BrNO.sub.3.times.0.1 HBr [374.34]
TABLE-US-00076 % C % H % N Cld.: 54.55 5.41 3.74 Fnd.: 54.52 5.36
3.66
[0755] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 9.10 (s, 1H),
7.54 (d, J=8.5 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 5.92 (dd, J=10.3,
4.5 Hz, 1H), 5.73 (d, J=10.3 Hz, 1H), 4.74 (s, 1H), 4.59 (s, 1H),
4.11 (s, 2H), 3.94 (s, 3H), 3.79 (s, 3H), 2.38 (d, J=15.3 Hz, 1H),
2.15 (m, 3H); .sup.13C-NMR (50 MHz, CDCl.sub.3): .delta. 167.3 (d),
151.3 (s), 146.2 (s), 136.9 (s), 133.0 (d), 129.8 (d), 126.4 (d),
115.0 (s), 112.9 (d), 87.0 (d), 58.9 (d), 56.4 (q), 54.0 (t), 51.5
(q), 45.9 (s), 31.1 (t), 29.7 (t)
EXAMPLE 108
[(.+-.)-(4a.alpha.,6.beta.,8aR*)]-4a,5,9,10-Tetrahydro-6-hydroxy-3-methoxy-
-1,11-dimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepinium, bromide,
1-methylgalanthaminium bromide (Pi-8)
[0756] TABLE-US-00077 ##STR272## ##STR273## 200 mg (0.66 mmol)
1-methylgalanthamine (XV) 118 mg (0.66 mmol) N-bromosuccinimide 5
ml chloroform
[0757] After 5 minutes, an orange-yellow precipitate was produced,
which was suctioned off after 15 minutes. The precipitate 162 mg)
was washed twice with diethyl ether. The filtrate was concentrated
by evaporation, taken up in a little ethanol and precipitated in
diethyl ether (54 mg).
[0758] Yield: 216 mg (0.57 mmol=86% of theory) of an orange-yellow
powder
[0759] C.sub.18H.sub.22BrNO.sub.3 [380.28]
[0760] TLC: R.sub.f=0.02 (CHCl.sub.3:MeOH=9:1)
[0761] Melting point: 223-226.degree. C.
[0762] C.sub.18H.sub.22BrNO.sub.3.times.0.35 HBr [408.60]
TABLE-US-00078 % C % H % N Cld.: 52.91 5.51 3.43 Fnd.: 52.99 5.52
3.48
[0763] .sup.1H-NMR (200 MHz, DMSO-d.sub.6): .delta. 9.06 (s, 1H),
7.04 (s, 1H), 5.81 (dd, J=10.1, 4.5 Hz, 1H), 5.54 (d, J=10.2 Hz,
1H), 4.74 (s, 1H), 4.17-3.95 (m, 4H), 3.91 (s, 3H), 3.86 (s, 3H),
2.53 (s, 3H), 2.40-1.96 (m, 4H); .sup.13C-NMR (50 MHz,
DMSO-d.sub.6): .delta. 166.4 (d), 150.5 (s), 144.7 (s), 140.4 (s),
136.7 (s), 128.4 (d), 127.9 (d), 114.9 (d), 113.9 (s), 86.5 (d),
58.7 (d), 56.3 (q), 54.4 (t), 50.5 (q), 47.0 (s), 35.1 (t), 29.4
(t), 18.9 (q)
EXAMPLE 109
[4aS-(4aa,6a,8aR*)]-4a,5,9,10-Tetrahydro-6-hydroxy-3-methoxy-11-methyl-6H--
benzofuro[3a,3,2-ef][2]benzazepinium, bromide, epigalanthaminium
bromide (Pi-13)
[0764] TABLE-US-00079 ##STR274## ##STR275## 0.78 g (2.71 mmol)
epigalanthamine (26) 0.48 g (2.71 mmol) N-brornosuccinimide 6 ml
absolute chloroform
[0765] After 3 minutes, a yellow precipitate was produced, which
was suctioned off and washed twice with diethyl ether. A second
fraction was obtained by concentration by evaporation of the
filtrate and adding in drops of diethyl ether to a level of 60 ml.
The second fraction was dissolved in a little ethanol for
purification and added in drops to diethyl ether.
[0766] Yield: 0.91 g (2.48 mmol=92% of theory)
[0767] C.sub.17H.sub.20BrNO.sub.3 [366.25]
[0768] TLC: R.sub.f=0.05 (CHCl.sub.3:MeOH=9:1+1% NH.sub.4OH)
[0769] Melting point: 205-210.degree. C.
[0770] C.sub.17H.sub.20BrNO.sub.3 .times.0.3 HBr [390.52]
TABLE-US-00080 % C % H % N Cld.: 52.28 5.24 3.59 Fnd.: 52.12 5.18
3.88
[0771] .sup.1H-NMR (200 MHz, DMSO-d.sub.6): .delta. 9.10 (s, 1H),
7.51 (d, J=11.5 Hz, 1H), 7.20 (d, J=11.5 Hz, 1H), 5.82 (d, J=12.7
Hz, 1H), 5.68 (d, J=12.7 Hz, 1H), 4.80 (bs, 1H), 4.40-4.21 (m, 1H),
4.21-4.04 (m, 2H), 3.94 (s, 3H), 3.77 (s, 3H), 2.60 (s, 1H),
2.30-2.10 (m, 2H), 1.81-1.60 (m, 1H); .sup.13C-NMR (50 MHz,
DMSO-d.sub.6) 167.3 (d), 151.2 (s), 146.5 (s), 137.3 (s), 134.4
(d), 133.0 (d), 126.0 (d), 115.0 (s), 113.0 (d), 88.0 (d), 60.7
(d), 56.4 (q), 54.2 (t), 51.4 (q), 46.2 (s), 31.5 (t), 30.8 (t)
General Operating Instructions for the Production of
Galanthamine-12-Carbonitrile Derivatives
EXAMPLES 110-113
[0772] TABLE-US-00081 ##STR276## ##STR277## 1 equivalent a
galanthaminium derivative 3 equivalents potassium cyanide 30 ml
water/1 g of a galanthaminium derivative 10 ml diethyl ether/1 g of
a galanthaminium derivative
[0773] The educt was dissolved in a separatory funnel in water, and
the solution was covered with a layer of ether, than solid
potassium cyanide (freshly pulverized) was added thereto, whereby a
white precipitate immediately formed in the aqueous phase. After
about 2-3 minutes, the product was extracted by shaking in the
ether phase. The aqueous phase was exhaustively extracted with
ether and with sparingly soluble derivatives with chloroform, the
organic phases were combined, washed with saturated aqueous common
salt solution, dried on Na.sub.2SO.sub.4, filtered, and the solvent
was drawn off. If necessary, the product that was obtained was
purified on a silica gel column (mobile solvent: CHCl.sub.3:MeOH
9:1, unless otherwise indicated).
EXAMPLE 110
[4aS-(4a.alpha.,6.beta.,8aR*)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methox-
y-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepine-12-carbonitrile,
galanthamine-12-carbonitrile (MH-123)
[0774] TABLE-US-00082 ##STR278## ##STR279## ##STR280## 3.50 g (9.56
mmol) galantharninium bromide (L) 1.90 g (28.7 mmol) = potassium
cyanide 3 equivalents 100 ml water 40.0 ml diethyl ether
[0775] The reaction was performed according to the general
operating instructions.
[0776] Raw yield>2 g
[0777] The oily raw mixture, consisting of an isomer ratio of about
9:1, was dissolved in as little ethanol as possible, and the main
isomer was brought to crystallization while being stirred. The
precipitate was suctioned off, washed with ethanol, and the
filtrate was combined with the washing solution and concentrated by
evaporation. The process was repeated until the main amount of pure
main isomer was isolated.
[0778] Yield: 990 mg (3.28 mmol=34% of theory) of a white
powder
[0779] C.sub.8H.sub.20N.sub.2O.sub.3 [312.37]
[0780] A mixture that consists of two isomers (ratio 9:1) and
galanthamine remains, and said mixture is produced during the
isolation of the main isomer, which could be purified by columns.
The isomer mixture is eluted again at a ratio of 9:1 from the
column, since it is converted into one another on the column.
[0781] TLC: R.sub.f=0.77 main isomer
[0782] 0.63 Secondary isomer (CHCl.sub.3:MeOH=9:1)
[0783] Melting point: 151-155.degree. C.
[0784] C.sub.18H.sub.20N.sub.2O.sub.3.times.0.1 H.sub.2O [314.17]
TABLE-US-00083 % C % H % N Cld.: 68.82 6.48 8.92 Fnd.: 68.85 6.32
8.69
[0785] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 6.70 (s, 2H),
6.35 (d, J=10.2 Hz, 1H), 6.07 (dd, J=10.2, 5.3 Hz, 1H), 4.71 (s,
1H), 4.61 (m, 1H), 4.15 (dt, J=11.1, 5.0 Hz, 1H), 3.85 (s, 3H),
3.50 (dd, J=15.0, 13.6 Hz, 1H), 2.91 (dt, J=15.0, 3.2 Hz, 1H),
2.74-2.61 (m, 1H), 2.61 (s, 3H), 2.38 (d, J=11.4 Hz, 1H), 1.98-2.08
(m, 2H), 1.78 (ddd, J=13.7, 5.0, 1.2 Hz, 1H); .sup.13C-NMR (50 MHz,
CDCl.sub.3): .delta. 146.7 (s), 145.6 (s), 132.9 (s), 128.2 (d),
126.9 (d), 124.2 (s), 122.5 (s), 111.6 (d), 88.9 (d), 61.6 (d+d),
55.9 (q), 49.9 (t), 48.1 (s), 46.1 (q), 36.4 (t), 29.7 (t)
EXAMPLE 111
[(.+-.)-(4a.alpha.,6.beta.,8aR*)]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-me-
thoxy-1,11-dimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepine-12-carbonitrile,
1-methylgalanthamine-12-carbonitrile (Pi-12)
[0786] TABLE-US-00084 ##STR281## ##STR282## 300 mg (0.79 mmol)
1-methylgalanthaminium bromide (LI) 154 mg (2.36 mmol) = potassium
cyanide 3 equivalents 20.0 ml water
[0787] 205 mg of a white crude product was isolated.
[0788] An attempt was made to achieve column-chromatographic
separation of the diastereomers with a pure ethyl acetate as a
mobile solvent. In this case, however, no separation of the
diastereomer mixture could be accomplished.
[0789] Yield: 151 mg (0.46 mmol=59% of theory)
[0790] C.sub.19H.sub.22N.sub.2O.sub.3 [326.39]
[0791] TLC: R.sub.f=0.20/0.65 (diastereomer mixture; ethyl
acetate)
[0792] Melting point: 72-73.degree. C.
[0793] C.sub.19H.sub.22N.sub.2O.sub.3.times.0.5 H.sub.2O [335.39]
TABLE-US-00085 % C % H % N Cld.: 68.04 6.91 8.35 Fnd.: 67.91 6.62
8.20
[0794] .sup.1H-NMR (Mixture that consists of 2 isomers, 200 MHz,
CDCl.sub.3): .delta. 6.59 (s, 1H), 6.31 (d, J=8.9 Hz, 0.4H), 6.27
(d, J=8.9 Hz, 0.6H), 6.01 (dd, J=9.2, 5.0 Hz, 1H), 4.96 (s, 0.6H),
4.83 (s, 0.4H), 4.57 (bs, 0.6H), 4.50 (bs, 0.4H), 4.12 (dt, J=15.5,
4.9 Hz, 1H), 3.83 (s, 3H), 3.47 (ddd, J=13.9, 9.8, 3.4 Hz, 1H),
2.88 (dt, J=14.6, 3.8 Hz, 1H), 2.70 (bs, 1H), 2.62 (s, 1.8H), 2.60
(s, 1.2H), 2.31 (s, 3H), 2.10-1.92 (m, 2H), 1.87-1.68 (m, 1H);
.sup.13C-NMR (mixture that consists of 2 isomers, 100 MHz,
CDCl.sub.3): .delta. 145.5 (s), 145.4 (s), 145.3 (s), 144.8 (s),
135.7 (s), 133.6 (s), 129.7 (d), 129.3 (d), 129.6 (s), 128.7 (s),
128.4 (d), 127.7 (d), 122.9 (s), 122.8 (s), 116.7 (s), 115.3 (s),
114.5 (d), 114.4 (d), 89.4 (d), 88.9 (d), 62.3 (d), 62.2 (d), 57.9
(d), 56.6 (d), 56.5 (q), 56.3 (q), 51.0 (t), 50.3 (t), 49.0 (s),
47.9 (s), 47.2 (q), 47.2 (s), 36.8 (t), 33.7 (t), 30.2 (t), 20.3
(q), 19.3 (q)
EXAMPLE 112
[4aS-(4aa,6a,8aR*)]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-11-methy-
l-6H-benzofuro[3a,3,2-ef][2]benzazepine-12-carbonitrile,
epigalanthamine-12-carbonitrile (Pi-14)
[0795] TABLE-US-00086 ##STR283## ##STR284## 500 mg (1.37 mmol)
epigalanthaminium bromide (LII) 270 mg (4.10 mmol) = potassium
cyanide 3 equivalents 15.0 ml water
[0796] Yield: 0.33 g (1.06 mmol=77% of theory)
[0797] C.sub.18H.sub.20N.sub.2O.sub.3 [312.37]
[0798] TLC: R.sub.f=0.75 (CHCl.sub.3:MeOH=9:1)
[0799] Melting point: 90-96.degree. C.
[0800] .sup.1H-NMR (Mixture that consists of 2 isomers, 200 MHz,
CDCl.sub.3): .delta. 6.92 (d, J=8.3 Hz, 0.3H), 6.72 (d, J=8.0 Hz,
0.3H), 6.68 (d, J=8.0 Hz, 0.7H), 6.62 (d, J=8.3 Hz, 0.7H), 6.31
(dt, J=10.5, 1.6 Hz, 0.7H); 6.03 (d, J=10.5 Hz, 0.3H), 5.85 (d,
J=10.3 Hz, 1H), 5.22 (s, 0.3H), 4.64 (s, 0.7H), 4.58 (bs, 1H), 3.86
(s, 0.9H), 3.85 (s, 2.1H), 3.12 (dt, J=14.8, 3.2 Hz, 0.3H),
2.98-2.70 (m, 1.7H), 2.58 (s, 2.1H), 2.38 (s, 0.9H), 2.27-2.04 (m,
1.2H), 1.85 (dd, J=13.5, 4.2 Hz, 1.4H), 1.71 (ddd, J=13.5, 10.7,
2.5 Hz, 1.4H); .sup.13C-NMR (mixture that consists of 2 isomers, 50
MHz, CDCl.sub.3): .delta. 147.5 and 147.2 (s), 145.2 and 145.0 (s),
132.6 (s), 132.5 and 131.9 (d), 126.6 (d), 124.0 and 123.3 (s),
121.8 and 120.1 (d), 116.5 (s), 111.3 and 111.2 (d), 88.7 and 88.4
(d), 62.8 (d), 61.4 and 58.4 (d), 55.8 (q), 50.0 (t), 47.9 (s),
45.9 (q), 36.9 (t), 32.0 and 31.7 (t)
EXAMPLE 113
[(.+-.)-(4a.alpha.,6.alpha.,8aR*)]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-m-
ethoxy-1,11-dimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepine-12-carbonitrile-
, 1-methylepigalanthamine-12-carbonitrile (Pi-19)
[0801] ##STR285##
[0802] 1-Methylepigalanthaminium bromide was produced according to
general operating instructions for the production of galanthaminium
derivatives, whereby no precipitate formed, however. The reaction
solution was therefore evaporated to the dry state, the remaining
residue was taken up in ether, suctioned off and washed. The
remaining crude product was used directly in the subsequent
reaction according to NMR analysis. TABLE-US-00087 500 mg (1.32
mmcl) 1-methylepigalanthaminium bromide (LIII) 260 mg (3.96 mmol) =
3 potassium cyanide equivalents 50 ml water
[0803] The purification was carried out by means of column
chromatography (CHCl.sub.3:MeOH=9:1).
[0804] Yield: 220 mg (0.67 mmol=51% of theory) of a white foam
[0805] C.sub.19H.sub.22N.sub.2O.sub.3 [326.391
[0806] TLC: R.sub.f=0.70/0.60 (diastereomer mixture;
CHCl.sub.3:MeOH=9:1)
[0807] .sup.1H-NMR (Mixture that consists of 2 isomers, 200 MHz,
CDCl.sub.3): .delta. 6.57 (s, 1H), 6.26 (d, J=10.4 Hz, 1H), 5.82
(d, J=10.4 Hz, 1H), 4.94 and 4.82 (s, 1H), 4.74-4.55 (m, 1H), 4.50
and 4.45 (m, 1H), 3.87 and 3.84 (s, 3H), 3.55-3.32 (m, 1H),
3.05-2.68 (m, 2H), 2.58 and 2.57 (s, 3H), 2.33 and 2.30 (s, 3H),
2.23-2.07 (m, 1H), 1.93-1.63 (m, 2H); .sup.13C-NMR (mixture that
consists of 2 isomers, 50 MHz, CDCl.sub.3): .delta. 146.0 (s),
145.8 (s), 144.5 (s), 144.1 (s), 135.0 (s), 133.0 (s), 132.2 (d),
131.7 (d), 129.5 (d), 128.5 (s), 127.6 (s), 127.1 (d), 122.4 (s),
122.2 (s), 116.4 (s), 114.8 (s), 113.9 (d), 113.8 (d), 88.5 (d),
88.4 (d), 63.0 (d), 62.6 (d) 57.2 (d), 56.4 (d), 56.0 (q), 55.8
(q), 50.7 (t), 50.0 (t), 48.4 (s), 47.3 (s), 46.7 (q), 36.9 (t),
34.1 (t), 31.7 (t), 19.8 (q) 18.8 (q)
General Operating Instructions for the Production of
12-Methylqalanthamine Derivatives
EXAMPLES 114-117
[0808] TABLE-US-00088 ##STR286## ##STR287## 1 equivalent a
galanthaminium derivative 2-4 equivalents methylmagnesium iodide (3
M in diethyl ether) 20 ml absolute diethyl ether/1 g of a
galanthaminium derivative
[0809] The entire amount of Grignard reagent was introduced under
N.sub.2 atmosphere, and then the solid galanthaminium derivative
was added without solvent. After the length of time indicated in
each case, diethyl ether was added and stirred for a specific
length of time, whereby the solid material dissolved. Then, it was
hydrolyzed with water, the reaction solution was made basic with
concentrated ammonia and extracted with ethyl acetate. The organic
phases were washed with saturated common salt solution, dried on
sodium sulfate, filtered, and the solvent was drawn off.
EXAMPLE 114
[4aS-(4aa,6.beta.,8aR)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-11,12-dimethyl-
-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol, 12-methylgalanthamine
(Pi-4)
[0810] TABLE-US-00089 ##STR288## ##STR289## 2.00 g (5.46 mmol)
galanthaminium bromide (L) 6.70 ml (20.2 mmol) = methylmagnesium
iodide (3 M in 3.7 equivalents diethyl ether) 40 ml absolute
diethyl ether
[0811] After 40 minutes, the solvent was added and stirred for 5
hours, before it was hydrolyzed.
[0812] Yield: 760 mg (2.52 mmol=46% of theory) of a light yellow
foam
[0813] C.sub.18H.sub.23NO.sub.3 [301.38]
[0814] TLC: R.sub.f=0.65 (CHCl.sub.3:MeOH=9:1+1% NH.sub.4OH)
[0815] Melting point: 46-48.degree. C.
[0816] .sup.1H-NMR (Mixture that consists of 2 isomers, 200 MHz,
CDCl.sub.3): .delta. 6.66 (d, J=8.3 Hz, 0.8H), 6.65 (s, 0.2H), 6.64
(s, 0.2H), 6.57 (d, J=8.3 Hz, 0.8H), 6.13 (d, J=10.1 Hz, 0.2H),
6.07 (d, J=10.1 Hz, 0.8H), 5.94 (dd, J=10.1, 4.4 Hz, 1H), 4.54 (bs,
1H), 4.26 (q, J=7.0 Hz, 0.2H), 4.08 (t, J=4.4 Hz, 1H), 3.88 (q,
J=7.4 Hz, 0.8H), 3.80 (s, 0.6H), 3.78 (s, 2.4H), 3.62 (ddd, J=14.6,
13.2, 1.0 Hz, 0.8H), 3.45 (d, 14.2 Hz, 0.2H), 3.12 (dt, J=14.8, 3.3
Hz, 0.2H), 2.85 (td, J=15.5, 3.5 Hz, 0.8H), 2.76 (bs, 1H), 2.63 (d,
J=15.6 Hz, 1H), 2.43 (s, 3H), 2.16 (d, J=2.7 Hz, 0.2H), 1.98 (dt,
J=15.5, 2.3 Hz, 0.8H), 1.95 (dd, J=15.5, 2.3 Hz, 0.2H), 1.51 (d,
J=7.3 Hz, 2.4H), 1.47 (d, J=7.3 Hz, 0.6H); .sup.13C-NMR (mixture
that consists of 2 isomers, 50 MHz, CDCl.sub.3): .delta. 146.1 and
145.6 (s), 143.8 and 143.4 (s), 134.9 and 132.6 (s), 132.4 and
131.3 (s), 129.3 (d), 127.6 and 127.3 (d), 126.9 (d), 122.0 and
119.9 (d), 111.5 and 110.8 (d), 88.6 and 88.5 (d), 64.0 (d), 61.9
and 61.6 (d), 58.3 and 55.7 (q), 48.8 (s), 44.1 (t), 41.3 (q), 31.5
and 31.0 (t), 29.9 and 29.7 (t), 21.8 and 17.5 (q)
EXAMPLE 115
[4aS-(4a?,6?,8aR*,12R*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-11,12-dimethy-
l-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,
(=12-methylgalanthamine); (main isomer)
[0817] ##STR290##
[0818] The isomer mixture was purified by column chromatography on
silica gel (CHCl.sub.3:MeOH=9:1+1% NH.sub.4OH), whereby a pure
isomer was obtained.
[0819] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 6.66 (d, J=8.3
Hz, 1H), 6.57 (d, J=8.3 Hz, 1H), 6.07 (d, J=10.1 Hz, 1H), 5.94 (dd,
J=10.1, 4.4 Hz, 1H), 4.54 (bs, 1H), 4.08 (t, J=4.4 Hz, 1H), 3.88
(q, J=7.4 Hz, 1H), 3.78 (s, 3H), 3.62 (dd, J=14.6 (13.2 Hz, 1H),
2.85 (td, J=15.5, 3.5 Hz, 1H), 2.63 (d, J=15.6 Hz, 1H), 2.43 (s,
3H), 2.11 (dt, J=13.3, 2.4 Hz, 1H), 1.95 (ddd, J=16.5, 5.0, 1.8 Hz,
1H), 1.51 (d, J=7.3 Hz, 3H), 1.47 (dd, J=13.3 Hz, 1H); .sup.13C-NMR
(50 MHz, CDCl.sub.3) .delta. 146.2 (s), 143.5 (s), 135.1 (s), 131.4
(s), 129.4 (d), 127.4 (d), 122.2 (d), 111.6 (d), 88.8 (d), 64.0
(d), 61.8 (d), 55.8 (q), 48.9 (s), 44.2 (t), 41.5 (q), 31.7 (t),
29.8 (t), 21.9 (q)
EXAMPLE 116
[(.+-.)-(4a.alpha.,6.beta.,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-6H-1-
,11,12-trimethyl-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,
1,12-dimethylgalanthamine (Pi-21)
[0820] TABLE-US-00090 ##STR291## ##STR292## 500 mg (1.31 mmol)
1-methylgalanthaminium bromide (LI) 1.00 ml (3.00 mmol) =
methylmagnesium iodide (3 M in 2.3 equivalents diethyl ether) 15 ml
absolute diethyl ether
[0821] During the addition of educt, 5 ml of diethyl ether was
added to keep the reaction mixture stirrable. After the addition of
educt was completed (30 minutes), another 10 ml of diethyl ether
was added. After 2.5 hours, the reaction mixture was
hydrolyzed.
[0822] Yield: 73 mg (0.23 mmol 18% of theory)
C.sub.19H.sub.25NO.sub.3 [315.41]
[0823] TLC: R.sub.f=0.50 (CHCl.sub.3:MeOH=9:1+1% NH.sub.4OH)
[0824] Melting point: 45-50.degree. C.
[0825] .sup.1H-NMR (Mixture that consists of 2 isomers, 200 MHz,
CDCl.sub.3): .delta. 6.57 (s, 1H), 6.06 (d, J=10.2 Hz, 1H), 5.95
(dd, J=10.2, 4.5 Hz, 1H), 4.59-4.44 (m, 1H), 4.17-4.03 (m, 2H),
3.81 (s, 3H), 3.75-3.55 (m, 1H), 2.97-2.77 (m, 1H), 2.73-2.55 (m,
1H), 2.51 (s, 0.5H), 2.46 (s, 2.5H), 2.25 (s, 3H), 2.15-1.87 (m,
2H), 1.51 (d, J=7.3 Hz, 3H), 1.30-1.18 (m, 1H); .sup.13C-NMR
(mixture that consists of 2 isomers, 50 MHz, CDCl.sub.3) .delta.
144.7 (s), 142.9 (s) 132.5 and 131.7 (s), 130.4 and 129.0 (s),
129.3 (d), 127.8 and 126.8 (s), 127.5 (d), 114.3 and 114.0 (d),
88.7 and 88.4 (d), 62.2 and 61.8 (d), 59.3 and 58.8 (d), 56.0 and
55.8 (q), 49.4 and 48.4 (s), 44.3 (t), 41.5 (q), 31.7 (t), 29.9
(t), 19.7 and 19.2 (q), 18.8 (q)
EXAMPLE 117
[(4aS-(4aa,6a,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-11,12-dimethyl-6H-
-benzofuro[3a,3,2-ef][2]benzazepin-6-ol, 12-methylepigalanthamine
(Pi-22)
[0826] TABLE-US-00091 ##STR293## ##STR294## 300 mg (0.82 mmol)
epigalantharninium bromide (LII) 1.00 ml (3.00 mmol) =
methylmagnesium iodide (3 M in 3.70 equivalents diethyl ether)
[0827] The Grignard reagent was added over 30 minutes, then 5 ml of
ether was added. After 20 minutes, another 15 ml of ether was added
and hydrolyzed for 3 hours.
[0828] The purification was carried out by column chromatography
(CHCl.sub.3:MeOH=9:1)
[0829] Yield: 60 mg (0.20 mmol=24% of theory)
[0830] C.sub.18H.sub.23NO.sub.3 [301.391
[0831] TLC: R.sub.f=0.78 (CHCl.sub.3:MeOH=9:1+1% NH.sub.4OH)
[0832] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 6.65 (d, J=8.3
Hz, 1H), 6.53 (d, J=8.3 Hz, 1H), 6.04 (d, J=10.4 Hz, 1H), 5.76 (d,
J=10.4 Hz, 1H), 4.70-4.57 (m, 1H), 4.54 (bs, 1H), 3.93-3.82 (m,
1H), 3.81 (s, 3H), 3.61 (t, J=13.6 Hz, 1H), 2.94-2.67 (m, 3H), 2.41
(s, 3H), 2.20 (td, J=13.2, 2.4 Hz, 1H), 1.69 (ddd, J=13.6, 10.6,
2.0 Hz, 1H), 1.52 (d, J=7.3 Hz, 3H), 1.59-1.44 (m, 1H);
.sup.13C-NMR (50 MHz, CDCl.sub.3): .delta. 147.0 (s), 143.2 (s),
134.5 (s), 131.3 (d), 131.1 (s), 128.9 (d), 121.5 (d), 111.2 (d),
88.6 (d), 64.1 (d), 62.7 (d), 55.6 (q), 48.6 (s), 44.4 (t), 41.2
(q), 32.0 (t+t), 21.8 (q)
EXAMPLE 118
[4aS-(4.alpha.a,6.beta.,8aR*)]-4a,5,9,10-Tetrahydro-6-hydroxy-3-methoxy-11-
-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-12(11H)-one
(MH-128)
[0833] TABLE-US-00092 ##STR295## ##STR296## 200 g (0.64 mmol)
galanthamine-12-carbonitrile (LV) 0.64 ml (0.64 mmol) sodium
trimethylsilanolate (1 M in CH.sub.2Cl.sub.2) 5 ml absolute
tetrahydrofuran
[0834] The educts were stirred under N.sub.2 atmosphere at room
temperature for 72 hours, whereby a precipitate formed, which was
suctioned off, washed with tetrahydrofuran and dried.
[0835] Yield: 177 mg (0.59 mmol=92% of theory) of a light yellow
powder
[0836] C.sub.17H.sub.19NO.sub.4 [301.35]
[0837] TLC: R.sub.f=0.65 (CHCl.sub.3:MeOH=9:1)
[0838] Melting point: 251-255.degree. C.
[0839] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 7.49 (d, J=8.5
Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 5.87 (dd, J=9.8, 5.3 Hz, 1H), 5.53
(d, J=9.8 Hz, 1H), 4.74 (bs, 1H), 4.13 (dt, J=10.1, 4.8 Hz, 1H),
3.91 (s, 3H), 3.80 (dt, J=14.1, 2.1 Hz, 1H), 3.25-3.16 (m, 1H),
3.19 (s, 3H), 2.71 (dt, J=15.7, 1.7 Hz, 1H), 2.31 (dt, J=14.1, 3.9
Hz, 1H), 2.06 (ddd, J=15.7, 5.0, 2.3 Hz, 1H), 1.83 (dt, J=14.6, 2.5
Hz, 1H); .sup.13C-NMR (50 MHz, CDCl.sub.3) .delta. 168.3 (s), 146.9
(s), 145.1 (s), 131.7 (s), 131.6 (d), 125.2 (d), 124.4 (d), 123.4
(s), 111.9 (d), 89.2 (d), 61.0 (d), 55.8 (q), 49.5 (t), 48.0 (S),
38.3 (t), 34.9 (q), 29.3 (t)
EXAMPLE 119
[4aS-(4a.alpha.,6.beta.,8aR*)]-4a,5,9,10-Tetrahydro-3-methoxy-6H-benzofuro-
[3a,3,2-ef][2]benzazepin-6-ol, 11-oxide (MH-142)
[0840] TABLE-US-00093 ##STR297## ##STR298## 4.25 g (15.55 mmol)
demethylgalanthamine (27) 35 mg (0.77 mmol) = 5% selenium dioxide
70 ml 10% aqueous H.sub.2O.sub.2 solution (35%) in acetone
(oxidation solution)
[0841] Demethylgalanthamine was dissolved in the oxidation solution
in an environment devoid of atmospheric humidity and cooled to
0.degree.. Then, SeO.sub.2 was added, and it was stirred first for
20 minutes at 0.degree. C. and then for 4 hours at room
temperature, whereby a white precipitate settled out, which was
suctioned off, washed with acetone and dried. The filtrate was
mixed with water, the acetone was distilled off in a vacuum, and
the remaining aqueous phase was extracted with methylene chloride.
The collected organic phases were washed with saturated common salt
solution, dried on sodium sulfate, filtered, and the solvent was
drawn off. The oily residue was taken up in acetone, whereby a
precipitate settled out, which could be obtained as a second
fraction. By repeated concentration by evaporation of the filtrate
and taking-up in acetone, other fractions were obtained.
[0842] Yield: 3.53 g (12.29 mmol=79% of theory) of a white
powder
[0843] C.sub.16H.sub.17NO.sub.4 [287.31]
[0844] TLC: R.sub.f=0.42 (CHCl.sub.3:MeOH 9:1+1% concentrated
NH.sub.4OH)
[0845] Melting point: 232-233.degree. C. (CHCl.sub.3); release of a
liquid starting from 215.degree. C.
[0846] C.sub.16H.sub.17NO.sub.4.times.0.2 H.sub.2O [290.91]
TABLE-US-00094 % C % H % N Cld.: 66.06 6.03 4.81 Fnd.: 66.11 6.05
4.73
[0847] .sup.1H-NMR (200 MHz, DMSO-d.sub.6): .delta. 7.82 (s, 1H),
6.90 (s, 2H), 5.81 (dd, J=10.1, 4.4 Hz, 1H), 5.54 (d, J=10.1 Hz,
1H), 4.64 (bs, 1H), 4.36 (d, J=5.5 Hz, 1H), 4.14-4.02 (m, 2H), 3.79
(s, 3H), 2.39-1.99 (m, 4H); .sup.13C-NMR (50 MHz, DMSO-d.sub.6):
.delta. 146.1 (s), 144.6 (s), 134.6 (d), 131.8 (s), 128.3 (d),
127.6 (d), 122.4 (d) 118.3 (s), 112.6 (d), 86.7 (d), 61.8 (d), 59.1
(t), 55.7 (q) 45.3 (s), 34.2 (t), 29.7 (t)
EXAMPLE 119
[4aS-(4a.alpha.,6.beta.,8aR*)]-4a,5,9,10,13,14a-Hexahydro-6-hydroxy-3-meth-
oxy-6H,14H-benzofuro[3a,3,2-ef]isoxazolo[3,2-a][2]benzazepine-13
(or 14)-carboxylic acid, methyl ester (MH-143)
[0848] TABLE-US-00095 ##STR299## ##STR300## 175 mg (0.61 mmol)
galanthamine nitrone (LXXXIV) 0.05 ml (0.61 mmol) acrylic acid
methyl ester 6 ml absolute toluene
[0849] The reagents were refluxed for 48 hours under argon
atmosphere, then the solvent was drawn off. The residue was
purified by column chromatography (CHCl.sub.3:MeOH=9:1+1%
concentrated NH.sub.4OH).
[0850] Yield: 225 mg (0.60 mmol=99% of theory) of a light brown,
glass-like solidifying oil
[0851] C.sub.20H.sub.23NO.sub.6 [373.40]
[0852] TLC: R.sub.f=0.74 (CHCl.sub.3:MeOH=9:1+1% concentrated
NH.sub.4OH)
[0853] C20H23NO6.times.0.5 H.sub.2O [382.40] TABLE-US-00096 % C % H
% N Cld.: 62.82 6.33 3.66 Fnd.: 62.88 6.17 3.65
[0854] Mixture that consists of stereoisomers and regioisomers. The
more specific treatment of spectra is found in Chapter 2.2,
Strukturaufklarungen [Structural Explanations].
EXAMPLE 120
(4aS-(4a.alpha.,6.beta.,8aR*,14aS)]-4a,5,9,10-Tetrahydro-6-hydroxy-3-metho-
xy-6H,14aH-benzofuro[3a,3,2-ef]isoxazolo[3,2-a][2]benzazepine-14-carboxyli-
c acid, methyl ester (MH-145)
[0855] TABLE-US-00097 ##STR301## ##STR302## 200 mg (0.70 mmol)
galanthamine nitrone (LXXXIV) 0.06 ml (0.70 mmol)
acetylenecarboxylic acid methyl ester (propiolic acid methyl ester)
5 ml absolute toluene
[0856] The reagents were refluxed for 10 minutes under argon
atmosphere, whereby the solution was already colored orange during
heating, then the solvent was drawn off. The residue was purified
by column chromatography (CHCl.sub.3:MeOH=9:1). The oily residue
was recrystallized from ethanol, whereby yellow needles were
obtained.
