U.S. patent application number 10/102569 was filed with the patent office on 2002-10-17 for novel heterocyclic compounds.
Invention is credited to Andersen, Knud Erik, Fischer, Erik, Hohlweg, Rolf, Jorgensen, Tine Krogh, Olsen, Uffe Bang, Polivka, Zdenek, Sindelar, Kaler.
Application Number | 20020151539 10/102569 |
Document ID | / |
Family ID | 27220704 |
Filed Date | 2002-10-17 |
United States Patent
Application |
20020151539 |
Kind Code |
A1 |
Jorgensen, Tine Krogh ; et
al. |
October 17, 2002 |
Novel heterocyclic compounds
Abstract
The present invention relates to novel N-substituted
azaheterocyclic compounds of the general formula 1 wherein X, Y, Z,
R.sup.1, R.sup.2 and m are as defined in the detailed part of the
present description, or salts thereof, to methods for their
preparation, to compositions containing them, and to their use for
the clinical treatment of painful, hyperalgesic and/or inflammatory
conditions in which C-fibers play a pathophysiological role by
eliciting neurogenic pain or inflammation, as well as their use for
treatment of indications caused by or related to the secretion and
circulation of insulin antagonising peptides, e.g.
non-insulin-dependent diabetes mellitus (NIDDM) and
ageing-associated obesity.
Inventors: |
Jorgensen, Tine Krogh;
(Olstykke, DK) ; Andersen, Knud Erik; (Smorum,
DK) ; Hohlweg, Rolf; (Kvistgaard, DK) ; Olsen,
Uffe Bang; (Vallensbak, DK) ; Fischer, Erik;
(Copenhagen S, DK) ; Polivka, Zdenek; (Praha,
CZ) ; Sindelar, Kaler; (Praha, CZ) |
Correspondence
Address: |
Reza Green, Esq.
Novo Nordisk of North America, Inc.
Suite 6400
405 Lexington Avenue
New York
NY
10174-6401
US
|
Family ID: |
27220704 |
Appl. No.: |
10/102569 |
Filed: |
March 14, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10102569 |
Mar 14, 2002 |
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09535216 |
Mar 27, 2000 |
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6391890 |
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09535216 |
Mar 27, 2000 |
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09102863 |
Jun 23, 1998 |
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6054458 |
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60052980 |
Jul 7, 1997 |
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Current U.S.
Class: |
514/212.04 ;
514/211.13; 514/217; 514/252.13; 514/253.03; 514/254.11;
514/255.03; 514/319; 514/320; 540/519; 540/547; 544/374;
544/381 |
Current CPC
Class: |
C07D 295/15 20130101;
C07D 409/14 20130101; C07D 409/04 20130101; C07D 211/70
20130101 |
Class at
Publication: |
514/212.04 ;
514/211.13; 514/217; 514/252.13; 514/253.03; 514/255.03;
514/254.11; 514/319; 514/320; 540/519; 540/547; 544/381;
544/374 |
International
Class: |
A61K 031/554; A61K
031/55; A61K 031/496 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 25, 1997 |
DK |
0750/97 |
Apr 3, 1998 |
DK |
0471/98 |
Claims
1. A compound of formula I 26wherein R.sup.1 and R.sup.2
independently are hydrogen, halogen, trifluoromethyl, hydroxy,
C.sub.1-6-alkyl or C.sub.1-6-alkoxy; X is ortho-phenylene, --O--,
--S--, --C(R.sup.6R.sup.7)--, --CH.sub.2CH.sub.2--,
--CH.dbd.CH--CH.sub.2--, --CH.sub.2--CH.dbd.CH--,
--CH.sub.2--(C.dbd.O)--, --(C.dbd.O )--CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.dbd.CH--,
--N(R.sup.8)--(C.dbd.O)--, --(C.dbd.O)--N(R.sup.8)--,
--O--CH.sub.2--, --CH.sub.2--O--, --OCH.sub.2O--, --S--CH.sub.2--,
--CH.sub.2--S--, --(CH.sub.2)N(R.sup.8)--,
--N(R.sup.8)(CH.sub.2)--, --N(CH.sub.3)SO.sub.2--,
SO.sub.2N(CH.sub.3)--, --CH(R.sup.10)CH.sub.2--,
--CH.sub.2CH(R.sup.10)--, --(C.dbd.O)--, --N(R.sup.9)-- or
--(S.dbd.O)-- wherein R.sup.6, R.sup.7, R.sup.8 and R.sup.9 ently
are hydrogen or C.sub.1-6-alkyl, and wherein R.sup.10 is
C.sub.1-6-alkyl or phenyl; Y is C or N; is optionally a single bond
or a double bond, and is a single bond when Y is N; m is 1, 2, 3, 4
5 or 6; and Z is --COOR.sup.3 or 27wherein R.sup.3 is H or
C.sub.1-6-alkyl; or a pharmaceutically acceptable salt thereof.
2. A compound of formula Ia 28wherein R.sup.1 and R.sup.2
independently are hydrogen, halogen, trifluoromethyl, hydroxy,
C.sub.1-6-alkyl or C.sub.1-6-alkoxy; X is ortho-phenylene, --O--,
--S--, --C(R.sup.6R.sup.7)--, --CH.sub.2CH.sub.2--,
--CH.dbd.CH--CH.sub.2--, --CH.sub.2--CH.dbd.CH--,
--CH.sub.2--(C.dbd.O)--, --(C.dbd.O)CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.dbd.CH--,
--N(R.sup.8)--(C.dbd.O)--, --(C.dbd.O)--N(R.sup.8)--,
--O--CH.sub.2--, --CH.sub.2--O--, --OCH.sub.2O--, --S--CH.sub.2--,
--CH.sub.2--S--, --(CH.sub.2)N(R.sup.8)-- -, --N(R.sup.8)--,
--N(CH.sub.3)SO.sub.2--, --SO.sub.2N(CH.sub.3)--,
--CH(R.sup.10)CH.sub.2--, --CH.sub.2CH(R.sup.10)--, --(C.dbd.O)--,
--N(R.sup.9)-- or --(S.dbd.O)-- wherein R.sup.6, R.sup.7, R.sup.8
and R.sup.9 independently are hydrogen or C.sub.1-6-alkyl; and
wherein R.sup.10 is C.sub.1-6-alkyl or phenyl; Y is C or N; is
optionally a single bond or a double bond, and is a single bond
when Y is N; m is 1, 2, 3, 4, 5 or 6; and R.sup.3 is H or
C.sub.1-6-alkyl; or a pharmaceutically acceptable salt thereof.
3. A compound of formula I 29wherein R.sup.1 and R.sup.2
independently are hydrogen, halogen, trifluoromethyl, hydroxy,
C.sub.1-6-alkyl or C.sub.1-6-alkoxy; X is ortho-phenylene, --O--,
--S--, --C(R.sup.6R.sup.7)--, --CH.sub.2CH.sub.2--,
--CH.dbd.CH--CH.sub.2--, --CH.sub.2--CH.dbd.CH--,
--CH.sub.2--(C.dbd.O)--, --(C.dbd.O)--CH.sub.2--- ,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.dbd.CH--,
--N(R.sup.8)--(C.dbd.O)--, --(C.dbd.O)--N(R.sup.8)--,
--O--CH.sub.2--, --CH.sub.2--O--, --OCH.sub.2O--, --S--CH.sub.2--,
--CH.sub.2--S--, --(CH.sub.2)N(R.sup.8)-- -,
--N(R.sup.8)(CH.sub.2)--, --N(CH.sub.3)SO.sub.2--,
SO.sub.2N(CH.sub.3)--, --CH(R.sup.10)CH.sub.2--,
--CH.sub.2CH(R.sup.10)--- , --(C.dbd.O)--, --N(R.sup.9)-- or
--(S.dbd.O)-- wherein R.sup.6, R.sup.7, R.sup.8 and R.sup.9
independently are hydrogen or C.sub.1-6-alkyl, and wherein R.sup.10
is C.sub.1-6-alkyl or phenyl; Y is C or N; is optionally a single
bond or a double bond, and is a single bond when Y is N; m is 1, 2,
3, 4, 5 or 6; and Z is --COOR.sup.3 or 30wherein R.sup.3 is H or
C.sub.1-6-alkyl, provided that when R.sup.1 and R.sup.2 are
hydrogen; X is --O--, --S--, --CH.sub.2CH.sub.2--, --CH.dbd.CH--,
--O--CH.sub.2--, --CH.sub.2--O--, --S--CH.sub.2-- or
--CH.sub.2--S--; Y is C and is a double bond; m is 1, 2, 3, 4, 5 or
6, then Z is not --COOR.sup.3 wherein R.sup.3 is H or
C.sub.1-6-alkyl; or a pharmaceutically acceptable salt thereof.
4. A compound according to anyone of the preceding claims wherein
R.sup.1 and R.sup.2 are selected from hydrogen, halogen,
trifluoromethyl or C.sub.1-6-alkyl, preferably hydrogen.
5. A compound according to anyone of the preceding claims wherein m
is 1, 2, 3 or 4.
6. A compound according to anyone of the preceding claims wherein X
is selected from --S--, --CH.sub.2CH.sub.2, --CH.dbd.CH--,
--O--CH.sub.2--, --CH.sub.2--O--, --OCH.sub.2O--, --S--CH.sub.2--
or --CH.sub.2--S--.
7. A compound according to anyone of the preceding claims wherein X
is --CH.sub.2CH.sub.2--.
8. A compound according to anyone of the preceding claims wherein Y
is N.
9. A compound according to anyone of the preceding claims wherein Z
is --COOH.
10. A compound according to anyone of the claims 1 through 6
wherein X is --S--CH.sub.2-- or --CH.sub.2--S--.
11. A compound according to anyone of the claims 1 through 6
wherein Y is C and is a double bond.
12. A compound according to anyone of the claims 1 through 6
wherein Z is 31wherein R.sup.3 is H.
13. A compound selected from the following:
2-(4-(10,11-Dihydro-5H-dibenzo-
[a,d]cyclohepten-5-yl)piperazin-1-yl)acetic acid,
3-(4-(10,11-Dihydro-5h-d-
ibenzo[a,d]cyclohepten-5-yl)piperazin-1-yl)propionic acid,
4-(4-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperazin-1-yl)butyri-
c acid,
5-(4-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperazin-1-yl-
)pentanoic acid, or a pharmaceutically acceptable salt thereof.
