US2002151539A1PendingUtilityA1
Novel heterocyclic compounds
Priority: Jun 25, 1997Filed: Mar 14, 2002Published: Oct 17, 2002
Est. expiryJun 25, 2017(expired)· nominal 20-yr term from priority
Inventors:Tine JorgensenKnud Erik AndersenRolf HohlwegUffe Bang OlsenErik FischerZdenek PolivkaKaler Sindelar
C07D 211/70C07D 409/14C07D 409/04C07D 295/15
47
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Claims
Abstract
The present invention relates to novel N-substituted azaheterocyclic compounds of the general formula wherein X, Y, Z, R 1 , R 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.
Claims
exact text as granted — not AI-modified1 . A compound of formula I
wherein
R 1 and R 2 independently are hydrogen, halogen, trifluoromethyl, hydroxy, C 1-6 -alkyl or C 1-6 -alkoxy;
X is ortho-phenylene, —O—, —S—, —C(R 6 R 7 )—, —CH 2 CH 2 —, —CH═CH—CH 2 —, —CH 2 —CH═CH—, —CH 2 —(C═O)—, —(C═O )—CH 2 —, —CH 2 CH 2 CH 2 —, —CH═CH—, —N(R 8 )—(C═O)—, —(C═O)—N(R 8 )—, —O—CH 2 —, —CH 2 —O—, —OCH 2 O—, —S—CH 2 —, —CH 2 —S—, —(CH 2 )N(R 8 )—, —N(R 8 )(CH 2 )—, —N(CH 3 )SO 2 —, SO 2 N(CH 3 )—, —CH(R 10 )CH 2 —, —CH 2 CH(R 10 )—, —(C═O)—, —N(R 9 )— or —(S═O)— wherein R 6 , R 7 , R 8 and R 9 ently are hydrogen or C 1-6 -alkyl, and wherein R 10 is C 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 3 or
wherein
R 3 is H or C 1-6 -alkyl; or
a pharmaceutically acceptable salt thereof.
2 . A compound of formula Ia
wherein
R 1 and R 2 independently are hydrogen, halogen, trifluoromethyl, hydroxy, C 1-6 -alkyl or C 1-6 -alkoxy;
X is ortho-phenylene, —O—, —S—, —C(R 6 R 7 )—, —CH 2 CH 2 —, —CH═CH—CH 2 —, —CH 2 —CH═CH—, —CH 2 —(C═O)—, —(C═O)CH 2 —, —CH 2 CH 2 CH 2 —, —CH═CH—, —N(R 8 )—(C═O)—, —(C═O)—N(R 8 )—, —O—CH 2 —, —CH 2 —O—, —OCH 2 O—, —S—CH 2 —, —CH 2 —S—, —(CH 2 )N(R 8 )—, —N(R 8 )—, —N(CH 3 )SO 2 —, —SO 2 N(CH 3 )—, —CH(R 10 )CH 2 —, —CH 2 CH(R 10 )—, —(C═O)—, —N(R 9 )— or —(S═O)— wherein R 6 , R 7 , R 8 and R 9 independently are hydrogen or C 1-6 -alkyl; and wherein R 10 is C 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 3 is H or C 1-6 -alkyl; or
a pharmaceutically acceptable salt thereof.
3 . A compound of formula I
wherein
R 1 and R 2 independently are hydrogen, halogen, trifluoromethyl, hydroxy, C 1-6 -alkyl or C 1-6 -alkoxy;
X is ortho-phenylene, —O—, —S—, —C(R 6 R 7 )—, —CH 2 CH 2 —, —CH═CH—CH 2 —, —CH 2 —CH═CH—, —CH 2 —(C═O)—, —(C═O)—CH 2 —, —CH 2 CH 2 CH 2 —, —CH═CH—, —N(R 8 )—(C═O)—, —(C═O)—N(R 8 )—, —O—CH 2 —, —CH 2 —O—, —OCH 2 O—, —S—CH 2 —, —CH 2 —S—, —(CH 2 )N(R 8 )—, —N(R 8 )(CH 2 )—, —N(CH 3 )SO 2 —, SO 2 N(CH 3 )—, —CH(R 10 )CH 2 —, —CH 2 CH(R 10 )—, —(C═O)—, —N(R 9 )— or —(S═O)— wherein R 6 , R 7 , R 8 and R 9 independently are hydrogen or C 1-6 -alkyl, and wherein R 10 is C 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 3 or
wherein
R 3 is H or C 1-6 -alkyl, provided that when R 1 and R 2 are hydrogen; X is —O—, —S—, —CH 2 CH 2 —, —CH═CH—, —O—CH 2 —, —CH 2 —O—, —S—CH 2 — or —CH 2 —S—; Y is C and is a double bond; m is 1, 2, 3, 4, 5 or 6, then Z is not —COOR 3 wherein R 3 is H or C 1-6 -alkyl; or
a pharmaceutically acceptable salt thereof.
4 . A compound according to anyone of the preceding claims wherein R 1 and R 2 are selected from hydrogen, halogen, trifluoromethyl or C 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 2 CH 2 , —CH═CH—, —O—CH 2 —, —CH 2 —O—, —OCH 2 O—, —S—CH 2 — or —CH 2 —S—.