[0857] Yield: 261 mg (0.70 mmol=100% of theory) of light yellow
needles
[0858] C.sub.20H.sub.21NO.sub.6 [371.39]
[0859] TLC: R.sub.f=0.73 (CHCl.sub.3:MeOH=9:1)
[0860] Melting point: 151-154.degree. C. TABLE-US-00098 % C % H % N
Cld.: 64.68 5.70 3.77 Fnd.: 64.59 5.89 3.67
[0861] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 7.54 (s, 1H),
6.96 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 5.96-5.77 (m, 2H),
5.67 (s, 1H), 4.55 (bs, 1H), 4.10 (bs, 1H), 3.85 (s, 3H), 3.68 (s,
3H), 3.59 (ddd, J=14.3, 6.8, 3.8 Hz, 1H), 3.30 (ddd, J=12.9, 9.3,
3.4 Hz, 1H), 2.64 (dd, J=15.7, 3.7 Hz, 1H), 2.15 (td, J=7.7, 3.4
Hz, 1H), 2.01 (ddd, J=15.6, 5.3, 1.9 Hz, 1H), 1.54 (ddd, J=15.6,
6.7, 3.5 Hz, 2H); .sup.13C-NMR (50 MHz, CDCl.sub.3): .delta. 163.9
(s), 154.6 (d), 146.8 (s), 145.1 (s), 133.3 (s), 130.3 (d), 126.9
(d), 125.3 (s), 123.3 (d), 111.3 (d), 109.9 (s), 89.1 (d), 68.7
(d), 61.4 (d), 55.8 (q), 52.4 (t), 51.4 (q), 47.2 (s), 29.2 (t),
28.0 (t)
EXAMPLE 121
[4aS-(4a.alpha.,6.beta.,8aR*)-4a,5,9,10,13,14a-Hexahydro-6-hydroxy-3-metho-
xy-6H,14H-benzofuro[3a,3,2-ef]isoxazolo[3,2-a][2]benzazepine-13 (or
14)-carbonitrile (MH-146)
[0862] TABLE-US-00099 ##STR303## ##STR304## 200 mg (0.70 mmol)
galanthamine nitrone (LXXXIV) 0.05 ml (0.70 mmol) acrylonitrile 5
ml absolute toluene
[0863] The reagents were refluxed for 2 hours under argon
atmosphere, then the solvent was drawn off. The residue was
purified by column chromatography (CHCl.sub.3:MeOH=9:1).
[0864] Yield: 230 mg (0.68 mmol=97% of theory) of a light yellow
oil
[0865] C.sub.19H.sub.20N.sub.2O.sub.4 [340.38]
[0866] TLC: R.sub.f=0.74 (CHCl.sub.3:MeOH=9:1)
[0867] C.sub.19H.sub.20N.sub.2O.sub.4.times.0.2H.sub.2O [343.98]
TABLE-US-00100 % C % H % N Cld.: 66.34 5.98 8.14 Fnd.: 66.22 6.03
7.86
[0868] Mixture that consists of 4 stereoisomers and regioisomers.
The more specific treatment of spectra is found in Chapter 2.2,
Strukturaufklarungen.
EXAMPLE 122
[(4aS-(4a.alpha.,6.beta.,8aR*,14aS*)]-4a,5,9,10,13,14a-Hexahydro-6-hydroxy-
-3-methoxy-6H,14aH-benzofuro[3a,3,2-ef]isoxazolo[3,2-a][2]benzazepine-6,13-
-diol, 13-acetate (MH-153)
[0869] TABLE-US-00101 ##STR305## ##STR306## 200 mg (0.70 mmol)
galanthamine nitrone (LXXXIV) 0.24 ml (2.10 mmol) = vinyl acetate 4
equivalents 5 ml absolute toluene
[0870] The reagents were refluxed for 4 days under N.sub.2
atmosphere, whereby each day, 1 equivalent of vinyl acetate was
added. The solvent was then drawn off, and the residue was purified
by column chromatography (CHCl.sub.3:MeOH=9:1). The purified oil
was crystallized from methanol.
[0871] Yield: 256 mg (0.69 mmol=98% of theory) of beige
crystals
[0872] C.sub.20H.sub.23NO.sub.6 [373.41]
[0873] TLC: R.sub.f=0.70 (CHCl.sub.3:MeOH=9:1)
[0874] Melting point: 132-134.degree. C.
[0875] C.sub.20H.sub.23NO.sub.6.times.0.6 H.sub.2O [384.21]
TABLE-US-00102 % C % H % N Cld.: 62.52 6.35 3.65 Fnd.: 62.59 6.12
3.61
[0876] .sup.1H-NMR (Mixture that consists of 2 isomers, 200 MHz,
CDCl.sub.3): .delta. 6.76 and 6.73 (d, J=8.3 Hz, 1H), 6.68 and 6.60
(d, J=7.7 Hz, 1H), 6.36 (d, J=4.1 Hz, 1H), 6.30 (d, J=10.6 Hz, 1H),
6.08-5.91 (m, 1H), 4.60 and 4.50 (bs, 1H), 4.32 (dd, J=11.3, 5.6
Hz, 1H), 4.13 (bs, 1H), 3.84 (s, 3H), 3.80 (dd, J=19.1, 9.8 Hz,
1H), 3.22 (ddd, J=10.0, 6.8, 2.8 Hz, 1H), 2.92 (dd, J=12.3, 5.8 Hz,
1H), 2.78-2.57 (m, 2H), 2.09 (s, 3H), 2.07-1.79 (m, 2H);
.sup.13C-NMR (Mixture that consists of 2 isomers, 50 MHz,
CDCl.sub.3): .delta. 169.6 (s), 145.8 (s), 143.8 (s), 134.1 (s),
129.8 (d), 128.0 and 127.7 (d), 127.0 (s), 118.7 and 118.5 (d),
111.4 and 110.9 (d), 95.3 and 94.5 (d), 88.7 and 88.2 (d), 61.4
(d+d), 55.7 and 55.5 (q), 54.5 (t), 47.3 (s), 41.7 (t), 29.7 (t),
29.3 (t), 21.0 and 20.9 (q)
EXAMPLE 123
[4aS-(4a.alpha.,6.beta.,8aR*,14aS*)-4a,5,9,10-Tetrahydro-6-hydroxy-3-metho-
xy-6H,14aH-benzofuro[3a,3,2-ef]isoxazolo[3,2-a][2]benzazepine-14-carbonitr-
ile (MH-159)
[0877] TABLE-US-00103 ##STR307## ##STR308## 500 mg (1.74 mmol)
galanthamine nitrone (LXXXIV) 90 mg (1.74 mmol) acetylene
carbonitrile 10 ml absolute toluene
[0878] The reagents were stirred for 7 days under argon atmosphere
at room temperature, whereby the solution was colored yellow, then
the solvent was drawn off. The residue was crystallized from
methanol, suctioned off, and washed with methanol. The filtrate was
concentrated by evaporation and a second product fraction was
obtained from the residue by column chromatography
(CHCl.sub.3:MeOH=9:1).
[0879] Yield: 570 mg (1.68 mmol=97% of theory) of colorless
crystals
[0880] C.sub.19H.sub.18N.sub.2O.sub.4 [338.37]
[0881] TLC: R.sub.f=0.60 (CHCl.sub.3:MeOH=9:1)
[0882] Melting point: 137-139.degree. C. TABLE-US-00104 % C % H % N
Cld.: 67.45 5.36 8.28 Fnd.: 67.17 5.41 8.19
[0883] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 7.09 (d, J=8.6
Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 5.98 (s, 2H), 5.54 (s, 1H), 4.52
(bs, 1H), 4.11 (bs, 1H), 3.83 (s, 3H), 3.75-3.59 (m, 1H), 3.42-3.25
(m, 1H), 2.64 (dd, J=15.9, 3.2 Hz, 1H), 2.44 (d, J=11.5 Hz, 1H),
2.11-1.94 (m, 2H), 1.71-1.52 (m, 1H); .sup.13C-NMR (50 MHz,
CDCl.sub.3) .delta. 156.5 (d), 147.1 (s), 145.5 (s), 132.7 (s),
129.6 (d), 127.9 (d), 123.8 (s), 120.8 (d), 114.0 (s), 111.7 (d),
88.9 (d), 88.6 (s), 68.4 (d), 61.3 (d), 55.9 (q), 52.5 (t), 47.2
(s), 29.3 (t), 28.3 (t)
EXAMPLE 125
Step 1
1-Bromo-5-methoxy-2-(2-methoxyethen-1-yl)-4-(1-methylethoxy)benzene
[0884] ##STR309##
[0885] While being cooled with ice, potassium-tert-butylate (20.5
g, 183 mmol) is added to a suspension of
(methoxymethyl)-triphenylphosphonium chloride (50.0 g, 152 mmol) in
absolute THF (330 ml). After 15 minutes,
2-bromo-4-methoxy-5-(1-methylethoxy)benzaldehyde (33.1 g, 121 mmol)
is added in portions.
[0886] After 15 minutes, the residue that is obtained after the
solvent is removed in a rotary evaporator is dispersed between
water (300 ml) and ether (300 ml). The organic phase is dried
(sodium sulfate), filtered, and the residue that is obtained after
concentration by evaporation (37.3 g) is purified by means of MPLC
(petroleum ether:ethyl acetate=2:1, flow 70 ml/min). In this way,
the product is obtained in the form of colorless crystals (32.5 g,
85%).
[0887] Melting point: 43-45.degree. C.
[0888] TLC: Petroleum ether:ethyl acetate=2:1 Rf=0.75
[0889] .sup.1H: NMR (CDCl.sub.3) .delta. 7.00 (s, 1H); 6.90 (s,
1H), 6.83 (d, J=12.7 Hz, 1H.sub.trans), 6.13 (d, J=7.6 Hz,
1H.sub.cis), 5.98 (d, J=12.7 Hz, 1H.sub.trans), 5.50 (d, J=7.6 Hz,
1H.sub.cis), 4.49 (septet, J=6.4 Hz, 1H), 3.81 (s, 3H), 3.74 (s,
3H.sub.trans), 3.70 (s, 3H.sub.cis), 1.35 (d, J=6.4 Hz, 6H);
[0890] .sup.13C-NMR (CDCl.sub.3) .delta. 149.2 and 149.6 (s), 147.6
and 148.9 (s), 146.0 and 146.7 (d), 127.5 and 128.4 (s), 115.7 and
117.2 (d), 113.6 and 116.2 (d), 113.3 and 113.7 (s), 103.8 and
104.2 (d), 71.5 and 71.9 (d), 56.1 and 56.4 (q), 56.0 and 60.6 (q),
21.9 and 22.0 (q)
Step 2
2-Bromo-4-methoxy-5-(1-methylethoxy)benzene acetaldehyde
[0891] ##STR310##
[0892]
1-Bromo-5-methoxy-2-(2-methoxyethen-1-yl)-4-(1-methylethoxy)benzen-
e (20.0 g, 66.4 mmol) is stirred in tetrahydrofuran (250 ml)/2N Hcl
(10 ml) for three hours at boiling temperature.
[0893] After the solvent is drawn off in a rotary evaporator, the
residue is dispersed between water (200 ml) and ether (200 ml), the
aqueous phase is extracted with ether (3.times.100 ml), the
combined organic phases are washed with water (4.times.150 ml),
saturated sodium bicarbonate solution (2.times.200 ml) and
saturated common salt solution (1.times.200 ml), dried (sodium
sulfate/activated carbon) and filtered. After concentration by
evaporation, the product is obtained as a yellow oil (18.7 g,
98%).
[0894] TLC: Petroleum ether:ethyl acetate=4:1, Rf=0.77
[0895] .sup.1H: NMR (CDCl.sub.3) .delta. 9.71 (t, J=1.71 Hz, 1H),
7.06 (s, 1H) 6.80 (s, 1H), 4.49 (septet, J=6.4 Hz, 1H), 3.90 (s,
3H), 3.73 (d, J=1.71 Hz, 2H), 1.35 (d, J=6.4 Hz, 6H);
[0896] .sup.13C NMR (CDCl.sub.3) .delta. 191.8 (d), 146.6 (s),
145.1 (s), 125.4 (s) 118.1 (s), 115.8 (d), 113.7 (d), 71.5 (d),
56.4 (q), 49.8 (t), 21.8 (q)
Step 3
2-Bromo-4-methoxy-5-(1-methylethoxy)benzene ethanol
[0897] ##STR311##
[0898] 2-Bromo-5-(1-methylethoxy)-4-methoxybenzene acetaldehyde
(2.60 g, 9.05 mmol) is added at 15.degree. C. within 30 minutes to
a suspension of sodium borohydride (0.341 g, 9.05 mmol) in absolute
ethanol (40 ml), and it is stirred for two hours at this
temperature.
[0899] The ethanol is removed in a rotary evaporator, and the
residue is dispersed between saturated sodium bicarbonate solution
(200 ml) and ether (200 ml). The aqueous phase is extracted with
ether (3.times.50 ml). The combined organic phases are washed with
water (3.times.200 ml) and saturated common salt solution
(1.times.200 ml), dried (sodium sulfate/activated carbon), dried
and filtered. After concentration by evaporation, the product is
obtained in the form of colorless crystals (2.60 g, 99%).
[0900] TLC: PE:EE=9:1, 0.25
[0901] .sup.1H NMR (CDCl.sub.3) .delta. 6.98 (s, 1H), 6.80 (s, 1H),
4.47 (septet, J=6.3 Hz, 1H), 3.82 (t, J=7.0 Hz, 2H), 3.80 (s, 3H),
2.90 (t, J=7.0 Hz, 2H), 1.32 (d, J=7.3 Hz, 6H);
[0902] .sup.13C NMR (CDCl.sub.3) .delta. 149.7 (s), 146.4 (s),
129.6 (s), 118.5 (d), 116.3 (d), 114.8 (s), 71.8 (d), 62.2 (t),
56.1 (q), 38.8 (t), 21.9 (q)
[0903] MT-163 JOS 1682
[0904] C.sub.2H.sub.7BrO.sub.3 TABLE-US-00105 Cld.: C, 49.84; H,
5.93 Fnd.: C, 49.69; H, 5.79
Step 4
1-Bromo-2-(2-iodoethyl)-5-methoxy-4-(1-methylethoxy)benzene
[0905] ##STR312##
[0906] Triphenylphosphine (24.7 g, 94.0 mmol), imidazole (12.8 g,
188.0 mmol) and iodine (23.06 g, 90.9 mmol) are stirred in absolute
CH.sub.2Cl.sub.2 (150 ml) for one hour at 15.degree. C.
[0907] 2-Bromo-5-(1-methylethoxy)-4-methoxybenzene ethanol (18.0 g,
62.2 mmol) in absolute CH.sub.2Cl.sub.2 (100 ml) is added in drops
at this temperature within 10 minutes, and the mixture is stirred
for two hours at room temperature.
[0908] The mixture is filtered, and the filtrate is washed with
water (1.times.200 ml). The aqueous phase is extracted with
CH.sub.2Cl.sub.2 (2.times.50 ml), and the combined organic phases
are washed with sodium thiosulfate solution (1.times.200 ml), water
(1.times.200 ml), copper sulfate solution (1.times.200 ml), water
(1.times.200 ml) and saturated common salt solution (1.times.200
ml), dried (sodium sulfate/activated carbon), filtered, and the
solvent is removed in a rotary evaporator.
[0909] After purification by column chromatography (1000 g of
silica gel/petroleum ether:ethyl acetate=96:4), the product is
obtained in the form of colorless needles (19.0 g, 77%).
[0910] .sup.1H NMR (CDCl.sub.3) .delta. 7.00 (s, 1H), 6.77 (s, 1H),
4.49 (septet, J=6.3 Hz, 1H), 3.81 (s, 3H), 3.39-3.24 (m, 2H),
3.24-3.09 (m, 2H), 1.36 (d, J=7.3 Hz, 6H);
[0911] .sup.13C NMR (CDCl.sub.3) .delta. 150.0 (s), 146.5 (s),
131.7 (s), 118.0 (d), 116.3 (d), 114.3 (s), 71.8 (d), 56.1 (q),
40.0 (t), 22.0 (q), 4.2 (t)
[0912] MT 164 JOS 1704
[0913] C.sub.12H.sub.16BrIO.sub.2 TABLE-US-00106 Cld.: C, 36.12; H,
4.04 Fnd.: C, 36.38; H, 3.91
Step 5
2-[2-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]ethyl]-propanedioic
acid dimethyl ester
[0914] ##STR313##
[0915] 1-Bromo-2-(2-iodoethyl)-4-(1-methylethoxy)-5-methoxybenzene
(18.0 g, 45.1 mmol), potassium carbonate (32.0 g, 321 mmol,
anhydrous, freshly ground) and malonic acid dimethyl ester (50.0 g,
378 mmol) are stirred in absolute DMF (200 ml) for 12 hours at
80.degree. C.
[0916] The mixture is filtered, the solvent is removed in a rotary
evaporator, and the residue is dispersed between water (300 ml) and
ether (300 ml). The aqueous phase is extracted with ether
(3.times.50 ml), the combined organic phases are washed with water
(4.times.150 ml) and saturated common salt solution (1.times.200
ml), dried (sodium sulfate/activated carbon), filtered, excess
malonic ester is removed by distillation from the residue that is
obtained after the solvent is distilled off (160.degree. C./15
mbar), and it is purified by means of bulb tube distillation
(170.degree. C./0.06 mbar), by which the product is obtained as a
colorless oil (18.9 g, 72%).
[0917] .sup.1H: NMR (CDCl.sub.3) .delta. 6.99 (s, 1H), 6.73 (s,
1H), 4.49 (septet, J=6.3 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 0.6H),
3.39 (t, J=7.9 Hz, 1H), 2.68 (t, J=7.9 Hz, 2H), 2.18 (q, J=7.9 Hz,
2H), 1.34 d, J=6.3 Hz, 6H);
[0918] .sup.13C NMR (CDCl.sub.3) .delta. 169.6 (s), 149.7 (s),
146.6 (s), 131.7 (s), 117.8 (d), 116.3 (d), 114.6 (s), 71.8 (d),
56.2 (q), 52.5 (q), 50.9 (d), 33.1 (t), 29.0 (t), 22.0 (q)
[0919] MT-165 JOS 1771
[0920] C.sub.17H.sub.23BrO.sub.6 TABLE-US-00107 Cld.: C, 50.63; H,
5.75 Fnd.: C, 50.87; H, 5.62
Step 6
2-[2-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]ethyl]-2-[4-(1-methyletho-
xy)phenylmethyl]propanedioic acid methyl ester
[0921] ##STR314##
[0922] 1-Bromo-2-(2-iodoethyl)-4-(1-methylethoxy)-5-methoxybenzene
(18.0 g, 45.1 mmol), potassium carbonate (32.0 g, 321 mmol,
anhydrous, freshly ground) and (50.0 g, 378.4 mmol) of malonic acid
dimethyl ester are stirred (200 ml) in anhydrous DMF for 12 hours
at 80.degree. C.
[0923] The mixture is filtered, the solvent is drawn off, and the
residue is dispersed between 300 ml of water and 300 ml of ether.
The aqueous phase is extracted three times with 50 ml each, the
combined organic phases are washed four times with 150 ml of water
each and once with 200 ml of saturated common salt solution, dried
on sodium sulfate/activated carbon, filtered, and the solvent is
drawn off. Excess malonic acid dimethyl ester is separated by
distillation (160.degree. C./15 mbar), and the residue is purified
by means of bulb tube distillation (170.degree. C. (0.06 mbar), by
which the product is obtained in the form of a colorless oil (18.9
g, 72%).
[0924] MT 166 JOS 1694
[0925] C.sub.27H.sub.35BrO.sub.7 TABLE-US-00108 Cld.: C, 58.81; H,
6.40 Fnd.: C, 59.03; H, 6.24
Step 7
4-[2-Bromo-4-methoxy-5-(1-methylethoxy)]-.alpha.-[4-(1-methylethoxy)-pheny-
lmethyl]benzenebutanoic acid
[0926] ##STR315##
[0927]
2-[2-[2-Bromo-5-(1-methylethoxy)-4-methoxyphenyl]ethyl]-2-[4-(1-me-
thylethoxy)phenylmethyl]propanedioic acid dimethyl ester (18.1 g,
32.8 mmol) and potassium hydroxide (17.5 g, 312 mmol) are stirred
in a mixture that consists of ethanol (100 ml) and water (20 ml)
for 12 hours at boiling temperature.
[0928] The reaction mixture is acidified with concentrated
hydrochloric acid to a pH of 1 and kept under reflux for one
hour.
[0929] The residue that remains after the solvent is removed is
dispersed between water (250 ml) and ether (250 ml). The aqueous
phase is extracted with ether (2.times.100 ml), the combined,
organic phases are washed neutral with water, washed with saturated
common salt solution (150 ml) and dried (sodium sulfate/activated
carbon). The residue that remains after the solvent is removed is
decarboxylated in a bulb tube for 30 minutes at 160.degree. C.
under high vacuum and then distilled at 210.degree. C./0.008 mbar.
In this way, the product is obtained in the form of colorless
crystals (13.3 g, 84%).
[0930] .sup.1H: NMR (CDCl.sub.3) .delta. 7.04 (d, J=9.5 Hz, 2H),
6.99 (s, 1H), 6.80 (d, J=9.5 Hz, 2H), 6.77 (s, 1H), 4.60-4.39 (m,
2H), 3.79 (s, 3H), 3.09-2.58 (m, 5H), 2.09-1.72 (m, 2H), 1.43-1.29
(m, 1H)
[0931] .sup.13C NMR (CDCl.sub.3): 181.0 (s), 156.2 (s), 149.3 (s),
146.3 (s) 132.3 (s), 130.7 (s), 129.6 (d), 117.6 (d), 116.1 (d),
115.7 (d) 114.3 (s), 71.6 (d), 69.6 (d), 55.9 (q), 46.7 (d), 37.0
(t), 33.1 (t), 317 (t), 21.8 (q)
Step 8
4-[2-Bromo-4-methoxy-5-(1-methylethoxy)]-.alpha.-[4-(1-methylethoxy)-pheny-
lmethyl]benzenebutanoic acid amide
[0932] ##STR316##
[0933] Oxalic acid dichloride (15 ml) is added in drops at
0.degree. C. within 15 minutes to
4-[2-bromo-4-methoxy-5-(1-methylethoxy)]-.alpha.-[4-(1-methylethoxy)-phen-
ylmethyl]benzenebutanoic acid (24.0 g, 50.1 mmol) in absolute
CH.sub.2Cl.sub.2 (200 ml), and the mixture is stirred for two hours
at this temperature.
[0934] The solvent is removed in a rotary evaporator, the residue
is taken up in absolute THF (100 ml), and ammonia is introduced at
0.degree. C. for two hours. The mixture is stirred for one hour at
0.degree. C. and poured onto water (1000 ml).
[0935] The precipitated crystals are filtered off and digested with
water (4.times.500 ml). In this way, the product is obtained in the
form of colorless crystals (19.9 g, 83%).
[0936] .sup.1H NMR (CDCl.sub.3) .delta. 7.04 (d, J=9.5 Hz, 2H),
6.96 (s, 1H), 6.72 (d, J=9.5 Hz, 2H), 6.70 (s, 1H), 6.00 (b, 1H),
5.55 (b, 1H), 4.60-4.30 (m, 2H), 3.77 (s, 3H), 2.96-2.52 (m, 4H),
2.51-2.28 (m, 1H), 2.03-1.60 (m, 2H), 1.36-1.20 (m, 12H)
[0937] .sup.13C NMR (CDCl.sub.3) 1774, (s), 156.2 (s), 149.2 (s),
146.4 (s) 132.7 (s), 131.1 (d), 129.7 (d), 117.5 (s), 116.1 (d),
115.7 (d) 114.4 (d), 71.6 (d), 69.6 (d), 56.0 (q), 48.6 (d), 38.0
(t), 33.3 (t), 32.5 (t), 21.9 (q).
[0938] MT-168 JOS 1770
[0939] C.sub.24H.sub.32BrNO.sub.4 TABLE-US-00109 Cld.: C, 60.25; H,
6.74; N, 2.93 Fnd.: C, 60.15; H, 6.55; N, 2.77
Step 9
4-(2-Bromo-5-hydroxy-4-methoxy)-.alpha.-(4-hydroxyphenylmethyl)-benzenebut-
anoic acid amide
[0940] ##STR317##
[0941] Boron trichloride (45 ml, 1.6 M in CH.sub.2Cl.sub.2) is
added in drops at -78.degree. C. to
4-[2-Bromo-4-methoxy-5-(1-methylethoxy)-.alpha.-[4-(1-methylethoxy)-pheny-
lmethyl]benzenebutanoic acid amide (10.0 g, 20.9 mmol) in absolute
CH.sub.2Cl.sub.2 (150 ml), and it is stirred for one hour at this
temperature. Then, the mixture is heated to room temperature and
stirred for two hours.
[0942] It is mixed with water (400 ml), and the organic solvent is
distilled off in a rotary evaporator, whereby the crude product
precipitates as crystals, which is filtered off and is digested
with water (6.times.200 ml) and diisopropyl ether (2.times.40 ml).
In this case, the product is obtained in the form of colorless
crystals (7.11 g, 86%).
[0943] MT 171 JOS 1714
[0944] C.sub.18H.sub.20BrNO.sub.400.25H.sub.2O TABLE-US-00110 Cld.:
C, 54.22; H, 5.18; N, 3.51 Fnd.: C, 54.05; H, 4.95; N, 3.54
Step 10
1-Bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-oxa-6H-benzo[a]cyclohepta[h]-
benzofuran-10-carboxylic acid amide (SPH-1478)
[0945] ##STR318##
[0946]
.alpha.-[[2-Bromo-5-hydroxy-4-methoxyphenyl]methyl]-4-hydroxybenze-
nebutanoic acid amide (3.00 g, 7.61 mmol) is suspended in
chloroform (300 ml) and mixed with a solution of potassium
hexacyanoferrate (III) (13.2 g, 40.0 mmol) in potassium carbonate
solution (75 ml, ten percent).
[0947] The mixture is stirred vigorously at room temperature for 40
minutes and filtered on Hyflo. The aqueous phase is extracted with
chloroform (2.times.50 ml), the combined organic phases are washed
with water (2.times.200 ml) and saturated common salt solution
(1.times.150 ml), dried (sodium sulfate/silica gel), and the crude
product that is obtained after the solvent is concentrated by
evaporation is purified via column chromatography (50 g of silica
gel, ethyl acetate). In this way, the product is obtained in the
form of colorless crystals (179 mg, 6%).
[0948] TLC: ethyl acetate, R.sub.f=0.6
[0949] .sup.1H NMR (CDCl.sub.3): .delta. 6.95 (s, 1H), 6.71 (dd,
J=12.1 Hz, J=2.0 Hz, 1H), 6.02 (d, J=12.1 Hz, 1H), 5.70 (b, 2H),
4.82 (s, 1H), 3.81 (s, 3H), 3.58 (dd, J=16.5 Hz, J=6.0 Hz, 1H),
3.13 (dd, J=6.0 Hz, J=16.5 Hz, 1H), 2.82-2.57 (m, 3H), 2.48-2.15
(m, 2H), 2.12-1.62 (m, 2H);
[0950] .sup.13C NMR (DMSO-d.sub.6): .delta. 196.7 (s), 178.2 (s),
147.3 (d), 145.6 (s), 143.9 (s), 132.5 (s), 131.4 (s), 127.5 (d),
117.0 (s), 114.8 (d), 88.3 (d), 53.5 (q), 49.7 (s), 43.7 (d), 40.9
(t), 39.7 (t), 38.0 (t), 32.1 (t);
[0951] .sup.13C NMR (CDCl.sub.3): .delta. 193.8 (s), 176.7 (s),
146.7 (d), 143.5 (s), 143.2 (s), 131.0 (s), 129.9 (s), 127.7 (d),
116.5 (s), 115.1 (d), 87.6 (d), 56.1 (q), 49.1 (s), 44.2 (d), 39.4
(t), 37.0 (t), 32.0 (t), 31.7 (t)
EXAMPLE 126
1-Bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzo[a]cyclohept-
a[hi]benzofuran-10-carboxylic acid amide (SPH-1479)
[0952] ##STR319##
[0953] L-Selectride.sup.R (2.0 ml, 2.0 mmol, 1 M in THF) is added
at 0.degree. C. within 15 minutes to a suspension of
1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-G-oxa-6H-benzo
a]cyclohepta[hi]benzofuran-10-carboxylic acid amide (160 mg, 0.41
mmol) in absolute THF (5 ml), and the mixture is stirred for 12
hours at room temperature. It is hydrolyzed with water (2 ml) and
dispersed between water (10 ml) and ethyl acetate (10 ml), the
aqueous phase is extracted with ethyl acetate (3.times.5 ml), the
combined organic phases are washed with 1N hydrochloric acid
(3.times.10 ml), water (2.times.10 ml), saturated sodium
bicarbonate solution (1.times.10 ml) and saturated common salt
solution (1.times.10 ml), dried (sodium sulfate/activated carbon),
filtered, and the crude product that is obtained after the solvent
is distilled off is purified by means of column chromatography (10
g of silica gel, ethyl acetate). In this way, the product is
obtained in the form of colorless crystals (137 mg, 85%).
[0954] MT-194 JOS 1712
[0955] C.sub.18H.sub.20BrNO.sub.4 TABLE-US-00111 Cld.: C, 54.84; H,
5.11; N, 3.55 Fnd.: C, 54.55; H, 5.22; N, 3.34
[0956] TLC: ethyl acetate, R.sub.f=0.5
[0957] .sup.1H NMR (MeOH-d.sub.4): .delta. 6.99 (s, 1H), 6.03 (d,
J=16.5 Hz, 1H), 5.94 (dd, J=16.5 Hz, J=5.9 Hz, 1H), 4.52 (s, 1H),
4.16 (s, 1H), 3.76 (s, 3H), 3.49 (dd, J=19.8 Hz, J=5.9 Hz, 1H),
2.90 (t, J=17.5 Hz, 1H), 2.77 (t, J=17.5 Hz, 1H), 2.46 (d, J=17.6
Hz, 1H), 2.29-2.10 (m, 2H), 1.98-1.53 (m, 3H);
[0958] .sup.13C NMR (MeOH-d.sub.4): .delta. 181.6 (s), 148.1 (s),
145.4 (s), 135.4 (s), 132.3 (s), 129.5 (d), 128.7 (d), 117.8 (d),
115.4 (s), 89.0 (d), 70.3 (d), 62.6 (d), 57.2 (q), 45.7 (s), 42.5
(t), 33.5 (t) 33.1 (1), 31.9 (t) ##STR320##
EXAMPLE 127
Step 1
5-(6-Acetyloxy-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2
(1H)-one
[0959] ##STR321##
[0960] 6-Acetyloxyhexanoic acid chloride (16.7 g, 86.6 mmol) in
absolute CH.sub.2Cl.sub.2 (50 ml) is added in drops at 0.degree. C.
within 10 minutes to a suspension of anhydrous aluminum chloride
(61.5 g, 461.6 mmol) in absolute CH.sub.2Cl.sub.2 (500 ml), and it
is stirred for 15 minutes at this temperature.
5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one (10.0 g (57.7
mmol) in absolute CH.sub.2Cl.sub.2 (100 ml) is added in drops
within 15 minutes at 0.degree. C., then it is heated to boiling
temperature and stirred for 30 minutes. It is cooled to 0.degree.
C., hydrolyzed with ice and dispersed between water (300 ml) and
CH.sub.2Cl.sub.2 (100 ml). The aqueous phase is extracted with
CH.sub.2Cl.sub.2 (2.times.100 ml), the combined organic phases are
washed with 2N hydrochloric acid (2.times.250 ml), water
(2.times.250 ml), semi-concentrated aqueous Na.sub.2CO.sub.3
solution (2.times.250 ml), concentrated aqueous Na.sub.2CO.sub.3
solution (2.times.250 ml) and concentrated common salt solution
(1.times.250 ml), dried (sodium sulfate/activated carbon), and the
solvent is removed in a rotary evaporator.
[0961] After recrystallization from methanol (150 ml), the product
is obtained in the form of light yellow crystals (14.3 g,
75.5%).
[0962] MT-304 JOS 1675
[0963] C.sub.19H.sub.23NO.sub.4 TABLE-US-00112 Cld.: C, 69.28; H,
7.04; N, 4.25 Fnd.: C, 69.27; H, 6.99; N, 4.25
[0964] .sup.1H NMR (CDCl.sub.3): .delta. 7.72 (s, 2H), 4.06 (t,
J=6.5 Hz, 2H), 3.72 (t, J=5.7 Hz, 2H), 3.54 (s, 2H), 2.90 (t, J=7.0
Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 2.09-1.93 (m, 5H), 1.85-1.56 (m,
4H), 1.50-1.30 (m, 2H);
[0965] .sup.13C NMR (CDCl.sub.3): .delta. 198.9 (s), 174.2 (s),
171.1 (s), 145.5 (s), 131.3 (s), 127.8 (d), 122.9 (s), 122.4 (d),
119.5 (s), 64.3 (t), 38.9 (t), 38.0 (t), 36.1 (t), 28.5 (t), 25.7
(t), 24.4 (t), 24.1 (t), 21.0 (q), 20.9 (t)
Step 2
5-(6-Hydroxy-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2
(1H)-one
[0966] ##STR322##
[0967]
5-(6-Acetyloxy-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoli-
n-2(1H)-one (10.0 g, 30.6 mmol) is suspended in anhydrous ethanol
(150 ml), mixed with catalyst amounts of 4-methylbenzenesulfonic
acid monohydrate and stirred for five hours at boiling temperature.
The solvent volume is concentrated by evaporation to one third, and
the product is obtained in the form of light yellow needles (8.22
g, 93.5%) by crystallization at -20.degree. C.
[0968] MT-305 JOS 1672
[0969] C.sub.1/H.sub.21NO.sub.3 TABLE-US-00113 Cld.: C, 71.06; H,
7.37; N, 4.87 Fnd.: C, 71.30; H, 7.37; N, 4.87
[0970] .sup.1H NMR (CDCl.sub.3): .delta. 7.67 (s, 2H), 3.80-3.52
(m, 4H), 3.48 (s, 2H), 2.97-2.66 (m, 4H), 2.08-1.86 (m, 2H),
1.82-1.26 (m, 6H);
[0971] .sup.13C NMR (CDCl.sub.3): .delta. 199.3 (s), 174.2 (s),
145.4 (s), 131.2 (s), 127.8 (d), 122.8 (s), 122.3 (d), 119.4 (s),
62.3 (t), 38.7 (t), 38.0 (t), 36.0 (t), 32.3 (t), 25.4 (t), 24.3
(t), 24.1 (t), 20.8 (t)
Step 3
5-(6-Iodo-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2
(1H)-one
[0972] ##STR323##
[0973] Triphenylphosphine (2.02 g, 7.74 mmol), iodine (3.08 g,
12.12 mmol) and imidazole (0.618 g, 9.08 mmol) are stirred in
absolute CH.sub.2Cl.sub.2 (30 ml) for 30 minutes at 15.degree.
C.
[0974]
5-(6-Hydroxy-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin--
2(1H)-one (2.0 g, 6.96 mmol) in anhydrous CH.sub.2Cl.sub.2 (10 ml)
is added in drops within 5 minutes at this temperature, then it is
stirred for 40 minutes at room temperature.
[0975] It is mixed with semisaturated sodium sulfate solution (50
ml), the phases are separated, the aqueous phase is extracted with
CH.sub.2Cl.sub.2, the combined organic phases are washed with 2N
hydrochloric acid (3.times.100 ml), water (2.times.100 ml),
saturated sodium bicarbonate solution (2.times.100 ml) and
saturated common salt solution (1.times.100 ml), dried (sodium
sulfate/activated carbon), filtered, and the crude product that is
obtained after the solvent is removed in a rotary evaporator is
recrystallized from methanol (10 ml).
Variant A:
[0976] The residue is purified by column chromatography (100 g of
silica gel, chloroform), by which the product is obtained in the
form of light yellow crystals (2.44 g, 88.3%).
Variant B:
[0977] The residue is recrystallized one additional time from
methanol (10 ml), by which the product is obtained in the form of
light yellow crystals (2.28 g, 82.4%).
MT-308
[0978] JOS 1670 C.sub.17H.sub.20INO.sub.2 TABLE-US-00114 Cld.: C,
51.40; H, 5.07; N, 5.53 Fnd.: C, 51.56; H, 4.97; N, 3.46
[0979] .sup.1H NMR (CDCl.sub.3): .delta. 7.70 (s, 2H), 3.72 (t,
J=5.7 Hz, 2H), 3.52 (s, 2H), 3.18 (t, J=6.9 Hz, 2H), 2.91 (t, J=7.2
Hz, 2H), 2.80 (t, J=6.1 Hz, 2H), 2.12-1.61 (m, 6H), 1.57-1.36 (m,
2H);
[0980] .sup.13C NMR (CDCl.sub.3): .delta. 198.7 (s), 174.1 (s),
145.5 (s), 131.2 (s), 127.8 (d), 122.9 (s), 122.3 (d), 119.4 (s),
38.8 (t), 37.9 (t), 36.0 (t), 33.2 (t), 30.1 (t), 24.0 (t), 23.3
(t), 20.9 (t), 6.6 (t)
Step 4
5-(6-Methylsulfonyloxy-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]-
quinolin-2(1H)-one
[0981] ##STR324##
[0982] Methanesulfonic acid chloride (458 mg, 4.00 mmol) is added
in drops within 5 minutes at 15.degree. C. to
5-(6-hydroxy-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-o-
ne (1.0 g, 3.48 mmol) and N-ethyldiisopropylamine (560 mg, 4.35
mmol) in anhydrous CH.sub.2Cl.sub.2 (10 ml), and it is then stirred
for two hours at room temperature.