14. A compound selected from the following:
1-(3-(4-(6,11-Dihydrodibenzo[b-
,e]thiepin-11-ylidene)-1-piperidinyl)-1-propyl)-3-piperidinecarboxylic
acid,
(R)-1-(2-(4-(6,11-Dihydrodibenzo[b,e]thiepin-11-ylidene)piperidin-1-
-yl)ethyl)-3-piperidinecarboxylic acid, or a pharmaceutically
acceptable salt thereof.
15. A method of preparing a compound of formula I, characterized in
a) reacting a compound of formula II 32 wherein R.sup.1, R.sup.2
and X are as defined above and W is a suitable leaving group such
as halogen, p-toluene sulphonate or mesylate, with a compound of
formula III 33 wherein R.sup.4 is hydrogen, a suitable N-protecting
group, --(CH.sub.2).sub.m--CO.sub.2R.sup.3 or 34and m and R.sup.3
are as defined above, to form a compound of formula I, or b)
reacting a compound of formula IV 35 wherein R.sup.1, R.sup.2 and X
are as defined above, with a compound of formula
VHal(CH.sub.2).sub.m--Z (V) wherein Hal is a halogen, Z is
--COOR.sup.3 or 36and R.sup.3 and m are as defined above, to form a
compound of formula I.
16. A method of preparing a compound of formula Ia, characterized
in a) reacting a compound of formula II 37 wherein R.sup.1, R.sup.2
and X are as defined above and W is a suitable leaving group such
as halogen, p-toluene sulphonate or mesylate, with a compound of
formula III 38wherein R.sup.4 is hydrogen, a suitable N-protecting
group or --(CH.sub.2).sub.m--COOR.sup.3 and m and R.sup.3 are as
defined above, to form a compound of formula Ia, or b) reacting a
compound of formula IV 39 wherein R.sup.1.sub.1 R.sup.2and X are as
defined above) with a compound of formula
VHal(CH.sub.2).sub.m--CO.sub.2R.sup.3 (V)wherein Hal means a
halogen and R.sup.3 and m are as defined above, to form a compound
of formula Ia.
17. A pharmaceutical composition comprising as active component a
compound according to any of the claims 1 through 14 together with
a pharmaceutically carrier or diluent.
18. A pharmaceutical composition suitable for treating neurogenic
inflammation composing an effective amount of a compound according
to any of the claims 1 through 14 together with a pharmaceutically
acceptable carrier or diluent.
19. A pharmaceutical composition suitable for treating neuropathy
comprising an effective amount of a compound according to any of
the claims 1 through 14 together with a pharmaceutically acceptable
carrier or diluent.
20. A pharmaceutical composition suitable for treating rheumatoid
arthritis comprising an effective amount of a compound according to
any of the claims 1 through 14 together with a pharmaceutically
acceptable carrier or diluent.
21. A pharmaceutical composition suitable for treating insulin
resistance comprising an effective amount of a compound according
to any of the claims 1 through 14 together with a pharmaceutically
acceptable carrier or diluent.
22. A pharmaceutical composition suitable for treating
non-insulin-dependent diabetes mellitus comprising an effective
amount of a compound according to any of the claims 1 through 14
together with a pharmaceutically acceptable carrier or diluent.
23. The pharmaceutical composition according to claims 17, 18, 19,
20, 21 and 22 comprising between 0.5 mg and 1000 mg of the compound
according to any of the claims 1 through 14 per unit dose.
24. A method of treating insulin resistance in a subject in need of
such treatment comprising administering to said subject an
effective amount of a compound according to any of the claims 1
through 14.
25. A method of treating insulin resistance in a subject in need of
such treatment comprising administering to said subject a
pharmaceutical composition according to claim 24.
26. The use of a compound according to any of the claims 1 through
14 for preparing a pharmaceutical composition for the treatment of
neurogenic inflammation.
27. The use of a compound according to any of the claims 1 through
14 for preparing a pharmaceutical composition for the treatment of
neuropathy.
28. The use of a compound according to any of the claims 1 through
14 for preparing a pharmaceutical composition for treatment of
rheumatoid arthritis.
29. The use of a compound according to any of the claims 1 through
14 for preparing a pharmaceutical composition for the treatment of
insulin resistance.
30. The use of a compound according to any of the claims 1 through
14 for preparing a pharmaceutical composition for the treatment of
non-insulin-dependent diabetes mellitus.
31. The use of a compound of formula I 40wherein R.sup.1 and
R.sup.2 are hydrogen; X is --O--, --S--, --CH.sub.2CH.sub.2--,
--CH.dbd.CH--, --O--CH.sub.2--, --CH.sub.2--O--, --S--CH.sub.2-- or
--CH.sub.2--S--; Y is C and is a double bond; m is 1, 2, 3, 4, 5 or
6; Z is --COOR.sup.3 and R.sup.3 is H or C.sub.1-6-alkyl, or a
pharmaceutically acceptable salt thereof, for preparing a
pharmaceutical composition for treating neurogenic
inflammation.
32. The use of a compound of formula I 41wherein R.sup.1 and
R.sup.2 are hydrogen; X is --O--, --S--, --CH.sub.2CH.sub.2--,
--CH.dbd.CH--, --O--CH.sub.2--, --CH.sub.2O--, --S--CH.sub.2-- or
--CH.sub.2--S--; Y is C and is a double bond; m is 1, 2, 3, 4, 5 or
6; Z is --COOR.sup.3 and R.sup.3 is H or C.sub.1-6-alkyl, or a
pharmaceutically acceptable salt thereof, for preparing a
pharmaceutical composition for treating neuropathy.
33. The use of a compound of formula I 42wherein R.sup.1 and
R.sup.2 are hydrogen; X is --O--, --S--, --CH.sub.2CH.sub.2--,
--CH.dbd.CH--, --O--CH.sub.2--, --CH.sub.2O--, --S--CH.sub.2-- or
CH.sub.2--S--; Y is C and is a double bond; m is 1, 2, 3, 4, 5 or
6; Z is --COOR.sup.3 and R.sup.3 is H or C.sub.1-6-alkyl, or a
pharmaceutically acceptable salt thereof, for preparing a
pharmaceutical composition for treating rheumatoid arthritis.
34. The use of a compound of formula I 43wherein R.sup.1 and
R.sup.2 are hydrogen; X is --O--, --S--, --CH.sub.2CH.sub.2--,
--CH.dbd.CH--, --O--CH.sub.2--, --CH.sub.2--O--, --S--CH.sub.2-- or
--CH.sub.2--S--; Y is C and is a double bond; m is 1, 2, 3, 4, 5
or6; Z is --COOR.sup.3 and R.sup.3 is H or C.sub.1-6-alkyl, or a
pharmaceutically acceptable salt thereof, for preparing a
pharmaceutical composition for reducing blood glucose.
35. The use of a compound of formula I 44wherein R.sup.1 and
R.sup.2 are hydrogen; X is --O--, --S--, --CH.sub.2CH.sub.2--,
--CH.dbd.CH--, --O--CH.sub.2--, --CH.sub.2--O--, --S--CH.sub.2-- or
--CH.sub.2--; Y is C and is a double bond; m is 1, 2, 3, 4, 5 or 6;
Z is --COOR.sup.3 and R.sup.3 is H or C.sub.1-6-alkyl, or a
pharmaceutically acceptable salt thereof, for preparing a
pharmaceutical composition for treating insulin resistance.
36. The use of a compound of formula I 45wherein R.sup.1 and
R.sup.2 are hydrogen; X is --O--, --S--, --CH.sub.2CH.sub.2--,
--CH.dbd.CH--, --O--CH.sub.2--, --CH.sub.2--O--, --S--, CH.sub.2--
or --CH.sub.2--S--; Y is C and is a double bond; m is 1, 2, 3, 4, 5
or 6; Z is --COOR.sup.3 and R.sup.3 is H or C.sub.1-6-alkyl, or a
pharmaceutically acceptable salt thereof, for preparing a
pharmaceutical composition for treating non-insulin-dependent
diabetes mellitus (NIDDM).
37. The use according to any of the claims 31 through 36 wherein X
is --CH.sub.2CH.sub.2--, --S--CH.sub.2-- or --CH.sub.2--S--.
38. The use according to any of the claims 31 through 37 wherein m
is 1, 2 or 3.
39. The use according to any of the claims 31 through 38 wherein
R.sup.3 is H.
40. The use according to any of the claims 31 through 39 wherein
the compound is selected from
3-(4-(6,11-Dihydrodibenzo[b,e]thiepin-11-yliden-
e)-1-piperidine)propionic acid,
2-(4-(6,11-Dihydrodibenzo[b,e]thiepin-11-y-
lidene)-1-piperidinyl)acetic acid,
4-(4-(6,11-Dihydrodibenzo[b,e]thiepin-1-
1-ylidene)-1-piperidinyl)butyric acid,
3-(4-(10,11-Dihydro-5H-dibenzo[a,d]-
cyclohepten-5-ylidene)-1-piperidine)propionic acid, or a
pharmaceutically acceptable salt thereof.
41. The use according to any of the claims 31 through 40 wherein
said compound is administered in a range between 0.5 and 1000 mg of
the compound per unit dose.
42. A method for treating neurogenic inflammation in a subject in
need of such treatment comprising administering to said subject an
effective amount of a compound of formula I 46wherein R.sup.1 and
R.sup.2 are hydrogen; X is --O--, --S--, --CH.sub.2CH.sub.2--,
--CH.dbd.CH--, --O--CH.sub.2--, --CH.sub.2--O--, --S--CH.sub.2-- or
--CH.sub.2S--; Y is C and is a double bond; m is 1, 2, 3, 4, 5 or
6; Z is --COOR.sup.3 and R.sup.3 is H or C.sub.1-6-alkyl, or a
pharmaceutically acceptable salt thereof.
43. A method for treating neuropathy in a subject in need of such
treatment comprising administering to said subject an effective
amount of a compound of formula I 47wherein R.sup.1 and R.sup.2 are
hydrogen; X is --O--, --S--, --CH.sub.2CH.sub.2--, --CH.dbd.CH--,
--O--CH.sub.2--, --CH.sub.2--O--, --S--CH.sub.2-- or
--CH.sub.2--S--; Y is C and is a double bond; m is 1, 2, 3, 4, 5 or
6; Z is --COOR.sup.3 and R.sup.3 is H or C.sub.1-6-alkyl, or a
pharmaceutically acceptable salt thereof.
