Aminoazetidine,-pyrrolidine and -piperidine derivatives

Details Aminoazetidine,-pyrrolidine and -piperidine derivatives Aminoazetidine,-pyrrolidine and -piperidine derivatives

2002-09-12

2004-01-06

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S557000, C548S526000, C548S953000, C546S207000, C546S224000, C514S210030, C514S321000, C514S329000, C514S422000

Reexamination Certificate

active

06673829

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel aminoazetidine, -pyrrolidine and -piperidine derivatives, to the use of these compounds as pharmaceutical compositions, to pharmaceutical compositions comprising the compounds, and to a method of treatment employing these compounds and compositions. The present compounds show a high and selective binding affinity to the histamine H3 receptor indicating histamine H3 receptor antagonistic, inverse agonistic or agonistic activity. As a result, the compounds are useful for the treatment of diseases and disorders related to the histamine H3 receptor.
BACKGROUND OF THE INVENTION
The existence of the histamine H3 receptor has been known for several years and the receptor is of current interest for the development of new medicaments (see eg Stark et al.,
Drugs Fut.
1996, 21, 507-520; Leurs et al.,
Progress in Drug Research
1995, 45, 107-165). Recently, the human histamine H3 receptor has been cloned, cf Lovenberg et al,
Molecular Pharmacology,
June 1999, 55, 1101-1107. The histamine H3 receptor is a presynaptic autoreceptor located both in the central and the peripheral nervous system, the skin and in organs such as the lung, the intestine, probably the spleen and the gastrointestinal tract. Recent evidence suggests that the H3 receptor shows intrinsic, constitutive activity, in vitro as well as in vivo (ie it is active in the absence of an agonist; see eg Morisset et al.,
Nature
2000, 408, 860-864). Compounds acting as inverse agonists can inhibit this activity. The histamine H3 receptor has been demonstrated to regulate the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. A histamine H3 receptor antagonist or inverse agonist would therefore be expected to increase the release of these neurotransmitters in the brain. A histamine H3 receptor agonist, on the contrary, leads to an inhibition of the biosynthesis of histamine and an inhibition of the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. These findings suggest that histamine H3 receptor agonists, inverse agonists and antagonists could be important mediators of neuronal activity. Accordingly, the histamine H3 receptor is an important target for new therapeutics.
Compounds similar to the compounds of the present invention have previously been disclosed, cf U.S. Pat. No. 3,963,745, U.S. Pat. No. 3,966,957, DE 25 58 348, U.S. Pat. No. 6,090,802, WO 97/23483, WO 97/09308, JP 07048375, EP 518 558
, Acta Pharm Suec. Suppl.
1, 200-218, 1983
, Life Sci.,
32(25), 2877-2886, 1983, U.S. Pat. No. 4,109,005, BE 861790
, Aviat. Space Environ. Med.,
48(9), 867-871, 1977, U.S. Pat. No. 4,049,821, U.S. Pat. No. 4,039,678
, Therapie
1977, 32(1), 121-132, U.S. Pat. No. 4,002,757 DE 19 64 516, NL 6500326, U.S. Pat. No. 3,787,419, Irikura,
Yakugaku Zasshi
1962, 82, 356, DE 24 61 802
, Eur. J. Chem. Chim. Ther.
1982, 17, 437
, J. Med. Chem.
1992, 35, 4334
, Chem. Pharm. Bull.
1995, 43, 947
, Arzneim. Forsch.
1999, 49, 96, U.S. Pat. No. 5,571,832
, NIDA Res. Monogr.
1993, 140 (Problems of Drug Dependence, volume 1), 179-195. However, these references neither disclose nor suggest that these compounds may have a histamine H3 receptor antagonistic or agonistic activity.
Several publications disclose the preparation and use of histamine H3 agonists and antagonists. Most of these are imidazole derivatives (see eg Stark et al.,
Drugs of the Future
1996, 21, 507-520; Tozer, Kalinddjian,
Expert Opinion on Therapeutic Patents
2000, 10, 1045-1055). However, recently some imidazole-free ligands of the histamine H3 receptor have been described (see eg Walczynski et al.,