[0983] It is mixed with water (20 ml), the phases are separated,
the aqueous phase is extracted with CH.sub.2Cl.sub.2 (1.times.10
ml), the combined organic phases are washed with 2N hydrochloric
acid (3.times.10 ml), water (2.times.10 ml), saturated sodium
bicarbonate solution (2.times.10 ml) and saturated common salt
solution (1.times.10 ml), dried (sodium sulfate/activated carbon),
filtered, and the crude product that is obtained after the solvent
is removed in a rotary evaporator is digested with diisopropyl
ether (10 ml), by which the product is obtained in the form of
light yellow crystals (1.17 g, 92.2%).
[0984] .sup.1H NMR (CDCl.sub.3): .delta. 7.70 (s, 2H), 4.22 (t,
J=6.5 Hz, 2H), 3.71 (t, J=5.8 Hz, 2H), 3.52 (s, 2H), 2.99 (s, 3H),
2.92 (t, J=7.0 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 2.17-1.92 (m, 5H),
1.90-1.64 (m, 4H), 1.60-1.37 (m, 2H);
[0985] .sup.13C NMR (CDCl.sub.3): .delta. 198.7 (s), 174.2 (s),
145.6 (s), 131.2 (s), 127.8 (d), 123.0 (s), 122.4 (d), 119.5 (s),
69.8 (t), 38.8 (t), 37.8 (t), 37.3 (q), 36.1 (t), 28.9 (t), 25.1
(t), 24.3 (t), 23.7 (t), 20.9 (t)
Step 5
5-[6-[(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-6H-benzof-
uro[3a,3,2-ef][2]benzazepine-11-yl]-1-oxohexyl]-5,6-dihydro-4H-pyrrolo[3,2-
,1-ij]quinolin-2-(1H)-one (SPH-1500)
[0986] ##STR325##
[0987] Norgalanthamine (1.13 g, 1.64 mmol),
5-(6-iodo-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one
(1.50 g, 3.75 mmol) and N-ethyldiisopropylamine (1.46 g, 11.3 mmol)
are stirred in absolute chloroform (20 ml) for 54 hours at boiling
temperature.
[0988] The residue that is obtained after the solvent is removed in
a rotary evaporator is purified by column chromatography (200 g of
silica gel, chloroform:methanol:ammonia=96:3:1), by which the
product is obtained as a light yellow foam (1.31 g, 64.3%).
[0989] .sup.1H NMR (CDCl.sub.3): .delta. 7.63 (s, 2H), 6.68-6.46
(m, 2H), 6.00 (d, J=10.3 Hz, 1H), 5.90 (dd, J=10.3 Hz, J=4.6 Hz,
1H), 4.51 (s, 1H), 4.19-3.96 (m, 2H), 3.75 (s, 1H), 3.73 (s, 3H),
3.70-3.58 (m, 2H), 3.44 (s, 2H), 3.35-2.98 (m, 2H), 2.96-6.67 (m,
4H), 2.66-2.29 (m, 4H), 2.15-1.84 (m, 4H), 1.82-1.11 (m, 6H);
[0990] .sup.13C NMR (CDCl.sub.3): .delta. 199.1 (s), 174.1 (s),
145.6 (s), 145.3 (s), 143.8 (s), 133.0 (s), 131.2 (s), 129.3 (s),
127.7 (d), 127.4 (d), 126.8 (d), 122.8 (s), 122.3 (d), 121.7 (d),
119.4 (s), 111.0 (d), 88.5 (d), 61.8 (d), 57.6 (t), 55.7 (q), 51.4
(t), 51.2 (t), 48.2 (s), 38.7 (t), 38.0 (t), 36.0 (t), 32.8 (t),
29.8 (t), 27.1 (t), 26.9 (t), 24.3 (t), 24.2 (t), 20.8 (t),
Step 6
5-[6-[(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-6H-benzof-
uro[3a,3,2-ef][2]benzazepine-11-yl]-1-oxohexyl]-5,6-dihydro-4H-pyrrolo[3,2-
,1-ij]quinolin-2(1H)-one fumarate (SPH-1499)
[0991] The precipitation of the fumarate was carried out
analogously to Example 4.
[0992] MT-311 JOS 1762
[0993] C.sub.37H.sub.42N.sub.2O.sub.9*H.sub.2O TABLE-US-00115 Cld.:
C, 65.67; H, 6.55; N, 4.14 Fnd.: C, 65.93; H, 6.54; N, 4.03
EXAMPLE 128a
Step 1
2-[[4-(1-Methylethoxy)phenyl]methyl]propanedioic acid dimethyl
ester
[0994] ##STR326##
[0995] 1-(Chloromethyl)-4-(1-methylethoxy)benzene (20.5 g, 111
mmol), malonic acid dimethyl ester (102.5 g, 776 mmol) and
potassium carbonate (46.5 g, 332 mmol, anhydrous, freshly ground)
are stirred in absolute DMF (250 ml) for 24 hours at 70.degree.
C.
[0996] The mixture is filtered, and the residue that is obtained
after the filtrate is concentrated by evaporation in a rotary
evaporator is dispersed between ether (250 ml) and water (250 ml).
The organic phase is washed with water (3.times.200 ml) and
saturated common salt solution (1.times.200 ml), dried (sodium
sulfate/activated carbon), filtered, and the solvent is
removed.
[0997] The excess malonic acid dimethyl ester is separated by
vacuum distillation (85.degree. C./15 mbar), and the crude product
that remains in the residue is purified by bulb tube distillation
(130.degree. C./0.001 mbar). In this way, the product is obtained
as a colorless oil (23.6 g, 78%).
[0998] MT-67 JOS 1774
[0999] C.sub.15H.sub.20O.sub.5 TABLE-US-00116 Cld.: C, 64.27; H,
7.19 Fnd.: C, 64.28; H, 7.07
Step 2
4-(1-Methylethoxy)benzenepropanoic acid
[1000] ##STR327##
[1001] 2-[[4-(1-Methylethoxy)phenyl]methyl]-propanedioic acid
dimethyl ester (23.6 g, 84.2 mmol) is stirred into 2N potassium
hydroxide solution (15 ml)/ethanol (25 ml) for 18 hours at boiling
temperature.
[1002] The ethanol is distilled off in a rotary evaporator, the
residue is brought to a pH of 1 with concentrated hydrochloric acid
and extracted with ether (3.times.150 ml). The combined organic
phases are washed with water (6.times.200 ml) and saturated common
salt solution (200 ml), dried (sodium sulfate/activated carbon) and
filtered. The residue that is obtained after concentration by
evaporation in a rotary evaporator is decarboxylated in a bulb tube
(140.degree. C./0.08 mbar) and then distilled (155.degree. C./0.08
mbar) In this way, the product is obtained in the form of colorless
crystals (14.4 g, 82%).
[1003] .sup.1H NMR (CDCl.sub.3): .delta. 7.12 (d, J=9.5 Hz, 2H),
6.82 (d, J=9.5 Hz, 2H), 4.50 (septet, J=6.3 Hz, 1H), 2.89 (t, J=7.9
Hz, 2H), 2.63 (t, J=7.9 Hz, 2H), 1.32 (d, J=6.3 Hz, 6H);
[1004] .sup.13C NMR (CDCl.sub.3): .delta. 178.8 (s), 156.4 (s),
132.1 (s), 129.2 (d), 116.0 (d), 69.9 (d), 35.8 (t), 29.7 (t), 22.1
(q)
Step 3
2-Bromo-4-methoxy-5-(1-methylethoxy)benzene acetonitrile
[1005] ##STR328##
[1006] 1-Bromo-2-(chloromethyl)-5-methoxy-4-(1-methylethoxy)benzene
(7.00 g, 23.8 mmol) and potassium cyanide (1.70 g, 26.1 mmol,
freshly ground) are stirred in absolute DMSO (70 ml) for 12 hours
at room temperature.
[1007] The mixture is poured onto water (700 ml), the aqueous phase
is extracted with ether (3.times.150 ml), the combined organic
phases are washed with water (5.times.150 ml) and saturated common
salt solution (1.times.200 ml), dried (sodium sulfate/activated
carbon), filtered, and the residue that is obtained after
concentration by evaporation is digested with diisopropyl ether (15
ml). In this way, the product is obtained in the form of colorless
crystals (6.46 g, 95%).
[1008] MT-72 JOS 1695
[1009] C.sub.12H.sub.14BrNO.sub.2 TABLE-US-00117 Cld.: C, 50.72; H,
4.97; N, 4.93 Fnd.: C, 50.73; H, 4.84; N, 4.89
[1010] .sup.1H NMR (CDCl.sub.3): .delta. 7.02 (s, 1H), 6.97 (s,
1H), 4.50 (septet, J=6.3 Hz, 1H), 3.81 (s, 3H), 3.72 (s, 2H), 1.36
(d, J=6.3 Hz, 6H);
[1011] .sup.13C NMR (CDCl.sub.3): .delta. 150.8 (s), 147.1 (s),
12.1 5 (s), 117.3 (s), 116.7 (d), 116.3 (d), 113.9 (s), 72.1 (d)
56.2 (q), 24.2 (t), 21.9 (q)
Step 4
4-(1-Methylethoxy)benzenepropanoic acid-(1-methyl)ethyl ester
[1012] ##STR329##
[1013] 4-Hydroxybenzenepropanoic acid (50.0 g, 300 mmol), potassium
carbonate (210 g, 1.5 mol, anhydrous, freshly ground) and
2-bromopropane (221 g, 1.8 mol) are stirred in absolute DMF (500
ml) for 24 hours at 60.degree. C.
[1014] The solution is filtered, and the residue that is obtained
after the concentration by evaporation in a rotary evaporator is
dispersed between ether (500 ml) and 2N sodium hydroxide solution
(500 ml). The organic phase is washed with 2N sodium hydroxide
solution (2.times.200 ml), water (3.times.500 ml) and saturated
common salt solution (200 ml), dried (sodium sulfate/activated
carbon) and filtered. The residue that is obtained after the
solvent is distilled off in a rotary evaporator is purified by bulb
tube distillation (139-142.degree. C./0.025 mbar), by which the
product is obtained as a colorless oil (70.8 g, 94%).
[1015] MT-159 JOS 1768
[1016] C.sub.15H.sub.22O.sub.3 TABLE-US-00118 Cld.: C, 71.97; H,
8.86 Fnd.: C, 71.84; H, 8.75
[1017] .sup.1H NMR (CDCl.sub.3) .delta. 7.10 (d, J=9.5 Hz, 2H),
6.81 (d, J=9.5 Hz, 2H), 4.99 (septet, J=6.2 Hz, 1H), 4.48 (septet,
J=6.3 Hz, 1H), 2.87 (t, J=7.9 Hz, 2H), 2.54 (t, J=7.9 Hz, 2H), 1.20
(d, J=6.3 Hz, 6H), 1.31 (d, J=6.3 Hz, 6H);
[1018] .sup.13C NMR (CDCl.sub.3): .delta. 172.4 (s), 156.2 (s),
132.4 (s), 129.1 (d), 115.8 (d), 69.7 (d), 67.4 (d), 36.4 (t), 30.1
(t), 22.0 (q), 21.7 (q)
Step 5
4-(1-Methylethoxy)benzenepropanol
1. From 4-(1-methylethoxy)benzenepropanoic acid
[1019] ##STR330##
[1020] 4-(1-Methylethoxy)benzenepropanoic acid (7.57 g, 36.3 mmol)
in absolute THF (80 ml) is added in drops at 0.degree. C. to a
suspension of lithium aluminum hydride (4.17 g, 110 mmol) in
absolute THF (80 ml) within 30 minutes, and it is stirred for 12
hours at room temperature. It is hydrolyzed with water (30 ml) and
mixed with concentrated hydrochloric acid until the solution
becomes clear, dispersed between water (30 ml) and ether (60 ml),
the aqueous phase is extracted with ether (2.times.20 ml), the
combined organic phases are washed with 2N hydrochloric acid
(3.times.100 ml), water (1.times.100 ml), saturated sodium
bicarbonate solution (2.times.100 ml) and saturated common salt
solution (1.times.100 ml), dried (sodium sulfate/activated carbon)
and filtered. After the solvent is distilled off in a rotary
evaporator, the product is obtained in the form of colorless
crystals (6.84 g, 97%)
2. From 4-(1-Methylethoxy)benzenepropanoic acid-(1-methyl)ethyl
ester
[1021] ##STR331##
[1022] 4-(1-Methylethoxy)benzenepropanoic acid-(1-methyl)ethyl
ester (10.0 g, 39.9 mmol) in absolute THF (100 ml) is added in
drops at 0.degree. C. to a suspension of lithium aluminum hydride
(3.04 g, 80 mmol) in absolute THF (100 ml) within 30 minutes, and
it is stirred for 12 hours at room temperature.
[1023] It is hydrolyzed with water (30 ml) and mixed with
concentrated hydrochloric acid, until the solution becomes clear,
dispersed between water (30 ml) and ether (60 ml), the aqueous
phase is extracted with ether (2.times.20 ml), the combined organic
phases are washed with 2N hydrochloric acid (3.times.100 ml), water
(1.times.100 ml), saturated sodium bicarbonate solution
(2.times.100 ml) and saturated common salt solution (1.times.100
ml), dried (sodium sulfate/activated carbon) and filtered.
[1024] After the solvent is distilled off in a rotary evaporator,
the product is obtained in the form of colorless crystals (7.04 g,
99%).
[1025] MT-89 JOS 1700
[1026] C.sub.12H.sub.18O.sub.2 TABLE-US-00119 Cld.: C, 74.19; H,
9.34 Fnd.: C, 73.93; H, 9.07
[1027] .sup.1H NMR (CDCl.sub.3): .delta. 7.10 (d, J=9.5 Hz, 2H),
6.82 (d, J=9.5 Hz, 2H), 4.50 (septet, J=6.3 Hz, 1H), 3.68 (t, J=7.9
Hz, 2H), 2.66 (t, J=7.9 Hz, 2H), 2.0 (b, 1H), 1.93-1.78 (m, 2H),
1.32 (d, J=6.3 Hz, 6H);
[1028] .sup.13C NMR (CDCl.sub.3): .delta. 155.9 (s), 133.7 (s),
129.2 (d), 115.9 (d), 69.9 (d), 62.0 (t), 34.3 (t), 31.1 (t), 22.0
(q)
Step 6
1-(3-Iodopropyl)-4-(1-methylethoxy)benzene
[1029] ##STR332##
[1030] Triphenylphosphine (13.1 g, 49.9 mmol), iodine (19.9 g, 78.4
mmol) and imidazole (4.0 g, 58.8 mmol) are stirred in absolute
CH.sub.2Cl.sub.2 (250 ml) for 20 minutes at room temperature.
4-(1-Methylethoxy)benzenepropanol (8.74 g, 45.0 mmol) in
CH.sub.2Cl.sub.2 (100 ml) is added in drops at 15.degree. C. and
stirred for 12 hours at room temperature.
[1031] It is dispersed between water (300 ml) and CH.sub.2Cl.sub.2
(150 ml), the aqueous phase is extracted with CH.sub.2Cl.sub.2
(2.times.50 ml), the combined organic phases are washed with water
(1.times.200 ml), semisaturated copper(II) sulfate solution
(2.times.200 ml), water (1.times.200 ml), 10% sodium sulfite
solution (1.times.200 ml), saturated common salt solution
(1.times.200 ml), dried (sodium sulfate/activated carbon),
filtered, and the residue that is obtained after concentration by
evaporation in a rotary evaporator is taken up in diisopropyl ether
(200 ml). The residue that is obtained from the filtrate after the
solvent is drawn off in a rotary evaporator is filtered and
purified by column chromatography (900 g of silica gel; petroleum
ether ethyl acetate=95:5). In this way, the product is obtained as
a colorless oil (10.9 g, 79%).
[1032] MT-151 JOS 1755
[1033] C.sub.12H.sub.17IO TABLE-US-00120 Cld.: C, 47.39; H, 5.63
Fnd.: C, 47.37; H, 5.41
[1034] .sup.1H NMR (CDCl.sub.3): .delta. 7.11 (d, J=9.5 Hz, 2H),
6.82 (d, J=9.5 Hz, 2H), 4.53 (septet, J=6.3 Hz, 1H), 3.18 (t, J=7.9
Hz, 2H), 2.67 (t, J=7.9 Hz, 2H), 2.10 (quintet, J=7.9 Hz, 2H), 1.35
(d, J=6.3 Hz, 6H);
[1035] .sup.13C NMR (CDCl.sub.3): .delta. 156.2 (s), 132.2 (s),
129.4 (d), 115.9 (d), 69.8 (d), 35.2 (t), 35.0 (t), 22.1 (q), 6.5
(t)
Step 7
.alpha.-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]4-(1-methylethoxy)-ben-
zenepentane nitrile
[1036] ##STR333##
[1037] n-Butyllithium (12.7 ml, 27.5 mmol, 2.2 M in hexane) is
added within 15 minutes at a temperature of -78.degree. C. to a
solution of diisopropylamine (3.55 g, 35.08 mmol) in absolute THF
(50 ml), then the mixture is heated to -30.degree. C. and stirred
for 30 minutes at this temperature.
[1038] The solution is cooled to -78.degree. C., mixed with
2-bromo-4-methoxy-5-(1-methylethoxy)-benzene acetonitrile (7.94 g,
27.9 mmol) in absolute THF (100 ml), stirred for 20 minutes at this
temperature, heated to room temperature, and stirred for another
hour. The mixture is cooled to -78.degree. C., then 1
(3-iodopropyl)-4-(1-methylethoxy)benzene (8.50 g, 27.9 mmol) in
absolute THF (50 ml) is added in drops with 15 minutes, and the
mixture is stirred for 45 minutes.
[1039] It is mixed with saturated ammonium chloride solution (50
ml) and heated to room temperature. The residue that is obtained
after concentration by evaporation is dispersed between 2N
hydrochloric acid (200 ml) and ether (200 ml). The aqueous phase is
extracted with ether (3.times.50 ml), the combined organic phases
are washed with water (3.times.200 ml), saturated sodium
bicarbonate solution (1.times.200 ml) and saturated common salt
solution (1.times.200 ml), dried (sodium sulfate/activated carbon),
filtered, and the residue that remains after the solvent is removed
in a rotary evaporator is purified by column chromatography (1000 g
of silica gel, petroleum ether:ethyl acetate=98:2). The product is
thus obtained as a colorless oil (11.46 g, 71%).
[1040] MT-158 JOS 1699
[1041] C.sub.24H.sub.30BrNO.sub.3 TABLE-US-00121 Cld.: C, 62.61; H,
6.57; N, 3.04 Fnd.: C, 62.32; H, 6.21; N, 2.97
Step 8
.alpha.-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]-4-(1-methylethoxy)-be-
nzene pentanoic acid amide
[1042] ##STR334##
[1043]
.alpha.-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]-4-(1-methylet-
hoxy)benzene pentane nitrile (30.0 g, 65.2 mmol) in ethanol (600
ml) is mixed with potassium hydroxide (60.0 g, 1.07 mol) in water
(100 ml) and stirred for 6 hours at boiling temperature.
[1044] The residue that is obtained after concentration by
evaporation is dispersed between 2N hydrochloric acid (200 ml) and
ether (300 ml). The aqueous phase is extracted with ether
(3.times.75 ml). The combined organic phases are washed with water
(3.times.200 ml), saturated sodium bicarbonate solution
(1.times.200 ml) and saturated common salt solution (1.times.200
ml), dried (sodium sulfate/activated carbon), filtered, and the
residue that remains after the solvent is removed is purified by
column chromatography (1000 g of silica gel, petroleum
ether:ether=1:2). The higher-running fraction is taken up in
absolute CH.sub.2Cl.sub.2 (100 ml), mixed at 0.degree. C. with
oxalic acid chloride (3 ml) and a drop of DMF and stirred for two
hours. The residue that is obtained after the solvent is drawn off
in a rotary evaporator is suspended in absolute THF (100 ml),
whereupon ammonia is introduced under the surface for two hours.
The mixture is filtered, and the residue that is obtained after
concentration by evaporation is dispersed between water (100 ml)
and ether (100 ml). The aqueous phase is extracted with ether
(3.times.50 ml), the combined organic phases are washed with water
(3.times.200 ml) and saturated common salt solution (1.times.200
ml), dried (sodium sulfate/activated carbon), filtered, and the
residue that is obtained after concentration by evaporation is
combined with the deeper-running fraction that is obtained by
column chromatography, crystallized under diisopropyl ether and
digested with diisopropyl ether (100 ml). In this way, the product
is obtained in the form of colorless crystals (26.0 g, 83.5%).
[1045] .sup.1H NMR (CDCl.sub.3): .delta. 7.01 (d, J=8.9 Hz, 2H),
6.98 (s, 1H), 6.92 (s, 1H), 6.75 (d, J=8.9 Hz, 2H), 5.98 (b, 1H),
5.52 (b, 1H), 4.47 (septet, J=6.3 Hz, 2H), 3.91 (t, J=7.0 Hz, 1H),
3.82 (s, 3H), 2.74-2.40 (m, 2H), 2.22-2.00 (m, 1H), 1.91-1.36 (m,
3H), 1.35-1.22 (m, 6H);
[1046] .sup.13C NMR (CDCl.sub.3): .delta. 175.2 (s), 155.8 (s),
149.9 (s), 147.0 (s), 133.9 (s), 130.8 (s), 129.1 (d), 115.7 (d),
114.8 (d), 114.7 (d), 71.4 (d), 69.7 (d), 56.0 (g), 49.7 (d), 34.6
(t), 31.9 (t) 29.1 (t), 22.0 (q) 21.8 (q), 21.7 (q)
Step 9
.alpha.-[2-Bromo-5-hydroxy-4-methoxyphenyl]-4-hydroxybenzenepentanoic
acid amide
[1047] ##STR335##
[1048]
.alpha.-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]-4-(1-methylet-
hoxy)benzenepentanoic acid amide (24.0 g, 50.2 mmol) in absolute
CH.sub.2Cl.sub.2 (300 ml) is mixed at -78.degree. C. with boron
trichloride (150 ml, 150 mmol, 1 M in CH.sub.2Cl.sub.2) and stirred
for four hours at room temperature.
[1049] Water (200 ml) is added in drops, and the organic phase is
removed in a rotary evaporator. The precipitated crystals are
digested with water (6.times.200 ml), by which the product is
obtained in the form of colorless crystals (19.8 g, quant.).
[1050] MT-161 JOS 1713
[1051] C.sub.18H.sub.20BrNO.sub.4 TABLE-US-00122 Cld.: C, 54.84; H,
5.11; N, 3.55 Fnd.: C, 54.56; H, 5.40; N, 3.25
Step 10
1-Bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-oxa-6H-benzo[a]cyclohepta[hi-
]benzofuran-12-carboxylic acid amide (SPH-1484)
[1052] ##STR336##
[1053]
.alpha.-[2-Bromo-5-hydroxy-4-methoxyphenyl)-5-hydroxybenzenepentan-
oic acid amide (3.00 g, 7.61 mmol) is suspended in chloroform (300
ml) and mixed with a solution of potassium hexacyanoferrate (III)
(13.2 g, 40.0 mmol) in potassium carbonate solution (75 ml, ten
percent).
[1054] The mixture is vigorously stirred at room temperature for 40
minutes and filtered on Hyflo. The aqueous phase is extracted with
chloroform (2.times.50 ml), the combined organic phases are washed
with 2N hydrochloric acid (2.times.100 ml), water (2.times.200 ml)
and saturated common salt solution (1.times.150 ml), dried (sodium
sulfate/activated carbon), and the crude product that is obtained
after concentration by evaporation of the solvent is purified via
column chromatography (50 g of silica gel, ethyl acetate). In this
way, the product is obtained as a mixture that consists of two
diastereomeric enantiomer pairs, whereby the deeper-running is
isomerized to the higher-running.
[1055] By column chromatography (chloroform methanol 96:4), the
enantiomer pair with the higher Rf-value is obtained in the form of
colorless crystals (0.24 g, 8% of theory).
[1056] MT-162/OF JOS 1679
[1057] C.sub.18H.sub.18BrNO.sub.4 TABLE-US-00123 Cld.: C, 55.12; H,
4.63; N, 3.57 Fnd.: C, 55.15; H, 4.71; N, 3.38
[1058] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.57 (, 1H), 7.48 (d,
J=14.5 Hz, 1H), 7.14 (s, 2H), 5.89 (d, J=14.5 Hz, 1H), 4.66 (s,
1H), 4.32 (s, 1H), 4.01 (q, J=7.7 Hz, 1H), 3.78 (s, 3H), 3.02 (d,
J=19.6 Hz, 1H), 2.79 (d, J=19.6 Hz, 1H), 2.52 (d, J=16.5 Hz, 1H),
2.16 (d, J=16.5 Hz, 1H), 1.96-1.67 (m, 2H), 1.14 (t, J=7.7 Hz,
1H)
[1059] .sup.13C NMR (DMSO-d.sub.6): .delta. 195.6 (s), 174.6 (s),
149.5 (d), 147.9 (s), 144.4 (s), 133.6 (s), 130.6 (s), 126.5 (d),
117.5 (s), 117.1 (d), 88.4 (d), 56.8 (q), 52.1 (s), 51.6 (d), 37.9
(t), 36.6 (t), 33.3 (t), 21.5 (t)
EXAMPLE 128b
(6R)-1-Bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzo[a]cycl-
ohepta[hi]benzofuran-12-carboxylic acid amide (SPH-483)
[1060] ##STR337##
[1061] L-Selectride.RTM. (4.6 ml, 4.6 mmol, 1. M in THF) is added
at 0.degree. C. within 15 minutes to a suspension of
1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-oxa-6H-benzo[a]cyclohepta[h-
i]benzofuran-12-carboxylic acid amide (600 mg, 1.52 mmol) in
absolute THF (5 ml), and the mixture is stirred for 12 hours at
room temperature. It is hydrolyzed with water (3 ml) and dispersed
between water (10 ml) and ethyl acetate (10 ml), the aqueous phase
is extracted with ethyl acetate (3.times.5 ml), the combined
organic phases are washed with 1N hydrochloric acid (3.times.10
ml), water (2.times.10 ml), saturated sodium bicarbonate solution
(1.times.10 ml) and saturated common salt solution (1.times.10 ml),
dried (sodium sulfate/activated carbon), filtered, and the crude
product that is obtained after the solvent is distilled off is
purified by means of column chromatography (50 g of silica gel,
ethyl acetate). In this way, the product is obtained in the form of
colorless crystals (798 mg, 83%).
[1062] MT-169/OF JOS 1677
[1063] C.sub.18H.sub.20BrNO.sub.4 TABLE-US-00124 Cld.: C, 54.84; H,
5.11; N, 3.55 Fnd.: C, 54.67; H, 5.10; N, 3.46
[1064] .sup.1H NMR (CDCl.sub.3/DMSO-d.sub.6): .delta. 6.97 (s, 1H),
6.79 (b, 1H), 6.49 (b, 1H), 6.12 (d, J=11.4 Hz, 1H), 5.83 (dd,
J=11.4 Hz, J=5.1 Hz, 1H), 4.42 (s, 1H), 4.31-4.21 (m, 1H), 3.78 (s,
3H), 3.42-3.18 (m, 2H), 2.68-2.29 (m, 2H), 2.14-1.38 (m, 5H);
[1065] .sup.13C NMR (CDCl.sub.3/DMSO-d.sub.6): .delta. 173.4 (s),
146.3 (s), 143.6 (s) 134.2 (s), 128.8 (d), 128.6 (d), 126.8 (s),
116.1 (s), 115.6 (d), 87.1 (d), 60.1 (q), 55.6 (d), 50.1 (s), 49.5
(d), 37.5 (t), 31.0 (t); 29.8 (t), 20.3 (t)
EXAMPLE 128c
(6R)-10-Amino-1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-ben-
zo[a]cyclohepta[hi]benzofuran-6-ol (SPH-1482)
[1066] ##STR338##
[1067] Bis(trifluoroacetoxy)iodobenzene (300 mg, 0.76 mmol) is
dissolved in acetonitrile (1.5 ml, HPLC-quality) and mixed with
water (1.5 ml, HPLC-quality). Then,
(6R)-1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzo[a]cyc-
lohepta[hi]benzofuran-12-carboxylic acid amide (338 mg, 0.76 mmol)
is added in substance within 2 hours, and the mixture is stirred
for 24 hours at room temperature. The solvent is distilled off in a
rotary evaporator, the residue is taken up in chloroform (5 ml),
filtered and purified by column chromatography (30 g of silica gel,
chloroform:methanol:ammonia=96:3:1). In this way, the product is
obtained in the form of colorless crystals (161 mg, 58%).
[1068] MT-170 JOS 1705
[1069] C.sub.17H.sub.20BrNO.sub.3.0.66H.sub.2O TABLE-US-00125 Cld.:
C, 54.02; H, 5.68; N, 3.71 Fnd.: C, 53.96; H, 5.52; N, 3.60
[1070] .sup.1H NMR (MeOH-d.sub.4): .delta. 7.08 (s, 1H), 6.41 (d,
J=14.5 Hz, 1H), 5.8883 (dd, J=14.5 Hz, J=5.1 Hz, 1H); 4.72 (s, 1H),
4.58 (s, 1H), 4.13 (t, J=3.6 Hz, 1H), 3.82 (s, 3H), 2.49 (d, J=17.2
Hz, 1H), 2.45-2.07 (m, 4H), 1.92-1.58 (m, 4H);
[1071] .sup.13C NMR (MeOH-d.sub.4): .delta. 147.2 (s), 144.7 (s),
134.5 (s), 133.3 (s), 130.9 (d), 126.4 (d), 116.6 (d), 115.5 (s),
87.8 (d), 61.2 (d), 57.3 (q), 54.0 (d), 48.6 (s), 38.3 (t), 35.2
(t), 30.1 (t) 17.9 (t)
EXAMPLE 128d
(6R)-10-Amino-4a,59,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzo
a]cyclohepta[hi]benzofuran-6-ol
[1072] ##STR339##
[1073]
(6R)-10-Amino-1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydrox-
y-6H-benzo[a]cyclohepta[hi]benzofuran-6-ol (70 mg, 0.19 mmol) and
calcium chloride (300 mg, 2.7 mmol) are added in substance to a
black suspension of zinc (production: zinc powder (500 mg) and
copper(I) iodide (500 mg) are treated under argon in water (4 ml)
and ethanol (4 ml) for 45 minutes in an ultrasound bath), and the
mixture is stirred for 5 hours at boiling temperature. It is mixed
with concentrated aqueous ammonia solution (1 ml), the solvent is
removed in a rotary evaporator, the residue is taken up in
chloroform (15 ml), filtered, and the residue that is obtained
after the filtrate is concentrated by evaporation in a rotary
evaporator is purified by column chromatography (30 g of silica
gel, chloroform methanol ammonia=96:3:1). In this way, the product
is obtained in the form of colorless crystals (42 mg, 78%).
[1074] .sup.1H NMR (CDCl.sub.3): .delta. 6.81-6.61 (m, 3H), 6.97
(dd, J=14 Hz, J=4 Hz, 1H), 4.44 (s, 1H), 4.30 (s, 1H), 4.24 (t, J=3
Hz, 1H), 3.85 (s, 3H), 2.63 (dd, J=17 Hz, J=6 Hz, 1H), 2.40 (q,
J=15 Hz, 1H), 2.19-2.08 (m, 1H), 2.02 (dd, J=18 Hz, J=4 Hz, 1H),
1.97-1.52 (m, 9H)
[1075] .sup.13C NMR (CDCl.sub.3): .delta. 145.4 (s), 143.2 (s),
134.1 (s), 132.6 (s), 129.9 (d), 125.4 (d), 121.9 (d), 109.9 (d),
87.7 (d), 61.1 (d), 54.8 (q), 48.5 (s), 37.0 (t), 34.4 (t), 29.0
(t), 25.8 (t), 16.9 (t)
EXAMPLE 129
8-[6-[(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-6H-benzof-
uro[3a,3,2-ef][2]benzazepine-11-yl]-1-oxohexyl]-1,2,5,6-tetrahydro-4H-pyrr-
olo[3,2,1-ij]quinolin-4-one (SPH-1516)
[1076] ##STR340## 1. Synthesis in Solution:
[1077] Norgalanthamine (1.13 g, 4.13 mmol),
8-(6-iodo-1-oxohexyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-o-
ne (1.50 g, 3.75 mmol) and N-ethyldiisopropylamine (1.46 g, 11.3
mmol) are stirred in absolute chloroform (20 ml) for 54 hours at
boiling temperature.
[1078] The residue that is obtained after the solvent is removed in
a rotary evaporator is purified by column chromatography (200 g of
silica gel, chloroform:methanol: ammonia 96:3:1), by which the
product is obtained as a light yellow foam (1.87 g, 92%).
[1079] TLC: CHCl.sub.3:MeOH:NH.sub.3=89:10:1, R.sub.f=0.5
[1080] .sup.1H NMR (CDCl.sub.3): .delta. 7.62 (s, 1H), 7.67 (s,
1H), 6.68-6.43 (m, 2H), 6.00 (d, J=9.7 Hz, 1H), 5.93-5.81 (m, 1H),
4.51 (s, 1H), 4.22-3.91 (m, 4H), 3.92-3.64 (m, 4H), 3.48-2.28 (m,
13H), 2.20-1.12 (m, 10H);
[1081] .sup.13C NMR (CDCl.sub.3): .delta. 198.7 (s), 167.5 (s),
145.5 (s), 145.1 (s), 143.7 (s), 132.8 (s), 132.6 (s), 129.1 (s),
128.9 (s), 127.2 (d), 126.7 (d), 126.3 (d), 123.6 (d), 121.6 (d),
119.3 (s), 110.8 (d), 88.3 (d), 61.6 (d), 57.4 (t), 55.6 (q), 51.2
(t), 51.0 (t), 48.1 (s), 45.4 (t), 38.0 (t), 32.6 (t), 31.1 (t),
29.7 (t), 27.0 (t), 26.8 (t), 24.2 (t), 23.9 (t)
Production of Fumarate (SPH-1519) Analogously to Example 4
[1082] MT-407 JOS 1761
[1083] C.sub.37H.sub.42N.sub.2O.sub.2*H.sub.2O TABLE-US-00126 Cld.:
C, 65.67; H, 6.55; N, 4.14 Fnd.: C, 65.69; H, 6.49; N, 4.02
2. By Solid-Phase Synthesis
[1084] 0.300 g (0.102 mmol) of
norgalanthamine-6-yloxy)-1,5-dioxopentyloxymethyl-Merrifield resin
is steeped in a 5-ml-polyethylene frit that is sealed on both sides
for 30 minutes in 3 ml of dimethylformamide/acetone (1/1) and after
filtering, it is suspended in a solution of 0.125 g (0.315 mmol) of
8-(6-iodo-1-oxohexyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-o-
ne and 54 .mu.l (0.041 g, 0.315 mmol) of ethyldiisopropylamine in 3
ml of dimethylformamide/acetone (1/1).
[1085] The suspension is shaken at room temperature for 19 hours. A
negative chloranil test indicates the complete conversion of the
secondary amine. The resin is washed three times with
dimethylformamide (2 minutes, 3 ml) and six times with
tetrahydrofuran/methanol (4/1, 2 minutes, 3 ml). The resin is
suspended below in a solution that consists of 0.113 g (0.63 mmol)
of 30% sodium methanolate-methanol solution and 3.0 ml of
tetrahydrofuran/methanol (4/1). After 15 hours, the solution is
filtered off, and the resin is extracted six times with 3 ml each
of dichloromethane.