44. A method for treating rheumatoid arthritis in a subject in need
of such treatment comprising administering to said subject an
effective amount of a compound of formula I 48wherein R.sup.1 and
R.sup.2 are hydrogen; X is --O--, --S--, --CH.sub.2CH.sub.2--,
--CH.dbd.CH--, --O--CH.sub.2--, --CH.sub.2--O--, --S--CH.sub.2-- or
--CH.sub.2--S--; Y is C and is a double bond; m is 1, 2, 3, 4, 5 or
6; Z is --COOR.sup.3 and R.sup.3 is H or C.sub.1-6-alkyl, or a
pharmaceutically acceptable salt thereof.
45. A method for reducing blood glucose in a subject in need of
such treatment comprising administering to said subject an
effective amount of a compound of formula I 49wherein R.sup.1 and
R.sup.2 are hydrogen; X is --O--, --S--, --CH.sub.2CH.sub.2--,
--CH.dbd.CH--, --O--CH.sub.2--, --CH.sub.2--O--, --S--CH.sub.2-- or
--CH.sub.2--S--; Y is C and is a double bond; m is 1, 2, 3, 4, 5 or
6; Z is --COOR.sup.3 and R.sup.3 is H or C.sub.1-6-calkyl, or a
pharmaceutically acceptable salt thereof.
46. A method for treating insulin resistance in a subject in need
of such treatment comprising administering to said subject an
effective amount of a compound of formula I 50wherein R.sup.1 and
R.sup.2 are hydrogen; X is --O--, --S--, --CH.sub.2CH.sub.2--,
--CH.dbd.CH--, --O--CH.sub.2--, --CH.sub.2O--, --S--CH.sub.2-- or
--CH.sub.2--S--; Y is C and is a double bond; m is 1, 2, 3, 4, 5 or
6; Z is --COOR .sup.3 and R.sup.3 is H or C.sub.1-6-calkyl, or a
pharmaceutically acceptable salt thereof.
47. A method for treating non-insulin-dependent diabetes mellitus
(NIDDM) in a subject in need of such treatment comprising
administering to said subject an effective amount of a compound of
formula I 51wherein R.sup.1 and R.sup.2 are hydrogen; X is --O--,
--S--, --CH.sub.2CH.sub.2--, --CH.dbd.CH--, --O--CH.sub.2--,
--CH.sub.2--O--, --S--CH.sub.2-- or --CH.sub.2--S--; Y is C and is
a double bond; m is 1, 2, 3, 4, 5 or 6; Z is --COOR.sup.3 and
R.sup.3 is H or C.sub.1-6-alkyl, or a pharmaceutically acceptable
salt thereof.
48. A method according to any of the claims 42 through 47 wherein X
is --CH.sub.2CH.sub.2--, --S--CH.sub.2-- or --CH.sub.2--S--.
49. A method according to any of the claims 42 through 48 wherein m
is 1, 2 or 3.
50. A method according to any of the claims 42 through 49 wherein
R.sup.3 is H.
51. A method according to any of the claims 42 through 50 wherein
the compound is selected from
3-(4-(6,11-Dihydrodibenzo[b,e]thiepin-11-yliden-
e)-1-piperidine)propionic acid,
2-(4-(6,11-Dihydrodibenzo[b,e]thiepin-11-y-
lidene)-1-piperidinyl)acetic acid,
4-(4-(6,11-Dihydrodibenzo[b,e]thiepin-1-
1-ylidene)-1-piperidinyl)butyric acid,
3-(4-(10,11-Dihydro-5H-dibenzo[a,d]-
cyclohepten-5-ylidene)-1-piperidine)propionic acid, or a
pharmaceutically acceptable salt thereof.
52. A method according to any of the claims 42 through 51 wherein
said compound is administered in a range between 0.5 and 1000 mg of
the compound per unit dose.
53. Any novel feature or combination of features as described
herein.
Description
FIELD OF INVENTION
[0001] The present invention relates to novel N-substituted
azaheterocyclic compounds in which a substituted alkyl chain forms
part of the N-substituent or salts thereof, to methods for their
preparation, to compositions containing them, to the use of the
compounds for preparing compositions for the clinical treatment of
painful, hyperalgesic and/or inflammatory conditions in which
C-fibres play a pathophysiological role by eliciting neurogenic
pain or inflammation, and to methods of treating said painful,
hyperalgesic and/or inflammatory conditions. The invention also
relates to the use of the present compounds for the treatment of
insulin resistance in non-insulin-dependent diabetes mellitus
(NIDDM) as well as ageing-associated obesity, the present compounds
being known to interfere with neuropeptide containing C-fibres and
hence to inhibit the secretion and circulation of insulin
antagonising peptides like CGRP or amylin.
BACKGROUND OF INVENTION
[0002] The nervous system exerts a profound effect on the
inflammatory response. Antidromic stimulation of sensory nerves
results in localised vasodilation and increased vascular
permeability (Janecso et al. Br. J. Pharmacol. 1967, 31, 138-151),
and a similar response is observed following injection of peptides
known to be present in sensory nerves. From this and other data it
is postulated that peptides released from sensory nerve endings
mediate many inflammatory responses in tissues like skin, joint,
urinary tract, eye, meninges, gastro-intestinal and respiratory
tracts. Hence inhibition of sensory nerve peptide release and/or
activity may be useful in treatment of for example arthritis,
dermatitis, rhinitis, asthma, cystitis, gingivitis,
thrombo-phlelitis, glaucoma, gastrointestinal diseases or
migraine.
[0003] Further, the potent effects of CGRP on skeletal muscle
glycogen synthase activity and muscle glucose metabolism, together
with the notion that this peptide is released from the
neuromuscular junction by nerve excitation, suggest that CGRP may
play a physiological role in skeletal muscle glucose metabolism by
directing the phosphorylated glucose away from glycogen storage and
into the glycolytic and oxidative pathways (Rossetti et al. Am. J.
Physiol. 264, E1-E10, 1993). This peptide may represent an
important physiological modulator of intracellular glucose
trafficking in physiological conditions, such as exercise, and may
also contribute to the decreased insulin action and skeletal muscle
glycogen synthase in pathophysiological conditions like NIDDM or
ageing-associated obesity (Melnyk et al. Obesity Res. 3, 337-344,
1995) where circulating plasma levels of CGRP are markedly
increased. Hence inhibition of release and/or activity of the
neuropeptide CGRP may be useful in the treatment of insulin
resistance related to type 2 diabetes or ageing.
[0004] In U.S. Pat. No. 4,383,999 and U.S. Pat. No. 4,514,414 and
in EP 236342 as well as in EP 231996some derivatives of
N-(4,4-disubstituted-3-- butenyl)azaheterocyclic carboxylic acids
are claimed as inhibitors of GABA uptake. In EP 342635 and EP
374801, N-substituted azaheterocyclic carboxylic acids in which an
oxime ether group and vinyl ether group forms part of the
N-substituent respectively are claimed as inhibitors of GABA
uptake. Further, in WO 9107389 and WO 9220658, N-substituted
azacyclic carboxylic acids are claimed as GABA uptake inhibitors.
EP 221572 claims that 1-aryloxyalkylpyridine-3-carboxylic acids are
inhibitors of GABA uptake.
[0005] EP 451772 and EP 406739 as well as Chem. Pharm. Bull. 42,
2285 (1994) discloses (dibenzo[a,d]cyclohepten-5-ylidene)piperidine
derivatives and related compounds which have antihistaminergic and
antiallergic activity.
SUMMARY OF THE INVENTION
[0006] The present invention relates to compounds of the general
formulae I and Ia, wherein X, Y, Z. R.sup.1, R.sup.2, R.sup.3 and m
are as defined in the detailed part of the present description.
[0007] The present compounds are useful for the treatment,
prevention, elimination, alleviation or amelioration of an
indication related to all painful, hyperalgesic and/or inflammatory
conditions in which C-fibres play a pathophysiological role, e.g.
neurogenic pain, neurogenic inflammation, migraine, neuropathy,
itching and rheumatoid arthritis, as well as indications caused by
or related to the secretion and circulation of insulin antagonising
peptides and other peptides derived from the sensory nervous
system, e.g. non-insulin-dependent diabetes mellitus (NIDDM) and
ageing-associated obesity.
[0008] In another aspect, the present invention includes within its
scope pharmaceutical compositions comprising, as an active
ingredient, at least one of the compounds of the general formulae
or a pharmaceutically acceptable salt thereof together with a
pharmaceutically acceptable carrier or diluent.
[0009] In another aspect of the present invention there is provided
a method of treating painful, hyperalgesic and/or inflammatory
conditions in which C-fibres play a pathophysiological role, e.g.
neurogenic pain, neurogenic inflammation, migraine, neuropathy,
itching and rheumatoid arthritis, as well as a method of treating
indications caused by or related to the secretion and circulation
of insulin antagonising peptides, e.g. non-insulin-dependent
diabetes mellitus (NIDDM) and ageing-associated obesity.
[0010] The method of treatment may be described as the treatment,
prevention, elimination, alleviation or amelioration of one of the
above indications, which comprises the step of administering to the
said subject a neurologically effective amount of a compound of the
invention, or a pharmaceutically acceptable salt thereof.
[0011] A further aspect of the invention relates to the use of a
compound of the present invention for the preparation of a
pharmaceutical composition for the treatment of all painful,
hyperalgesic and/or inflammatory conditions in which C-fibres play
a pathophysiological role, e.g. neurogenic pain, neurogenic
inflammation, migraine, neuropathy, itching and rheumatoid
arthritis, as well as for the treatment of indications caused by or
related to the secretion and circulation of insulin antagonising
peptides, e.g. non-insulin-dependent diabetes mellitus (NIDDM) and
ageing-associated obesity.
[0012] Further objects will become apparent from the following
description.