7 . A compound according to anyone of the preceding claims wherein X is —CH 2 CH 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 2 — or —CH 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
wherein R 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-dibenzo[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)butyric 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 wherein
R 1 , R 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
wherein
R 4 is hydrogen, a suitable N-protecting group, —(CH 2 ) m —CO 2 R 3 or
and m and R 3 are as defined above, to form a compound of formula I, or
b) reacting a compound of formula IV wherein
R 1 , R 2 and X are as defined above, with a compound of formula V
Hal(CH 2 ) m —Z (V)
wherein
Hal is a halogen, Z is —COOR 3 or
and R 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 wherein
R 1 , R 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
wherein R 4 is hydrogen, a suitable N-protecting group or —(CH 2 ) m —COOR 3 and m and R 3 are as defined above, to form a compound of formula Ia, or
b) reacting a compound of formula IV wherein
R 1 1 R 2 and X are as defined above) with a compound of formula V
Hal(CH 2 ) m —CO 2 R 3 (V)
wherein Hal means a halogen and R 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
wherein
R 1 and R 2 are hydrogen;
X is —O—, —S—, —CH 2 CH 2 —, —CH═CH—, —O—CH 2 —, —CH 2 —O—, —S—CH 2 — or —CH 2 —S—;
Y is C and is a double bond;
m is 1, 2, 3, 4, 5 or 6;
Z is —COOR 3 and R 3 is H or C 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
wherein
R 1 and R 2 are hydrogen;
X is —O—, —S—, —CH 2 CH 2 —, —CH═CH—, —O—CH 2 —, —CH 2 O—, —S—CH 2 — or —CH 2 —S—;
Y is C and is a double bond;
m is 1, 2, 3, 4, 5 or 6;
Z is —COOR 3 and R 3 is H or C 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
wherein
R 1 and R 2 are hydrogen;
X is —O—, —S—, —CH 2 CH 2 —, —CH═CH—, —O—CH 2 —, —CH 2 O—, —S—CH 2 — or CH 2 —S—;
Y is C and is a double bond;
m is 1, 2, 3, 4, 5 or 6;
Z is —COOR 3 and R 3 is H or C 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
wherein
R 1 and R 2 are hydrogen;
X is —O—, —S—, —CH 2 CH 2 —, —CH═CH—, —O—CH 2 —, —CH 2 —O—, —S—CH 2 — or —CH 2 —S—;
Y is C and is a double bond;
m is 1, 2, 3, 4, 5 or6;
Z is —COOR 3 and R 3 is H or C 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
wherein
R 1 and R 2 are hydrogen;
X is —O—, —S—, —CH 2 CH 2 —, —CH═CH—, —O—CH 2 —, —CH 2 —O—, —S—CH 2 — or —CH 2 —;
Y is C and is a double bond;
m is 1, 2, 3, 4, 5 or 6;
Z is —COOR 3 and R 3 is H or C 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
wherein
R 1 and R 2 are hydrogen;
X is —O—, —S—, —CH 2 CH 2 —, —CH═CH—, —O—CH 2 —, —CH 2 —O—, —S—, CH 2 — or —CH 2 —S—;
Y is C and is a double bond;
m is 1, 2, 3, 4, 5 or 6;
Z is —COOR 3 and R 3 is H or C 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 2 CH 2 —, —S—CH 2 — or —CH 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 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-ylidene)-1-piperidine)propionic acid,
2-(4-(6,11-Dihydrodibenzo[b,e]thiepin-11-ylidene)-1-piperidinyl)acetic acid,
4-(4-(6,11-Dihydrodibenzo[b,e]thiepin-11-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
wherein
R 1 and R 2 are hydrogen;
X is —O—, —S—, —CH 2 CH 2 —, —CH═CH—, —O—CH 2 —, —CH 2 —O—, —S—CH 2 — or —CH 2 S—;
Y is C and is a double bond;
m is 1, 2, 3, 4, 5 or 6;
Z is —COOR 3 and R 3 is H or C 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
wherein
R 1 and R 2 are hydrogen;
X is —O—, —S—, —CH 2 CH 2 —, —CH═CH—, —O—CH 2 —, —CH 2 —O—, —S—CH 2 — or —CH 2 —S—;
Y is C and is a double bond;
m is 1, 2, 3, 4, 5 or 6;
Z is —COOR 3 and R 3 is H or C 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
wherein
R 1 and R 2 are hydrogen;
X is —O—, —S—, —CH 2 CH 2 —, —CH═CH—, —O—CH 2 —, —CH 2 —O—, —S—CH 2 — or —CH 2 —S—;
Y is C and is a double bond;
m is 1, 2, 3, 4, 5 or 6;
Z is —COOR 3 and R 3 is H or C 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
wherein
R 1 and R 2 are hydrogen;
X is —O—, —S—, —CH 2 CH 2 —, —CH═CH—, —O—CH 2 —, —CH 2 —O—, —S—CH 2 — or —CH 2 —S—;
Y is C and is a double bond;
m is 1, 2, 3, 4, 5 or 6;
Z is —COOR 3 and R 3 is H or C 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
wherein
R 1 and R 2 are hydrogen;
X is —O—, —S—, —CH 2 CH 2 —, —CH═CH—, —O—CH 2 —, —CH 2 O—, —S—CH 2 — or —CH 2 —S—;
Y is C and is a double bond;
m is 1, 2, 3, 4, 5 or 6;
Z is —COOR 3 and R 3 is H or C 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
wherein
R 1 and R 2 are hydrogen;
X is —O—, —S—, —CH 2 CH 2 —, —CH═CH—, —O—CH 2 —, —CH 2 —O—, —S—CH 2 — or —CH 2 —S—;
Y is C and is a double bond;
m is 1, 2, 3, 4, 5 or 6;
Z is —COOR 3 and R 3 is H or C 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 2 CH 2 —, —S—CH 2 — or —CH 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 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-ylidene)-1-piperidine)propionic acid,
2-(4-(6,11-Dihydrodibenzo[b,e]thiepin-11-ylidene)-1-piperidinyl)acetic acid,
4-(4-(6,11-Dihydrodibenzo[b,e]thiepin-11-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.Join the waitlist — get patent alerts
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