[1086] The combined filtrates are neutralized with methanolic
hydrochloric acid, diluted with 10 ml of dichloromethane, washed
twice with 15 ml of saturated sodium chloride solution, dried on
sodium sulfate, filtered and concentrated by evaporation in a
rotary evaporator under reduced pressure. The crude product is
separated by means of MPLC (200 g of silica gel, v=285 nm,
chloroform/methanol/concentrated ammonia=96/3/1). After the
concentration by evaporation, a yellow oil that crystallizes while
standing is obtained: 0.043 g (0.041 g, 0.075 mmol, 74%) of
yellowish crystals (M.sub.w=542.7), HPLC, TLC identical to a
reference sample:
[1087] TLC: R.sub.f=0.55 (chloroform/methanol=8/2+2% concentrated
ammonia)
[1088] HPLC: t.sub.Ref=13.7 minutes, 95.7% (Merck Purospher column,
4.0 mm.times.125 mm, RP-18e, 5.0 .mu.m, 1 ml/min, 285 nm,
acetonitrile/20 mmol of Cl.sub.3CCO.sub.2H in H.sub.2O (5/95 v/v
for 5 minutes, 5/95.fwdarw.60/40 v/v in 18 minutes (convex), 60/40
vv for 5 minutes)
EXAMPLE 130a
(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a-
,3,2-ef][2]benzazepin-6-ol, galanthamine (HM 424)
[1089] ##STR341##
[1090] Lithium aluminum hydride (104 mg, 2.73 mmol) was added to a
suspension of galanthaminium bromide HM 407 (1.0 g, 2.73 mmol) in
absolute tetrahydrofuran (50 ml) and stirred for 3 hours at room
temperature. Then, excess lithium aluminum hydride, annihilated
with ethyl acetate, was added to water (49 mg, 2.73 mmol) to form a
precipitate that could be filtered, and precipitated. The
Al.sub.2O.sub.3 that was produced was filtered off, the filtrate
was dried on sodium sulfate, and the solvent was removed in
Rotavapor. 750 mg (96% of theory) of galanthamine was obtained as a
white foam.
[1091] TLC: CHCl.sub.3:MeOH/NH.sub.3 (9:1)
[1092] .sup.1H NMR (CDCl.sub.3): .delta. 6.66-6.58 (m, 2H),
6.08-5.94 (m, 2H), 4.58 (b, 1H), 4.15 (b, 1H), 4.06 (d, J=15.2 Hz,
1H), 3.78 (s, 3H), 3.66 (d, J=15.2 Hz, 1H), 3.25 (ddd, J=14.4, 2.2,
1.9 Hz, 1H), 3.05 (ddd, J=14.9, 3.1, 3.1 Hz, 1H), 2.68 (ddd,
J=15.7, 1.8, 1.8, 1H), 2.40 (s, 3H), 2.15-1.90 (m, 2H), 1.55 (ddd,
J=13.7, 4.1, 2.0 Hz, 1H); .sup.13C NMR (CDCl.sub.3): .delta. 145.8
(s), 144.1 (s), 133.1 (s), 129.2 (s), 127.6 (d), 126.8 (d), 122.1
(d), 111.1 (d), 88.7 (d), 62.0 (d), 60.4 (t), 55.8 (q), 53.7 (t),
48.2 (s), 41.9 (q) 33.4 (t), 29.9 (t)
EXAMPLE 130b
(4aS,6R,8aS)-4a,5,9,10,11-Pentahydro-12-deutero-3-methoxy-11-methyl-6H-ben-
zofuro[3a,3,2-ef][2]benzazepin-6-ol, (12-deuterogalanthamine,
SPH-1520)
[1093] ##STR342##
[1094] Lithium aluminum deuteride (28 mg, 0.68 mmol) was added to a
suspension of galanthaminium bromide HM 407 (250 mg, 0.683 mmol) in
absolute tetrahydrofuran (15 ml) and stirred for 3 hours at room
temperature. Then, excess lithium aluminum deuteride was destroyed
with ethyl acetate and precipitated with deuterium oxide (12 mg,
0.68 mmol) of Al.sub.2O.sub.3 The Al.sub.2O.sub.3 that was produced
was filtered off, the filtrate was dried on sodium sulfate, and the
solvent was removed in Rotavapor. 100 mg (51% of theory) of HM 427
was obtained as a white foam.
[1095] TLC: CHCl.sub.3:MeOH/NH.sub.3 (9:1)
[1096] .sup.1H NMR (CDCl.sub.3): .delta. 6.66-6.58 (m, 2H),
6.08-5.94 (m, 2H), 4.58 (b, 1H), 4.14 (b, 1H), 4.06 (d, J=15.2 Hz,
0.5H), 3.78 (s, 3H), 3.66 (d, J=15.2 Hz, 0.5H), 3.25 (ddd, J=14.4,
2.2, 1.9 Hz, 1H), 3.05 (ddd, J=14.9, 3.1, 3.1 Hz, 1H), 2.68, (ddd,
J=15.7, 1.8, 1.8, 1H), 2.40 (s, 3H), 2.15-1.90 (m, 2H), 1.55 (ddd,
J=13.7, 4.1, 2.0 Hz, 1H); .sup.13C NMR (CDCl.sub.3): .delta. 145.8
(s), 144.1 (s) 133.1 (s), 129.2 (s), 127.6 (d), 126.8 (d), 122.1
and 122.0 (d), 111.1 (d), 88.7 (d), 62.0 (d), 60.4 (t), 55.8 (q),
53.8 and 53.7 (t), 48.2 (s), 42.1 and 4.1.9 (q), 33.8 and 33.7 (t),
29.9 (t)
[1097] LC/MS:30*2.1 mm of Zorbax SB C18 3 .mu.m, 40% MeOH for 2
minutes to 100% @ 10 minutes for 10 minutes; remainder of H2O at
0.5 ml/minute, UV 210, 250, 280 and 310 nm, a single peak (RT about
6.0 minutes). PI-MS m/z 289 ([M+H].sup.+), 271
([M+H.H.sub.2O].sup.+) NI-MS m/z 287 ([M-H].), 269
([M.H.H.sub.2O]).
EXAMPLE 131
Norsanguinine (SPH-1486)
[1098] ##STR343##
[1099] A solution of norgalanthamine (1.0 g, 3.66 mmol) in 40 ml of
absolute THF is mixed at room temperature with 17 ml of
L-selectride.sup.R (1 M in THF) and stirred for 24 hours at boiling
temperature.
[1100] It is cooled to room temperature, mixed with ethyl acetate
(20 ml), then with water (100 ml), and the phases are separated.
The organic phase is extracted with water (4.times.20 ml), the
combined aqueous phases are extracted with ethyl acetate
(2.times.20 ml) and the residue that remains after concentration by
evaporation is purified via column chromatography (100 g) of silica
gel, chloroform:ammonia=90:9:1) and crystallized under acetone. In
this way, the product is obtained in the form of colorless crystals
(0.78 g, 82.3%).
[1101] .sup.1H NMR (DMSO-d.sub.6) .delta. 6.52-6.37 (m, 2H), 6.03
(d, J=10.3 Hz, 1H), 5.78 (dd, J=10.3 Hz, J=4.6 Hz, 1H), 4.43 (s,
1H), 4.09 (s, 1H), 3.90 (d, J=16 Hz, 1H), 3.71 (d, J=16 Hz, 1H),
3.25-2.92 (m, 2H), 2.24-2.90 (m, 2H), 2.39 (d, J=14 Hz, 2H)
[1102] .sup.13C NMR (DMSO-d.sub.6): .delta. 145.6 (s), 140.4 (s),
133.0 (s), 132.3 (s), 127.7 (d), 127.6 (d), 119.6 (d), 114.8 (d),
86.5 (d), 60.1 (d), 53.1 (t), 48.3 (s), 46.6 (t), 40.2 (t), 30.8
(t)
EXAMPLE 132
(4a,S,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-methyl-6H-benzofuro[3a,3,2-ef][2-
]benzazepin-6-ol (SPH-1487)
[1103] ##STR344##
[1104]
(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-trifluoromethylsulfonylox-
y-6H-benzofuro[3a,3,2-ef[2]benzazepin-6-ol (200 mg, 0.49 mmol),
tetramethylstannane (106 mg, 0.59 mmol), anhydrous lithium chloride
(62 mg, 1.47 mmol) and tetrakis triphenylphosphine palladium (28
mg, 0.025 mmol, 0.05 equivalent) are stirred in absolute DMF (3 ml)
for 24 hours at 100.degree. C. It is dispersed between water (20
ml) and ethyl acetate (30 ml), the aqueous phase is extracted with
ethyl acetate (5.times.30 ml), the combined organic phases are
washed with water (3.times.10 ml) and saturated common salt
solution (15 ml), and the residue that is obtained after
concentration by evaporation is purified by column chromatography
(20 g of silica gel, chloroform methanol ammonia=96:3:1). In this
way, the product is obtained in the form of colorless crystals (102
mg, 77%).
[1105] MT-298 JOS 1711
[1106] C.sub.17H.sub.21NO.sub.2*0.25H.sub.2O TABLE-US-00127 Cld.:
C, 74.02; H, 7.86; N, 5.08 Fnd.: C, 73.77; H, 7.67; N, 5.04
[1107] .sup.1H NMR (CDCl.sub.3): .delta. 6.90 (d, J=7.0 Hz, 1H),
6.46 (d, J=7.0 Hz, 1H), 6.08 (d, J=11.5 Hz, 1H), 6.00 (dd, J=8.5
Hz, J=5.2 Hz, 1H), 4.54 (s, 1H), 4.13 (s, 1H), 4.11 (d, J=16.5 Hz,
1H), 3.70 (d, J=16.5 Hz, 1H), 3.20 (t, J=12.7 Hz, 1H), 3.08 (d,
J=12.7 Hz), 2.66 (dd, J=15.2 Hz, J=5.0 Hz, 1H), 2.42 (s, 3H), 2.18
(s, 3H), 2.17-2.00 (m, 2H), 1.57 (dd, J=13.3 Hz, J=5.0 Hz, 1H);
[1108] .sup.13C NMR (CDCl.sub.3): .delta. 156.4 (s), 135.3 (s),
131.6 (s), 130.1 (d), 127.7 (d), 127.6 (d), 122.0 (d), 119.8 (s),
88.1 (d), 62.7 (d), 61.3 (t), 54.2 (t), 48.5 (s), 42.4 (d), 33.9
(t), 30.4 (t), 15.3 (q).
EXAMPLE 136
SPH-1146 IK 66/1
(-) Cyclopropylmethylgalanthaminium bromide
[1109] ##STR345##
[1110] Production analogously to Examples 90-99, melting point
230-237.degree. C.
[1111] a.sup.D.sub.20=-110 (C=1.5 in water)
EXAMPLE 137
SPH-1149 HM 104
(-) (3-Methylbut-2-en-1-yl)-galanthaminium bromide
[1112] ##STR346##
[1113] Production analogously to Examples 90-99, melting point
198-201.degree. C.
[1114] a.sup.D.sub.20=-118.2 (1.5 in water)
EXAMPLE 138
SPH-1162 Cl 2-1 3au
3-((6R)-1-Bromo-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3-
a,3,2-ef][2]benzazepin-11(12H)-yl)propanoic acid ethyl ester
[1115] ##STR347##
[1116] Production analogously to Example 143
[1117] Reaction time: 8 hours, yield: 80% colorless foam
[1118] Same skeleton as in Example 143, here only the signals that
are different are indicated:
[1119] .sup.1H NMR (CDCl.sub.3) .delta. 4.13 (q, J=6.0 Hz, 2H),
2.85 (t, 7.0 Hz, 2H), 2.58 (t, J=7.0 Hz, 2H), 1.27 (t, J=6 Hz,
3H);
[1120] .sup.13C NMR (CDCl.sub.3) .delta. 172.4 (s), 60.3 (t), 57.3
(t), 32.9 (t) 14.1 (q).
EXAMPLE 139
SPH-1184 LCz 225/1
(-) (4-Bromophenyl)methylgalanthaminium bromide hemihydrate
[1121] ##STR348##
[1122] Production analogously to Examples go-99, TABLE-US-00128
Cld.: C 52.77, H 5.17, N 2.56 Fnd.: C 52.45, H 5.15, N 2.52
EXAMPLE 140
SPH-1191 LCz 205
(-) (3-Chloropropyl)-galanthaminium bromide, 1.25 H.sub.2O
[1123] ##STR349##
[1124] Production analogously to Examples 90-99, TABLE-US-00129
Cld.: C 51.40, H 6.36, N 3.00 Fnd.: C 51.08, H 6.07, N 2.92
EXAMPLE 141
SPH-1208 CB 2
(6R)-1-Bromo-6-hydroxy-N.sup.11-isopropyl-3-methoxy-5,6,9,10-tetrahydro-4a-
H-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboxylic acid
amide
[1125] ##STR350##
[1126] Production analogously to Example 142, yield: 96%;
[1127] .sup.1H NMR (CDCl.sub.3) .delta. 6.87 (s, 1H), 6.04 (dd,
J=16.0; 10.0 Hz, 2H), 4.88 (d, J=18.0 Hz, 1H), 4.61 (m, 1H), 4.28
(d, J=18.0, 1H), 4.13 (b, 1H), 3.90 (m, 1H), 3.85 (s, 3H), 3.26 (t,
J=12.0 Hz, 1H), 2.67 (dd, J=16.0; 3.0 Hz, 1H), 2.29 (d, J=10.0 Hz,
1H), 1.99 (m, 2H), 1.72 (d, J=17 Hz, 1H); 1.12 (dd, J=20.0; 5.0 Hz,
6H); .sup.13C NMR (CDCl.sub.3) .delta. 156.0 (s), 146.5 (s), 144.9
(s), 133.8 (s), 128.6 (d), 128.2 (s), 127.5 (s), 125.8 (d), 115.1
(d) 112.3 (d), 88.5 (d), 61.6 (d), 56.1 (q), 50.3 (t), 49.1 (s),
45.2 (t), 42.7 (d), 36.6 (t), 29.6 (t), 23.4 (q), 23.0 (q). Anal.
[C.sub.20H.sub.25BrN.sub.2O.sub.4.0.3H.sub.2O) TABLE-US-00130 Cld.:
C 54.26 H 5.83 N 6.33 Fnd.: C 54.28 H 5.79 N 6.14
EXAMPLE 142
SPH-1209 CB 5
(6R)-1-Bromo-6-hydroxy-3-methoxy-N11-methyl
5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-thi-
ocarboxylic acid amide
[1128] ##STR351##
[1129] Methyl isothiocyanate (42.0 mg, 0.57 mmol) was added in
drops to a stirred solution of bromonorgalanthamine (0.2 g, 0.57
mmol) in toluene (10 ml), and it was refluxed for three hours.
After concentration by evaporation, the residue was taken up in 2N
HCl (20 ml) and washed with AcOEt (1.times.10 ml). The aqueous
solution was brought to a pH>8.5 with concentrated ammonia and
extracted with AcOEt (3.times.10 ml). The combined organic phases
were washed with saturated common salt solution, dried
(Na.sub.2SO.sub.4) and concentrated by evaporation, by which the
product was obtained in the form of colorless crystals with a
melting point of 183-185.degree. C. (0.22 g, 99%);
[1130] .sup.1H NMR (CDCl.sub.3) .delta. 7.35 (b, 1H), 6.89 (m, 1H),
6.10 (m, 2H), 5.50 (d, J=12.0 Hz, 1H), 5.11 (d, J=12.0 Hz, 1H),
4.69 (b, 1H), 4.52 (d, J=12.0 Hz, 1H), 4.17 (b, 1H), 3.85 (s, 3H),
3.60 (t, J=18.0 Hz, H), 3.10 (d, J=3.4 Hz, 3H), 2.72 (dd, J=18.8;
2.0 Hz, 1H), 2.13 (m, 2H), 1.79 (d, J=12.0 Hz, 1H); .sup.13C-NMR
(CDCl.sub.3) .delta. 181.5 (s), 146.8 (s), 145.4 (s), 133.9 (s),
128.9 (d), 128.2 (s), 125.5 (d), 115.3 (d), 112.5 (d), 88.6 (d),
61.5 (d), 56.2 (q), 51.7 (t), 51.2 (t), 48.9 (s), 35.8 (t), 33.0
(q), 29.6 (t).
[1131] Anal. (C.sub.18H.sub.21BrN.sub.2O.sub.3S.0.5 H.sub.2O)
TABLE-US-00131 Cld.: C 50.83 H 4.98 N 6.59 Fnd.: C 50.73 H 5.02 N
6.63
EXAMPLE 143
SPH-1210 CB 4
3-((6R)-1-Bromo-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[I]benzofuro[3-
a,3,2-ef][2]benzazepine-11(12H)-yl)propanenitrile
[1132] ##STR352##
[1133] Acrylonitrile (0.05 ml, 0.85 mmol) and calcium chloride (200
mg, 1.80 mmol) were added to a solution of norgalanthamine (200 mg,
0.57 mmol) in 50% EtOH (20 ml), and the reaction was refluxed for 3
hours. The reaction was concentrated, the residue was taken up in
2N.HCl (50 ml) and washed with EtOAc (3.times.25 ml, the organic
phase was discarded). The aqueous solution was brought to pH>8.5
with concentrated NH.sub.3 and extracted with methylene chloride
(3.times.25 ml). The combined organic phases were washed with
saturated sodium chloride solution (200 ml), dried
(Na.sub.2SO.sub.4) and concentrated by evaporation, and the
product, 220 mg (95.7%), was obtained as a colorless foam.
[1134] .sup.1H NMR (CDCl.sub.3) .delta. 6.90 (s, 1H), 6.04 (dd,
J.sub.1=16.0 Hz, J.sub.2=10.0 Hz, 2H), 4.60 (b, 1H), 4.38 (d,
J=16.0, 1H), 4.12 (b, 1H), 4.08 (d, J=16.0 Hz, 1H), 3.83 (s, 3H),
3.47 (t, J=10.0 Hz, 1H), 3.18 (d, J=18.0 Hz, 1H), 2.80 (t, J=10.0
Hz, 2H), 2.63 (m, 2H), 2.61 (m, 1H), 2.03 (m, 2H), 1.60 (d, J=10.0
Hz, 1H); .sup.13C-NMR (CDCl.sub.3) .delta. 145.6 (s), 144.5 (s),
134.1 (s), 128.4 (d), 127.1 (s), 126.1 (d), 118.6 (s), 115.8 (d),
114.3 (d), 88.7 (d), 61.7 (d), 56.1 (q), 54.9 (t), 52.0 (t), 48.9
(s), 47.2 (t), 33.3 (t), 29.7 (t), 16.8 (t)
[1135] Anal. (C.sub.19H.sub.21BrN.sub.2O.sub.3) TABLE-US-00132
Cld.: C 56.31 H 5.22 N 6.91 Fnd.: C 56.53 H 5.44 N 6.64
EXAMPLE 144
SPH-1227
[4aS-(4a.alpha.,6.alpha.,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-eth-
yl-6H-benzofuro[3a,3,2-ef][2]benzazepine-6-amine
Step 1
[1136] ##STR353##
[1137] A solution of 300 mg (1.05 mmol) of galanthamine, 208 mg
(1.20 mmol) of azadicarboxylic acid diethyl ester, 314 mg (1.20
mmol) of triphenylphosphine and 1.20 mmol of phthalimide in 30 ml
of absolute tetrahydrofuran is stirred for 24 hours at room
temperature. Then, the tetrahydrofuran is spun off, the residue is
taken up in 30 ml of 2N hydrochloric acid, washed three times with
30 ml each of ethyl acetate and made basic with concentrated
aqueous ammonia. Then, the solution is extracted three times with
30 ml each of ethyl acetate, the combined organic phases are washed
once with saturated aqueous sodium chloride solution, dried
(Na.sub.2SO.sub.4), filtered and concentrated by evaporation. The
crude product is purified by FLC (15 g of silica gel, mobile
solvent: CHCl.sub.3:MeOH=97:3).
[1138] 83% colorless crystals, melting point: 60-63.degree. C.
[1139] TLC: CHCl.sub.3:MeOH=9:1
Step 2
[1140] ##STR354##
[1141] 146 mg (1.44 mmol) of triethylamine and 162 mg (1.58 mmol)
of 3-(dimethylamino)propylamine are added in drops to a solution,
cooled to --5.degree. C., of 0.72 mmol of educt in 5 ml of absolute
methanol. Then, the reaction mixture is allowed to stir at room
temperature for 24 hours, and then methanol, triethylamine and
3-(dimethylamino)propylamine are spun off. The crude product that
is obtained is purified by FLC (15 g of silica gel, mobile solvent:
CHCl.sub.3:MeOH=9:1 with 0.5% concentrated aqueous ammonia), by
which colorless crystals with a melting point of 119-121.degree. C.
with a rotation of .alpha..sub.D.sup.20 [c=0.1,
CHCl.sub.3]=-264.degree. of product are obtained.
[1142] TLC: CHCl.sub.3:MeOH=9:1
[1143] .sup.1H NMR (CDCl.sub.3): .delta. 1.56-1.89, m, 2H, 2.78, m,
1H; 3.02, m, 1H; 3.24, m, 1H; 3.48, m, 1H; 2.32, s, 1H; 3.83, s,
1H; 3.63, d, 1H; 4.07, d, 1H; 4.62, b, 1H; 4.98, b, 1H; 5.74, d,
1H; 6.11, d, 1H; 6.54, d, 1H; 6.64, d, 1H.
EXAMPLE 145
SPH-1273 CB 99
(4aS,6R,8aS)-11-Methyl-3-phenoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro-
[3a,3,2-ef](2]benzazepin-6-ol
[1144] ##STR355##
[1145] 0.44 g (3.6 mmol) of benzeneboric acid, 2.5 ml (9 mmol) of
triethylamine, 0.67 g (3.6 mmol) of copper(II) acetate and 1 g of
molecular sieve (4 .ANG., crushed) were added to a solution of 1.0
g (3.6 mmol) of O-demethylgalanthamine in 50 ml of dichloromethane.
The reaction mixture was stirred for 44 hours at room temperature.
The solid was filtered off. The filtrate was extracted twice with
30 ml each of saturated sodium bicarbonate solution. The aqueous
phase was re-extracted three times with 30 ml of methylene chloride
in each case. The combined organic phases were dried on sodium
sulfate, and the solvent was distilled off. The crude product (0.55
g, 43.7% of theory) was purified by means of column chromatography
(CHCl.sub.3:MeOH=95:5).
[1146] Yield: 0.3 g (23.8% of theory)
[1147] TLC: CHCL.sub.3: CH.sub.3OH=9:1
[1148] CB 99:
[1149] .sup.1H NMR (CDCl.sub.3): .delta. 7.29 (m, 2H), 7.04 (t,
J=7.2 Hz, 1H), 6.89 (d, J=8.7 Hz, 2H), 6.73 (dd, J.sub.1=31.6 Hz,
J.sub.2=8.7 Hz, 2H), 6.03 (m, 2H), 4.59 (s, 1H), 4.51 (b, 1H), 4.17
(d, J=15.3 Hz, 1H), 3.77 (d, J=15.3 Hz, 1H), 3.33 (t, J=13.0 Hz,
1H), 3.10 (d, J=14.5 Hz, 1H), 2.53 (m, 1H), 2.43 (s, 3H), 2.15 (m,
1H), 1.89 (m, 1H), 1.62 (d, J=13.8, 1H); .sup.13C-NMR (CDCl.sub.3):
.delta. 157.3 (s), 148.1 (s), 139.6 (s), 134.2 (s), 129.6 (2*d),
128.1 (d), 126.2 (d), 122.8 (d), 122.7 (d), 120.2 (d), 116.8 (d),
88.7 (d), 61.7 (d), 59.9 (t), 53.2 (t), 48.1 (s), 41.2 (q), 32.8
(t) 29.7 (t).
[1150] Anal. (C.sub.22H.sub.23NO.sub.3*0.2 CHCl.sub.3)
TABLE-US-00133 Cld.: C 71.43 H 6.26 N 3.75 Fnd.: C 71.43 H 6.61 N
3.84
EXAMPLE 146
SPH-1288 HM 122.DD 13
(6R)-3,6-Dihydroxy-N.sup.11-isopropyl-5,6,9,10-tetrahydro-4aH-[1]benzofuro-
[3a,3,2-ef][2]benzazepine-11(12H)-carboxylic acid amide
[1151] ##STR356##
[1152] A solution of 0.42 ml (4.3 mmol) of boron tribromide in 4 ml
of absolute dichloromethane was slowly added in drops under argon
at -5.degree. C. to a solution of 1.6 mmol of educt in 17 ml of
absolute dichloromethane. After 3 hours of stirring at -5 to
0.degree. C., the reaction mixture was poured onto 20 ml of water
and saturated with sodium bicarbonate. The aqueous phase was
extracted four times with 15 ml each of n-butanol, and the solvent
was distilled off. The residue was purified by means of column
chromatography (LM: CHCl.sub.3 CH.sub.3OH=97:3) and dried at
50.degree. C./50 mbar.
[1153] .sup.1H NMR (CDCl.sub.3) .delta. 6.57 (dd, J.sub.1=18.7 Hz,
J.sub.2=8.0 Hz, 2H), 5.94 (dd, J.sub.1=21.4 Hz, J.sub.2=10.4 Hz,
2H), 4.90 (dd, J.sub.1=10.6 Hz, J.sub.2=6.0 Hz, 1H), 4.36 (m, 3H),
3.85 (m, 1H), 3.33 (t, J=12.1 Hz, 1H), 2.93 (m, 1H), 2.25 (m, 1H),
1.87 (m, 2H), 1.24 (m, 1H), 1.06 (dd, J.sub.2=21.3 Hz, J.sub.2=6.5
Hz, 6H); .sup.13C-NMR (CDCl.sub.3): .delta. 156.7 (s), 146.5 (s),
141.0 (s), 131.5 (s), 130.1 (s), 128.1 (d), 127.1 (d), 120.1 (d),
115.5 (d), 88.2 (d), 51.6 (t), 48.0 (s), 45.9 (t), 42.8 (d), 42.0
(d), 36.8 (t), 34.2 (t), 23.5 (q), 23.1 (q)
[1154] Anal. (C.sub.19H.sub.24N.sub.2O.sub.4*0.8 CHCl.sub.3) (JOS
1622). TABLE-US-00134 Cld.: C 54.0 H 5.68 N 6.37 Fnd.: C 54.08 H
5.61 N 6.33
EXAMPLE 147
SPH-1302 HM 203
(4aa,6.beta.,8aR*)-4a,5,9,10-Tetrahydro-6-hydroxy-3-methoxy-6H-benzofuro[3-
a,3,2-ef][2]benzazepine-11(12H)-carboxylic acid-1,1-dimethylethyl
ester (8d)
[1155] ##STR357##
[1156] A solution of 9.00 g (41.30 mmol) of pyrocarbonic
acid-di-tert-butyl ester in 150 ml of absolute tetrahydrofuran was
added in drops while being cooled with ice to a solution of 12.0 g
of a mixture of norgalanthamine and galanthamine at a ratio of 94:6
(corresponding to 41.3 mmol of norgalanthamine) and 7.10 g (70.2
mmol) of triethylamine in 400 ml of absolute tetrahydrofuran. After
10 minutes, the ice-cooling was removed, and it was stirred for 16
hours at room temperature. Then, the organic solvent was
evaporated, the residue was taken up in ethyl acetate, and it was
washed three times with 150 ml each of 1N aqueous hydrochloric
acid, three times with 200 ml each of saturated sodium bicarbonate
solution and twice with 200 ml each of saturated sodium chloride
solution. The solvent was dried on sodium sulfate, concentrated by
evaporation, and the crude product was purified by means of MPLC:
mobile solvent: chloroform:methanol 99:1.fwdarw.90:10. 11.2 g of
white foam was obtained at HM 203 (73% of theory).
[1157] TLC: CHCl.sub.3:MeOH/NH.sub.3 9:1
[1158] .sup.1H-NMR (CDCl.sub.3, 200 MHz): 1.35-1.45 (m, 9H), 1.75
(m, 1H), 1.97 (m, 1H), 2.05 (m, 1H), 2.40 (m, 1H), 2.69 (b, 1H),
3.30 (b, 1H), 3.85 (OCH.sub.3, s, 3H), 4.08-4.17 (m, 3H), 4.60 (b,
1H), 5.97-6.06 (m, 2H), 6.70-6.78 (m, 2H)
[1159] Anal. (C.sub.2H.sub.27NO.sub.5, 0.4 MeOH) TABLE-US-00135
Cld.: C 66.54 H 7.46 N 3.63 Fnd.: C 66.59 H 7.59 N 3.47
EXAMPLE 149
SPH-1339 HM 264-1
(4aS,6R,8aS)-11-Propyl-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro-
[3a,3,2-ef][2]benzazepin-6-ol
[1160] ##STR358## Method 1:
[1161] A solution of 250 mg (0.92 mmol) of (-)-norgalanthamine and
160 mg (2.76 mmol) of propanal in 20 ml of absolute acetonitrile
were mixed in portions with 145 mg (2.3 mmol) of sodium
cyanoborohydride and stirred for 12 hours at room temperature.
Then, 145 mg (2.3 mmol) of sodium cyanoborohydride was repeatedly
added in portions, and the reaction mixture was stirred for another
6 hours. After the solvent was evaporated, the working-up was
carried out according to instructions A1. Further purification was
carried out by means of MPLC (mobile solvent:
chloroform:methanol/NH.sub.3=95:5). 200 mg (70% of theory) of HM
264 was obtained.
[1162] TLC: CHCl.sub.3:MeOH/NH.sub.3 9:1
Method 2:
[1163] A solution of 200 mg (0.73 mmol) of (-) norgalanthamine and
120 mg (1.46 mmol) of sodium acetate in 12 ml of water, 4 ml of
absolute ethanol and 0.62 ml of glacial acetic acid was cooled to
0.degree. C., mixed with 211 mg (3.65 mmol) of propanal and stirred
for 5 minutes. Then, 138 mg (3.65 mmol of sodium borohydride in 10
mg portions was added. After 20 minutes, another 211 mg (3.65 mmol)
of propanal and 138 mg (3.65 mmol) of sodium borohydride were added
and stirred for 30 minutes. Then, the reaction mixture was worked
up as described in Instructions A1. 210 mg (91% of theory) of HM
264 was obtained.
[1164] TLC: CHCl.sub.3:MeOH/NH.sub.3 9:1
[1165] .sup.1H-NMR (CDCl.sub.3, 200.13 MHz): .delta. 0.88 (t,
J=7.2, 3H), 1.96-2.11 (m, 2H), 2.45 (sextet, J=7.8, J=4.6, J=5.0
Hz, 2H), 2.68 (ddd, J=15.7, J=1.8, J=1.8, 1H), 3.18 (ddd, J=14.9,
J=3.1, J=3.1 Hz, 1H), 3.35 (ddd, J=14.4, J=2.2, J=1.9, 1H), 3.80
(d, J=15.3 Hz, 1H), 3.85 (s, 3H), 4.10 (d, J=15.3, 1H), 4.12 (b,
1H), 4.60 (b, 1H), 5.96-6.13 (m, 2H), 6.61 (d, J=8.2, 1H), 6.68 (d,
J=8.2, 1H); .sup.13C-NMR (CDCl.sub.3, 50.32 MHz): .delta. 11.8 (q),
20.5 (t), 29.9 (t), 32.9 (t), 48.4 (s), 51.4 (t), 53.5 (t), 55.8
(q), 57.7 (t), 62.0 (d), 88.6 (d), 111.1 (d), 121.9 (d), 127.0 (d),
127.4 (d), 129.6 (s), 133.1 (s), 143.9 (s), 145.7 (s)
EXAMPLE 150
SPH-1340 HM 265-1
N-Demethyl-N-propargyl-galanthamine
[1166] ##STR359##
[1167] A solution that consists of 0.50 g (1.83 mmol) of
(-)demethylgalanthamine, 0.51 g (3.66 mmol) of potassium carbonate
and 0.55 g (3.66 mmol) of sodium iodide in 25 ml of is
dimethylformamide was mixed with 2.20 mmol of reagent and heated
for six hours to 70-80.degree. C. Then, the solvent was evaporated.
The residue was taken up in 50-100 ml of 2N aqueous hydrochloric
acid and washed twice with 40-70 ml each of ethyl acetate. Then, it
was made basic with concentrated aqueous ammonia and extracted
three times with 40-70 ml each of dichloromethane. The combined
organic phases were washed twice with 40-70 ml each of saturated
sodium chloride solution, dried on sodium sulfate, and the solvent
was evaporated.
[1168] The further purification was carried out by means of MPLC
(mobile solvent: chloroform:methanol/NH.sub.3=95:5).
[1169] Yield: 0.26 g (46% of theory) of a colorless oil
[1170] TLC: CHCl.sub.3:MeOH/NH.sub.39:1
[1171] .sup.1H-NMR (CDCl.sub.3, 200.13 MHz): .delta. 1.53 (ddd,
J=13.8, J=3.7, =2.1, 1H), 1.89-2.09 (m, 4H), 2.27 (t, J=2.3, 2H),
2.65 (ddd, J=15.8, J=1.6, J=1.6, 1H), 3.15-3.43 (m, 2H), 3.79 (d,
J=15.0 Hz, 1H), 3.85 (s, 3H), 4.11 (d, J=15.0 Hz, 1H), 4.13 (b,
1H), 4.58 (b, 1H), 5.91-6.09 (m, 2H), 6.63 (b, 2H) .sup.13C-NMR
(CDCl.sub.3, 50.32 MHz): .delta. 29.9 (t), 34.5 (t), 44.2 (t), 48.0
(s), 51.5 (t), 55.8 (q), 58.2 (t), 61.9 (d), 72.8 (s), 79.4 (d),
88.6 (d), 111.3 (d), 122.0 (d), 126.8 (d), 127.6 (d), 128.7 (s),
132.9 (s), 144.1 (s), 145.8 (s)
EXAMPLE 151
[1172] SPH-1357 MF 8 ##STR360##
[1173] Production analogously to Example 6/step 3, but with use of
2-(4-bromobutyl)-5-methoxyindan-1-one, colorless foam.
[1174] .sup.1H-NMR (ppm, CDCl.sub.3): .delta. 7.65 (d, J=8.1 Hz,
1H), 6.87 (d, J=7.7 Hz, 2H), 6.62 (dd, J.sub.1=12.9 Hz, J.sub.2=8.4
Hz, 2H), 6.04 (m, 2H), 4.60 (b, 1H), 4.14 (m, 2H), 3.85 (s, 3H),
3.83 (s, 3H), 3.81 (m, 1H), 3.61 (d, J=6.24 Hz, 1H), 3.25 (m, 2H),
2.88 (d, J=15.1, 5H), 2.52 (b, 1H), 2.07 (m, 3H), 1.93 (m, 1H),
1.64-1.48 (m, 4H);
[1175] .sup.13C-NMR (ppm, CDCl.sub.3) 207.0 (s), 165.3 (s), 162.5
(s), 156.6 (s), 145.8 (s), 144.1 (s), 133.1 (s), 129.5 (s), 127.6
(d), 126.9 (d), 122.0 (d), 115.2 (d), 111.2 (d), 109.6 (d), 88.7
(d), 62.0 (t), 57.6 (t), 55.9 (q), 55.8 (q), 51.5 (t), 48.4 (d),
47.6 (d), 32.8 (t), 31.5 (t), 29.9 (t), 29.6 (t), 27.4 (t), 25.1
(t).
EXAMPLE 155
SPH-1377 BK-34-2
2-[4-[(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-6H-benzof-
uro[3a,3,2-ef][2]benzazepine-11-yl]butyl]-5-methoxyindan-1-one,
fumarate
[1176] ##STR361##
[1177] Production of Example 151 analogously to Example
7/production of fumarate.
[1178] Melting point: 107-110.degree. C.