DETAILED DESCRIPTION OF THE INVENTION
[0013] Accordingly, the present invention relates to novel
N-substituted azaheterocyclic compounds of the general formula I
2
[0014] wherein
[0015] R.sup.1 and R.sup.2 independently are hydrogen, halogen,
trifluoromethyl, hydroxy, C.sub.1-6-alkyl or C.sub.1-6alkoxy;
[0016] X is ortho-phenylene, --O--, --S--, --C(R.sup.6R.sup.7)--,
--CH.sub.2CH.sub.2--, --CH.dbd.CH--CH.sub.2--,
--CH.sub.2--CH.dbd.CH--, --CH.sub.2--(C.dbd.O)--,
--(C.dbd.O)--CH.sub.2--, --CH.sub.2CH.sub.2CH.su- b.2--,
--CH.dbd.CH--, --N(R.sup.8)--(C.dbd.O)--,
--(C.dbd.O)--N(R.sup.8)--- , --O--CH.sub.2--, --CH.sub.2--O--,
--OCH.sub.2O--, --S--CH.sub.2--, --CH.sub.2--S--,
--(CH.sub.2)N(R.sup.8)--, --N(R.sup.8)(CH.sub.2)--,
--N(CH.sub.3)SO.sub.2--, --SO.sub.2N(CH.sub.3)--,
--CH(R.sup.10)CH.sub.2-- -, --CH.sub.2CH(R.sup.10)--,
--(C.dbd.O)--, --N(R.sup.9)-- or --(S.dbd.O)-- wherein R.sup.6,
R.sup.7, R.sup.8 and R.sup.9 independently are hydrogen or
C.sub.1-6-alkyl, and wherein R.sup.10 is C.sub.1-6-alkyl or
phenyl;
[0017] Y is C or N; is optionally a single bond or a double bond,
and is a single bond when Y is N;
[0018] m is 1,2,3,4,5or 6; and
[0019] Z is --COOR.sup.3 or 3
[0020] wherein
[0021] R.sup.3 is H or C.sub.1-6-alkyl;
[0022] or a pharmaceutically acceptable salt thereof.
[0023] The present invention also relates to the novel
N-substituted azaheterocyclic compounds of the general formula Ia
4
[0024] wherein
[0025] R.sup.1 and R.sup.2 independently are hydrogen, halogen,
trifluoromethyl, hydroxy, C.sub.1-6-alkyl or C.sub.1-6-alkoxy;
[0026] X is ortho-phenylene, --O--, --S--, --C(R.sup.6R.sup.7)--,
--CH.sub.2CH.sub.2--, --CH.dbd.CH--CH.sub.2--,
--CH.sub.2--CH.dbd.CH--, --CH.sub.2--(C.dbd.O)--,
--(C.dbd.O)--CH.sub.2--, --CH.sub.2CH.sub.2CH.su- b.2--,
--CH.dbd.CH--, --N(R.sup.8)--(C.dbd.O)--,
--(C.dbd.O)--N(R.sup.8)--- , --O--CH.sub.2--, --CH.sub.2--O--,
--OCH.sub.2O--, --S--CH.sub.2--, --CH.sub.2--S--,
--(CH)N(R.sup.8)--, --N(R.sup.8)(CH.sub.2)--,
--N(CH.sub.3)SO.sub.2--, --SO.sub.2N(CH.sub.3)--,
--CH(R.sup.10)CH.sub.2-- -, --CH.sub.2CH(R.sup.10)--,
--(C.dbd.O)--, --N(R.sup.9)-- or --(S.dbd.O)-- wherein R.sup.6,
R.sup.7, R.sup.8 and R.sup.9 independently are hydrogen or
C.sub.1-6-alkyl, and wherein R.sup.10 is C.sub.1-6-alkyl or
phenyl;
[0027] Y is C or N; is optionally a single bond or a double bond,
and is a single bond when Y is N;
[0028] m is 1, 2, 3, 4, 5 or 6; and
[0029] R.sup.3 is H or C.sub.1-6-alkyl;
[0030] or a pharmaceutically acceptable salt thereof.
[0031] Compounds of the general formulae wherein R.sup.1 and
R.sup.2 are hydrogen; X is --O--, --S--, --CH.sub.2CH.sub.2--,
--CH.dbd.CH--, --O--CH.sub.2--, --CH.sub.2--O--, --S--CH.sub.2-- or
--CH.sub.2--S--; Y is C and is a double bond; m is 1, 2, 3, 4, 5 or
6; Z is --COOR.sup.3 and R.sup.3 is H or C.sub.1-6-alkyl are known
from EP A 451772 and EP A 406739 as well as Chem. Pharm. Bull. 42,
2285 (1994) as compounds having antihistaminergic and antiallergic
activity.
[0032] The compounds according to the invention may exist as
geometric and optical isomers and all isomers, as separated, pure
or partially purified stereoisomers or racemic mixtures thereof are
included in the scope of the invention. Isomers may be separated by
means of standard methods such as chromatographic techniques or
fractional crystallisation of suitable salts.
[0033] Preferably, the compounds according to the invention exist
as the individual geometric or optical isomers.
[0034] The compounds according to the invention may optionally
exist as pharmaceutically acceptable acid addition salts, metal
salts or, optionally alkylated, ammonium salts.
[0035] Examples of such salts include inorganic and organic acid
addition salts such as hydrochloride, hydrobromide, sulphate,
phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate,
oxalate or similar pharmaceutically acceptable inorganic or organic
acid addition salts. Further examples of pharmaceutically
acceptable inorganic or organic acid addition salts include the
pharmaceutically acceptable salts listed in Journal of
Pharmaceutical Science, 66, 2 (1977) which are known to the skilled
artisan.
[0036] Also intended as pharmaceutically acceptable acid addition
salts are the hydrates which the present compounds are able to
form.
[0037] The acid addition salts may be obtained as the direct
products of compound synthesis. In the alternative, the free base
may be dissolved in a suitable solvent containing the appropriate
acid, and the salt isolated by evaporating the solvent or otherwise
separating the salt and solvent.
[0038] The compounds according to the invention may be administered
in a pharmaceutically acceptable acid addition salt form or where
possible as a metal or a lower alkylammonium salt. Such salt forms
exhibit approximately the same order of activity as the free base
forms.
[0039] In the above structural formulae and throughout the present
specification, the following terms have the indicated meaning:
[0040] The term "C.sub.1-6-alkyl" as used herein, alone or in
combination, refers to a straight or branched, saturated
hydrocarbon chain having 1 to 6carbon atoms. Typical
C.sub.1-6-alkyl groups include, but are not limited to, methyl,
ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, n-pentyl, iso-pentyl, 2-methylbutyl, 3-methylbutyl,
n-hexyl, iso-hexyl, 4-methylpentyl, neopentyl, 1,2-dimethylpropyl,
2,2-dimethylpropyl, 1,2,2-trimethylpropyl and the like.
[0041] The term "C.sub.1-6-calkoxy" as used herein, alone or in
combination is intended to include those C.sub.1-6alkyl groups of
the designated length in either a linear or branched or cyclic
configuration linked through an ether oxygen having its free
valence bond from the ether oxygen. Examples of linear alkoxy
groups are methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
Examples of branched alkoxy are isopropoxy, sec-butoxy,
tert-butoxy, isopentoxy and isohexoxy. Example of cyclic alkoxy are
cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
The term "halogen" means fluorine, chlorine, bromine or iodine.
[0042] In a preferred embodiment of the invention R.sup.1 and
R.sup.2 are selected from hydrogen, halogen, trifluoromethyl or
C.sub.1-6-alkyl. Preferably R.sup.1 and R.sup.2 are hydrogen.
[0043] In another preferred embodiment of the invention Y is N.
[0044] In another preferred embodiment of the invention Y is C and
is a double bond.
[0045] In another preferred embodiment of the invention X is
selected from --S--, --CH.sub.2CH.sub.2--, --CH.dbd.CH--,
--O--CH.sub.2--, --CH.sub.2--O--, --S--CH.sub.2-- or
--CH.sub.2--S--. Preferably X is --CH.sub.2CH.sub.2--.
[0046] In another preferred embodiment of the invention X is
--S--CH.sub.2-- or --CH.sub.2--S--.
[0047] In another preferred embodiment of the invention m is 1, 2,
3 or 4.
[0048] In another preferred embodiment of the invention Z is
--COOR.sup.3.
[0049] In another preferred embodiment of the invention Z is
--COOR.sup.3. 5
[0050] In yet another preferred embodiment of the invention R.sup.3
is H.
[0051] Preferred compounds of the present invention include:
[0052]
2-(4-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperazin-1-yl)-
acetic acid,
[0053]
3-(4-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperazin-1-yl)-
propionic acid,
[0054]
4-(4-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperazin-1-yl)-
butyric acid,
[0055]
5-(4-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperazin-1-yl)-
pentanoic acid,
[0056] or a pharmaceutically acceptable salt thereof.
[0057] Other preferred compounds of the present invention
include:
[0058]
1-(3-(4-(6,11-Dihydrodibenzo[b,e]thiepin-11-ylidene)-1-piperidinyl)-
-1-propyl)-3-piperidinecarboxylic acid,
[0059]
(R)-1-(2-(4-(6,11-Dihydrodibenzo[b,e]thiepin-11-ylidene)piperidin-1-
-yl)ethyl)-3-piperidinecarboxylic acid,
[0060] or a pharmaceutically acceptable salt thereof.
[0061] It has been demonstrated that the compounds according to the
invention inhibit neurogenic inflammation which involves the
release of neuropeptides from peripheral and central endings of
sensory C-fibres. Experimentally this can be demonstrated in animal
models of histamine induced paw oedema Amann et al. (Europ. J.
Pharmacol. 279, 227-231, 1995) in which the compounds according to
the invention exhibit a potent inhibitory effect. The compounds
according to the invention may be used to treat all painful,
hyperalgesic and/or inflammatory conditions in which C-fibres play
a pathophysiological role by eliciting neurogenic pain or
inflammation, i.e.:
[0062] Acutely painful conditions exemplified by migraine,
postoperative pain, burns, bruises, post-herpetic pain (Zoster) and
pain as it is generally associated with acute inflammation;
chronic, painful and/or inflammatory conditions exemplified by
various types of neuropathy (diabetic, post-traumatic, toxic),
neuralgia, rheumatoid arthritis, spondylitis, gout, inflammatory
bowel disease, prostatitis, cancer pain, chronic headache,
coughing, asthma, itching, chronic pancreatitis, inflammatory skin
disease including psoriasis and autoimmune dermatoses, osteoporotic
pain.
[0063] Also included within the present invention are the use of
the compounds of the general formula I 6
[0064] wherein
[0065] R.sup.1 and R.sup.2 are hydrogen;
[0066] X is --O--, --S--, --CH.sub.2CH.sub.2--, --CH.dbd.CH--,
--O--CH.sub.2--, --CH.sub.2--O--, --S--CH.sub.2-- or
--CH.sub.2--S--;
[0067] Y is C and is a double bond;
[0068] m is , 2, 3, 4, 5 or 6;
[0069] Z is --COOR.sup.3 and R.sup.3 is H or C.sub.1-6alkyl,
[0070] or a pharmaceutically acceptable salt thereof, for the
preparation of pharmaceutical compositions for the treatment of
neurogenic inflammation, painful and/or inflammatory conditions
e.g. neuropathy and rheumatoid arthritis.