Arch. Pharm. Pharm. Med. Chem.
1999, 332, 389-398; Linney et al.,
J. Med. Chem.
2000, 43, 2362-2370; Ganellin et al.,
Arch. Pharm. Pharm. Med. Chem.
1998, 331, 395-404; Walczynski et al.,
II Farmaco
1999, 54, 684-694; WO 99/42458, EP 0 978 512, WO 97/17345, U.S. Pat. No. 6,316,475, WO 01/66534, WO 01/74810, WO 01/44191, WO 01/74815, WO 01/74773, WO 01/74813, WO 01/74814 and WO 02/12190.
However, these compounds differ structurally from the present compounds.
In view of the art's interest in histamine H3 receptor agonists, inverse agonists and antagonists, novel compounds which interact with the histamine H3 receptor would be a highly desirable contribution to the art. The present invention provides such a contribution to the art being based on the finding that a novel class of aminoazetidine, -pyrrolidine and -piperidine derivatives has a high and specific affinity to and potency at the histamine H3 receptor.
Due to their interaction with the histamine H3 receptor, the present compounds are useful in the treatment of a wide range of conditions and disorders in which an interaction with the histamine H3 receptor is beneficial. Thus, the compounds may find use eg in the treatment of diseases of the central nervous system, the peripheral nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinological system.
SUMMARY OF THE INVENTION
The invention relates to a compound of the general formula (I):
wherein
R
1
represents
hydrogen,
C
1-8
-alkyl, C
3-8
-alkenyl or C
3-8
-alkynyl, which may optionally be substituted with one or more halogen atoms,
C
3-7
-cycloalkyl, C
3-7
-cycloalkenyl, C
4-8
-bicycloalkyl, C
3-7
-cycloalkyl-C
1-3
-alkyl or C
3-7
-cycloalkenyl-C
1-3
-alkyl, which may optionally be substituted at any position with one or more halogen-atoms,
R
2
represents C
1-6
-alkyl,
f is 0, 1 or 2,
X represents —(CH
2
)
m
—(Z)
n
—(CH
2
)
o
—,
m and o independently are 0, 1, 2, 3 or 4,
n is 0 or 1,
Z is —O—, —NH—, —N(CH
3
)—, —C(═O)—, —CH(OH)—, —CH(O—C
1-6
-alkyl)-, —C(═N—OH)—, —S—, —S(═O)—, —S(═O)
2
—, —CH═CH— or —C≡C—,
Y is
(a) aryl or heteroaryl, which may optionally be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, C
1-6
-alkanoyl, C
1-6
-alkylthio, C
1-6
-alkylsulfonyl, C
1-6
-alkyl, C
1-6
-alkoxy, C
3-8
-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR
3
R
4
and —O(C═O)NR
3
R
4
, or wherein two substituents in adjacent positions form a radical —O—(CH
2
)
1-3
—O—,
wherein R
3
and R
4
independently are hydrogen, C
1-6
-alkyl, C
3-8
-cycloalkyl, C
1-6
-alkanoyl or aryl, or R
3
and R
4
together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated azetidinyl, pyrrolidinyl, piperidyl or azepanyl ring,
aryl, aryloxy, aryl-C
1-6
-alkyl and aryl-C
1-6
-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, C
1-6
-alkanoyl, C
1-6
-alkylthio, C
1-6
-alkylsulfonyl, C
1-6
-alkyl, C
1-6
-alkoxy, C
3-8
-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR
5
R
6
and —O(C═O)NR
5
R
6
, or wherein two substituents in adjacent positions form a radical —O—(CH
2
)
1-3
—O—,
wherein R
5
and R
6
independently are hydrogen, C
1-6
-alkyl, C
3-8
-cycloalkyl, C
1-6
-alkanoyl or aryl, or R
5
and R
6
together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated azetidinyl, pyrrolidinyl, piperidyl or azepanyl ring,
(b) C
3-8
-cycloalkyl or C
5-8
-cycloalkenyl, which may optionally be substituted with one or more substituents selected from
C
1-6
-alkyl, C
1-6
-alkoxy, C
1-6
-alkylthio, cyano, trifluoromethyl, trifluoromethoxy and halogen,
aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, C
1-6
-alkanoyl, C
1-6
-alkylthio, C
1-6
-alkylsulfonyl, C
1-6
-alkyl, C
1-6
-alkoxy, C
3-8
-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR
7
R
8
and —O(C═O)NR
7
R
8
, or wherein two substituents in adjacent positions form a radical —O—(CH
2
)
1-3
—O—,
wherein R
7
and R
8
independently are hydrogen, C
1-6
-alkyl, C
3-8
-cycloalkyl, C
1-6
-alkanoyl or aryl, or R
7
and R
8
together with the nitrogen atom to which they are attached fo

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