[1179] C.sub.30H.sub.35NO.sub.5 5/4C.sub.4H.sub.4O.sub.4 1H.sub.2O
TABLE-US-00136 Cld.: C, 64.07 H, 6.44 N, 2.11 Fnd.: C, 64.26 H,
6.41 N, 2.23
[1180] .sup.1H NMR (ppm, CDCl.sub.3): .delta. 7.56 (d, J=10 Hz,
1H), 7.10 (s, 1H), 6.98 (d, J=10 Hz, 1H), 6.80 (m, 2H), 6.63 (s,
2H), 6.13 (d, J=12.0 Hz, 1H), 5.89 (m, 1H), 4.61 (s, 1H), 4.50 (d,
J=8.0 Hz, 1H), 4.07 (b, 2H), 3.88 (s, 3H), 3.72 (s, 3H), 3.52 (t,
J=12 Hz, 1H), 3.31 (m, 2H), 2.69 (m, 5H), 2.30 (d, J=12 Hz, 1H),
2.07 (m, 2H), 1.74 (m, 4H), 1.38 (m, 3H); .sup.13C-NMR (ppm,
CDCl.sub.3) 206.3 (s), 166.9 (s), 165.3 (s), 157.2 (s), 146.3 (s),
144.6 (s), 133.1 (d), 129.7 (s), 129.4 (s), 126.4 (d), 125.1 (d),
122.5 (d), 115.8 (d), 112.7 (d), 110.3 (d), 86.8 (d), 65.3 (t),
60.0 (t), 56.1 (q), 55.8 (q), 51.1 (t), 47.5 (d), 46.9 (d), 32.5
(t), 32.5 (t), 31.9 (t), 31.2 (t), 30.8 (t), 24.9 (t), 24.2
(t).
EXAMPLE 157
SPH-1515
(4aS,6R,8aS)-3,6-Dihydroxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef]-
[2]benzazepine-11(12H)-yl)carboxylic acid allyl ester (ML-7)
[1181] ##STR362##
[1182] 2.11 ml (1.538 g, 19.3 mmol) of triethylamine and 0.81 ml
(0.693 g, 6.384 mmol) of trimethylsilyl chloride are sprayed under
inert-gas atmosphere by means of a syringe through a septum into a
suspension of 0.788 g (0.552 g, 2.13 mmol) of norsanguinine (HPLC
purity 70%) and 10 ml of absolute dichloromethane, and the
suspension is stirred for three hours at room temperature. In the
meantime, a flocculent precipitate settles out. Then, 0.34 ml
(0.385 g, 3.192 mmol) of allyl chloroformate is added while being
cooled in an ice bath (exothermic). The reaction mixture is heated
within two hours to room temperature while being stirred, by the
ice bath being allowed to thaw. The reaction is halted by adding 13
ml of 2N hydrochloric acid, and the phases are separated. The
organic phase is washed four times with 10 ml each of 2N
hydrochloric acid and once with common salt solution, the combined
aqueous phases are re-extracted once with 20 ml of dichloromethane.
The combined organic phases are dried on sodium sulfate and
filtered. After the solvent is distilled off in a rotary
evaporator, the crude product (HPLC purity 87.5%) is purified by
means of MPLC (50 g of silica gel, v=285 nm,
chloroform/methanol=95/5). After concentration by evaporation and
drying in a high vacuum, the product is obtained as a yellowish,
highly viscous oil, which crystallizes during concentration by
evaporation from dichloromethane. Yield: 0.443 g (1.29 mmol, 61%)
of colorless crystalline solid, (M.sub.w=343.4), TLC: R.sub.f=0.55
(chloroform/methanol=9/1).
[1183] Melting point: 197-198.degree. C. (dichloromethane)
[1184] .sup.1H-NMR: (200.13 MHz, CDCl.sub.3, TMS) .delta. 7.66 (bs,
0.3H), 6.52-6.76 (m, 2H), 5.95 (bs, 2H), 5.72-5.90 (m, 1H),
5.06-5.36 (m, 2H), 4.90 (d, J=12.7 Hz, 0.5H), and 4.79 (d, J=12.7
Hz, 0.5H), 4.51 (bs, 3H), 4.00-4.41 (m, 3H), 3.22-3.53 (m, 1H),
3.13 (bs, 0.3H), 2.58 (bd, J=13.4 Hz, 1H), 1.63-2.10 (m, 3H),
.sup.13C-NMR: (50.32 MHz, CDCl.sub.3, TMS), .delta. 155.4 and 155.2
(s), 145.4 (s), 140.6 (s), 132.7 and 132.6 (d), 131.9 and 131.7
(s), 128.3 (s), 127.1 (d), 127.0 (d), 121.6 and 121.1 (d), 117.4
and 116.8 (t), 115.8 and 115.7 (d), 87.7 (d), 66.1 and 65.9 (t),
61.8 (d), 51.9 and 51.5 (t), 48.4 (s), 45.9 and 45.4 (t), 37.0 and
36.0 (t), 29.5 (t). ##STR363## ##STR364##
EXAMPLE 158
SPH-1522
4aS,6R,8aS)--N.sup.11-(N-tert-Butoxycarbonyl-6-aminohexyl)-6-hydroxy-3-met-
hoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro-[3a,3,2-ef]-[2]benzazepine-11(12-
H) carboxamide (CK-52-6)
[1185] ##STR365##
[1186] 0.600 g (0.426 mmol) of
N-tert-butoxycarbonylnorgalanthamine-6-yloxy-1,5-dioxopentyloxymethyl-Mer-
rifield resin is steeped in a 10-ml-polyethylene frit that can be
sealed on both sides for 30 minutes in a sufficient amount of
dichloromethane and demasked analogously to the protection removal
instructions to immobilize N-tert-butoxycarbonylnorgalanthamine
(Example 147) and washed (in each case 6 ml of solvent). Then, the
resin is reacted analogously to the above instructions with 730
.mu.l (0.551 g, 4.260 mmol) of ethyldiisopropylamine and 0.379 g
(1.278 mmol) of triphosgene in 6 ml of absolute dichloromethane.
After the resin is washed and dried in a vacuum overnight, 0.653 g
of
N-chclorocarbonylnorgalanthamine-6-yloxy-1,5-dioxopentyloxymethyl-Merrifi-
eld resin is obtained.
[1187] After the resin (0.103 g, 0.065 mmol) is steeped and
filtered, it is suspended in a solution that consists of 0.164 g
(0.650 mmol) of
N-tert-butoxycarbonyl-1,6-diaminohexanehydrochloride, 222 .mu.l
(0.168 g, 1.300 mmol) of ethyldiisopropylamine, 0.053 .mu.l (0.051
g, 0.650 mmol) of pyridine and 2.0 ml of dimethylformamide (to
dissolve the hydrochloride, the solution is heated beforehand).
Then, the suspension is shaken at room temperature for 5.5 hours.
The resin is washed three times with dimethylformamide (2 minutes,
1 ml) and six times with dichloromethane (2 minutes, 1 ml). After
drying in a vacuum, the resin is shaken in 2 ml of tetrahydrofuran
for 30 minutes, and after filtering, it is mixed with a solution
that consists of 0.059 g (0.018 g, 0.325 mmol), 30% of sodium
methanolate-methanol solution and 1.5 ml of
tetrahydrofuran/methanol (4/1). After 9.5 hours of shaking at room
temperature, the solution is filtered off, and the resin is
extracted three times with 1.5 ml each of dichloromethane/methanol
(1/1) and three times with 1.5 ml each of dichloromethane. The
combined filtrates are neutralized with methanolic hydrochloric
acid, diluted with 10 ml of dichloromethane, washed once with 15 ml
of 2N hydrochloric acid and twice with 15 ml each of saturated
sodium chloride solution, dried on sodium sulfate, filtered and
concentrated by evaporation under reduced pressure in a rotary
evaporator. The crude product (0.051 g) is separated by means of
column chromatography (5 g of silica gel,
chloroform/methanol=50/1).
[1188] After concentration by evaporation, a colorless oil is
obtained.
[1189] Yield: 0.030 g (0.058 mmol, 89%), colorless oil
(M.sub.w=515.7)
[1190] TLC: R.sub.f=0.47 (chloroform/methanol=9/1)
[1191] .sup.1H-NMR: (200.13 MHz, CDCl.sub.3, TMS)
[1192] 6.73 (d, J=8.1 Hz, 1H), 6.66 (d, J=8.3 Hz, 1H), 5.90-6.07
(m, 2H), 4.23-4.70 (m, 5H), 4.13 (bs, 1H), 3.82 (s, 3H), 3.35 (t,
J=13.5 Hz, 1.0H), 2.96-3.20 (m, 4H), 2.67 (bd, J=15.7 Hz, 1H);
1.65-2.10 (m, 3H), 1.42 (s, 9H), 1.06-1.40 (m, 8H)
[1193] .sup.13C NMR: (50.32 MHz, CDCl.sub.3, TMS)
[1194] .delta. 157.2, 156.0, 147.0, 144.7, 132.5, 129.2, 128.1,
126.5, 120.2, 111.2, 88.4, 61.9, 55.9, 51.7, 48.5, 45.7, 42.1,
40.5, 39.3, 36.6, 30.0, 29.7, 28.4, 26.1, 23.5
[1195] HPLC: t.sub.Ref=17.8 minutes, 98.7% (Merck Purospher column,
4.0 mm.times.125 mm, RP-18e, 5.0 .mu.m, 1 ml/minute, 285 nm,
acetonitrile/20 mmol of Cl.sub.3CCO.sub.2H in H.sub.2O (20/80 for 5
minutes, 20/80.fwdarw.60/40 in 12 minutes, 60/40 for 5 minutes,
v/v)
EXAMPLE 159
N-tert-Butyloxycarbonylglycine-[4-[(4aS,6R,8aS)-6-hydroxy-3-ethoxy-5,6,9,1-
0-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl]-3-aza-4-
-oxobutyl]amide (CK-58-2)
[1196] ##STR366##
[1197] 0.199 g (0.102 mmol) of
norgalanathamine-6-yloxy-1,5-dioxopentyloxymethyl-Merrifield resin
is steeped in a 5-ml-polyethylene frit that can be sealed on both
sides for 30 minutes in 2 ml of dichloromethane, and after
filtering, it is suspended in a solution of 120 .mu.l (0.091 g,
0.700 mmol) of ethyldiisopropylamine in 1.5 ml of dichloromethane.
Then, the suspension is mixed with a solution, cooled to 0.degree.
C., that consists of 0.062 g (0.210 mmol) of triphosgene and 0.5 ml
of dichloromethane and shaken at room temperature for two hours.
The resin is washed three times with dichloromethane (2 minutes, 2
ml) and three times with dimethylformamide (2 minutes, 2 ml). A
solution that consists of 47 .mu.l (0.042 g, 0.700 mmol) of
ethylenediamine and 2.0 ml of dimethylformamide is subsequently
added, and the suspension is shaken at room temperature. After
three hours, the solution is filtered off, and the resin is washed
six times with 2 ml each of dimethylformamide (2 minutes). (The
Kaiser Test cannot be evaluated. The beads exhibit brown-red
staining.) The resin is mixed with a solution that consists of
0.037 g (0.210 mmol) of N--BOC-glycine, 0.028 g (0.210 mmol) of
1-hydroxybenzotriazole and 1 ml of dimethylformamide, and the
suspension is shaken for five minutes. Then, 0.043 g (0.210 mmol)
of dicyclohexylcarbodiimide, dissolved in 1 ml of dichloromethane,
is added. The suspension is shaken for three hours at room
temperature, the resin is filtered, and it is washed three times
with dimethylformamide (2 ml, 2 minutes) and six times with
dichloromethane (2 ml, 2 minutes). After drying in a vacuum, 0.239
g of resin, which is shaken in tetrahydrofuran for 30 minutes, is
obtained, and after filtering, it is mixed with a solution that
consists of 0.076 g (0.023 g, 0.63 mmol) of 30% sodium
methanolate-methanol solution and 2.0 ml of
tetrahydrofuran/methanol (4/1). After 8.25 hours of shaking, the
solution is filtered off, and the resin is extracted three times
with 2 ml each of dichloromethane/methanol (1/1) and three times
with 2 ml each of dichloromethane. The combined filtrates are
neutralized with methanolic hydrochloric acid, diluted with 10 ml
of dichloromethane, washed twice with 15 ml of saturated sodium
chloride solution, dried on sodium sulfate, filtered and
concentrated by evaporation in a rotary evaporator under reduced
pressure. The crude product (0.064 g) is separated by means of
column chromatography (5 g of silica gel, chloroform/methanol=25/1
15/1). After the concentration by evaporation, a colorless oil is
obtained.
[1198] Yield: 0.030 g (0.025 g, 0.048 mmol, 47%), colorless oil
(M.sub.w=516.6)
[1199] TLC: R.sub.f=0.38 (chloroform/methanol=9/1)
[1200] .sup.1H-NMR: (200.13 MHz, CDCl.sub.3, TMS)
[1201] .delta. 6.90 (bs, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.60-6.71 (m,
1H), 5.88-6.08 (m, 2H), 5.39 (bs, 1H), 5.19 (bs, 1H), 4.50-4.70 (m,
2H), 4.04-4.34 (m, 3H), 3.82 (s, 3H), 3.70 (d, J=6.1 Hz, 1H), 3.65
(d, J=5.6 Hz, 1H), 3.11-3.49 (m, 5H), 2.68 (d, J=15.9 Hz, 1H), 2.41
(d, J=10.9 Hz, 1H), 1.65-2.09 (m, 3H), 1.44 (s, 9H)
[1202] HPLC: t.sub.Ref=15.2 minutes, 82.3% (Merck Purospher column,
4.0 mm.times.125 mm, RP-18e, 5.0 .mu.m, 1 ml/minute, 285 nm,
MeOH/H.sub.2O (5/95 for 5 minutes, 5/95.fwdarw.100/0 in 15 minutes
(convex), 100/0 for 10 minutes, v/v)
[1203] LC/MS: t.sub.Ref=30.6 minutes, (Phenomenex Luna column, 3.0
mm.times.50 mm, RP-18, 3.0 .mu.m, 0.8 ml/minute,
[1204] methanol/H.sub.2O (10/90 for 2 minutes, 10/90 100/0 in 15
minutes, 100/0 for 5 minutes, vv)
[1205] APCI-PI-MS
[1206] 517 (17), 499 (5), 461 (55), 443 (39), 417 (100), 399 (18),
274 (43), 256 (16)
EXAMPLE 160
SPH-1524
(4aS,6R,8aS)-6-(Benzoyloxy)-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro-
[3a,3,2-ef][2]benzazepine-11(12H)-yl)carboxylic acid allyl ester
(CK-65-1)
[1207] ##STR367##
[1208] 0.075 g (0.210 mmol) of N-allyloxycarbonylnorgalanthamine,
0.475 g (2.098 mmol) of benzoic acid anhydride and 0.013 g (0.105
mmol) of dimethylaminopyridine are introduced into 2 ml of
dichloromethane and then mixed with 0.185 ml (0.136 g, 1.049 mmol)
of ethyldiisopropylamine. After 13 hours at room temperature, the
solution is taken up with 5 ml of saturated sodium bicarbonate
solution, and extracted three times with 5 ml each of ethyl
acetate. The combined organic extracts are washed with 10 ml of
saturated sodium bicarbonate solution, twice with 10 ml of 2N
hydrochloric acid and twice with 10 ml of saturated sodium chloride
solution, dried on sodium sulfate, filtered and concentrated by
evaporation in a rotary evaporator under reduced pressure. The
residue is digested twice in each case with 10 ml of petroleum
ether, and the solution is decanted off. The residue (0.100 g) is
purified by column chromatography (10 g of silica gel, mobile
solvent=petroleum ether/ethyl acetate=2/1).
[1209] Yield: 0.066 g (0.080 mmol, 68%), colorless foam
(M.sub.w=461.5)
[1210] TLC: R.sub.f=0.52 (ethyl acetate/petroleum ether=2/1)
[1211] Melting point: 45-49.degree. C. (ethyl acetate/petroleum
ether=2/1)
[1212] IR: KBr
[1213] v (cm.sup.-1) 2946 (m), 1708 (s), 1509 (m), 1483 (m), 1276
(s), 1108 (m), 1056 (m), 714 (m)
[1214] .sup.1H-NMR: (200.13 MHz, CDCl.sub.3, TMS)
[1215] .delta. 8.06 (d, J=7.1 Hz, 1H), 7.29-7.61 (m, 3H), 6.59-6.84
(m, 2H), 6.28 (d, J=10.3 Hz, 5H), 6.07 (dd, J=5.0 Hz, J=10.2 Hz,
1H), 5.76-5.99 (m, 1H), 5.59 (t, J=4.4 Hz, 1H), 5.09-5.35 (m, 2H),
4.87 (dd, J=15.7 Hz, J=22.0 Hz, 1H), 4.05-4.70 (m, 5H), 3.89 (s,
3H), 3.29-3.60 (m, 1H), 2.81 (bd, J=16.1 Hz, 1H), 1.74-2.25 (m,
3H)
[1216] .sup.13C-NMR: (50.32 MHz, CDCl.sub.3, TMS)
[1217] .delta. 166.2 (s), 155.3 and 155.1 (s), 147.4 and 147.3 (s),
144.3 (s), 132.99 and 132.85 (d), 131.7 (d), 131.4 and 131.0 (s),
130.4 (s), 129.9 (d), 128.4 (d), 127.1 (d), 120.7 and 120.2 (d),
117.4 and 116.8 (t), 111.4 and 111.3 (d), 86 (d), 66.1 and 66.0
(t), 63.4 (d), 56.0 (q), 63.8 (d), S1.9 and 51.4 (t), 48.3 (s),
45.8 and 45.4 (t), 37.9 and 37.0 (t), 27.8 (t) ##STR368##
EXAMPLE 161
SPH-1525
Immobilization of
(4aS,6R,8aS)-3,6-Dihydroxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef-
]-[2]benzazepine-11(12H)-yl)carboxylic acid allyl ester on a
para-hydroxymethylphenoxy-polystyrene resin (Wang resin)
[1218] ##STR369## Method A (CK-63-2)
[1219] 0.257 g (0.244 mmol) of Wang resin.sup.2 is stirred under
argon atmosphere in 3 ml of absolute dichlororomethane for 15
minutes. Then, 86 .mu.l (0.141 g, 1.19 mmol) of thionyl chloride is
added in drops within five minutes at 0.degree. C. The suspension
is stirred at 0.degree. C. for one hour. Then, the resin is moved
to a polyethylene frit that can be sealed on both sides, and it is
washed five times with dichloromethane (2 minutes, 2.5 ml), twice
with methanol (2 minutes, 2.5 ml), once with dichloromethane (2
minutes, 2.5 ml) and once with diethyl ether (2 minutes, 2.5 ml).
The resin is then dried in a vacuum on phosphorus pentoxide.
.sup.2P-Alkoxybenzyl alcohol resin, D-1250, Bachem Feinchemikalien
AG
Step 1
[1220] 0.2334 g of the chlorine-Wang resin that is thus produced,
0.232 g (0.713 mmol) of cesium carbonate, 0.088 g (0.238 mmol) of
tetra-n-butylammonium iodide and 0.245 g (0.713 mmol) of
N-alloc-norsanguinine are suspended in 3 ml of absolute
dimethylformamide while being stirred. Then, the suspension is
stirred for 24 hours at 60.degree. C. After five hours, 1 ml of
dimethylformamide is added to suspend the deposited precipitate.
Then, the resin is moved to a polyethylene frit that can be sealed
on both sides with dimethylformamide/water solution (2/1), and it
is washed twice with dimethylformamide/water solution (2/1, 2
minutes, 2.5 ml), twice with dimethylformamide/water-solution (1/2,
2 minutes, 2.5 ml), twice with methanol/water solution (1/1, 2
minutes, 2.5 ml), twice with methanol (2 minutes, 2.5 ml) and six
times with dichloromethane (2 minutes, 2.5 ml).
Method B (CK-63-1)
[1221] 0.121 ml (0.192 g, 1.247 mmol) of carbon tetrachloride is
introduced into 2.0 ml of absolute dichloromethane at 0.degree. C.
While being stirred (KPG-stirrer), 0.311 g (1.188 mmol) of
triphenylphosphine, dissolved in 1.0 ml of absolute
dichloromethane, is added in drops within 15 minutes at 0.degree.
C. It is stirred for another ten minutes at 0.degree. C. and then
for another ten hours at room temperature, until triphenylphosphine
can no longer be detected by thin-layer chromatography. 0.2506 g
(0.238 mmol) of Wang resin.sup.1 and 1.5 ml of dichloromethane are
subsequently added, and the suspension is stirred for 35 hours at
room temperature (300 s.sup.-1). The working-up of the chlorinated
Wang resin is carried out analogously to method A. After drying,
0.2403 g of chlorine-Wang resin, which is reacted analogously to
step 1 above with the same amounts of cesium carbonate,
tetra-n-butylammonium iodide and N-alloc-norsanguinine, is
obtained.
EXAMPLE 162
SPH-1526
Determination of Concentration,
(4aS,6R,8aS)-6-(Benzoyloxy)-3-hydroxy-5,6,9,10-tetrahydro-4aH-[1]benzofur-
o[3a,3,2-ef][2]benzazepine-11(12H)-yl)carboxylic acid allyl
ester
1.1.1 Step 1 (CK-63-2)
[1222] To determine the concentration and to detect that the
N-alloc-norsanguinine is bonded via the phenol function to the
resin, the resin, which is obtained by method A and step 1, is
mixed successively with a solution that consists of 0.537 g (2.375
mmol) of benzoic acid anhydride and 2 ml of dichloromethane and a
solution that consists of 0.015 g (0.119 mmol) of
dimethylaminopyridine, 0.203 ml (0.154 g, 1.188 mmol) of
ethyldiisopropylamine and 0.5 ml of dichloromethane. Then, the
suspension is shaken out at room temperature. After 18 hours, the
resin is filtered off, washed six times with 2.5 ml each of
dichloromethane (2 minutes) and once with 2.5 ml of diethyl ether
(2 minutes) and dried in a vacuum on phosphorus pentoxide. 0.3085 g
of substituted resin, which is suspended in absolute
dichloromethane for 15 minutes and then is thoroughly filtered, is
obtained.
Step 2
[1223] For cleavage, the resin is mixed with 2.5 ml of
trifluoroacetic acid/dichloromethane solution (15/85), shaken for
30 minutes at room temperature, filtered and shaken again with 2.5
ml of trifluoroacetic acid/dichloromethane solution (15/85),
filtered and finally extracted four times with 2.5 ml of
dichloromethane in each case. The combined filtrates or extracts
are taken up with 10 ml of distilled water and set at pH 6 with
sodium bicarbonate. The phases are separated, and the aqueous phase
is extracted three times with 10 ml of dichloromethane. The
combined organic extracts are washed twice with 10 ml each of
saturated sodium chloride solution, dried on sodium sulfate,
filtered and concentrated. The purification of the crude product
(0.078 g) is carried out by means of column chromatography (10 g of
silica gel, ethyl acetate/petroleum ether=2/1). After concentration
by evaporation and drying under high vacuum, 0.078 g of a colorless
foam is obtained that is 95% pure according to HPLC analysis. The
colorless foam can be purified by recrystallization from diethyl
ether at -22.degree. C. (deep freeze from the refrigerator).
[1224] Yield: 0.059 g (0.056, 0.0125 mmol, thus a concentration of
0.41 mmol/g, 61% of theoretical maximum concentration.sup.2 is
calculated), colorless foam (M.sub.w447.5) .sup.20.67 mmol/g=0.95
mmol/g/(1 g+1 g*0.95 mol/g*(447.5 g/mol-18 g/mol)/1000
[1225] TLC: R.sub.f=0.29 (ethyl acetate/petroleum ether=1/1)
[1226] Melting point: 158-159.degree. C. (diethyl ether)
[1227] .sup.1H-NMR: (200.13 MHz, d.sub.6-DMSO)
[1228] .delta. 7.99 (d, J=6.5 Hz, 2H), 7.38-7.71 (m, 3H), 6.39-6.63
(m, 3H), 5.73-6.17 (m, 2H), 5.47 (t, J=4.3 Hz, 1H), 5.04-5.33 (m,
2H), 4.00-4.72 (m, 6H), 2.60-2.89 (m, 1H), 2.55 (bd, J=18.6 Hz,
1H), 2.25 (bd, J=15.7 Hz, 1H), 1.70-1.93 (m, 2H)
[1229] .sup.13C-NMR: (50.32 MHz, d.sub.6-DMSO)
[1230] .delta. 165.4 (s), 154.6 and 154.4 (s), 146.3 (s), 141.3
(s), 133.5 (d), 133.3 (d), 133.2 (d), 131.8 (d), 131.5 (s), 130.2
(s), 129.5 (d), 128.6 (d), 128.0 (s), 122.2 (d), 120.4 and 120.0
(d), 117.0 and 116.1 (t), 115.0 (d), 84.7 (d), 65.2 and 65.0 (t),
63.8 (d), 51.0 and 50.5 (t), 48.0 (s), 45.1 and 44.7 (t), 37.3 and
36.4 (t), 27.4 (t)
[1231] HPLC: t.sub.Ref=21.41 minutes, 95.1% (Merck Purospher
column, 4.0 mm.times.125 mm, RP-18e, 5 .mu.m, 285 nm, 1 ml/minute,
acetonitrile/20 mmol of Cl.sub.3CCO.sub.2H in H.sub.2O (15/85 for 5
minutes, 15/85 60/40 in 12 minutes, 60/40 for 5 minutes, v/v)
[1232] (CK-63-1)
[1233] The resin, which is obtained by method B and step 1, is
reacted analogously to step 1 with benzoic acid anhydride, and
after drying under vacuum, 0.3004 g of the substituted resin is
obtained. The cleavage of the product and the aqueous working-up
are carried out analogously to step 2. After the concentration by
evaporation and the drying in a vacuum, 0.070 g of crude product,
which is purified by means of column chromatography (10 g of silica
gel, ethyl acetate/petroleum ether=2/1), is obtained. After
concentration by evaporation and drying under high vacuum, 0.051 g
of a colorless foam, which is 93% pure according to HPLC analysis,
is obtained.
[1234] Yield: 0.051 g (0.047 g, 0.0106 mmol, thus a concentration
of 0.35 mmol/g, 52% of the theoretical maximum concentration.sup.3,
is calculated), colorless foam (M.sub.w=447.5) .sup.30.67
mmol/g=0.95 mmol/g/(1 g+1 g*0.95 mol/g*(447.5 g/mol-18
g/mol)/1000)
[1235] HPLC: t.sub.Ref=21.42 minutes, 92.7% (Merck Purospher
column, 4.0 mm.times.125 mm, RP-18e, 5 .mu.m, 285 nm, 1 ml minute,
acetonitrile/20 mmol of Cl.sub.3CCO.sub.2H in H.sub.2O (15/85 for 5
minutes, 15/85.fwdarw.60/40 in 12 minutes, 60/40 for 5 minutes,
v/v)
EXAMPLE 163
Synthesis of the Solid Phase/Manual
[1236] ##STR370##
EXAMPLE 163
Steps 1-7
Immobilization of
(4aR,6S,8aR)-3-Methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-e-
f][2]benazepin-6-ol on a Hydroxymethyl-Polystyrene Resin
(Merrifield Resin)
[1237] ##STR371## Method A (CK-4.1-1) Steps 1-2 and 5-7
[1238] 5.000 g (5.2 mmol) of hydroxymethyl-Merrifield resin.sup.4
is stirred in a three-neck glass reactor with a frit that is
recessed in the bottom and a KPG stirrer in 60 ml of
dichloromethane for one hour (300 s.sup.-1). After filtering, the
suspension is mixed with a solution of 2.373 g (20.8 mmol) of
glutaric acid anhydride, 4.45 ml (3.362 g, 26.0 mmol) of
ethyldiisopropylamine in 30 ml of absolute dichloromethane. The
suspension is stirred at room temperature for ten hours, filtered,
washed once with 50 ml of dichloromethane, once with 50 ml of
methanol and three times with 50 of dichloromethane in each case.
The resin is then dried in a vacuum. .sup.4Hydroxymethyl resin,
D-1160, Bachem Feinchemikalien AG
[1239] 4.385 g of the 4-carboxy-1-oxobut-1-yloxymethyl-Merrifield
resin that is thus produced is suspended for 30 minutes in 50 ml of
absolute dichloromethane while being stirred, and it is filtered.
Then, 4.569 g (12.23 mmol) of N-tert-butoxycarbonylnorgalanthamine
and 0.249 g (2.04 mmol) of dimethylaminopyridine, both dissolved in
15 ml of dichloromethane, and 2.10 ml (1.582 g, 12.23 mmol) of
ethyldiisopropylamine, dissolved in 5 ml of dichloromethane, are
added. While being stirred, a solution that consists of 1.89 ml
(1.544 g, 12.23 mmol) of diisopropylcarbodiimide and 5 ml of
dichloromethane is added in drops within five minutes at room
temperature. After 24 hours, the resin is filtered off, washed with
40 ml of methanol and filtered. Then, the resin is washed six times
with 40 ml of dichloromethane in each case (5 minutes) and dried in
a vacuum.
[1240] The resin is mixed with 42 ml of absolute dichloromethane
and 3 ml of anisole and stirred for 30 minutes (150 s.sup.1). Then,
while being stirred (300 s.sup.1), 15 ml of trifluoroacetic acid is
added within 15 minutes. Then, the suspension is stirred for 60
minutes (150 s.sup.1), filtered and washed with dichloromethane
(2.times.40 ml, 5 minutes), with
dichloromethane/dimethylformamide/triethylamine (5/4/1) (3.times.40
ml, 5 minutes) and finally with dichloromethane (5.times.40 ml, 5
minutes). After drying in a vacuum, 4.353 g of resin is
obtained.
[1241] To determine the concentration, 0.2384 g of resin in 3 ml of
dimethylformide is suspended in a polyethylene frit that can be
sealed on both sides. After filtering, the resin is shaken in a
solution that consists of 177 .mu.l (0.191 g, 1.875 mmol) of acetic
acid anhydride, 180 .mu.l (0.136 g, 1.050 mmol) of
ethyldiisopropylamine and 2 ml of dimethylformamide for nine hours
at room temperature. After washing (dimethylformamide (3.times.2.5
ml, 2 minutes) and tetrahydrofuran/methanol (4/1) (5.times.2.5 ml,
2 minutes), the resin shows no reaction with the chloranil test.
The polymer is suspended in a 0.3 M sodium methanolate solution in
tetrahydrofuran/methanol (4/1). The resin is shaken for 8 hours at
room temperature, filtered and extracted with
methanol/dichloromethane (1/1, 3.times.2.5 ml) and with
dichloromethane (3.times.2.5 ml). The combined filtrates are
neutralized with methanolic hydrochloric acid. The solution is
diluted with about 10 ml of dichloromethane, washed with 25 ml of
saturated sodium bicarbonate solution, 1N hydrochloric acid and
saturated sodium chloride solution in each case, dried on sodium
sulfate, filtered and concentrated. The purification is carried out
by means of column chromatography (10 g of silica gel, diethyl
ether/ethanol=100/15). After concentration by evaporation and
drying under high vacuum, 0.028 g of a yellowish foam, which
contain 10% other contaminants according to HPLC analysis, is
obtained.
[1242] Yield: 0.025 g (0.080 mmol. A concentration of 0.34 mmol/g,
45% of the theoretical maximum concentration.sup.5 thus is
calculated), yellowish foam (M.sub.w=315.4) .sup.50.75 mmol/g=1.04
mmol/g/(1 g+1 g*1.04 mol/g*(387.4 g/mol=18 g/mol)/1000)
[1243] TLC: R.sub.f=0.29 (diethyl ether/ethanol=100/15)
[1244] IR: KBr
[1245] v (cm.sup.-1) 3551 (v), 3305 (bm), 2926 (m), 2864 (v) 1650
(m), 1615 (s), 1443 (m), 1257 (m), 1070 (m)
[1246] .sup.1H-NMR: (200.13 MHz, CDCl.sub.3, TMS) .delta. 6.54-6.89
(m, 2H), 5.75-6.09 (m, 2H), 5.14-5.33 (m, 0.3H), 4.32-4.74 (m,
3.3H), 4.12 (bs, 1H), 3.86-4.00 (m, 0.3H), 3.81 and 3.79 (s, 3H),
3.56-3.76 (m, 0.8H), 3.23 (bt, J=12.6 Hz, 0.8H), 2.67 (bd, J=15.9
Hz, 1H), 2.38 (bs, 0.7H), 2.06 (m, 3H), 1.62-2.00 (m, 3H),
[1247] HPLC: t.sub.Ref=13.9 minutes, 89.8% (Merck Purospher column,
4.0 mm.times.125 mm, RP-18e, 5 .mu.m, 285 nm, 1 ml/minute,
acetonitrile/20 mmol of Cl.sub.3CCO.sub.2H in H.sub.2O (05/95 for 5
minutes, 05/95.fwdarw.60/40 in 10 minutes, 10/40 for 10 minutes,
v/v, pH 10)
Method B (CK-43-2), Steps 1 and 3-7
[1248] 3.500 g (3.64 mmol) of hydroxymethyl-Merrifield resin.sup.6
is reacted analogously to the method that is described under method
A with 1.661 g (14.6 mmol) of glutaric acid anhydride, 3.15 ml
(2.378 g, 18.39 mmol) of ethyldiisopropylamine and 0.044 g (0.364
mmol) of dimethylaminopyridine in 20 ml of absolute
dichloromethane. After washing, the resin is stirred successively
with a solution that consists of 3.15 ml (2.378 g, 18.39 mmol) of
ethyldiisopropylamine, and 10 ml of absolute dichloromethane and
with a solution that consists of 1.34 ml (1.317 g, 10.92 mmol) of
pivaloyl chloride and for nine hours at room temperature. After
washing (dichloromethane (4.times.30 ml, 5 minutes),
tetrahydrofuran (30 ml, 5 minutes) and dichloromethane (2.times.30
ml, 5 minutes), the resin is successively treated with 4.061 g
(10.87 mmol) of N-tert-butoxycarbonylnorgalanthamine and 0.222 g
(1.82 mmol) of dimethylaminopyridine, both dissolved in 15 ml of
dichloromethane, and 3.15 ml (2.378 g, 18.39 mmol) of
ethyldiisopropylamine, dissolved in 15 ml of dichloromethane. After
24 hours at room temperature, the solution is filtered off, and the
resin is mixed with 40 ml of a dry solution that consists of
methanol and dichloromethane, and it is stirred for ten minutes at
room temperature. After filtering, six cycles of washing with
dichloromethane and drying in a vacuum, the resin is washed and
dried with 40 ml of trifluoroacetic acid/dichloromethane/anisole
(25/70/5) analogously to method A. 4.145 g of a yellow resin is
obtained. 0.2214 g of the resin is reacted to determine the
concentration analogously to the method, and it is purified. 0.024
g of a yellowish foam, which is 90% pure according to HPLC
analysis, is obtained. .sup.6Hydroxymethyl resin, D-1160, Bachem
Feinchemikalien AG
[1249] Yield: 0.022 g (0.069 mmol. This corresponds to a
concentration of 0.31 mmol/g, 41% of the theoretical maximum
concentration).