[0071] Further, it has been demonstrated that the compounds
according to the invention improves the glucose tolerance in
diabetic ob/ob mice and that this may result from the reduced
release of CGRP from peripheral nervous endings. Hence the
compounds according to the invention may be used in the treatment
of NIDDM as well as ageing-associated obesity. Experimentally this
has been demonstrated by the subcutaneous administration of glucose
into ob/ob mice with or without previous oral treatment with a
compound according to the invention.
[0072] Also included within the present invention are the use of
the compounds of the general formula I 7
[0073] wherein
[0074] R.sup.1 and R.sup.2 are hydrogen;
[0075] X is --O--, --S--, --CH.sub.2CH.sub.2--, --CH.dbd.CH--,
--O--CH.sub.2--, --CH.sub.2--O--, --S--CH.sub.2-- or
--CH.sub.2--S--;
[0076] Y is C and is a double bond;
[0077] m is 1, 2, 3, 4, 5 or 6;
[0078] Z is --COOR.sup.3 and R.sup.3 is H or C.sub.1-6-alkyl,
[0079] or a pharmaceutically acceptable salt therof, for the
preparation of pharmaceutical compositions for reducing blood
glucose. Hence these compounds may be used in the treatment
non-insulin-dependent diabetes mellitus (NIDDM), as well as in the
treatment of insulin resistance in NIDDM.
[0080] The compounds of the general formula I, wherein Y is N, may
be prepared by the following methods: 8
[0081] A compound of formula II wherein R.sup.1, R.sup.2 and X are
as defined above and W is a suitable leaving group such as halogen,
p-toluene sulphonate or mesylate may be reacted with a piperazine
of formula III wherein R.sup.4 is hydrogen, a suitable N-protecting
group, --(CH.sub.2).sub.m--CO.sub.2R.sup.3 or 9
[0082] wherein R.sup.3 is as defined above. Introduction and
removal of such groups is described in "Protective Groups in
Organic Chemistry" J. F. W. McOmie ed. (New York, 1973).
[0083] This alkylation reaction may be carried out in a solvent
such as acetone, dibutylether, 2-butanone, dioxane, ethyl acetate,
tetrahydrofuran (THF) or toluene in the presence of a base e.g.
sodium hydride or potassium carbonate and a catalyst, e.g. an
alkali metal iodide at a temperature up to reflux temperature for
the solvent used for e.g. 1 to 120 h.
[0084] When R.sup.4 in formula III is hydrogen, a second
N-alkylation with a compound Hal(CH.sub.2).sub.m--CO.sub.2R.sup.3
or 10
[0085] follows, where Hal means a halogen and R.sup.3 and m are as
defined above.
[0086] When R.sup.4 in formula III is a protecting group then,
after deprotection, a second N-alkylation with a compound
Hal(CH.sub.2).sub.m--CO.sub.2R.sup.3 or 11
[0087] follows. When R.sup.3 is an C.sub.1-6-alkyl group, a final
deprotection step may be performed.
[0088] The compounds of the general formula I, wherein Y is C, may
be prepared by the following methods: 12
[0089] A compound of formula IV wherein R.sup.1, R.sup.2 and X are
as defined may be reacted with a compound of formula V, where Hal
means a halogen, Z means --COOR.sup.3 or 13
[0090] and R.sup.3 and m are as defined above. This alkylation
reaction may be carried out in a solvent such as acetone,
dibutylether, 2-butanone, dioxane, ethyl acetate, tetrahydrofuran
(THF) or toluene in the presence of a base e.g. sodium hydride or
potassium carbonate and a catalyst, e.g. an alkali metal iodide at
a temperature up to reflux temperature for the solvent used for
e.g. 1 to 120 h.
[0091] When R.sup.3 is an C.sub.1-6-alkyl group, a final
deprotection step may be performed.
[0092] The compounds of formula Ia, wherein Y is N, may be prepared
by the following methods: 14
[0093] A compound of formula II wherein R.sup.1, R.sup.2 and X are
as defined above and W is a suitable leaving group such as halogen,
p-toluene sulphonate or mesylate may be reacted with a piperazine
of formula III wherein R.sup.4 is hydrogen, a suitable N-protecting
group or --(CH.sub.2).sub.m--CO.sub.2R.sup.3 wherein R.sup.3 is as
defined above. Introduction and removal of such groups is described
in "Protective Groups in Organic Chemistry" J. F. W. McOmie ed.
(New York, 1973).
[0094] This alkylation reaction may be carried out in a solvent
such as acetone, dibutylether, 2-butanone, dioxane, ethyl acetate,
tetrahydrofuran (THF) or toluene in the presence of a base e.g.
sodium hydride or potassium carbonate and a catalyst, e.g. an
alkali metal iodide at a temperature up to reflux temperature for
the solvent used for e.g. 1 to 120 h.
[0095] When R.sup.4 in formula III is hydrogen, a second
N-alkylation with a compound Hal(CH.sub.2).sub.m--CO.sub.2R.sup.3
follows, where Hal means a halogen and R.sup.3 and m are as defined
above.
[0096] When R.sup.4 in formula III is a protecting group then,
after deprotection, a second N-alkylation with a compound
Hal(CH.sub.2).sub.m--CO.sub.2R.sup.3 follows. When R.sup.3 is an
C.sub.1-6-alkyl group, a final deprotection step may be
performed.
[0097] Compounds of formula Ia, wherein Y is C, may be prepared by
the following methods: 15
[0098] A compound of formula IV wherein R.sup.1, R.sup.2 and X are
as defined may be reacted with a compound of formula V, where Hal
means a halogen and R.sup.3 and m are as defined above.
[0099] This alkylation reaction may be carried out in a solvent
such as acetone, dibutylether, 2-butanone, dioxane, ethyl acetate,
tetrahydrofuran (THF) or toluene in the presence of a base e.g.
sodium hydride or potassium carbonate and a catalyst, e.g. an
alkali metal iodide at a temperature up to reflux temperature for
the solvent used for e.g. 1 to 120 h.
[0100] When R.sup.3 is an C.sub.1-6-alkyl group, a final
deprotection step may be performed.
[0101] Compounds of formula IV and V may readily be prepared by
methods familiar to those skilled in the art.
Pharmaological Methods
[0102] I. Histamine induced paw oedema
[0103] The rat histamine paw oedema test was performed essentially
as described by Amann et al. (Europ. J. Pharmacol. 279, 227-231,
1995). In brief 250-300 g male Sprague-Dawley rats were
anaesthetized with pentobarbital sodium, and placed on a 32 degree
heated table. Ten minutes later histamine (50 micoliter, 3 mg/ml)
was injected in the right hind paw and 20 minutes hereafter the paw
swelling was determined by water plethysmography (Ugo Basile). Test
compounds were administered intraperitoneally at 15 minutes before
the anaesthetics.
[0104] II. Histamine Induced Hyperglycemia in Mice
[0105] Conscious unfasted 25 g male NMRI mice are administered
histamine chloride (90 nmol) icv according to the method of
Nishibori et al. (J. Pharmacol. Exp. Therap. 241, 582-286, 1987).
Blood glucose is determined at time 0 and 40 min after the
histamine injection. Test compounds are administered at 1.0 mg/kg
ip 30 min before the histamine injection, and % inhibition refers
to the capacity of the compounds to inhibit the histamine induced
blood glucose rise.
[0106] III. Reduced Release of CGRP
[0107] ob/ob female mice, 16 weeks of age, where injected glucose
(2 g/kg) subcutaneously. At times hereafter blood glucose was
determined in tail venous blood by the glucose oxidase method. At
the end of the study the animals were decapitated and trunck blood
collected. Immunoreactive CGRP was determined in plasma by
radio-immuno-assay. Two groups of animals were used. The one group
was vehicle treated, whereas the other group received a compound of
formula I via drinking water (100 mg/l) for five days before the
test.
[0108] Values for inhibition of histamine induced oedema response
for a representative compound is listed in table 1.
1TABLE I Inhibition of histamine induced paw oedema at 1.0 mg/kg
Example no. % inhibition 2 44 10 33
[0109] Values for inhibition of histamine induced hyperglycemia for
a representative compound is listed in table II.
2TABLE II Inhibition of histamine induced hyperglycemia at 1.0
mg/kg Example no. % inhibition 10 69
Pharmaceutical Compositions
[0110] The present invention also relates to pharmaceutical
compositions comprising, as an active ingredient, at least one of
the compounds of the invention or a pharmaceutically acceptable
salt thereof and, usually, such compositions also contain a
pharmaceutically acceptable carrier or diluent.
[0111] Pharmaceutical compositions comprising a compound of the
present invention may be prepared by conventional techniques, e.g.
as described in Remington: The Science and Practise of Pharmacy,
19.sup.th Ed., 1995. The compositions may appear in conventional
forms, for example capsules, tablets, aerosols, solutions,
suspensions or topical applications.
[0112] Typical compositions include a compound of the invention or
a pharmaceutically acceptable acid addition salt thereof,
associated with a pharmaceutically acceptable excipient which may
be a carrier or a diluent or be diluted by a carrier, or enclosed
within a carrier which can be in the form of a capsule, sachet,
paper or other container. In making the compositions, conventional
techniques for the preparation of pharmaceutical compositions may
be used. For example, the active compound will usually be mixed
with a carrier, or diluted by a carrier, or enclosed within a
carrier which may be in the form of a ampoule, capsule, sachet,
paper, or other container. When the carrier serves as a diluent, it
may be solid, semi-solid, or liquid material which acts as a
vehicle, excipient, or medium for the active compound. The active
compound can be adsorbed on a granular solid container for example
in a sachet. Some examples of suitable carriers are water, salt
solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated
castor oil, syrup, peanut oil, olive oil, gelatine, lactose, terra
alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc,
gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers
of cellulose, silicic acid, fatty acids, fatty acid amines, fatty
acid monoglycerides and diglycerides, pentaerythritol fatty acid
esters, polyoxyethylene, hydroxymethylcellulose and
polyvinylpyrrolidone. Similarly, the carrier or diluent may include
any sustained release material known in the art, such as glyceryl
monostearate or glyceryl distearate, alone or mixed with a wax. The
formulations may also include wetting agents, emulsifying and
suspending agents, preserving agents, sweetening agents or
flavouring agents. The formulations of the invention may be
formulated so as to provide quick, sustained, or delayed release of
the active ingredient after administration to the patient by
employing procedures well known in the art.