[1250] HPLC: t.sub.Ref=14.4 minutes, 89.0% (Merck Purospher column,
4.0 mm.times.125 mm, RP-18e, 5 .mu.m, 285 nm, 1 ml/minute,
acetonitrile/20 mmol of Cl.sub.3CCO.sub.2H in H.sub.2O (05/95 for 5
minutes, 05/95.fwdarw.60/40 in 10 minutes, 60/40 for 10 minutes,
v/v, pH 10)
EXAMPLE 163
Steps 8-13
SPH-1528
1,2
N--P-METHOXYBENZOYL-PHENYLALANYL-PHENYLALANINE-((4AS,6R,8AS)-6-HYDROXY-
-3-METHOXY-5,6,9,10-TETRAHYDRO-4AH-[[1]BENZOFURO[3A,3,2-EF][2]BENZAZEPINE--
11(12H)--YL)-AMIDE (CK-47-1)
[1251] ##STR372##
[1252] 0.245 g (0.076 mmol) of
N-tert-butoxycarbonylnorgalanthamine-6-yloxy-1,5-dioxopentyloxymethyl-Mer-
rifield resin is steeped twice in a 5-ml-polyethylene frit that is
sealed on both sides for 15 minutes in 3 ml of dimethylformamide,
and after filtering, it is suspended in a solution of 0.065 g
(0.169 mmol) of Fmoc-phenylalanine and 0.062 g (0.169 mmol) of
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate in 1 ml of dimethylformamide each, and it is
shaken for five minutes at room temperature. Then, 58 .mu.l (0.044
g, 0.338 mmol) of ethyldiisopropylamine in 0.5 ml of
dimethylformamide is added. The suspension is shaken at room
temperature for 3 hours. The resin is washed six times with
dimethylformamide (1 minute, 2.5 ml) and suspended in a 20%
piperidine solution in dimethylformamide for two and ten minutes in
each case at room temperature. After six washing cycles with
dimethylformamide (1 minute, 2.5 ml), the resin is reacted
analogously to the first peptide coupling step with 0.065 g (0.169
mmol) of Fmoc-phenylalanine and 0.062 g (0.169 mmol) of
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate in 1 ml of dimethylformamide in each case and 58
.mu.l (0.044 g, 0.338 mmol) of ethyldiisopropylamine in 0.5 ml of
dimethylformamide, washed with dimethylformamide, shaken in 20%
piperidine-dimethylformamide solution and in turn washed six times
with dimethylformamide (1 minute, 2.5 ml). Then, solutions of 0.065
g (0.169 mmol) of Fmoc-Phe-OH in 1 ml of dimethylformamide, 0.062 g
(0.169 mmol) of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate in 1 ml of dimethylformamide and 58 .mu.l (0.044
g, 0.338 mmol) of ethyldiisopropylamine in 0.5 ml of
dimethylformamide are added successively, and the suspension is
shaken for 30 minutes at room temperature. The Kaiser test
indicates complete reaction. Then, it is washed analogously to the
above-described procedure, suspended in
piperidine-dimethylformamide solution and washed in turn with
dimethylformamide. After renewed successive addition of 0.026 g
(0.169 mmol) of p-methoxybenzoic acid in 1 ml of dimethylformamide,
0.062 g (0.169 mmol) of
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate in 1 ml of dimethylformamide and 58 .mu.l (0.044
g, 0.338 mmol) of ethyldiisopropylamine in 0.5 ml of
dimethylformamide, the resin is shaken overnight, since the Kaiser
test was not unambiguous after 30 minutes because of a green-bluish
staining. The resin is filtered, washed three times with
dimethylformamide, five times with dichloromethane and with
methanol and then dried in a vacuum. The resin (0.251 g) is
suspended for 30 minutes in THF, filtered and suspended in a
solution that consists of 0.250 g (1.39 mmol) of 30% sodium
methanolate-methanol solution and 2.5 ml of
tetrahydrofuran/methanol (4/1). After eight hours, the solution is
filtered off, and the resin is extracted six times with 3 ml of
dichloromethane/methanol in each case. The combined filtrates are
neutralized with 106 .mu.l (0.158 g, 1.39 mmol) of trifluoroacetic
acid, concentrated and separated with preparative thin-layer
chromatography (silica gel, chloroform/methanol=100/5). The
product-containing silica gel fraction is extracted with
chloroform/methanol (9/1), and the combined extracts are filtered
repeatedly with a filter (pore diameter 0.2 .mu.m), concentrated by
evaporation and dried in a vacuum.
[1253] Yield: 0.041 g (0.029 g, 0.041 mmol, 53%), rose-colored wax
(M.sub.w=701.8). The product contains a by-product (0.006 g, 0.008
mmol, 10%) that is a diastereomer of the main product according to
LC/MS.
[1254] TLC: R.sub.f=0.43 (chloroform/methanol=20/1)
[1255] HPLC: t.sub.Ref=2.7 minutes, 70.4% (Phenomenex Luna column,
3.0 mm.times.50 mm, RP-18, 3.0 .mu.m, 0.5 ml/minute, 285 nm,
methanol/20 mmol of Cl.sub.3CCO.sub.2H in H.sub.2O (30/70 v/v)
[1256] LC/MS: t.sub.Ref=30.6 minutes, 73%, (Phenomenex Luna column,
3.0 mm.times.50 mm, RP-18, 3.0 .mu.m, 0.5 ml/minute,
methanol/H.sub.2O (5/95 v/v for 2 minutes, 5/95.fwdarw.40/60 v/v in
15 minutes, 40/60 v/v for 5 minutes)
[1257] APCI-PI-MS
[1258] 702 (56), 421 (100), 274 (6), 256 (13)
[1259] APCI-NI-MS
[1260] 700
[1261] t.sub.Ref=35.6 minutes, 8%, (diastereomeric by-product)
[1262] APCI-PI-MS
[1263] 702 (56) 421 (100), 274 (6), 256 (13)
[1264] APCI-NI-MS
[1265] 700
1.3
1.4 EXAMPLES 163-167
Synthesis on Robots
1.5
1.6
N--P-CARBOXYL-DIPEPTOYL-((4AS,6R,8AS)-6-HYDROXY-3-METHOXY-5,6,9,10-TET-
RAHYDRO-4AH-[1BENZOPURO[3A,3,2-EF][2]BENZAZEPINE-11(12H)--YL)AMIDE
(CK-59-1)
[1266] ##STR373##
[1267] In each case, 0.300 g (0.102 mmol) of
norgalanthamine-6-yloxy-1,5-dioxopentyloxymethyl-Merrifield resin
is introduced into polyethylene reactors with frits of a synthesis
robot (Syro II MultiSynTech) and mixed with 3 ml of absolute
dimethylformamide. After five minutes of standing, the suspensions
are stirred at intervals for 25 minutes at 23.degree. C. All
subsequent operations are carried out at this temperature. Then,
the resins are washed once with 3 ml of dimethylformamide and mixed
successively with a solution that consists of 0.119 g (0.306 mmol)
of Fmoc-phenylalanine or 0.117 g (0.306 mmol) of
N-Fmoc-o-tert-butylserine and 1.5 ml of dimethylformamide and with
a solution that consists of 0.112 g (0.306 mmol) of
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate and 1 ml of dimethylformamide. Then, the resin
suspensions are stirred for five minutes. Then, 105 .mu.l (0.079 g,
0.612 mmol) of ethyldiisopropylamine in 0.5 ml of dimethylformamide
is added. The suspensions are stirred for 3 hours, suctioned off
for two minutes and in each case mixed with a solution that
consists of 241 .mu.l (0.260 g, 2.550 mmol) of acetic anhydride,
437 .mu.l (0.330 g, 2.550 mmol) of ethyldiiospropylamine and 3 ml
of dimethylformamide. After 15 minutes of stirring and two minutes
of filtering, the resins are washed six times with
dimethylformamide (3 ml, 2 minutes), and suspended or stirred in a
20% piperidine solution in dimethylformamide for six and 15 minutes
in each case. After six cycles of washing with dimethylformamide (2
minutes, 3 ml), the resins are reacted analogously to the first
peptide coupling step with Fmoc-phenylalanine or
N-Fmoc-O-tert-butylserine, the unreacted amine groups are masked
with acetic anhydride, and the Fmoc-protective group is cleaved off
with 20% piperidine-dimethylformide solution. It is then washed
analogously to the above-described procedure, mixed with a solution
that consists of 0.047 g (0.306 mmol) of p-methoxybenzoic acid or
0.038 g (0.306 mmol) of isonicotinic acid in 2.5 ml of
dimethylformamide and stirred for five minutes. Then, in each case,
solutions of 48 .mu.l (0.039 g, 0.306 mmol) of
diisopropylcarbodiimide 241 .mu.l and 0.5 ml of 1,2-dichloroethane
are added. It is stirred for three hours. The resins are filtered
(2 minutes), washed three times with dimethylformamide (2 minutes,
3 ml), six times with dichloromethane (2 minutes, 3 ml), dried for
ten minutes at 40.degree. C., suctioned off and then dried in a
vacuum on phosphorus pentoxide. The Kaiser test is negative in all
resins (0.250 to 0.377 g).
[1268] The resins that contain O-tert-butyl-protected serine
radicals are mixed successively with 1 ml of dichloromethane, 0.125
ml of phenol, 0.125 ml of anisole and 3.75 ml of trifluoroacetic
acid, and it is stirred for three hours at room temperature. Then,
the solutions are filtered off, and the resins are washed three
times with dichloromethane (2 minutes, 3 ml), three times with
dichloromethane/ethyldiisopropylamine (95/5, 2 minutes, 3 ml),
three times with dichloromethane (2 minutes, 3 ml) in each case,
and three times with tetrahydrofuran (2 minutes, 3 ml) and dried
under reduced pressure.
[1269] The resins are transferred to 5-ml polyethylene frits that
are sealed on both sides, suspended for 30 minutes in THF, filtered
and suspended in a solution that consists of 0.092 g (0.028 g,
0.510 mmol) of 30% sodium methanolate-methanol solution and 3 ml of
tetrahydrofuran/methanol (4/1). After six hours, the solution is
filtered off, and the resin is extracted five times with 3 ml of
tetrahydrofuran/methanol (4/1) in each case. The combined filtrates
are neutralized with Dowex 50W (one spatula tip full) and
NaHCO.sub.3 (one spatula tip full). The suspensions are filtered on
some Celite, and the filter Celite is flushed twice with 5 ml of
dichloromethane. The filtrates are concentrated and purified with
preparative thin-layer chromatography (mobile solvent:
chloroform/methanol=(10/1) for CK-49-1-IPP-3, CK-59-MPP-1,
CK-59-IPP-2, CK-59-AcPP-3, chloroform/methanol=(4/1) for
CK-59-IPP-4 and chloroform/methanol=(6/1) for CK-59-MPP-5). The
product-containing silica gel fractions are extracted with
chloroform/methanol (9/1) and filtered. The extracts that are
concentrated by evaporation are filtered repeatedly with a filter
(pore diameter 0.2 .mu.m), further concentrated by evaporation and
dried in a vacuum.
[1270] HPLC: Phenomenex Synergi Polar-RP-column, 4.6 mm.times.150
mm, 4.0 .mu.m, 1.0 ml/minute, methanol/20 mm of Cl.sub.3CCO.sub.2H
in H.sub.2O (20/80 for 5 minutes, 20/80.fwdarw.80/20 in 20 minutes,
80/20 for 10 minutes, v/v)
[1271] LC/MS Phenomenex Luna column, 3.0 mm.times.50 mm, RP-18, 3.0
.mu.m, 0.8 ml/minute, methanol/H.sub.2O (10/90 for 2 minutes,
10/90.fwdarw.100/0 in 15 minutes, 100/0 for 5 minutes, v/v)
[1272] Result TABLE-US-00137 Aminosaure Beispiel SPH-Nummer 1 und 2
Carboxylrest 3 R.sub.f-Wert CK-59- 163 SPH-1528 Ph, Ph
4-MeOC.sub.6H.sub.4 0.60 (CHCl.sub.3/CH.sub.3OH = 10/1) MPP-1-1
CK-59- Ph, Ph 4-MeOC.sub.6H.sub.4 0.45 (CHCl.sub.3/CH.sub.3OH =
10/1) MPP-1-2 CK-49-1- 166 SPH-1528 Ph, Ph p-NC.sub.5H.sub.4 0.40
(CHCl.sub.3/CH.sub.3OH = 9/1) IPP-3-1 CK-59- 164 SPH-1528 Ph, Ph Me
0.52 (CHCl.sub.3/CH.sub.3OH = 10/1) AcPP-3-1 CK-59- Ph, Ph Me 0.43
(CHCl.sub.3/CH.sub.3OH = 10/1) AcPP-3-2 CK-59-ISS- 165 SPH-1528 OH,
OH p-NC.sub.5H.sub.4 0.22 (CHCl.sub.3/CH.sub.3OH = 6/1) 4-1
CK-59-ISS- OH, OH p-NC.sub.5H.sub.4 0.17 (CHCl.sub.3/CH.sub.3OH =
6/1) 4-2 CK-59- 167 SPH-1528 OH, OH 4-MeOC.sub.6H.sub.4 0.37
(CHCl.sub.3/CH.sub.3OH = 6/1) MSS-5-1 CK-59- OH, OH
4-MeOC.sub.6H.sub.4 0.27 (CHCl.sub.3/CH.sub.3OH = 6/1) MSS-5-2 [Key
to Table:] Beispiel = Example SPH-Nummer = SPH Number Aminosaure 1
und 2 = Amino acid 1 and 2 Carboxylrest 3 = Carboxyl radical 3
R.sub.f-Wert = R.sub.f value
[1273] TABLE-US-00138 HPLC (t.sub.Ref, Ausbeute und Beispiel Code
Reinheit) LC/MS Bemerkung 163 CK-59- 29.90 min t.sub.Ref = 10.90
min 0.021 g (0.015 g, MPP-1-1 (71%) APCI, Neg 0.021 mmol, 21%) 700
(100) APCI, Pos 702 (63), 684 (8), 421 (100), 274 (5), 256 (15)
CK-59- 29.35 min t.sub.Ref = 10.90 min 0.014 g (0.003 g, MPP-1-2
(24%) APCI, Neg 0.005 mmol, 700 (100), 682 (7), 606 (13) 5%); APCI,
Pos racemisiertes 702 (63), 684 (26), 608 (28), 421 (100), 274
Produkt (11), 256 (19) 166 CK-49-1- 24.91 min t.sub.Ref = 20.22 min
0.067 g (0.040 g, IPP-3-1 (59%) APCI, Neg 0.059 mmol, 58%) 671
(100) APCI, Pos 673 (100), 655 (18), 421 (7), 274 (6), 256 (53) 164
CK-59- 26.50 min t.sub.Ref = 10.08 min 0.058 g (0.029 g, AcPP-3-1
(50%) APCI, Neg 0.048 mmol, 47%) 608 (100) APCI, Pos 610 (100), 592
(15), 421 (17), 274 (8), 256 (40) CK-59- 26.09 min t.sub.Ref =
10.01 min 0.019 g (0.011 AcPP-3-2 (54%) APCI, Neg mmol, 0.017 608
(100) mmol, 17%); APCI, Pos racemisiertes 610 (100), 592 (24), 421
(20), 274 (18), 256 Produkt (69) 165 CK-59- 14.67 min t.sub.Ref =
7.49 min 0.009 g (0.008 g, ISS-4-1 (92%) APCI, Neg 0.015 mmol, 15%)
551 (100), 533 (26), 521 (17), 491 (6) APCI, Pos 553 (100), 535
(36), 403 (6), 385 (9), 256 (100) CK-59- 15.90 min t.sub.Ref = 7.63
min 0.004 g (0.002 g, ISS-4-2 (48%) APCI, Neg 0.003 mmol, 551
(100), 533 (25), 521 (19), 491 (5) 3%); APCI, Pos racemisiertes 553
(100), 535 (70), 517 (7), 274 (9), 256 Produkt (57) 167 CK-59-
21.12 min t.sub.Ref = 8.35 min 0.013 g (0.007 g, MSS-5-1 (27%)
APCI, Neg 0.012 mmol, und 580 (100), 562 (17), 550 (15), 520 (6)
12%); 21.57 min APCI, Pos racemisiertes (26%) 582 (49), 564 (43),
546 (67), 361 (100), 256 Produkt (55) t.sub.Ref = 8.49 min APCI,
Neg 580 (100), 562 (21), 550 (16), 520 (9) APCI, Pos 582 (43), 564
(47), 546 (51), 361 (100), 256 (64) CK-59- 21.27 min t.sub.Ref =
8.39 min 0.008 g (0.002 g, MSS-5-2 (10%) und APCI, Neg 0.003 mmol,
21.58 580 (100) 3%); (15%) t.sub.Ref = 8.64 min racemisiertes APCI,
Neg Produkt 580 (100), 562 (35), 550 (14) APCI, Pos 582 (63), 564
(77), 546 (77), 361 (100), 256 (63) [Key to Table:] Beispiel =
Example HPLC (t.sub.Ref, Reinheit) = HPLC (t.sub.Ref, purity)
Ausbeute und Bemerkung = Yield and Remarks racemisiertes Product =
Racemized product
EXAMPLE 167b
SPH-1543
[1274] As a by-product,
N-acetyl-phenylalanine-((4aS,6R,8aS)-6-hydroxy-3-methoxy-5,6,9,10-tetrahy-
dro-4aH-[1]benzo-furo-[3a,3,2-ef]-[2]benzazepine-11(12H)-yl)amide
was obtained: TABLE-US-00139 ##STR374## HPLC (t.sub.Ret, Ausbeute
und Code Reinheit) LC/MS und Ri-Wert Bemerkung CK-59- 23.49 min
t.sub.Ret = 9.37 min 0.036 g (0.031 g, IPP-2-1 (67%) APCl, Neg
0.077 mmol, 76 461 (100) %) APCl, Ros 463 (100), 445 (8), 274 (17),
256 (31) 0.50 (CHCl.sub.3/CH.sub.3OH = 10/1) CK-59- 23.60 min
t.sub.Ret = 9.40 min 0.012 g (0.008 g, IPP-2-2 (66%) APCl Neg 0.17
mmol, 17 461 (100) %); APCl, Pos racemisiertes 463 (100), 445 (17),
274 (32), 256 (60) Produkt 0.36 (CHCl.sub.3/CH.sub.3OH = 10/1) [Key
to Table:] HPLC (t.sub.Ref, Reinheit) = HPLC (t.sub.Ref, purity)
LC/MS und R.sub.f-Wert = LC/MS and R.sub.f value Ausbeute und
Bemerkung = Yield and remarks racemisiertes Produkt = Racemized
product
EXAMPLE 170
SPH-1371
(4aa,6b,8aR*)-4a,5,9,10,11,12-Hexahydro-3-mothoxy-11-[3-(1-piperidinyl)pro-
pyl]-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol, Dihydrobromide,
Dihydrate
[1275] Production from the free base by treatment with Hbr/EtOH
[a].sub.D.sup.20=-92.5.degree. (c 0.24, H.sub.2O)
General Instructions--"Thiophene Derivatives"
EXAMPLES 171-172
[1276] 1.1 equivalents of norgalanthamine and 1 equivalent of the
corresponding thienyl-halide were heated to reflux temperature
together with 3 equivalents of fine-powder, anhydrous
K.sub.2CO.sub.3 in dry acetonitrile (10% by weight of solution) for
24 hours. Complete conversion was examined by means of TLC.
[1277] After the solution was cooled, it was filtered, and the
K.sub.2CO.sub.3 residue was washed several times with dry
acetonitrile while being monitored by TLC. The crude product that
was obtained after concentration by evaporation was purified by
means of flash chromatography,
EXAMPLE 171
SPH-1490
6,7-Dihydro-5-(4-((4aS,6R,8aS)-6-hydroxy-3-methoxy-4a,5,9,10-tetrahydro-6H-
-benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)-butyl)-benzo[b]thiophene-4-
(5H)-one
[1278] C.sub.28H.sub.33NO.sub.4S (479.64) TABLE-US-00140 SPH-1490
##STR375## Norgalanthamine: 500 mg (1.83 mmol) 5
(4-bromobutyl)-6,7-dihydro- 479 mg (1.67 mmol)
benzo[b]thiophene-4(5H)-one: K.sub.2CO.sub.3: 693 mg (5.01 mmol)
about 4 ml of acetonitrile
[1279] Crude product: 450 mg
[1280] Flash chromatography: Ethyl acetate:triethylamine 100:2
[1281] Yield: 440 mg (50%) of a light yellow powder
[1282] .sup.1H (400 MHz, CDCl.sub.3)
[1283] .delta. 7.34 (d, J=5.26, 1H), 7.04 (d, J=5.26, 1H), 6.66 (d,
J=8.18, 1H), 6.62 (d, J=8.18, 1H), 6.09 (m, 2H), 4.61 (m, 1H),
0.25-4.07 (m, 2H), 3.92-3.84 (m, 1H), 3.84-3.79 (m, 1H), 3.80 (s,
3H), 3.46-3.56 (m, 1H), 3.30-3.18 (m, 1H), 3.13-3.03 (m, 1H)
3.02-2.91 (m, 1H), 2.73-2.65 (m, 1H), 2.64-2.47 (m, 2H), 2.45-2.36
(m, 1H), 2.32-2.23 (m, 1H), 2.11-1.83 (m, 4H), 1.63-1.09 (m,
6H)
[1284] .sup.13C (100 MHz, CDCl.sub.3):
[1285] .delta.195.2 (s), 154.8 (2*s), 145.8 (s), 144.4 (s), 136.8
(s) 132.9 (s), 127.9 (d), 126.4 (d), 125.1 (d), 123.2 (d), 122.4
(d), 111.3 (d), 88.6 (d), 61.9 (d), 58.1 (t), 55.9 (q), 51.4 (t),
51.3 (t), 48.2 (s), 46.2 (d), 29.9 (t), 29.5 (t), 28.9 (t), 28.8
(t), 28.5 (t), 24.8 (t), 24.2 (t)
EXAMPLE 172
SPH-1491
6,7-Dihydro-5-(5-((4aS,6R,8aS)-6-hydroxy-3-methoxy-4a,5,9,10-tetrahydro-6H-
-benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)-pentyl)-benzo[b]thiophen-4-
(5H)-one
[1286] C.sub.29H.sub.35NO.sub.4S (493.67) TABLE-US-00141 SPH-1491
##STR376## Norgalathamine: 200 mg (0.73 mmol)
5-(5-bromopentyl)-6,7-dihydro-benzo[b]- 201 mg (0.67 mmol)
thiophen-4(5H)-one: K.sub.2CO.sub.3: 277 mg (2.00 mmol) about 4 ml
of acetonitrile
[1287] Crude product: 430 mg
[1288] Flash chromatography: ethyl acetate:triethylamine=100:2
[1289] Yield: 240 mg (66.3%) of a light yellow powder
[1290] .sup.1H NMR (400 MHz, CDCl.sub.3)
[1291] .delta. 7.35 (d, J=5.2 Hz, 1H), 7.03 (d, J=5.2 Hz, 1H), 6.64
(d, J=8.1 Hz, 1H), 6.61 (d, J=8.1 Hz, 1H), 6.05 (d, J=10.2 Hz, 1H),
5.99 (dd, J=10.2, 4.6 Hz, 1H), 4.60 (m, 1H), 3.83 (d, J=15.2, 1H),
4.14-4.10 (m, 1H), 3.83 (d, J=15.2 Hz, 1H), 3.81 (s, 3H), 3.41-3.31
(m, 1H), 3.22-3.14 (m, 1H), 3.07 (dt, J=17.2, 5.2 Hz, 1H), 2.96
(ddd, J=17.2, 9.1, 4.7 Hz, 1H), 2.70-2.62 (m, 1H), 2.56-2.34 (m,
4H), 2.26 (m, 1H), 2.10-1.8 (m, 4H), 1.61-1.21 (m, 8H)
[1292] .sup.13C NMR: (100 MHz, CDCl.sub.3)
[1293] .delta. 195.7 (s), 155.1 (2*s), 146.2 (s), 144.5 (s), 137.3
(s), 133.5 (s), 128.0 (d), 127.3 (d), 125.5 (d), 123.6 (d), 122.5
(d), 111.5 (d), 89.1 (d), 62.5 (d), 58.1 (t), 56.3 (q), 51.3 (t),
48.8 (s), 46.7 (d), 33.2 (t), 30.3 (t), 30.0 (t), 29.9 (t), 29.4
(t), 27.8 (t), 27.6 (t), 27.5 (t), 24.6 (t)
General Instructions--"Azacycloalkyl Derivatives"
EXAMPLES 173-176
[1294] One equivalent of norgalanthamine and 3 equivalents of the
corresponding aminoalkyl halide was heated to reflux temperature
together with 3 equivalents of fine-powder, dry K.sub.2CO.sub.3 in
dry acetonitrile (about 10% by weight of solution) for 24 hours.
Complete conversion was controlled by means of TLC.
[1295] After the solvent was distilled off, the remaining residue
was dissolved in 2N HCl. After two extraction cycles with diethyl
ether, it was made alkaline with 10% NaOH solution and extracted
exhaustively with chloroform. After drying on Na.sub.2SO.sub.4, it
was concentrated by evaporation and purified by means of flash
chromatography (CHCl.sub.3:MeOH:NH.sub.3=10:1:0.5). The indicated
yields of the reactions relate to 500 mg (1.83 mmol) of
norgalanthamine as a starting product and were determined according
to flash chromatography.
EXAMPLE 173
SPH-1492
(4aS,6R,8aS)-3-Methoxy-1-(6-piperidin-1-yl-hexyl)-5,6,9,10,11,12-hexahydro-
-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol
[1296] C.sub.27H.sub.40N.sub.2O.sub.3 (440.63) ##STR377##
[1297] Yield: 161 mg (20%) of a yellowish oil
[1298] .sup.1H (400 MHz, CDCl.sub.3):
[1299] .delta. 6.66 (d, J=8.0 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 6.10
(d, J=10.0 Hz, 1H), 6.01 (dd, J=10.0, 5.4 Hz, 1H), 4.62 (m, 1H),
4.14 (m, 1H), 4.13 (d, J=15.6, 1H), 3.84 (s, 3H), 3.81 (d, J=15.6,
1H), 3.4-3.3 (m, 1H), 3.2-3.15 (m, 1H), 2.69 (ddt, J=15.7, 3.4, 1.6
Hz, 1H), 2.55-2.25 (m, 8H), 2.10-2.0 (m, 1H), 2.01 (ddd, J=12.9,
5.0, 2.6 Hz, 1H), 1.65-1.2 (m, 16H)
[1300] .sup.13C (100 MHz, CDCl.sub.3):
[1301] .delta. 146.2 (s), 144.4 (s), 133.6 (s), 129.9 (s), 127.9
(d), 127.4 (d), 122.4 (d), 111.5 (d), 89.1 (d), 62.5 (d), 59.9 (t)
58.1 (t), 56.3 (q), 54.9 (4*t), 51.9 (t), 48.8 (s), 33.3 (t) 30.3
(t), 28.0 (t), 27.9 (t), 27.8 (t), 27.1 (t), 26.2 (t), 24.8 (t)
EXAMPLE 174
SPH-1493
(4aS,6R,8aS)-3-Methoxy-11-(6-(4-methylpiperazine)-1-yl-hexyl)-5,6,9,10,11,-
12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol
[1302] C.sub.27H.sub.41N.sub.3O.sub.3 (455.65) ##STR378##
[1303] Yield: 208 mg (25%) of a yellowish oil
[1304] .sup.1H (400 MHz, CDCl.sub.3)
[1305] .delta. 6.66 (d, J=8.18, 1H), 6.61 (d, J=8.18, 1H), 6.09 (d,
J=10.23, 1H), 6.0 (dd, J=9.94, 4.97, 1H), 4.61 (m, 1H), 4.20-4.08
(m, 2H), 3.84 (s, 3H), 3.80 (d, J=15.8, 1H), 3.40-3.30 (m, 1H),
3.23-3.10 (m, 1H), 2.73-2.63 (m, 1H), 2.63-2.30 (m, 12H), 2.29 (s,
3H), 2.10-1.94 (m, 2H), 1.57-1.17 (m, 10H)
[1306] .sup.13C (100 MHz, CDCl.sub.3)
[1307] .delta. 146.2 (s), 144.4 (s), 133.6 (s), 129.9 (s), 127.9
(d), 127.4 (d), 122.4 (d), 111.5 (d), 89.1 (d), 62.5 (d), 59.1 (t),
58.2 (t), 56.3 (q), 55.5 (2*t), 53.6 (3*t), 51.9 (t), 48.8 (s),
46.5 (q), 33.3 (t), 30.4 (t), 27.98 (t), 27.83 (t), 27.74 (t),
27.23 (t)
EXAMPLE 175
SPH-1494
(4aS,6R,8aS)-3-Methoxy-11-(6-[4-hydroxypiperidine)-1-yl-hexyl)-5,6,9,10,11-
,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol
[1308] C.sub.27H.sub.40N.sub.2O.sub.4 (456.63) ##STR379##
[1309] Yield: 200 mg (24%) of a yellowish oil
[1310] .sup.1H (400 MHz, CDCl.sub.3)
[1311] .delta. 6.64 (d, J=8.1 Hz, 1H), 6.59 (d, J=8.1 Hz, 1H), 6.07
(d, J=10.2 Hz, 1H), 5.97 (dd, J=10.2, 4.9 Hz, 1H), 4.58 (m, 1H),
4.11 (m, 1H), 4.07 (m, 1H), 3.81 (s+m, 4H), 3.71-3.61 (m, 1H), 3.35
(m, 1H), 3.15 (m, 1H), 2.81-2.71 (m, 2H), 2.67 (d, J=15.4, 1H),
2.52-2.36 (m, 4H), 2.34-2.26 (m, 2H), 2.20-2.08 (m, 2H), 2.06-1.94
(m, 2H), 1.93-1.84 (m, 2H), 1.63-1.53 (m, 2H), 1.52-1.38 (m, 5H),
1.32-1.20 (m, 4H)
[1312] .sup.13C (100 MHz, CDCl.sub.3):
[1313] .delta. 146.2 (s), 144.5 (s), 133.6 (s), 129.9 (s), 127.9
(d), 127.4 (d), 122.4 (d), 111.5 (d), 89.1 (d), 62.5 (2*d), 58.9
(2*t), 58.2 (t), 56.3 (q), 51.9 (2*t), 51.3 (t), 48.8 (s), 34.6
(t), 33.4 (t), 30.4 (t), 28.0 (t), 27.8 (2*t), 27.7 (t), 27.3
(t)
EXAMPLE 176
SPH-1521
1-(6-((4aS,6R,8aS)-6-Hydroxy-3-methoxy-4a,5,9,10-tetrahydro-6H-benzofuro[3-
a,3,2-ef][2]benzazepine-11(12H)-yl)-hexyl)-piperidin-4-one
[1314] C.sub.27H.sub.38N.sub.2O.sub.4 (454.61) ##STR380##
[1315] Yield: 125 mg (15%) of a yellowish oil
[1316] .sup.1H (400 MHz, CDCl.sub.3):
[1317] .delta. 6.65 (d, J=8.18 Hz, 1H), 6.60 (d, J=8.18 Hz, 1H),
6.07 (d, J=10.8 Hz, 1H), 5.99 (dd, J=10.8, 4.5 Hz, 1H), 4.60 (m,
1H), 4.18-4.08 (m, 2H), 3.82 (s, 3H), 3.79-3.76 (m, 1H), 3.40-3.30
(m, 1H), 3.22-3.10 (m, 1H), 2.74-2.68 (m, 4H), 2.67-2.62 (m, 1H),
2.53-2.34 (m, 8H), 2.09-1.93 (m, 2H), 1.57-1.42 (m, 6H), 1.37-1.21
(m, 4H)
[1318] .sup.13C (100 MHz, CDCl.sub.3)
[1319] .delta. 209.7 (s), 146.2 (s), 144.5 (s), 133.5 (s), 129.7
(s), 128.1 (d), 127.4 (d), 122.4 (d), 111.5 (d), 89.0 (d), 62.4
(d), 58.1 (2*t), 57.9 (2*t), 56.4 (q), 56.3 (t), 53.4 (t), 52.2
(t), 51.9 (t), 48.8 (s), 41.5 (t), 33.4 (t), 30.4 (t), 27.9 (t),
27.8 (t), 27.7 (t)
EXAMPLE 180
SPH-1363
(4aS,6R,8aS)-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3-
,2-ef][2]benzazepine-11(12H)-yl)methyl-azodicarboxylic
acid-di-tert-butyl ester (CK-24-2)
[1320] ##STR381##
[1321] A solution that consists of 0.300 g (0.104 mmol) of
galanthamine in 3 ml of dichloromethane is introduced at room
temperature, mixed with 0.264 g (1.150 mmol) of
di-tert-butylazodicarboxylate and stirred for four days at room
temperature. After concentration by evaporation in a rotary
evaporator, the residue (0.258 g) is purified by means of flash
chromatography on silica gel (25 g, mobile solvent
dichloromethane/petroleum ether=2/3+4% triethylamine). After drying
under high vacuum, 0.292 g of a white foam is obtained.
[1322] Yield: 0.292 g (0.56 mmol, 54%), colorless foam,
(M.sub.w=517.6)
[1323] TLC: R.sub.f=0.71 (dichloromethane/methanol=9/1+2%
concentrated NH.sub.3 solution)
[1324] Melting point: 59-62.degree. C. (petroleum
ether/dichloromethane=1/1+4% triethylamine)
[1325] IR: KBr
[1326] v (cm.sup.-1) 3557 (v), 3340 (bm), 2932 (s), 2915 (s), 1726
(s), 1711 (s)
[1327] .sup.1H-NMR: (200.13 MHz, CDCl.sub.3, TMS)
[1328] .delta. 6.49-6.66 (m, 2H), 6.39 (s, 0.6 H), 5.84-6.06 (m,
2H), 4.52 (s, 1H), 4.35 (bs, 1H), 3.99-4.17 (m, 2H), 3.71-3.88 (m,
1H), 3.76 (s, 3H), 3.07-3.40 (m, 2H), 2.61 (bd, J=15.7 Hz, 1H),
2.40 (bd, J=11.8 Hz, 0.3H), 1.79-2.05 (m, 2H), 1.56-1.72 (m, 1H),
1.46 (s, 9H), 1.45 (s, 9H)
[1329] .sup.13C NMR: (50.32 MHz, CDCl.sub.3, TMS)
[1330] .delta. 156.7 (s), 155.9 (s), 145.9 (s), 144.0 (s), 132.8
(d), 129.8 (s), 127.6 (d), 126.7 (d), 121.5 (d), 111.1 (d), 88.5
(d), 68.9 (t), 62.4 (t), 61.8 (t) 61.8 (d), 56.6 (t), 55.8 (q),
49.7 (t), 48.1 (s), 35.2 (t), 29.8 (t), 14.32 (q), 14.26 (q)
[1331] LC/MS: t.sub.Ref=9.56 minutes, (Zorbax SB column, 2.1
mm.times.30 mm, RP-18, 3 .mu.m, 0.5 ml/minute, methanol/H.sub.2O
(40/60.fwdarw.100/0 (v/v) in 2 minutes)
[1332] APCI-PI-MS
[1333] 518 (100), 500 (25), 462 (9), 285 (13), 274 (11) 256
(26)
[1334] APCI NI-MS
[1335] 516
EXAMPLE 181
SPH-1362
(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3-
,2-ef][2]benzazepine-11(12H)-yl)methyl-azodicarboxylic acid diethyl
ester (CK-21-3)
[1336] ##STR382##
[1337] 89 .mu.l (0.100 g, 0.57 mmol) of diethylazodicarboxylate is
added to a solution that consists of 0.150 g (0.52 mmol) of
galanthamine in 2 ml of dichloromethane, and the solution is
stirred for 72 hours at room temperature. After concentration by
evaporation in a rotary evaporator, the residue (0.258 g) is
purified by means of flash chromatography on silica gel (25 g,
mobile solvent dichloromethane/petroleum ether=1/1+4%
triethylamine). After drying under high vacuum, 0.168 g of a white
foam is obtained.