[0113] The pharmaceutical compositions can be sterilized and mixed,
if desired, with auxiliary agents, emulsifiers, salt for
influencing osmotic pressure, buffers and/or colouring substances
and the like, which do not deleteriously react with the active
compounds.
[0114] The route of administration may be any route, which
effectively transports the active compound to the appropriate or
desired site of action, such as oral, nasal, pulmonary, transdermal
or parenteral e.g. rectal, depot, subcutaneous, intravenous,
intraurethral, intramuscular, topical, intranasal, ophthalmic
solution or an ointment, the oral route being preferred.
[0115] If a solid carrier is used for oral administration, the
preparation may be tabletted, placed in a hard gelatin capsule in
powder or pellet form or it can be in the form of a troche or
lozenge. If a liquid carrier is used, the preparation may be in the
form of a syrup, emulsion, soft gelatin capsule or sterile
injectable liquid such as an aqueous or non-aqueous liquid
suspension or solution.
[0116] For nasal administration, the preparation may contain a
compound of formula I dissolved or suspended in a liquid carrier,
in particular an aqueous carrier, for aerosol application. The
carrier may contain additives such as solubilizing agents, e.g.
propylene glycol, surfactants, absorption enhancers such as
lecithin (phosphatidylcholine) or cyclodextrin, or preservatives
such as parabenes.
[0117] For parenteral application, particularly suitable are
injectable solutions or suspensions, preferably aqueous solutions
with the active compound dissolved in polyhydroxylated castor
oil.
[0118] Tablets, dragees, or capsules having talc and/or a
carbohydrate carrier or binder or the like are particularly
suitable for oral application. Preferable carriers for tablets,
dragees, or capsules include lactose, corn starch, and/or potato
starch. A syrup or elixir can be used in cases where a sweetened
vehicle can be employed.
[0119] A typical tablet which may be prepared by conventional
tabletting techniques may contain:
3 Core: Active compound (as free compound or salt thereof) 100 mg
Colloidal silicon dioxide (Aerosil) 1.5 mg Cellulose, microcryst.
(Avicel) 70 mg Modified cellulose gum (Ac-Di-Sol) 7.5 mg Magnesium
stearate Coating: HPMC approx. 9 mg *Mywacett 9-40 T approx. 0.9 mg
*Acylated monoglyceride used as plasticizer for film coating.
[0120] The compounds of the invention may be administered to a
mammal, especially a human in need of such treatment, prevention,
elimination, alleviation or amelioration of an indication related
to all painful, hyperalgesic and/or inflammatory conditions in
which C-fibres play a pathophysiological role such as e.g.
neurogenic pain, neurogenic inflammation, migraine, neuropathy,
itching and rheumatoid arthritis, as well as indications caused by
or related to the secretion and circulation of insulin antagonising
peptides, such as non-insulin-dependent diabetes mellitus (NIDDM)
or ageing-associated obesity. Such mammals include also animals,
both domestic animals, e.g. household pets, and non-domestic
animals such as wildlife.
[0121] The compounds of the invention may be administered in the
form of an alkali metal or earth alkali metal salt thereof,
concurrently, simultaneously, or together with a pharmaceutically
acceptable carrier or diluent, especially and preferably in the
form of a pharmaceutical composition thereof, in an effective
amount.
[0122] The compounds of the invention are effective over a wide
dosage range. For example, in the treatment of humans, dosages from
about 0.5 to about 1000 mg, preferably from about 1 to about 500 mg
of compounds of the present invention, conveniently given from 1 to
5 times daily. A most preferable dosage is from about 50 to about
200 mg per dose when administered to e.g. a human. The exact dosage
will depend upon the mode of administration, on the therapy
desired, form in which administered, the subject to be treated and
the body weight of the subject to be treated, and the preference
and experience of the physician or veterinarian in charge.
[0123] Generally, the compounds of the present invention are
dispensed in unit dosage form comprising from about 50 to about 200
mg of active ingredient in or together with a pharmaceutically
acceptable carrier per unit dosage.
[0124] Usually, dosage forms suitable for oral, nasal, pulmonal or
transdermal administration comprise from about 0.5 mg to about 1000
mg, preferably from about 1 mg to about 500 mg of the compounds of
formula I admixed with a pharmaceutically acceptable carrier or
diluent.
[0125] The method of treating may be described as the treatment of
an indication caused by or related to the secretion and circulation
of insulin antagonising peptides like CGRP or amylin in a subject
in need thereof, which comprises the step of administering to the
said subject a neurologically effective amount of a compound of the
invention, or a pharmaceutically acceptable salt thereof.
[0126] Any novel feature or combination of features described
herein is considered essential to this invention.
EXAMPLES
[0127] The process for preparing compounds of the present invention
and preparations containing them is further illustrated in the
following examples, which, however, are not to be construed as
limiting.
[0128] Hereinafter, TLC is thin layer chromatography, CDCl.sub.3 is
deuterio chloroform and DMSO-d.sub.6 is hexadeuterio
dimethylsulfoxide. The structures of the compounds are confirmed by
either elemental analysis or NMR, where peaks assigned to
characteristic protons in the title compounds are presented where
appropriate. .sup.1H NMR shifts (.delta..sub.H) are given in parts
per million (ppm). M.p. is melting point and is given in .degree.
C. and is not corrected. Column chromatography was carried out
using the technique described by W. C. Still et al, J. Org. Chem.
(1978), 43, 2923-2925 on Merck silica gel 60 (Art. 9385). Compounds
used as starting materials are either known compounds or compounds
which can readily be prepared by methods known per se.
Example 1
2-(4-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperazin-1-yl)acetic
acid
[0129] 16
[0130] 5-Chlorodibenzosuberane (10.0 g, 43 mmol) and piperazine
(18.0 g, 218 mmol) was suspended in 1,4-dioxane (300 ml) and heated
at reflux temperature for 6 h. The reaction mixture was cooled to
room temperature and filtered. To the filtrate water (300 ml) was
added, pH was adjusted to 10 with saturated sodium hydrogen
carbonate and the mixture was extracted with dichloromethane
(3.times.75 ml). The combined organic extracts were washed with
water (150 ml), dried (MgSO.sub.4) and concentrated in vacuo.
Dichloromethane (50 ml) was added, and the solution was filtered.
The filtrate was subjected to column chromatography on silica gel
(130 g) by first eluting with dichloromethane (150 ml) and then
dichloromethane/methanol=9:1 (250 ml). This furnished 4.5 g of
crude product which was recrystallised from heptane affording 4.2 g
(33%) of 1-(10,11-dihydro-5H-dibenzot[a,d]cyclohe-
pten-5-yl)piperazine.
[0131] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.7.10 (m, 8H), 4.00
(m,2H), 3.95 (s, 1H), 2.75 (m, 6H), 2.25 (s, 4H).
[0132] The piperazine from the step above (1.0 g, 3.6 mmol), ethyl
2-chloroacetate (0.5 g, 4.0 mmol), and potassium carbonate (0.5 g,
4 mmol) were suspended in acetonitrile (50 ml) and allowed to react
at 50.degree. C. for 4 h. The crude reaction mixture was subjected
to column chromatography on silica gel (30 g) by first eluting with
dichloromethane (50 ml) and then dichloromethane/methanol 9:1 (250
ml). This furnished 1.05 g (73%) of
2-(4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piper-
azin-1-yl)acetic acid ethyl ester.
[0133] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.7.0 (m, 8H), 4.13
(q,2H), 2.95 (m, 3H), 3.10 (s, 2H), 2.74 (m, 2H), 2.40 (d, 8H),
1.20 (t, 3H).
[0134] The ester from the above step (1.05 g, 2.9 mmol), sodium
hydroxide (0.8 g, 20 mmol) and water (2 ml) was dissolved in
ethanol (50 ml) and allowed to react at 50.degree. C. for 2 h.
After cooling to room temperature, water (150 ml) was added and the
reaction mixture was adjusted to pH 2 with 1 N hydrochloric acid
and extracted with dichloromethane (3.times.50 ml). The combined
organic extracts were dried (MgSO.sub.4) and concentrated in vacuo
. The resulting oil was stripped with acetone (2.times.20 ml),
dissolved in dichloromethane (20 ml) and precipitated with
petroleum ether. The resulting solid was dried under vacuum for 24
h leaving the title compound (0.56 g, 57%).
[0135] HPLC retention time=17.55 minutes (5 .mu.m C18 4.times.250
mm column, eluting with a 20-80% gradient of 0.1% trifluoroacetic
acid/acetonitrile and 0.1% trifluoroacetic acid/water over 30
minutes at room temperature).
[0136] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.7.10 (m, 8H), 4.12
(s, 1H), 3.87 (m, 2H), 3.63 (s, 2H), 3.22 (bs, 4H), 2.80 (m, 2H),
2.65 (s, 4H).
Example 2
3-(4-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperazin-1-yl)propion-
ic acid hydrochloride
[0137] 17
[0138] 1-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperazine
(prepared as described in Example 1, 1.0 g, 3.6 mmol), ethyl
3-bromopropionate (0.71 g, 3.9 mmol), and potassium carbonate (0.5
g, 4 mmol) were suspended in acetonitrile (50 ml) and allowed to
react at 50.degree. C. for 4 h. The crude reaction mixture was
subjected to column chromatography on silica gel (30 g) by first
eluting with dichloromethane (50 ml) and then
dichloromethane/methanol=9:1 (250 ml). This furnished 1.15 g (84%)
of 3-(4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piper-
azin-1-yl)propionic acid ethyl ester.
[0139] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.7.10 (m, 8H), 4.13
(q,2H), 2.95 (m, 3H), 2.77 (m, 2H), 2.62 (t, 2H), 2.41 (t, 2H),
2.30 (bd, 8H) 1.20 (t, 3H).
[0140] The ester from the above step (1.15 g, 3.0 mmol), sodium
hydroxide (0.8 g, 20 mmol) and water (2 ml) were dissolved in
ethanol (50 ml) and allowed to react at 50.degree. C. for 2 h.
After cooling to room temperature, water (150 ml) was added, and
the reaction mixture was adjusted to pH 2 with 1 N hydrochloric
acid and extracted with dichloromethane (3.times.50 ml). The
combined organic extracts were dried (MgSO.sub.4) and concentrated
in vacuo. The resulting oil was stripped with acetone (2.times.20
ml), reprecipitated from acetone and dried under vacuum for 24 h
leaving the title compound (0.80 g, 69%) as an amorphous solid.
[0141] Calculated for C.sub.22H.sub.26N.sub.2O.sub.2, HCl: C,
68.55%; H, 7.05%; N, 7.27%; Found: C, 68.29%; H, 7.03%; N,
7.24%.
[0142] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.7.10 (m, 8H), 4.17
(s, 1H), 3.88 (m, 2H), 3.50-3.10 (bs, 2H), 3.29 (t, 2H), 2.93 (t,
2H), 2.80 (m, 2H), 2.72 (s, 6H).
Example 3
4-(4-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperazin-1-yl)butyric
acid hydrochloride
[0143] 18
[0144] 1-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperazine
(prepared as described in Example 1, 1.0 g, 3.6 mmol), ethyl
4-bromobutyrate (0.76 g, 3.9 mmol), and potassium carbonate (0.5 g,
4 mmol) were suspended in acetonitrile (50 ml) and allowed to react
at 50.degree. C. for 3 h. The crude reaction mixture was subjected
to column chromatography on silica gel (30 g) by first eluting with
dichloromethane (50 ml) and then dichloromethane/methanol=9:1 (250
ml). This furnished 1.2 g (85%) of
4-(4-(10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5-yl)piper-
azin-1-yl)butyric acid ethyl ester.
[0145] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.7.10 (m, 8H), 4.09
(q, 2H), 2.95 (m, 3H), 2.78 (m, 2H), 2.30 (m, 12H), 1.76 (m, 2H),
1.20 (t, 3H).
[0146] The ester from the above step (1.2 g, 3.0 mmol), sodium
hydroxide (0.8 g, 20 mmol) and water (2 ml) were dissolved in
ethanol (50 ml) and allowed to react at 50.degree. C. for 3 h.
After cooling to room temperature, water (150 ml) was added and the
reaction mixture was adjusted to pH 2 with 1 N hydrochloric acid
and extracted with dichloromethane (3.times.50 ml). The combined
organic extracts were dried (MgSO.sub.4) and concentrated in vacuo.
The resulting oil was stripped with acetone (2.times.20 ml), washed
with acetone (20 ml) and dried under vacuum for 24 h leaving the
title compound (0.93 g, 77%) as an amorphous solid.
[0147] Calculated for C.sub.23H.sub.28N.sub.2O.sub.2, HCl: C,
68.80%; H, 7.33%; N, 6.89%; Found: C, 68.90%; H, 7.29%; N,
6.99%.
[0148] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.12.3 (s, 1H),
11.0 (s, 1H), 7.15 (m, 8H), 4.17 (s, 1H), 3.89 (m, 2H), 3.36 (d, 3H
(+H.sub.2O)), 2.9 (m, 4H), 2.74 (q, 2H), 2.50 (m, 5H (+DMSO)), 2.30
(t, 2H), 1.87 (m, 2H).
Example 4
5-(4-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperazin-1-yl)pentano-
ic acid hydrochloride
[0149] 19
[0150] 1-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperazine
(1.0 g, 3.6 mmol), methyl 5-bromovalerate (0.80 g, 4.0 mmol), and
potassium carbonate (0.5 g, 4 mmol) were suspended in acetonitrile
(50 ml) and allowed to react at 50.degree. C. for 4 h. The crude
reaction mixture was subjected to column chromatography on silica
gel (30 g) by first eluting with dichloromethane (50 ml) and then
dichloromethanelmethanol=9:1 (250 ml). This furnished 1.2 g (77%)
of 5-(4-(10,11-dihydro-5H-dibenzof[a,d]cy-
clohepten-5-yl)-piperazin1-yl)-pentanoic acid methyl ester.
[0151] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.7.10 (m, 8H), 4.0
(m, 2H), 2.94 (s, 1H), 3.63 (s, 3H), 2.75 (m, 2H), 2.30 (m, 12H),
1.60 (m, 2H), 1.46 (m, 2H).
[0152] The ester from the above step (1.2 g, 3.0 mmol), sodium
hydroxide (0.8 g, 20 mmol) and water (2 ml) was dissolved in
ethanol (50 ml) and allowed to react at 50.degree. C. for 3 h.
After cooling to room temperature, water (150 ml) was added and the
reaction mixture was adjusted to pH 2 with 1 N hydrochloric acid
and extracted with dichloromethane (3.times.50 ml). The combined
organic extracts were dried (MgSO.sub.4) and concentrated in vacuo.
The resulting oil was stripped with acetone (2.times.20 ml), washed
with acetone (20 ml) and dried under vacuum for 24 h leaving the
title compound (1.02 g, 80%) as an amorphous solid. PHPLC retention
time=17.55 minutes (5 .mu.m C18 4.times.250 mm column, eluting with
a 20-80% gradient of 0.1% trifluoroacetic acidlacetonitrile and
0.1% trifluoroacetic acid/water over 30 minutes at room
temperature)
[0153] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.12.1 (s, 1H),
10.8 (s, 1H), 7.10 (m, 8H), 4.16 (s, 1H), 3.87 (m, 2H), 3.32 (d,
3H), 2.95 (m, 4H), 2.73 (m, 2H), 2.59 (d, 2H), 2.40 (m, 3H) 2.24
(t, 2H), 1.75 (m, 2H), 1.46 (t, 2H).
Example 5
1-(3-(4-(6,11-Dihydrodibenzo[b,e]thiepin-11-ylidene)-1-piperidinyl)-1-prop-
yl)-3-piperidinecarboxylic acid dihydrochloride
[0154] 20
[0155] To a solution of
4-(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)pipe- ridine (5,86 g,
20 mmol, prepared similarly as described in Ger.Offen 2 423 721) in
2-butanone (60 ml), potassium carbonate (4.2 g, 30 mmol) and
3-bromo-1-propyl tetrahydro-2-pyranyl ether (5.75 g, 25.8 mmol)
were added and the reaction mixture was heated at reflux
temperature for 20 h. After cooling to room temperature the mixture
was filtered and the filtrate was evaporated. The residue was
dissolved in a mixture of methanol (60 ml) and 5 N hydrochloric
acid (20 ml). The solution was heated at reflux temperature for 15
minutes, methanol was distilled off and water (100 ml) followed by
5 N sodium hydroxide (40 ml) were added. The mixture was extracted
with benzene, the organic extract was dried (K.sub.2CO.sub.3),
filtered and the solvent was evaporated in vacuo. The residue was
purified by column chromatography on silica gel (50 g) using ethyl
acetate as eluent. This afforded 6.3 g (90%) of 4-
(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)-1-piperidinepropanol
as an oil.
[0156] TLC: R.sub.f=0.35 (SiO.sub.2: chloroformethanolammonium
hydroxide=20:1:0.1)
[0157] The above alcohol (5.8 g,16.5 mmol) was dissolved in benzene
(60 ml), triethylamine (5 ml) and methanesulfonyl chloride (2.25 g,
19.6 mmol) were added and the reaction mixture was stirred for 5 h.
After standing for 8 days, water (100 ml) was added and the phases
were separated. The organic phase was dried (MgSO.sub.4) and the
solvent was evaporated in vacuo. The residue (2.25 g) was dissolved
in 2-butanone (50 ml), and (R)-3-piperidinecarboxylic acid ethyl
ester tartrate (1.6 g, 5.3 mmol) and potassium carbonate (3.0 g,
21.7 mmol) were added and the mixture was heated at reflux
temperature for 20 h. After filtration the solvent was removed by
evaporation in vacuo. The residue was purified by column
chromatography on silica gel (40 g) using ethanol as eluent. This
afforded 1.7 g (22%) of 1-(3-(4-
(6,11-dihydrodibenzo[b,e]-thiepin-11-yli-
dene)-1-piperidinyl)-1-propyl)-3-piperidinecarboxylic acid ethyl
ester as an oil.
[0158] TLC R.sub.f=0.22 (SiO.sub.2: chloroform/ethanol/ammonium
hydroxide=20:3:0.1)
[0159] The above ester (0.86 g, 1.8 mmol) was dissolved in ethanol
(30 ml) and 5 N sodium hydroxide (2 ml) was added. The mixture was
stirred at 40.degree. C. for 24 h, ethanol was evaporated in vacuo
and the residue was dissolved in water. Acetic acid (2 ml) was
added and the mixture was extracted with dichloromethane (50 ml).
After drying (MgSO.sub.4), the solvent was evaporated in vacuo. The
residue was triturated with diethyl ether affording 0.42 g (52%) of
the title compound as an amorphous solid. The corresponding
dihydrochloride was prepared by dissolving the base in acetone (5
ml) and treating the mixture with hydrogen chloride in diethyl
ether. After dilution with ether (20 ml), filtration and drying,
the dihydrochloride was obtained.
[0160] M.p. 245-255.degree. C. (decomp.)
[0161] Calculated for C.sub.28H.sub.34N.sub.2O.sub.2S, 2 HCl, 0.25
H.sub.2O: C, 62.79%; H, 6.78%: Cl, 13.24%; N, 5.23%; S, 5.99%;
Found: C, 62.33%; H, 6.84%: Cl, 11.99%; N, 4.96%; S, 6.38%.
Example 6
(R)-1-(2-(4-(6,11-Dihydrodibenzo[b,e]thiepin-11-ylidene)piperidin-1-yl)eth-
yl)-3-piperidinecarboxylic acid dihydrochloride
[0162] 21
[0163] A mixture of
4-(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)piperidi- ne
hydrochloride (5.98 g, 18.1 mmol), 2-bromethanol (2.75 g, 22 mmol),
potassium carbonate (6.0 g, 43.5 mmol) and acetone (100 ml) was
stirred and heated at reflux temperature for 8 h. The mixture was
filtered and the filtrate evaporated in vacuo. The residue was
purified by column chromatography on silica gel (40 g) using a
mixture of chloroform and ethanol (10:1) as eluent. This afforded
1.6 g (34%) of
4-(6.11-dihydrodibenzo[b,e]thiepin-11-ylidene)-1-piperidineethanol
as an oil.
[0164] TLC: R.sub.f=0.31 (SiO.sub.2;
chloroform/ethanol/ammonia=20:1 :0.05).