[1338] Yield: 0.168 g (0.36 mmol, 70%), white foam,
(M.sub.w=461.6)
[1339] TLC: R.sub.f=0.66 (dichloromethane/methanol=9/1+2%
concentrated NH.sub.3 solution)
[1340] Melting point: 40-42.degree. C. (petroleum
ether/dichloromethane=1/1+4% triethylamine)
[1341] IR: KBr
[1342] v (cm.sup.-1) 3553 (v), 3305 (m), 2981 (s), 2935 (s), 1742
(s), 1722 (s)
[1343] .sup.1H-NMR (200.13 MHz, CDCl.sub.3, TMS)
[1344] .delta. 6.77 (bs, 1H), 6.64 (d, J=8.3 Hz, 1H), 6.58 (d,
J=8.1 Hz, 1H), 5.84-6.06 (m, 2H), 4.53 (s, 1H), 3.98-4.23 (m, 6H),
3.69-3.87 (m, 1H), 3.76 (s, 3H), 3.01-3.42 (m, 2H), 2.66 (bd,
J=15.7 Hz, 1H), 2.33 (bs, 0.2H), 1.65-1.77 (m, 2H), 1.35-1.47 (m,
1H), 1.09-1.35 (m, 6H)
[1345] .sup.13C-NMR: (50.32 MHz, CDCl.sub.3, TMS)
[1346] .delta. 155.1 (s), 145.9 (s), 143.9 (s), 132.8 (d), 130.2
(s), 127.5 (d), 126.9 (d), 121.4 (d), 111.1 (d) 81.2 (s), 80.9 (s),
69.5 (t), 61.9 (d), 56.8 (t) 55.8 (q), 49.8 (t), 48.1 (s), 35.6
(t), 29.8 (t), 28.1 (1), 28.0 (q)
[1347] LC/MS: t.sub.Ref=8.08 minutes, (Zorbax SB column, 2.1
mm.times.30 mm, RP-18, 3 .mu.m, 0.5 ml/minute, methanol/H.sub.2O
(40/60.fwdarw.100/0 (v/v) in 2 minutes)
[1348] APCI-PI-MS
[1349] 462 (100), 444 (32), 286 (34), 274 (12), 256 (29)
[1350] APCI-NI-MS
[1351] 460 Process for Synthesis of Norgalanthamine ##STR383##
Method A
[1352] 20 g (70 mmol) of galanthamine is reacted with 14.206 g
(0.07 mol) of m-chloroperbenzoic acid (85%) in 350 ml of
dichloromethane and subsequent addition of 9.730 g (35 mmol) of
Fe(II) SO.sub.4*7H.sub.2O in 100 ml of methanol. The reaction is
terminated after 20 minutes with 200 ml of 2N hydrochloric acid.
After the slightly volatile solvent is distilled off, after the
acids and bases are separated and after the I e(OH).sub.x
precipitate is filtered off by means of a Hyflo nutsch, the
filtrate is dried on Na.sub.2SO.sub.4, filtered and concentrated by
evaporation. About 18 g of the crude product is obtained in the
form of a yellow foam.
Working-up Variant 1 (CK-1-1)
[1353] The crude product (18.46 g) is taken up in about 200 ml of
ethyl acetate/methanol/triethylamine (90/10/2) while being heated
slightly. During cooling, I e(OH).sub.x is again precipitated,
which is filtered off. The purification is carried out by means of
MPLC chromatography (silica gel, h=25 cm, d=3.6 cm, v=300 nm) with
an altered mobile solvent mixture (ethyl
acetate/methanol/triethylamine=95/5/2-90/10/2.fwdarw.80/20/2). The
norgalanthamine content is only 68% according to an HPLC
quantification (caffeine as an internal standard).
[1354] Yield: 10.34 g (38 mmol, 54%), yellowish, amorphous solid
(M.sub.w=273.3)
Working-up Variant 2 (CK-1-11)
[1355] The crude product (16.48 g) is dissolved in 100 ml of
methanol, mixed with a solution that consists of 12.86 g (102 mmol)
of oxalic acid dihydrate in 100 ml of methanol and carefully heated
to homogenize the solution. Then, the solution is allowed to cool
to room temperature and then to cool to about 5.degree. C., the
crystallized product is filtered off, and the precipitate is washed
with methanol. The combined methanol solutions that are
concentrated by evaporation are again subjected to
recrystallization.
[1356] Yield: 16.108 g (43 mmol, 62%), colorless crystalline
solid
[1357] Cld. for C.sub.16H.sub.19NO.sub.3.C.sub.2H.sub.2O.sub.40.5
H.sub.2O TABLE-US-00142 C, 58.06 H, 5.95 N, 3.76 Fnd. C, 57.91 H,
5.88 N, 3.69
Method B (CK-1-10)
[1358] 2.000 g (6.96 mmol) of galanthamine and 0.981 g (10.44 mmol)
of hydrogen peroxide-urea-adduct are stirred for two days in 25 ml
of dichloromethane and 5 ml of methanol at room temperature, then
mixed with 0.030 g of platinum/activated carbon and stirred for one
hour at room temperature. When the catalyst is added, a strong gas
development can be observed. Then, 0.967 g (3.48 mmol) of Fe(II)
SO.sub.4*7H.sub.2O in 5 ml of MeOH is added, and the brown
suspension is vigorously stirred. The reaction is terminated after
20 minutes with 50 ml of saturated NaHCO.sub.3 solution. The
reaction solution is filtered by means of a Hyflo filter aid. The
phases are separated, and the aqueous phase is extracted
exhaustively with dichloromethane. The combined organic extracts
are washed with saturated NaHCO.sub.3 solution (50 ml) and with
saturated NaCl solution (50 ml), dried on Na.sub.2SO.sub.4,
filtered and concentrated by evaporation. The crude product (1.925
g) is dissolved in 10 ml of methanol, mixed with a solution that
consists of 1.332 g (10.6 mmol) of oxalic acid dihydrate in 10 ml
of methanol and carefully heated to homogenize the solution. Then,
the solution is allowed to cool to room temperature and then to
about 5.degree. C., the crystallized product is filtered off, and
the precipitate is washed with methanol. The combined methanol
solutions that are concentrated by evaporation are again subjected
to recrystallization.
[1359] Yield: 1.010 g (2.7 mmol, 39%), colorless crystalline solid
(M.sub.w=371.4), according to HPLC 97%
Method C:
Demethylation of Norgalanthamine by Means of
Diethylazodicarboxylate (CK-1-7)
[1360] 178 .mu.l (0.199 g, 1.144 mmol) of diethylazodicarboxylate
is added to a solution that consists of 0.300 g (1.04 mmol) of
galanthamine in 3 ml of dichloromethane, and the solution is
stirred for three days at room temperature. After concentration by
evaporation in a rotary evaporator at 40.degree. C., the residue is
dissolved in 5 ml of ethanol and 5 ml of 4N hydrochloric acid and
stirred at 80.degree. C. for one and one-half hours. The reaction
is cooled to room temperature, and the solution is diluted with 5
ml of water. The ethanol portion is distilled off in a rotary
evaporator, and the aqueous phase is extracted three times with 10
ml of diethyl ether in each case. The aqueous phase is set at pH
10-11 by adding sodium carbonate and sodium hydroxide, and it is
extracted four times with 20 ml of dichloromethane in each case.
The combined phases are washed with 40 ml of saturated common salt
solution and dried on Na.sub.2SO.sub.4. After filtering and
concentration by evaporation, the residue (0.268 g) is purified by
means of MPLC on silica gel (60 g, mobile solvent ethyl
acetate/ethanol/triethylamine=19/1/0.4). After drying under high
vacuum, 0.136 g of a yellowish foam is obtained.
[1361] Yield: 0.136 g (0.495 mmol, 48%), white-yellowish foam,
(M.sub.w=273.3), HPLC identical to a reference sample
[1362] HPLC: t.sub.Ref=3.79 minutes, 96.3% (Merck Purospher column,
4.0 mm.times.125 mm, RP-18e, 5 .mu.m, 250 nm, 1 ml/minute,
acetonitrile/20 mmol of trichloroacetic acid in H.sub.2O (15/80
v/v)
Method D:
Demethylation of Norgalanthamine by Means of
Di-tert-butylazodicarboxylate (CK-1-6)
[1363] 0.300 g (1.04 mmol) of galanthamine and 0.264 g (1.144 mmol)
of di-tert-butylazodicarboxylate in 3 ml of dichloromethane are
reacted analogously to the above-described procedure for three days
at room temperature, concentrated by evaporation and stirred in 5
ml of ethanol and 5 ml of 4N hydrochloric acid for 30 minutes at
80.degree. C. The reaction is cooled to room temperature, and the
solution is diluted with 5 ml of water. After the aqueous
working-up, the residue (0.259 g) is purified by means of MPLC on
silica gel (60 g, mobile solvent ethyl
acetate/ethanol/triethylamine=19/1/0.4). After drying under high
vacuum, 0.132 g of a white-yellowish foam is obtained.
[1364] Yield: 0.132 g (0.48 mmol, 46%), white-yellowish foam,
(M.sub.w=273.3), HPLC identical to a reference sample
[1365] HPLC: t.sub.Ref=3.74 minutes, 100% (Merck Purospher column,
4.0 mm.times.125 mm, RP-18e, 5 .mu.m, 250 nm, 1 ml/minute,
acetonitrile/20 mmol of trichloroacetic acid in H.sub.2O (15/80
v/v)
Method E:
Saponification of
(4aS,6R,8aS)-3-Methoxy-12-trifluoroacetyl-5,6,9,10,11,12-hexahydro-4aH-[1-
]benzofuro[3a,3,2-ef][2]benzazepin-6-ol
Method A (CK-40-2)
[1366] 3.3 ml of a 0.25 M potassium hydroxide solution (0.045 g
(0.81 mmol) in dioxane/methanol/water (10/2/5) is mixed with 0.100
g (0.27 mmol) of N-trifluoroacetylnorgalanthamine and stirred for
one hour at room temperature. Then, the solution is diluted with
0.4 ml of 2N hydrochloric acid, and the volatile components are
distilled off in a rotary evaporator. The residue is taken up with
saturated sodium carbonate solution and extracted five times with
dichloromethane. The combined extracts are washed with saturated
sodium chloride solution, dried on sodium sulfate, filtered and
concentrated by evaporation in a rotary evaporator under reduced
pressure. 0.070 g of a white-yellowish foam with a purity of 95%
(HPLC, caffeine as an internal standard) is obtained.
[1367] Yield: 0.070 g (0.067, 0.25 mmol, 91%), white-yellowish foam
(M.sub.w=273.3)
Method B (CK-40-3)
[1368] A solution that consists of 0.100 (0.27 mmol) of
N-trifluoroacetylnorgalanthamine and 0.243 g (1.35 mmol) of 30%
sodium methanolate-methanol solution in 3 ml of
tetrahydrofuran/methanol (1/1) is stirred for three hours at room
temperature. The solution is neutralized with 0.7 ml of 2N
hydrochloric acid, and the solution is evaporated to the dry state,
the residue is taken up with 25 ml of dichloromethane and washed
with saturated sodium carbonate solution and with saturated sodium
chloride solution, dried on sodium sulfate, filtered and
concentrated by evaporation in a rotary evaporator under reduced
pressure. After drying in a vacuum, a yellowish foam (0.067 g) with
a purity of 76% (HPLC, caffeine as an internal standard) is
obtained.
[1369] Yield: 0.067 g (0.051 g, 0.19 mmol, 69%), white-yellowish
foam (M.sub.w=273.3)
Method G:
Separation of (+) and (-) Isomers from rac.Norgalanthamine (4)
Production of (-) Norgalanthamine (8)
[1370] A solution of 7.72 g (20.0 mmol) of
(+)-O,O-di-p-toluoyltartaric acid in 15 ml of methanol is added in
drops to a solution of 10.92 g (40.0 mmol) of rac.norgalanthamine
(4) in 40 ml of methanol and then rewashed with 1 ml of methanol.
The solution is mixed with a seed crystal and allowed to stand for
two days at 4.degree. C. Then, a glass rod is passed vigorously
through the solution, and it is allowed to stand for another two to
five days at 4.degree. C., whereby a glass rod is always passed
vigorously through the solution again. Then, the precipitated salt
is suctioned off, rewashed three times with ice-cold methanol and
taken up in 100 ml of water. The aqueous phase is made basic with
concentrated aqueous ammonia and extracted three times with 60 ml
of ethyl acetate each. The combined organic phases are washed once
with saturated aqueous sodium chloride solution, dried
(Na.sub.2SO.sub.4, activated carbon), filtered and concentrated by
evaporation, by which 2.90 g (37.5% of theory) of colorless
crystals with an angle of rotation of .alpha..sub.D.sup.22
[CHCl.sub.3=-62.4 of (-) norgalanthamine (8) is obtained. The
methanolic mother liquor is concentrated by evaporation, the
residue is taken up in 100 ml of water and treated like the pure
salt above, by which 4.1 g (53.1% of theory) of crude product can
be recovered, which is used as follows for recovering (+)
norgalanthamine.
Production of (+) Norgalanthamine
[1371] A solution of 2.9 g (7.5 mmol) of
(-)-O,O-di-p-toluoyltartaric acid in 5.6 ml of methanol is added in
drops to a solution of 4.1 g (15.0 mmol) of recovered
norgalanthamine (this is concentrated in (+) isomers) in 21 ml of
methanol, whereby it is rewashed with 0.5 ml of ethanol. The
solution is mixed with a seed crystal and treated as in the
recovery of (-) norgalanthamine, by which 3.0 g (39% of theory) of
colorless crystals is obtained with an angle of rotation of
.alpha..sub.D.sup.22 [CHCl.sub.3]+57.5.degree. (+)
norgalanthamine.
[1372] As an alternative, (+) norgalanthamine is also obtained by
reaction of rac.norgalanthamine (4) with
(-)-O,O-di-p-toluoyltartaric acid analogously to the above
instructions with an angle of rotation of .alpha..sub.D.sup.22
[CHCl.sub.3]=+60.5.degree..
EXAMPLE 182
SPH-1534
(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro]3a,3-
,2-ef][2]benzazepine-11(12H)-yl)carboxylic acid triisopropyl silyl
ester (CK-9-2)
[1373] ##STR384##
[1374] 0.200 g (0.732 mmol) of norgalanthamine (68%(HPLC, CK-1-1))
and 0.47 ml (0.341 g, 3.37 mmol) of triethylamine are introduced at
-80.degree. C. in 6 ml of dichloromethane in a single-neck flask
with a septum and a CO.sub.2 tank, which is filled by evacuation
and flushing with carbon dioxide. Then, the solution is cooled to
the point that solid carbon dioxide precipitates in the reaction
solution. After one and one-half hours at about -80 to -90.degree.
C., triisopropyl silyl chloride (0.155 ml, 0.141 g, 0.732 mmol) is
added via a syringe. Then, the reaction solution is slowly heated
overnight to room temperature. In this case, a colorless
precipitate settles out. The reaction solution is taken up with 10
ml of 1N hydrochloric acid, the phases are separated, and the
aqueous phase is extracted twice with 10 ml of dichloromethane. The
combined organic phases are washed with 10 ml of 1N hydrochloric
acid and with 10 ml of saturated common salt solution, dried on
Na.sub.2SO.sub.4, filtered and concentrated by evaporation. The
yellow viscous oil (0.315 g) is purified by means of column
chromatography on silica gel with the mobile solvent petroleum
ether/ethyl acetate. After concentration by evaporation, 0.208 g of
the product is obtained in the form of a colorless foam.
[1375] Yield: 0.208 g (0.44 mmol, 60%), colorless foam,
(M.sub.w=473.7)
[1376] TLC: R.sub.f=0.35 (petroleum ether/ethyl acetate=1/1)
[1377] Melting point: 53-54.degree. C. (petroleum ether/ethyl
acetate=1/1)
[1378] IR: KBr
[1379] v (cm.sup.-1) 3556 (m), 3454 (m), 2946 (s), 1679 (s)
[1380] .sup.1H-NMR (200.13 MHz, CDCl.sub.3, TMS)
[1381] .delta. 6.60-6.85 (m, 2H), 5.93-6.09 (m, 2H), 4.90 (d,
J=15.3 Hz, 0.4H), 4.80 (d, J=15.7 Hz, 0.6H), 4.57 (s, 1H),
4.06-4.40 (m, 3H), 3.83 (s, 3H), 3.27-3.57 (m, 0.4H), 2.70 (bd,
J=16.3 Hz, 1H), 2.41 (bd, J=11.0 Hz, 0.6H), 1.60-2.11 (m, 3H), 1.29
(bh, J=5.1 Hz, 3H), 1.05 (d, J=6.8 Hz, 8H), 0.98 (d, J=6.9 Hz,
10H)
[1382] .sup.13C-NMR: (50.32 MHz, CDCl.sub.3, TMS)
[1383] .delta. 154.4 and 153.9 (s), 146.5 and 146.2 (s), 144.3 and
144.1 (s), 132.2 and 131.8 (d), 129.4 and 129.2 (s), 127.9 (d),
126.5 (d), 121.6 and 120.9 (d), 111.1 and 110.9 (d), 88.2 (d), 61.8
(d), 55.8 and 55.7 (q), 52.5 and 51.7 (t), 48.3 (s), 46.4 and 45.8
(t), 37.3 and 36.1 (t), 29.7 (t), 17.77 17.75, 17.68 and 17.65 (q),
11.9 (d)
EXAMPLE 183
SPH-1535
(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3-
,2-ef][2]benzazepine-11(12H)-yl)carboxylic
acid-tert-butyldiphenylsilyl ester
[1384] ##STR385##
[1385] Analogously to the instructions for the
N-triisopropylsilyloxycarbonylnorgalanthamine (TBDP-C1),
norgalanthamine (68% (HPLC, CK-1-1)) is reacted with 1 or 1.1
equivalents of tert-butyldiphenylsilyl chloride and 5 equivalents
of triethylamine. Then, the reaction is terminated with water or
dilute hydrochloric acid, the phases are separated, and the aqueous
phase is extracted with dichloromethane. After drying with
Na.sub.2SO.sub.4, filtering and concentration by evaporation, the
amorphous foam is purified by means of column chromatography
(silica gel, ethyl acetate/petroleum ether=1/1). A colorless foam
is obtained. TABLE-US-00143 Aqueous Yield (M.sub.w = Conditions:
Working-Up: 524.7): CK- 0.200 g (0.732 10 ml of 1N 0.282 g (0.538
10-1 mmol) of hydrochloric mmol, 73%) norgalanthamine, acid 0.172
ml (0.181 g, 0.732 mmol) of TBDP-C1 CK- 0.200 g (0.732 10 ml of
0.196 g (0.37 10-2 mmol) of distilled water mmol, 51%)
norgalanthamine, 0.172 ml (0.181 g, 0.732 mmol) of TBDP-C1 CK-
0.400 g (1.46 mmol) 20 ml of 0.3 M 0.505 g (0.96 10-3 of
norgalanthamine, hydrochloric mmol, 66%) 0.38 ml (0.398 g, acid
1.606 mmol) of TBDP-C1
[1386] TLC: R.sub.f=0.40 (petroleum ether/ethyl acetate=1/1)
[1387] Melting point: 71-80.degree. C. (petroleum ether/ethyl
acetate=1/1)
[1388] IR: KBr
[1389] v (cm.sup.-1) 3553 (m), 3454 (bm), 2932 (s), 1686 (s) 1625
(m)
[1390] .sup.1H-NMR: (200.13 MHz, CDCl.sub.3, TMS)
[1391] .delta. 7.20-7.68 (m, 10H), 6.56-6.77 (m, 2H), 4.83-5.03 (m,
1H), 5.03 (s, 1H), 4.02-4.40 (m, 3H), 3.83 (s, 3H), 3.63 (bt,
J=13.1 Hz, 0.3H), 3.41 (bf, J=12.9 Hz, 0.7H), 2.70 (bt, J=15.6 Hz,
1H), 2.41 (bd, J=19.7 Hz, 1H), 1.78-2.10 (m, 2H), 1.54-1.76 (m,
1H), 1.05 (s, 9H)
[1392] .sup.13C-NMR: (50.32 MHz, CDCl.sub.3, TMS)
[1393] .delta. 153.7 and 153.2 (s), 146.6 and 146.1 (s), 144.4 and
144.2 (s), 135.0 and 134.7 (d), 132.4 and 132.3 (s), 132.4 (s),
132.3 and 131.8 (s), 129.7 and 129.6 (d), 129.2 and 129.0 (s),
126.5 (s), 121.8 and 121.2 (d), 111.1 and 110.9 (d), 88.3 and 88.1
(d), 61.8 (d), 55.9 (q), 52.7 and 51.8 (t), 48.3 (s), 46.5 and 46.1
(t), 37.4 and 35.8 (t), 29.7 (t), 27.0 and 26.9 (q), 19.1 and 18.9
(d)
EXAMPLE 184
SPH-1536
(4aS,6R,8aS)-3-Methoxy-12-trifluoroacetyl-5,6,9,10,11,12-hexahydro-4aH-[1]-
benzofuro[3a,3,2-ef]-[2]benzazepin-6-ol
[1394] ##STR386## Method A (CK-32-1)
[1395] A solution that consists of 5 ml of dichloromethane and 4.6
ml (3.333 g, 32.9 mmol) of trifluoroacetic acid anhydride is added
in drops at 0.degree. C. within 15 minutes to a solution of 1.00 g
(3.66 mmol) of norgalanthamine (68% (HPLC, CK-1-1)), 1.5 ml (1.095
g, 10.8 mmol) of triethylamine in 5 ml of absolute dichloromethane.
Then, the solution is stirred for 1.75 hours at 0.degree. C., and
the reaction is then terminated by adding 5.5 ml of 2N hydrochloric
acid. The phases are separated, and the aqueous phase is extracted
three times with 20 ml of dichloromethane in each case. The
combined organic phases are washed with 30 ml of saturated common
salt solution, dried on Na.sub.2SO.sub.4, filtered and concentrated
by evaporation. The crude product (0.866 g) is purified by means of
MPLC (silica gel, h=25 cm, d=3.6 cm, v 300 nm, mobile solvent
petroleum ether/ethyl acetate 2/1). After concentration by
evaporation and drying in a vacuum, the product is obtained as a
white-yellowish foam (0.866 g).
[1396] Yield: 0.866 g (1.95 mmol, 53%), white-yellowish foam,
M.sub.w =369.3
Method B (CK-32-2)
[1397] 2.52 g of norgalanthamine (.apprxeq.90%, 2.268 g, 8.30 mmol)
and 3.45 ml (2.520 g, 24.9 mmol) of triethylamine are dissolved in
20 ml of absolute dichloromethane. Then, a solution that consists
of 1.211 ml (1.830 g, 8.71 mmol) of trifluoroacetic acid anhydride
and 10 ml of dichloromethane is added in drops within 30 minutes at
0.degree. C. It is heated to room temperature, additional
trifluoroacetic acid anhydride (1.2 ml, 1.830 g, 8.71 mmol) is
added in portions, and the reaction solution is stirred overnight.
The solution is diluted with 120 ml of ethyl acetate and washed
with 50 ml of 1N hydrochloric acid in each case, with 50 ml of
saturated NaHCO.sub.3 solution and twice with 50 ml of saturated
common salt solution in each case, dried on Na.sub.2SO.sub.4 and
filtered. After the concentration by evaporation, the residue is
dissolved in 150 ml of dichloromethane, and 141.1 g of a 5%
NH.sub.3 solution is added. The two-phase solution is vigorously
stirred at room temperature. After 30 minutes, the phases are
separated, and the aqueous phase is extracted with dichloromethane
(twice, 50 ml). The combined organic phases are washed with 1N
hydrochloric acid (twice, 50 ml) and with saturated common salt
solution (twice, 50 ml), dried on Na.sub.2SO.sub.4, filtered and
concentrated by evaporation. The residue (2.77 g) is purified by
means of MPLC (450 g of silica gel, v=300 nm, mobile solvent
petroleum ether/ethyl acetate=1/1). After concentration by
evaporation and drying in a vacuum, the product is obtained as a
white-yellowish foam (2.6171 g).
[1398] Yield: 2.6171 g (7.09 mmol, 85%), white-yellowish foam
(M.sub.w=369.3)
[1399] TLC: R.sub.f=0.23 (petroleum ether/ethyl acetate=1/1)
[1400] Melting point: 65-68.degree. C. (petroleum ether/ethyl
acetate=1/1)
[1401] IR: KBr
[1402] v (cm.sup.-1) 3546.3 (v), 3417 (by), 2924 (m), 1690 (s)
[1403] .sup.1H-NMR: (200.13 MHz, CDCl.sub.3, TMS)
[1404] .delta. 6.62-6.92 (m, 2H), 5.88-6.16 (m, 2H), 5.25 (d,
J=15.2 Hz, 0.5H), 4.85 (d, J=16.6 Hz, 0.5H), 4.42-4.77 (m, 2H),
4.02-4.34 (m, 2H), 3.84 (s, 3H), 3.60-3.83 (m, 0.5H), 3.27-3.50 (m,
0.5H), 2.72 (d, J=16.0 Hz, 1.0H), 2.29 (bs, 0.7H), 1.80-2.13 (m,
3H)
[1405] .sup.13C-NMR: (50.32 MHz, CDCl.sub.3, TMS)
[1406] .delta. 156.1 (m), 146.4 and 146 (s), 144.8 and 144.7 (s),
.delta. 132.0 (s), 128.8 and 128.5 (d), 126.6 and 126.1 (s), 125.7
and 125.3 (d), 120.9 and 119.1 (d), 121.9 (q, J=288 Hz), 111.3 (d),
88.1 and 88.0 (d), 61.6 (d), 55.8 (q), 52.6 and 51.8 (t), 47.9 (s),
46.5 and 46.3 (t), 38.4 and 35.4 (t), 29.64 and 29.58 (t)
EXAMPLE 185
SPH-1537
(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3-
,2-ef][2]benzazepine-11(12H)-yl)carboxylic acid allyl ester
[1407] ##STR387## Variant A (CK-17-1)
[1408] 3.000 g (11.0 mmol) of norgalanthamine is introduced at
0.degree. C. into a solution that consists of 10 ml of absolute
dichloromethane and 4.6 ml (3.333 g, 32.9 mmol) of triethylamine.
At 0.degree. C., a solution that consists of 1.454 g (12.1 mmol) of
allyl chloroformate and 5 ml of absolute dichloromethane is added
in drops within 20 minutes. The reaction solution is stirred
overnight and in this case heated to room temperature. The reaction
solution is taken up with 50 ml of 1N hydrochloric acid and 50 ml
of dichloromethane. The phases are separated, and the aqueous phase
is extracted three times with 50 ml of dichloromethane in each
case. The combined organic phases are washed with 100 ml of
saturated common salt solution, dried on Na.sub.2SO.sub.4, filtered
and concentrated by evaporation. The crude product (3.2 g) is
separated by means of MPLC (silica gel, h=25 cm, d=3.6 cm, v=200
nm, mobile solvent petroleum ether/ethyl acetate=2/1). After
concentration by evaporation and drying in a vacuum, the product is
obtained as a white-yellowish foam (2.594 g) and 0.232 g of a
by-product, which was identified as
N,O-diallyloxycarbonylnorgalanthamine.
[1409] Yield: 2.594 g (7.26 mmol, 66%)
[1410] TLC: R.sub.f=0.30 (petroleum ether/ethyl acetate=1/1)
[1411] Melting point: 44-46.degree. C. (petroleum ether/ethyl
acetate=1/1)
[1412] IR: KBr
[1413] v (cm.sup.-1) 3550 (m), 3458 (m), 1700 (s)
[1414] .sup.1H-NMR: (200.13 MHz, CDCl.sub.3, TMS)
[1415] .delta. 6.62-6.86 (m, 2H), 5.95-6.09 (m, 2H), 5.76-5.94 (m,
1H), 5.10-5.33 (m, 2H), 4.93 and 4.83 (d and d, J=15.1 Hz, and
J=15.7 Hz, 1H), 4.45-4.68 (m, 3H), 4.05-4.44 (m, 3H), 3.83 (s, 3H),
3.27-3.55 (m, 1H), 2.70 (bdd, J=15.1 Hz, and J=15.7 Hz, 1H), 2.26
(bs, 0.5H), 1.93-2.11 (m, 1H), 1.69-1.92 (m, 1H)
[1416] .sup.13C-NMR: (50.32 MHz, CDCl.sub.3, TMS)
[1417] .delta. 155.1 and 155.0 (s), 146.4 (s), 144.3 (s), 132.7
(d), 132.3 and 132.0 (s), 129.1 (s), 128.0 (d), 126.2 (d), 121.4
and 120.8 (d), 117.3 and 116.7 (t), 111.1 and 110.9 (d), 88.1 and
88.0 (d), 65.9 and 65.8 (t), 61.7 (d), 55.7 (q), 51.8 and 51.3 (t),
48.2 (s), 45.8 and 45.3 (t), 37.2 and 36.3 (t), 29.7 (t)
EXAMPLE 186
SPH-1538
(4aS,6R,8aS)-6-(2-Allyloxycarbonyloxy)-3-methoxy-5,6,9,10-tetrahydro-4aH-[-
1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)carboxylic acid
allyl ester
[1418] ##STR388##
[1419] Colorless wax, (M.sub.w=441.5)
[1420] TLC: R.sub.f=0.51 (petroleum ether/ethyl acetate 1/1)
[1421] IR: KBr
[1422] v (cm.sup.-1) 2947 (m), 1739 (s), 1700 (s)
[1423] .sup.1H-NMR: (200.13 MHz, CDCl.sub.3, TMS)
[1424] .delta. 6.56-6.81 (m, 2H), 6.22 (d, J=10.3 Hz, 1H),
5.73-6.04 (m, 3H), 5.08-5.40 (m, 5H), 4.90 (d, J=15.5 Hz, 0.5H),
4.80 (d, J=15.9 Hz, 0.5H), 4.44-4.64 (m, 5H), 4.04-4.43 (m, 2H),
3.82 (s, 3H), 3.24-3.54 (m, 1H), 2.78 (bd, J=16.4 Hz, 1H),
1.65-2.21 (m, 3H)
[1425] .sup.13C-NMR: (50.32 MHz, CDCl.sub.3, TMS)
[1426] .delta. 155.0 and 154.8 (s), 154.4 (s), 147.2 (s), 144.1 (s)
132.7 (d), 131.5 (d), 130.9 (s), 130.6 (d), 128.9 and 128.8 (s),
122.3 (d), 120.6 and 120.1 (d), 118.3 (t), 117.2 and 116.6 (t),
111.5 and 111.3 (d), 85.3 (d), 68.1 (t), 66.5 (d), 65.8 and 65.7
(t), 55.8 (q), 51.6 and 51.2 (t), 47.8 (s), 45.6 and 45.2 (t), 37.6
and 36.7 (t), 27.5 (t)
Variant B (CK-17-2)
[1427] 1.000 g (3.66 mmol) of norgalanthamine (68% (HPLC, CK-1-1)),
dissolved in 3 ml of absolute dichloromethane, and 0.441 g (3.66
mmol) of allyl chloroformate, dissolved in 2 ml of absolute
dichloromethane, are reacted analogously to method A with 1.48 ml
(1.448 g, 18.3 mmol) of pyridine. After aqueous working-up
analogously to method A and column chromatography (50 g of silica
gel, mobile solvent petroleum ether/ethyl acetate=2/1.fwdarw.1/1),
0.784 g of a colorless foam and 0.214 g of the same by-product are
obtained.
[1428] Yield: 0.784 g (2.19 mmol, 60%)
EXAMPLE 187
[1429] ##STR389##
Steps 1-4
Immobilization of
(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro-[3a-
,3,2-ef][2]benzoazepine-11(12H)-yl)carboxylic Acid Allyl Ester on a
Hydroxymethyl-Polystyrene Resin (Merrifield Resin)
[1430] In a 5-ml-polyethylene frit that is sealed on both sides,
0.200 g (0.208 mmol) of hydroxymethylpolystyrene resin (1.04
mmol/g, Merrifield resin.sup.3) is suspended in 3 ml of
dichloromethane, and it is shaken for 30 minutes at about 40.times.
per minute. After filtering, 0.095 g (0.832 mmol) of glutaric acid
anhydride, and 178 .mu.l (0.134 g, 1.04 mmol) of
ethyldiisopropylamine in 2 ml of dichloromethane are added, and the
suspension is shaken for 16 hours at room temperature at about
40.times. per minute. The reaction solution is filtered off, and
the resin is washed once with dichloromethane, once with methanol
and five times with dichloromethane with 2.5 ml in each case. The
resin is subsequently suspended in 77 .mu.l (0.075 g, 0.624 mmol)
of pivaloyl chloride, 178 .mu.l (0.134 g, 1.04 mmol) of
ethyldiisopropylamine in 1.75 ml of dichloromethane and shaken for
six hours at room temperature. After filtering and washing with
dichloromethane (1.times.2.5 ml), tetrahydrofuran (1.times.2.5 ml)
and dichloromethane (5.times.2.5 ml), the resin is shaken in a
solution that consists of 0.230 g (0.624 mmol) of
N-allyloxycarbonylnorgalanthamine, 0.013 g (0.104 mmol) of
4-dimethylaminopyridine and 178 .mu.l (0.134 g, 1.04 mmol) of
ethyldiisopropylamine in 2 ml of dichloromethane at room
temperature. After 22 hours, the reaction is terminated by
filtering off the reaction solution, the resin is washed with
dichloromethane (1.times.2.5 ml), with dimethylformamide
(2.times.2.5 ml) and with dichloromethane (5.times.2.5 ml), dried,
suctioned off and dried overnight in a vacuum at 30 to 50 mbar.
[1431] To determine the concentration, an aliquot of resin (0.262
g) in 2.5 ml of methanol/tetrahydrofuran (1/3) is steeped for 30
minutes, filtered and suspended in a solution of 0.168 g (0.933
mmol) of 30% sodium methanolate-methanol solution in 0.5 ml of
methanol and 1.5 ml of tetrahydrofuran. The mixture is shaken for
15.5 hours at room temperature, filtered off, and the resin is
extracted three times with methanol/dichloromethane (1/1, 2.5 ml)
and three times with dichloromethane (2.5 ml). The combined
filtrates are neutralized with 95 .mu.l (0.067 g, 1.248 mmol) of
trifluoroacetic acid and concentrated by evaporation in a rotary
evaporator. The residue is purified by means of column
chromatography (5 g of silica gel, mobile solvent petroleum
ether/ethyl acetate=1/1). After concentration by evaporation and
drying under high vacuum, 0.048 g of a colorless, vitreous solid is
obtained.
[1432] Yield: 0.048 g (0.13 mmol, 65% relative to the degree of
substitution of the hydroxymethyl resin), .sup.1H-NMR spectrum
identical to the starting material
EXAMPLE 187
Steps 5-8
SPH-1539
1-(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a-
,3,2-ef]-[2]benzazepine-11(12H)-yl)-6-(4-hydroxy-1-piperidyl)hexan-1-one
(CK-36-1)
[1433] ##STR390##
[1434] 0.273 g of resin, produced from 0.200 g (0.208 mmol) of
hydroxymethylpolystyrene resin.sup.7 (1.04 mmol/g) according to the
above-described method A, 0.120 g (0.104 mmol) of
Pd(Ph.sub.3P).sub.1, and 0.292 g (2.08 mmol) of dimedone are shaken
in 1.2 ml of tetrahydrofuran in a 5-ml-polyethylene frit that is
sealed on both sides for six hours at room temperature at about
40.times. per minute. The resin is filtered and washed with
dichloromethane (1.times.2.5 ml), with
dichloromethane/methanol/ethyldiisopropylamine (5/4/1) (3.times.2.5
ml) and finally with dichloromethane (5.times.2.5 ml). The resin is
subsequently mixed with a solution that consists of 96 .mu.l (0.133
g, 0.624 mmol) of 6-bromocaproyl chloride and 178 .mu.l (0.134 g,
1.04 mmol) of ethyldiisopropylamine in 2 ml of dichloromethane and
shaken for five hours at room temperature. After washing with
dimethylformamide (6.times.2.5 ml), the resin is shaken in a
solution that consists of 0.210 g (2.08 mmol) of
4-hydroxypiperidine and 2 ml of dimethylformamide for twelve hours
at room temperature. The resin is washed three times with 2.5 ml of
dichloromethane in each case and three times with 2.5 ml of
tetrahydrofuran in each case and subsequently suspended in a
solution of 0.168 g (0.933 mmol) of 30% sodium methanolate-methanol
solution in 0.5 ml of methanol and 1.5 ml of tetrahydrofuran. After
twelve hours at room temperature, the resin is filtered and
extracted with methanol/dichloromethane (1/1, 3.times.2.5 ml) and
with dichloromethane (3.times.2.5 ml). The combined filtrates are
neutralized with 95 .mu.l (0.067 g, 1.248 mmol) of trifluoroacetic
acid and concentrated by evaporation in a rotary evaporator at
about 2 ml volumes. The crude product is purified by means of
preparative thin-layer chromatography (PSC chromatoplate.sup.8,
mobile solvent dichloromethane/methanol=9/1+3% triethylamine).