[0165] The above alcohol (1.6 g, 4.74 mmol) was dissolved in
benzene (30 ml) and triethylamine (3 ml) was added. Methanesulfonyl
chloride (0.8 g, 7 mmol) was added and the reaction mixture was
stirred for 2 h. Water (50 ml) was added and the phases were
separated. The organic phase was dried (MgSO.sub.4) and the solvent
evaporated in vacuo, affording a residue which was dissolved in
N,N-dimethylformamide (10 ml). (R)-3-Piperidinecarboxylic acid
ethyl ester tartrate (1.6 g, 5.2 mmol) and potassium carbonate (1.5
g, 10.8 mmol) were added and the mixture was heated at 100.degree.
C. for 11 h. Benzene (100 ml) and water (100 ml) were added and the
phases were separated. The organic phase was dried
(K.sub.2CO.sub.3) and the solvent evaporated in vacuo. The residue
was purified by column chromatography on silica gel (20 g) using
first ethyl acetate and then ethanol as eluents. This afforded 1.3
g (58%) of
(R)-1-(2-(4-(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)piperidin-1-yl)et-
hyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
[0166] TLC: R.sub.f=0.20 (SiO.sub.2;
chloroform/ethanol/ammonia=20:3;0.05)- .
[0167] The above ester (1.3 g, 2.7 mmol) was dissolved in ethanol
(20 ml) and 5 N sodium hydroxide (2 ml) was added. The mixture was
stirred at room temperature for 72 h, ethanol was evaporated in
vacuo and water (40 ml) was added. The mixture was extracted with
diethyl ether (40 ml) and the phases were separated. Acetic acid (2
ml) was added to the water phase and the mixture was extracted with
dichloromethane (50 ml). The organic phase was dried (MgSO.sub.4)
and the solvent was evaporated in vacuo. The residue was dissolved
in acetone and neutralised with hydrogen chloride in diethyl ether
The precipitate was filtered off and crystallised from a mixture of
ethanol, acetone and diethyl ether to give 0.47 g (30%) of the
title compound as a solid.
[0168] M.p. 127-130.degree. C.
[0169] Calculated for C.sub.27H.sub.32N.sub.2O.sub.2S, 2 HCl,
H.sub.2O, 0.5 CH.sub.3COCH.sub.3: C, 60.20%; H, 6.91%; N, 4.93%; S,
5.64%; Found: C, 60.11%; H, 6.78%; N, 4.91%; S, 5.55%.
Example 7
3-(4-(6,11-Dihydrodibenzo[b,e]thiepin-11-ylidene)-1-piperidine)propionic
acid hydrochloride
[0170] 22
[0171] A mixture of
4-(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)piperidi- ne (4.0
g,0.01 36 mol. prepared similarly as described in Ger.Offen 2 423
721) and ethyl acrylate (2.45 g, 0.0245 mol) in ethanol (50 ml) was
heated at 70.degree. C. for 2 h. The volatile materials were
evaporated in vacuo and the residue (5.0 g) was dissolved in
ethanol (25 ml) and neutralised with solution of oxalic acid in
ethanol. Diethyl ether (30 ml) was added and the precipitated
hydrogen oxalate was filtered off, washed with diethyl ether and
crystallised from a mixture of ethanol and ether. After filtration
and drying, this afforded 5.6 g (91%) of
3-(4-(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)-1-piperidine)propionic
acid ethyl ester hydrogen oxalate.
[0172] A mixture of
3-(4-(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)-1-pi-
peridine)propionic acid ethyl ester (liberated from the above
hydrogen oxalate, 3.0 g, 0,0076 mol) was dissolved in ethanol (40
ml) and 4 N sodium hydroxide (10 ml) was added. The reaction
mixture was stirred at room temperature for 10 h; then poured into
dichloromethane (300 ml) and acidified with concentrated
hydrochloric acid. The dichloromethane layer was separated, dried
(MgSO.sub.4) and evaporated in vacuo. The oily residue was
re-evaporated twice with acetone and triturated with hot acetone to
give 2.3 g (75%) of the title compound as an amorphous solid.
[0173] M.p. 176-186.degree. C. (decomp.)
[0174] Calculated for C.sub.22H.sub.23NO.sub.2S, HCl, 0.25
H.sub.2O: C, 65.01%; H, 6.08%; Cl, 8.72%; N, 3,45%; S, 7.89%;
Found: C, 65.13%; H, 6.13%; Cl, 8.62%; N, 3.46%: S, 7.92%.
Example 8
2-(4-(6,11-Dihydrodibenzo[b,e]thiepin-11-ylidene)-1-piperidinyl)acetic
acid hydrochloride
[0175] 23
[0176] To a solution of
4-(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)pipe- ridine (8.66 g,
0.0295 mol) in N,N-dimethylformamide (36 ml), ethyl bromoacetate
(4.93 g, 0.0295 mol and potassium carbonate (9.75 g, 0.0885 mol)
were added and the reaction mixture was heated at 63-66.degree. C.
for 4.5 h. Water (250 ml) was added followed by benzene (150 ml).
The phases were separated and the organic phase was washed with
water (3.times.50 ml) and dried (MgSO.sub.4). After evaporation in
vacuo the residue was purified by column chromatography on silica
gel (140 g) using benzene and a mixture of benzene and chloroform
(1:1) as eluents. This afforded 3.26 g (29%) 2-(
4-(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)--
piperidin-1-yl)acetic acid ethyl ester as an oil.
[0177] TLC: R.sub.f=0.48 (SiO.sub.2: chloroform saturated with
ammonialethanol=20:1)
[0178] To a solution of the above ester (3.26 g. 0.00859 mol) in
ethanol (70 ml), 4 N sodium hydroxide (10 ml) was added and the
reaction mixture was stirred at room temperature overnight.
Concentrated hydrochloric acid (4.8 ml) and dichloromethane (480
ml) were added and the reaction mixture was shaken well. The phases
were separated and the organic layer was dried (MgSO.sub.4) and
evaporated in vacuo. This was followed by re-dissolution and
evaporation from acetone (2.times.100 ml). The residue was stirred
with boiling acetone (300 ml), cooled and the precipitate was
filtered to give 2.44 g (71.5%) of the title compound as a
solid.
[0179] M.p.170-175.degree. C.
[0180] Calculated for C.sub.21H.sub.21NO.sub.2S, HCl, 0.5 H.sub.2O:
C, 63.54%; H, 5.84%; N, 3.53%; Cl, 8.93%; S, 8.08%; Found: C,
63.25%; H, 5.67%; N, 3.62%; Cl, 9.14%; S, 8.04%.
Example 9
4-(4-(6,11-Dihydrodibenzo[b,e]thiepin-11-ylidene)-1-piperidinyl)butyric
acid acetate
[0181] 24
[0182] A mixture of
4-(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)piperidi- ne
hydrochloride (4.35 g, 13.2 mmol), 4-chlorobutyric acid ethyl ester
(3.4 g, 24.2 mmol), potassium carbonate (4.0 g, 29 mmol), sodium
iodide (1 g) and acetone (100 ml) was stirred and heated at reflux
temperature for 14 h. The mixture was filtered and the filtrate
evaporated in vacuo to give a residue which was purified by
chromatography on silica gel (50 g) using chloroform as eluent.
This afforded 2.85 g of
4-(4-(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)piperidine)-butyric
acid ethyl ester as an oil.
[0183] TLC: R.sub.f=0.55 (SiO.sub.2: benzene/diethyl
ether/ethanol=10:10:2)
[0184] The above ester (2.85 g, 7 mmol) was dissolved in ethanol
(50 ml) and 5 N sodium hydroxide (3 ml) was added. The mixture was
stirred at room temperature for 20 h, ethanol was evaporated in
vacuo and water (40 ml) was added. The mixture was extracted with
diethyl ether (40 ml) and the phases were separated. Acetic acid (3
ml) was added to the aqueous phase and the mixture was extracted
with dichloromethane (50 ml). The organic phase was dried
(MgSO.sub.4) and the solvent was evaporated in vacuo. The residue
was triturated with diethyl ether and the precipitate was filtered
off and dried to give 2.0 g (62%) of the title compound as an
amorphous solid.
[0185] Calculated for C.sub.23H.sub.25NO.sub.2S, CH.sub.3COOH: C,
68.31%; H, 6.65%; N, 3.19%; S, 7.29%; Found: C, 68.36%; H, 6.77%;
N, 3.12%; S, 7.39%.
Example 10
3-(4-(10,11-Dihydro-5H-dibenzot[a,d]cyclohepten-5-ylidene)-1-piperidine)pr-
opionic acid hydrochloride
[0186] 25
[0187] A mixture of
4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)- piperidine
(2.75 g, 0.01 mol) and ethyl acrylate (2.0 g, 0.02 mol) in ethanol
(50 ml) was heated at 70.degree. C. for 2 h. Volatile components
were evaporated in vacua, the residue (4.4 g) was dissolved in
diethyl ether (50 ml) and the mixture was neutralised with a
solution of oxalic acid (1.26 g) in ethanol (8 ml). The
precipitated hydrogen oxalate was filtered off, washed with diethyl
ether and crystallised from a mixture of ethanol and ether. After
filtration and drying, this afforded 3.9 g (89 %) of
3-(4-(10,11-dihydro-5H-dibenzof[a,d]cyclohepten-5-ylidene)-1-pi-
peridine)propionic acid ethyl ester hydrogen oxalate.
[0188]
3-(4-(10,11-Dihydro-5H-dibenzo[a,d]cyclohept-5-ylidene)-1-piperidin-
e)propionic acid ethyl ester (liberated from the above hydrogen
oxalate, 3.1 g, 0.00826 mol) was dissolved in ethanol (20 ml) and 4
N sodium hydroxide (6 ml) was added. The reaction mixture was
stirred at room temperature for 10 h, then poured into
dichloromethane (300 ml) and acidified with concentrated
hydrochloric acid to pH=1. The dichloromethane layer was separated,
dried (MgSO.sub.4) and evaporated in vacuo. The oily residue was
re-evaporated twice with acetone and then triturated with hot
acetone. This afforded 2.55 g (80%) of the title compound as a
solid.
[0189] M.p.203-205.degree. C.
[0190] Calculated for C.sub.22H.sub.25NO.sub.2, HCl: C, 71.96%; H,
6.83%; Cl, 9.23%; N, 3.65%; Found: C, 71.57%; H, 7.00%; Cl, 9.01%;
N, 3.73%.
* * * * *