Triethylammonium trifluoroacetate is then separated from the
product fraction that is concentrated by evaporation by means of
column filtration via aluminum oxide (pH 9-10, mobile solvent
dichloromethane/methanol=20/1). After concentration by evaporation
and drying under high vacuum, 0.012 g of the product is obtained in
the form of a yellowish foam. .sup.7Hydroxymethyl resin, D-1160,
Bachem Feinchemikalien AG .sup.8PSC chromatoplate by Merck, Art.
No.: 113 895, 20.times.20 cm, 1 mm, silica gel 60 F.sub.254
[1435] Yield: 0.012 g (0.025 mmol, 12% relative to the degree of
substitution of the hydroxymethyl resin), white-brownish wax
(M.sub.w=470.6)
[1436] TLC: R.sub.f=0.32 (dichloromethane/methanol=8/2+2%
triethylamine)
[1437] HPLC: t.sub.Ref=5.38 minutes, 98.6% (Waters Xterra column,
3.9 mm.times.100 mm, RP-18, 3.5 .mu.m, 250 nm, 1 ml/minute,
acetonitrile/20 mmol of Na.sub.2B.sub.4O.sub.7 in H.sub.2O (20/80
v/v, pH 10)
[1438] .sup.1H-NMR: (200.13 MHz, CDCl.sub.3, TMS)
[1439] .delta. 6.81-6.88 and 6.61-6.71 (m, 2H), 5.90-6.10 (m, 2H),
4.52-4.75 (m, 2H), 4.51 (d, J=16.5 Hz, 1H), 4.15 (bs, 1H), 3.84 (s,
3H), 3.82 (s, 1H), 3.40-3.60 and 3.10-3.30 (m, 1H), 2.81-3.03 (m,
2H), 2.70 (bd, J=16.3 Hz, 1H), 2.33-2.62 (m, 4H), 1.15-2.30 (M,
21H)
[1440] LC/MS: t.sub.Ref=8.7 minutes, 98%, (Zorbax SB C 13-column,
2.1 mm.times.30 mm, RP-18, 3 .mu.m, 0.5 ml/minute,
[1441] Methanol/H.sub.2O (40/60 100/0 (v/v) in 2 minutes)
[1442] APCI-NI-MS
[1443] 470
EXAMPLE 188
[1444] ##STR391##
EXAMPLE 188
Steps 1-7
SPH-1540
(4aS,6R,8aS)-6-Hydroxy-3-methoxy-N.sup.11-(1-naphthyl)-5,6,9,10-tetrahydro-
-4aH-[1]benzofuro-[3a,3,2-ef]-[2]benzazepine-11(12H)-carboxamide
[1445] ##STR392## Variant A (CK-41-3), Steps 1, 4 and 6-7
[1446] 0.228 g (0.212 mmol) of
4-carboxy-1-oxobut-1-yloxymethyl-Merrifield resin is steeped in a
5-ml-polyethylene frit that is sealed on both sides for 30 minutes
in 3 ml of dichloromethane, and after filtering, it is mixed in a
solution of 0.234 g (0.628 mmol) of
N-tert-butoxycarbonylnorgalanthamine, 0.013 g (0.105 mmol) of
4-dimethylaminopyridine and 108 .mu.l (0.082 g, 0.628 mmol) of
ethyldiisopropylamine in 1 ml of dichloromethane. Then, 97 .mu.l
(0.079 g, 0.628 mmol) of diisopropylcarbodiimide, dissolved in 1 ml
of dichloromethane, is added, and the suspension is shaken for 24
hours at about 40.times. per minute at room temperature. After
filtering, the resin is suspended for ten minutes in 2.5 ml of
dichloromethane/methanol (1/1) while being shaken, filtered and
washed with dichloromethane (5.times.2.5 ml). The resin is
subsequently suspended once for ten minutes and once for 50 minutes
in each case in 2.5 ml of a solution that consists of
trifluoroacetic acid, dichloromethane, and anisole (25/70/5). After
filtering, it is washed with dichloromethane (2.times.2.5 ml), with
dichloromethane/methanol/triethylamine (5/4/1, 3.times.2.5 ml) and
finally with dichloromethane (5.times.2.5 ml). The resin is shaken
for eleven hours in a solution that consists of 0.208 .mu.l (0.245
g, 1.45 mmol) of 1-naphthylisocyanate, 113 .mu.l (0.085 g, 0.657
mmol) of ethyldiisopropylamine and 2 ml of dichloromethane at room
temperature. After three cycles of washing in each case with
dichloromethane (2.5 ml) and tetrahydrofuran (2.5 ml), the polymer
is suspended in a solution of 1.88 g (1.045 mmol) of 30% sodium
methanolate-methanol solution in 0.4 ml of methanol and 1.6 ml of
tetrahydrofuran. After the resin was shaken for 24 hours at room
temperature, the resin is filtered and extracted with
methanol/dichloromethane (1/1, 3.times.2.5 ml) and with
dichloromethane (3.times.2.5 ml). The combined filtrates are
neutralized with concentrated hydrochloric acid. The suspension is
filtered on a silica gel column (10 g,
dichloromethane/methanol=9/1), and the filtrate is concentrated by
evaporation in a rotary evaporator. The crude product is purified
by means of preparative thin-layer chromatography (silica gel,
mobile solvent dichloromethane/methanol=4//3). After concentration
by evaporation and drying under high vacuum, 0.091 g of a yellowish
foam is obtained. To remove triethylammonium salts, the residue is
taken up in dichloromethane and extracted twice with 1N
hydrochloric acid and once with saturated common salt solution,
dried on MGSO.sub.4, filtered and concentrated by evaporation.
[1447] Yield: 0.042 g (0.095 mmol, 45% relative to the degree of
substitution of the 4-carboxy-1-oxobut-1-yloxymethyl-Merrifield
resin), brown-yellowish wax (M.sub.w=442.5)
[1448] TLC: R.sub.f=0.21 (dichloromethane/methanol=48/2)
[1449] HPLC: t.sub.Ref=5.15 minutes, 100% (Merck purospher column
4.0 mm.times.125 mm, RP-18e, 5 .mu.m, 250 nm, 1 ml/minute,
acetonitrile/20 mmol of Cl.sub.3CCO.sub.2H in H.sub.2O (40/60
v/v)
[1450] .sup.1H-NMR: (200.13 MHz, CDCl.sub.3, TMS)
[1451] .delta. 7.71 (d, J=6.9 Hz, 1H), 7.20-7.66 (m, 6H), 6.85 (d,
J=8.4 Hz, 1H), 6.63 (d, J=8.2 Hz, 1H), 5.96 (bs, 2H), 4.91 (d,
J=16.7 Hz, 1H), 4.25-4.62 (m, 3H), 4.09 (bs, 1H), 3.78 (s, 3H),
3.25-3.50 (m, 2H), 2.55-2.67 (m, 1H), 1.87-2.04 (m, 2H), 1.60-1.75
(m, 1H)
[1452] .sup.13C-NMR: (50.32 MHz, CDCl.sub.3, TMS)
[1453] .delta. 155.7, 146.9, 144.6, 134.4, 133.8, 132.5, 129.0,
128.7, 128.1, 128.0, 126.3, 125.6, 125.5, 124.8, 122.1, 120.7,
111.0, 88.2, 62.9, 55.9, 51.8, 48.3, 46.1, 36.4, 29.7
Variant B, Steps 2-5 and 7
[1454] 0.250 g (0.233 mmol) of
4-carboxy-1-oxobut-1-yloxymethyl-Merrifield resin is introduced
into a frit reactor of synthesis robot (Syro II MultiSynTech).
Then, the resin is steeped in a reactor for 30 minutes in
dichloromethane, suctioned off, washed three times with
dichloromethane and mixed successively with 0.150 g (1.163 mmol) of
ethyldiisopropylamine in 1 ml of dichloromethane and 0.084 g (0.698
mmol) of pivaloyl chloride in 1.5 ml of dichloromethane. After six
hours of stirring at 23.degree. C., the solution is suctioned off,
and the polymer is washed in each case with 3 ml of dichloromethane
(6.times.2 minutes). After the addition of 0.260 g (0.698 mmol) of
N-tert-butoxycarbonylnorgalanthamine, 0.014 g (0.116 mmol) of
4-dimethylaminopyridine and 0.150 g (1.163 mmol) of
ethyldiisopropylamine in 2.5 ml of dichloromethane, the suspension
is stirred at 23.degree. C. for 15 hours. After suctioning off, the
resin is stirred in 2.5 ml of dichloromethane/methanol (1/1) for
ten minutes, suctioned off, washed three times with
dichloromethane/methanol (1/1) (3 ml, 2 minutes) and five times
with dichloromethane (3 ml, 2 minutes). The polymer is subsequently
suspended once for ten minutes and once for 50 minutes in each case
in 2.5 ml of a solution that consists of trifluoroacetic acid,
dichloromethane and anisole (25/70/5). After suctioning off, it is
washed with dichloromethane (3.times.3 ml), with
dichloromethane/methanol/triethylamine (5/4/1, 3.times.3 ml) and
finally with dichloromethane (5.times.) in each case for two
minutes. Then, the residue is mixed with 0.197 g (1.163 mmol) of
1-naphthylisocyanate, 0.150 g (1.163 mmol) of ethyldiisopropylamine
and 2.5 ml of dimethylformamide and stirred for six hours at
50.degree. C. The reaction is terminated by the solution being
suctioned off, the resin being washed with 3 ml of dichloromethane
at 23.degree. C. six times for two minutes in each case, and the
resin being suctioned off in the dry state at 40.degree. C. for ten
minutes. For cleavage, the resin is transferred into a
5-ml-polyethylene frit that is sealed on both sides and steeped in
2.5 ml of tetrahydrofuran for 30 minutes. After filtering, the
polymer is suspended in a solution that consists of 0.209 g (1.163
mmol) of 30% sodium methanolate-methanol solution in 0.75 ml of
methanol and 1.25 ml of tetrahydrofuran, and it is shaken for 15
hours at about 40.times. per minute at room temperature. The resin
is filtered and extracted three times with methanol/dichloromethane
(1/1, 2.5 ml) and three times with dichloromethane (2.5 ml). The
combined extracts are neutralized with concentrated hydrochloric
acid, filtered and concentrated by evaporation. Then, the crude
product is purified by means of column chromatography on 10 g of
silica gel (mobile solvent dichloromethane/methanol=99/1). After
concentration by evaporation and drying in a vacuum, 0.029 g of a
rose-colored wax with a purity of 75% (HPLC), identical to the
product that is produced according to method A, is obtained.
[1455] Yield: 0.029 g (0.021 g, 0.047 mmol, 20% relative to the
degree of substitution of the
4-carboxy-1-oxobut-1-yloxymethyl-Merrifield resin)
[1456] HPLC: t.sub.Ref=14.32 minutes, 75% (Merck purospher column
4.0 mm.times.125 mm, RP-18e, 5 .mu.m, 250 nm, 1 ml/minute,
acetonitrile/20 mmol of Cl.sub.3CCO.sub.2H in H.sub.2O (30/70 v/v)
##STR393##
EXAMPLE 189
SPH-1541
Steps 1-2
(4aS,6,R,8aS)-3-Methoxy-11-tert-butoxycarbonyl-5,6,9,10-tetrahydro-4aH-[1]-
benzofuro[3a/3,2-ef][2]benzazepine-6(12H)-yloxy)-5-oxopentanoic
acid (CK-48-1)
[1457] ##STR394##
[1458] 5.000 g (18.295 mmol) of norgalanthamine (98% (HPLC)) and
3.804 ml (2.777 g, 27.442 mmol) of triethylamine in 75 ml of
absolute dichloromethane are introduced at 0.degree. C. While being
stirred, a solution that consists of 4.393 g (20.124 mmol) of
di-tert-butyldicarbonate is added in drops within 15 minutes at
0.degree. C. After 40 minutes at 0.degree. C., the reaction
solution is stirred for three days at room temperature. After two
days, 1.598 g (7.318 mmol) of di-tert-butyldicarbonate and 1.27 ml
(0.926 g, 9.147 mmol) of triethylamine are added again. The
reaction solution is taken up with 150 ml of dichloromethane, and
the organic phase is washed three times with 100 ml of 1N
hydrochloric acid in each case, three times with 100 ml of a
saturated NaHCO.sub.3 solution in each case and twice with 100 ml
of saturated common salt solution, dried on Na.sub.2SO.sub.4,
filtered and concentrated by evaporation under reduced pressure.
The residue (7.065 g, 18.9 mmol, 103% raw yield) is dissolved in 75
ml of absolute dichloromethane, and 4.175 g (36.590 mmol) of
glutaric acid anhydride, 0.224 g (1.829 mmol) of
4-dimethylaminopyridine and 3.804 ml (2.777 g, 27.442 mmol) of
triethylamine are added to this solution. The solution is stirred
for three days at room temperature. The reaction is terminated by
adding 200 ml of diethyl ether and 500 ml of aqueous ammonia
solution (pH 10-11). The cloudy aqueous phase is separated (poor
phase separation, addition of some methanol, optionally before the
dichloromethane solution is distilled off) and extracted three
times with 200 ml of diethyl ether and then set at pH 2 with
concentrated hydrochloric acid. In this case, the cloudy solution
becomes clear. The aqueous phase is extracted four times with 400
ml of dichloromethane in each case. The combined organic extracts
are washed three times with 300 ml of distilled water in each case
and twice with 300 ml of saturated common salt solution, dried on
Na.sub.2SO.sub.4, filtered, mixed with 50 ml of diisopropyl ether
and concentrated under reduced pressure until the product
crystallizes out. The solution is allowed to stand for a little
while and then the crystallized colorless solid is filtered off,
which is dried in a vacuum.
[1459] Yield: 7.546 g (15.48 mmol, 84.6% over two stages),
colorless crystalline solid, (M.sub.w=487.6)
[1460] TLC: R.sub.f=0.45 (petroleum ether/ethyl acetate=1/2)
[1461] R.sub.f=0.28 (aluminum oxide, petroleum ether/ethyl
acetate=1/2)
[1462] Melting point: 159-163.degree. C.
(dichloromethane/diisopropyl ether=1/1)
[1463] IR: KBr
[1464] v (cm.sup.-1) 3245 (bs), 2978 (s), 1715 (s), 1683 (s)
[1465] .sup.1H-NMR: (200.13 MHz, CDCl.sub.3, TMS)
[1466] .delta. 6.53-6.79 (m, 2H), 6.13-6.29 (m, 1H), 5.82-5.97 (m,
1H), 5.33 (1, J=4.9 Hz, 1.0H), 4.87 (d, J=15.6 Hz, 0.3H), 4.67 (d,
J=15.7 Hz, 0.7H), 4.53 (s, 1H), 3.99-4.38 (m, 2H), 3.83 (s, 3H),
3.19-3.50 (m, 1H), 2.68 (d, J=16.0 Hz, 1.0H), 2.40 (t, J=7.3 Hz,
2.0H), 2.39 (t, J=7.0 Hz, 2.0H), 2.01-2.17 (m, 1H), 1.93 (qui,
J=7.1 Hz, 2.0H), 1.66-1.84 (m, 1H), 1.41 (s, 3H), 1.37 (s, 6H)
[1467] .sup.13C-NMR: (50.32 MHz, CDCl.sub.3, TMS)
[1468] .delta. 178.2 (s), 172.6 (s), 154.9 (s), 147.1 (s), 144.0
(s), 131.3 (s), 130.5 (d), 129.6 (s), 123.0 (d), 120.2 (d), 111.0
(d), 85.8 (d), 79.9 (s), 63.2 (d), 55.8 (q), 51.8 and 51.2 (t),
48.0 (s), 45.2 (t), 37.9 and 37.0 (t), 33.4 (t), 32.9 (t), 28.2
(q), 27.5 (t), 19.7 (t)
EXAMPLE 190
SPH-1542
[1469] (See Diagram, Step 3)
[1470] Immobilization of
(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro-[3a-
,3,2-ef][2]benzoazepine-11(12H)-yl)carboxylic acid-tert-butyl Ester
on a Hydroxymethyl-Polystyrene Resin (Merrifield Resin) (CK-43-5)
##STR395##
[1471] 5.00 g (5.2 mmol) of hydroxymethylpolystyrene resin (1.04
mmol/g, Merrifield resin.sup.9) is stirred in a three-neck glass
reactor with a frit that is recessed in the bottom and a KPG
stirrer in 50 ml of dimethylformamide (300 s.sup.-1). After
filtering, a solution that consists of
N-tert-butoxycarbonylnorgalanthamine-6-yloxy-5-oxopentanoic acid
(7.607 g, 15.6 mmol), 4-dimethylaminopyridine (0.635 g, 5.2 mmol)
in 30 ml of absolute dimethylformamide is added to the resin. At
room temperature, a solution that consists of
diisopropylcarbodiimide (2.42 ml, 1.969 g, 15.6 mmol) and 10 ml of
dimethylformamide is then added in portions. After 20 hours of
stirring at room temperature, it is filtered, the resin is washed
six times with dichloromethane (40 ml, 5 minutes) and once with
diethyl ether (40 ml, 5 minutes) and dried in a vacuum.
.sup.9Hydroxymethyl resin, D-1160, Bachem Feinchemikalien AG
[1472] To determine the concentration, an aliquot of resin (0.2465
g) in a polyethylene frit that can be sealed on both sides in 2.5
ml of methanol/tetrahydrofuran (1/4) is steeped for 30 minutes,
filtered, and suspended in a solution of 0.280 g (1.56 mmol) of 30%
sodium methanolate-methanol solution in 0.5 ml of methanol and 2 ml
of tetrahydrofuran. The mixture is shaken for nine hours at room
temperature, filtered off, and the resin is extracted three times
with methanol/dichloromethane (1/1, 2.5 ml) and three times with
dichloromethane (2.5 ml). The combined filtrates are neutralized
with 119 .mu.l (0.178 g, 1.56 mmol) of trifluoroacetic acid and
concentrated by evaporation in a rotary evaporator. The residue is
taken up in 30 ml of ethyl acetate, washed twice with saturated
NaHCO.sub.3 solution (10 ml), with distilled water (10 ml) and with
saturated common salt solution (10 ml), dried on Na.sub.2SO.sub.4,
filtered and concentrated by evaporation again. The residue (0.080
g) is purified by means of column chromatography (10 g of silica
gel, mobile solvent petroleum ether/ethyl acetate=1/1.fwdarw.1/2).
After concentration by evaporation and drying under high vacuum,
0.0661 g of a colorless, vitreous solid is obtained.
[1473] Yield: 0.0661 g (0.177 mmol. A concentration of 0.718
mmol/g, 103% of the theoretical maximum concentration.sup.10 thus
is calculated), .sup.1H-NMR spectrum that is identical to the
starting material .sup.10=1.04 mmol/g/(1 g+1 g*1.04 mol/g*(487.6
mol/g-18 mol/g)/1000)
[1474] HPLC: t.sub.Ref=9.18 minutes, 93.8% (270 nm), 97.7% (285
nm), (Phenomenex Luna column, 3.0 mm.times.50 mm, RP-18, 3.0 .mu.m,
0.5 ml/minute, methanol/20 mmol of trichloroacetic acid in H.sub.2O
(50/50 v/v)
Step 4
Recycling Excess
(4aS,6R,8aS)-3-Methoxy-11-tert-butoxycarbonyl-5,6,9,10-tetrahydro-4aH-[[1-
]benzofuro[3a,3,2-ef][2]benzazepine-6(12H)-yloxy)-5-oxopentanoic
Acid from the Resin Immobilization (CK-51-1)
[1475] The filtrate of the reaction solution and the first five
dichloromethane filtrates are combined and washed three times with
100 ml of 1N hydrochloric acid, three times with 100 ml of
distilled water and twice with saturated sodium chloride solution,
dried with Na.sub.2SO.sub.4, filtered and concentrated by
evaporation. The amorphous residue (6.806 g) is suspended in 50 ml
of ethanol and 30 ml of distilled water, then 1.97 g (46.9 mmol) of
lithium hydroxide monohydrate is added. The suspension is stirred
for three days at room temperature. The reaction solution is
extracted three times with 100 ml of dichloromethane in each case,
and the combined extracts are extracted in each case three times
with 100 ml of 1N hydrochloric acid and twice with 100 ml of
saturated common salt solution. After drying on Na.sub.2SO.sub.4,
filtering and concentration by evaporation under reduced pressure,
the organic phase produces 5.06 g of a colorless foam, which
contains about 60% N-tert-butoxycarbonylnorgalanthamine according
to HPLC. The residue is reacted analogously to the above-described
procedure with 0.164 g (1.339 mmol) of dimethylaminopyridine, 3.056
g (26.78 mmol) of glutaric acid anhydride and 2.8 ml (2.033 g,
20.09 mmol) of triethylamine in 50 ml of dichloromethane. The
reaction is terminated by the addition of 200 ml of diethyl ether
and 250 ml of aqueous ammonia solution (pH 10-11). The cloudy,
aqueous phase is separated and extracted twice with 200 ml of
diethyl ether and then set to pH 2 with concentrated hydrochloric
acid. The aqueous phase is extracted three times with 200 ml of
dichloromethane in each case. The combined organic extracts are
washed three times with 200 ml of distilled water in each case and
twice with 200 ml of saturated common salt solution, dried on
Na.sub.2SO.sub.4, filtered, concentrated by evaporation to about 50
ml, mixed with 50 ml of diisopropyl ether and further concentrated
under reduced pressure until the product crystallizes out. The
solution is allowed to stand for a little while, and then the
crystallized colorless solid is filtered off, which is dried in a
vacuum.
[1476] Yield: 4.909 g (10.07 mmol, 96.6% relative to the excess
that is used in the immobilization)
[1477] HPLC: t.sub.Ref=13.9 minutes, 99.8% (Merck Purospher column,
4.0 mm.times.125 mm, RP-18e, 5 .mu.m, 285 nm, 1 ml/minute,
acetonitrile/20 mmol of Cl.sub.3CCO.sub.2H in H.sub.2O (40/60 v/v,
pH 10)
EXAMPLE 192
Step 1
N-(Adamantan-1-yl)-6-bromohexanoic acid amide
[1478] ##STR396##
[1479] Adamantane-1-amine, hydrochloride (2.50 g, 13.3 mmol) and
N-ethyldiisopropylamine (3.79 g, 29.3 mmol) are stirred in absolute
CH.sub.2Cl.sub.2 (50 ml) for 15 minutes at room temperature. Then,
6-bromohexanoic acid chloride (3.13 g, 14.7 mmol) in
CH.sub.2Cl.sub.2 (10 ml) is added in drops at 0.degree. C. and
stirred for one hour at room temperature.
[1480] It is extracted with 2N HCl (2.times.50 ml), water
(1.times.50 ml), saturated sodium bicarbonate solution (2.times.50
ml) and saturated common salt solution (1.times.100 ml), dried
(sodium sulfate/activated carbon), filtered, and the residue that
is obtained after the solvent is removed in a rotary evaporator is
recrystallized from petroleum ether (25 ml)/diisopropyl ether (25
ml), by which the product is obtained in the form of colorless
crystals with a melting point of 73-75.degree. C. (3.51 g, 80%)
[1481] TLC: CHCl.sub.3:MeOH=9:1, R.sub.f=0.9
[1482] .sup.1H NMR (CDCl.sub.3): .delta. 5.43 (b, 1H), 3.33 (t,
J=6.0 Hz, 2H), 2.21-1.15 (m, 23H);
[1483] .sup.13C NMR (CDCl.sub.3): .delta. 171.6 (s), 51.4 (s), 41.3
(t), 37.0 (t), 36.1 (t), 33.5 (t), 32.2 (t), 29.1 (d), 27.4 (t),
24.6 (t)
Step 2
SPH-1517
N-(Adamantan-1-yl)-6-[(4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-6-hydroxy-3-m-
ethoxy-6H-benzofuro[3a,3,2-ef][2]benzazepine-11-yl]-bromohexanoic
acid amide, fumarate
[1484] ##STR397##
[1485] Norgalanthamine (1.00 g, 3.66 mmol),
N-(adamantan-1-yl)-6-bromohexanoic acid amide (1.20 g, 3.66 mmol)
and potassium carbonate (anhydrous, freshly ground, 1.52 g, 11.3
mmol) are stirred in absolute acetonitrile (10 ml) for 8 hours at
boiling temperature.
[1486] The residue that is obtained after the solvent is removed in
a rotary evaporator is purified by column chromatography (200 g of
silica gel, chloroform:methanol: ammonia=96:3:1), by which the
product is obtained as a light yellow foam (1.73 g, 91%).
[1487] The conversion into fumarate was carried out analogously to
the production of MT-311 and MT-407 and yielded the product in the
form of light yellow crystals with a melting point of
109-114.degree. C.
[1488] TLC: CHCl.sub.3:MeOH:NH.sub.3=89:10:1, R.sub.f=0.6
[1489] Microelement analysis (JOS 1763):
[1490] C.sub.37H.sub.42N.sub.2O.sub.9H.sub.2O TABLE-US-00144 Cld.:
C, 66.03; H, 7.70; N, 4.28 Fnd.: C, 66.27; H, 7.61; N, 4.22
[1491] .sup.1H NMR (DMSO-d.sub.6): .delta.=7.20 (b, 1H), 6.90-6.63
(m, 2H), 6.51 (s, 2H), 6.11 (d, J=10.2 Hz, 1H), 5.82 (dd, J=11.4
Hz, J=4.7 Hz, 1H), 4.56 (s, 1H), 4.41 (d, J=14.8 Hz, 1H), 4.22-3.86
(m, 2H), 3.76 (s, 3H), 3.62-3.12 (m, 3H), 2.81-2.47 (m, 3H),
2.44-1.04 (m, 26H);
[1492] .sup.13C NMR (DMSO-d.sub.6): .delta. 171.6 (s), 167.4 (s),
146.3 (s), 144.1 (s), 134.7 (d), 132.9 (s), 129.0 (d), 126.3 (d),
124.6 (s), 122.0 (d), 111.7 (d), 86.7 (d), 59.8 (d), 55.5 (q), 50.7
(t), 50.5 (t), 47.3 (s), 41.1 (t), 36.1 (t), 36.0 (s), 32.0 (t),
31.0 (t), 28.9 (d), 26.0 (t), 25.2 (t), 24.9 (t)
EXAMPLE 193
Step 1
2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione
[1493] ##STR398##
[1494] 1H-Benz[de]isoquinoline-1,3(2H)-dione (10.0 g, 50.7 mmol) in
DMF (50 ml) is slowly added in drops at room temperature to a
suspension of sodium hydride (2.33 g, 55.8 mmol of a 55%
dispersion, white oil is removed by washing with absolute petroleum
ether) in absolute DMF (50 ml). It is stirred for 30 minutes,
heated to 60.degree. C., 1.5 dibromopentane (46.64 g, 202.8 mmol)
is added once, and it is stirred for 12 hours at this
temperature.
[1495] It is filtered, and the residue that is obtained after the
solvent is removed in a rotary evaporator is dispersed between
water (200 ml) and ether (200 ml). The aqueous phase is extracted
with ether (3.times.50 ml), the combined organic phases are washed
with water (3.times.200 ml), 2N NaOH (2.times.100 ml) and saturated
common salt solution (1.times.200 ml), dried (sodium sulfate), and
solvent is removed in a rotary evaporator. Excess dibromopentane is
separated by distillation (100.degree. C./20 mbar), the residue is
recrystallized from methanol (200 ml), by which the product is
obtained in the form of colorless crystals (15.45 g, 88%) of
melting point 114-116.degree. C.
[1496] TLC: Petroleum ether:ethyl acetate=4:1, R.sub.f=0.35
[1497] .sup.1H NMR (CDCl.sub.3): .delta. 8.48 (dd, J=7.0 Hz, J=1.3
Hz, 2H), 8.13 (dd, J=7.0 Hz, J=1.3 Hz, 2H), 8.48 (t, J=7.0 Hz, 2H),
4.21 (t, J=7.6 Hz, 2H), 3.89 (t, J=6.6 Hz, 2H), 1.89 (quintet,
J=6.6 Hz, 2H), 1.79-1.43 (m, 4H);
[1498] .sup.13C NMR (CDCl.sub.3): .delta. 163.8 (s), 133.7 (d),
131.3 (s), 130.9 (d), 127.8 (s), 126.7 (d), 122.4 (d), 39.8 (t),
33.5 (t), 32.2 (t), 27.0 (t), 25.5 (t)
Step 2
SPH-1496
2-[5-[(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-6H-benzof-
uro[3a,3,2-ef][2]benzazepine-11-yl]pentyl]-1H-benz[de]isoquinoline-1,3(2H)-
-dione, fumarate
[1499] ##STR399##
[1500] Norgalanthamine (1.00 g, 3.66 mmol),
2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione (1.15 g,
3.33 mmol) and potassium carbonate (anhydrous, freshly gound, 1.15
g, 10.0 mmol) are stirred in absolute acetonitrile (10 ml) for 12
hours at boiling temperature.
[1501] The residue that is obtained after the solvent is removed in
a rotary evaporator is purified by column chromatography (100 g of
silica gel, chloroform:methanol: ammonia=96:3:1), by which the
product is obtained as a light yellow foam (1.58 g, 88%).
[1502] The conversion into fumarate was carried out analogously to
the production of MT-311 and MT-407 and yielded the product in the
form of light yellow crystals with a melting point of
129-134.degree. C.
[1503] TLC: CHCl.sub.3:MeOH:NH.sub.3=89:10:1, R.sub.f=0.5
[1504] Microelement analysis (JOS 1790):
[1505] C.sub.37H.sub.38N.sub.2O.sub.9*1.5H.sub.2O TABLE-US-00145
Cld.: C, 65.19; H, 6.06; N, 4.11 Fnd.: C, 65.02; H, 5.82; N,
3.98
[1506] .sup.1H NMR (DMSO d.sub.6): .delta. 8.34 (d, J=7.0 Hz, 4H),
7.76 (d, J=7.0 Hz, 2H), 6.81-6.49 (m, 4H), 6.07 (d, J=11.4 Hz, 1H),
5.81 (dd, J=11.4 Hz, J=4.7 Hz, 1H), 4.49 (s, 1H), 4.29 (d, J=14.0
Hz, 1H), 4.16-3.74 (m, 4H), 3.70 (s, 3H), 3.43-3.01 (m, 2H), 2.50
(b, 2H), 2.27 (d, J=14.8 Hz, 1H), 2.12-1.88 (m, 2H), 1.78-1.12 (m,
8H);
[1507] .sup.13C NMR (DMSO-d.sub.6) .delta. 167.3 (s), 163.3 (s),
146.2 (s), 143.8 (s), 134.7 (d), 134.2 (d), 132.8 (s), 131.2 (s),
130.6 (d), 128.7 (d), 127.2 (d), 127.1 (S), 126.5 (d), 126.1 (s),
121.9 (s), 121.6 (d), 111.5 (d), 86.7 (d), 59.8 (d), 56.0 (t), 55.5
(q), 50.7 (t), 50.2 (t), 47.4 (s), 39.5 (t), 32.2 (t), 30.9 (t),
27.3 (t), 25.3 (t), 24.1 (t)
EXAMPLE 194
Step 1
6-Bromo-1-(3,4-dimethoxyphenyl)-1-hexanone
[1508] ##STR400##
[1509] 6-Bromohexanoic acid chloride (4.9 g, 22.7 mmol) is added in
drops within 10 minutes at a temperature of 0 to 5.degree. C. to a
mixture that consists of 1,2-dimethoxybenzene (3.10 g, 22.7 mmol)
and aluminum chloride (3.0 g, 22.7 mmol) in absolute carbon
disulfide (50 ml). It is heated within 30 minutes to 40.degree. C.,
and it is stirred for one hour at this temperature. It is
hydrolyzed with 2N hydrochloric acid (20 ml), dispersed between
benzene (30 ml) and 2N hydrochloric acid (30 ml), and the aqueous
phase is extracted with benzene (2.times.15 ml), the combined
organic phases are washed with 2N hydrochloric acid (3.times.50
ml), water (1.times.50 ml), saturated sodium bicarbonate solution
(3.times.50 ml), saturated common salt solution (1.times.50 ml),
dried (sodium sulfate/activated carbon), filtered, and the residue
that is obtained after concentration by evaporation in a rotary
evaporator recrystallizes from pentane (35 ml), by which the
product is obtained in the form of colorless crystals with a
melting point of 44-45.degree. C. (3.2 g, 44.7%).
[1510] TLC: Petroleum ether:ethyl acetate=4:1; Rf=0.85
[1511] .sup.1H NMR (CDCl.sub.3): .delta. 7.54 (dd, J=1.9 Hz, J=8.9
Hz, 1H) 7.51 (d, J=1.9 Hz, 1H), 6.89 (d, J=8.9 Hz, 1H), 3.97 (s,
6H), 3.40 (t, J=6.4 Hz, 2H), 2.92 (t, J=7.0 Hz, 2H), 1.90 (quintet,
J=6.4 Hz, 2H), 1.73 (quintet, J=7.0 Hz, 2H), 1.63-1.48 (m, 2H);
[1512] .sup.13C NMR (CDCl.sub.3): .delta. 198.6 (s), 153.2 (s),
149.0 (s), 130.2 (s), 122.6 (d), 110.1 (d), 110.0 (d), 56.0 (q),
55.9 (q), 37.7 (t), 33.6 (t), 32.6 (t), 27.9 (t), 23.6 (t)
Step 2
SPH-1497
1-(3,4-Dimethoxyphenyl)-6-[(4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-6-hydrox-
y-3-methoxy-6H-benzofuro[3a,3,2-ef][2]benzazepine-11-yl]hexan-1-one,
fumarate
[1513] ##STR401##
[1514] Norgalanthamine (1.00 g, 2.66 mmol),
6-bromo-1-(3,4-dimethoxyphenyl)-1-hexanone (1.15 g, 3.66 mmol) and
potassium carbonate (anhydrous, freshly ground, 1.15 g, 10.0 mmol)
is stirred in absolute acetonitrile (15 ml) for 12 hours at boiling
temperature.
[1515] The residue that is obtained after the solvent is removed in
a rotary evaporator is purified by column chromatography (100 g of
silica gel, chloroform:methanol: ammonia=96:3:1), by which the
product is obtained as a light yellow foam (1.70 g, 91%).
[1516] The conversion into fumarate was carried out according to
standard instructions.
[1517] The conversion into fumarate was carried out analogously to
the production of MT-311 and MT-407 and yielded the product in the
form of light yellow crystals with a melting point of 88-94.degree.
C.
[1518] TLC: CHCl.sub.3:MeOH:NH.sub.3=89:10:1, R.sub.f=0.5
[1519] Microelement analysis (JOS 1782):
[1520] C.sub.35H.sub.43NO.sub.10*0.5H.sub.2O TABLE-US-00146 Cld.:
C, 65.00; H, 6.86; N, 2.17 Fnd.: C, 64.81; H, 6.64; N, 2.09
[1521] .sup.1H NMR (DMSO-d.sub.6): .delta. .delta. 7.61 (d, J=8.9
Hz, 1H), 7.43 (s, 1H), 7.01 (d, J=8.9 Hz, 1H), 6.81-6.66 (m, 2H),
6.58 (s, 2H), 6.11 (d, J=11 Hz, 1H), 5.82 (dd, J=11 Hz, J=5 Hz,
1H), 4.61-4.33 (m, 2H), 4.20-3.92 (m, 2H), 3.84 (s, 3H), 3.80 (s,
3H), 3.72 (s, 3H), 3.62-3.12 (m, 2H), 3.10-2.81 (m, 2H), 2.78-2.43
(m, 3H), 2.39-1.86 (m, 5H), 1.78-1.40 (m, 5H), 1.38-1.14 (m,
2H);
[1522] .sup.13C NMR (DMSO-d.sub.6) .delta. 198.5 (s), 167.2 (s),
153.0 (s), 148.6 (s), 146.3 (s), 144.2 (s), 134.6 (d), 132.9 (s),
129.7 (s), 129.0 (s), 126.2 (d), 124.0 (d), 122.7 (d), 122.1 (d),
111.7 (d), 110.9 (d), 110.2 (d), 86.6 (d), 65.0 (d), 59.8 (q), 55.8
(q), 55.5 (q), 50.8 (t), 50.4 (t), 47.3 (s), 37.2 (t), 31.9 (t),
31.0 (t), 26.1 (t), 24.7 (t), 23.8 (t), 15.2 (t)
* * * * *
References