Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS20030186963 A1
Publication typeApplication
Application numberUS 10/245,236
Publication dateOct 2, 2003
Filing dateSep 12, 2002
Priority dateSep 14, 2001
Also published asUS7767695, US20040248938
Publication number10245236, 245236, US 2003/0186963 A1, US 2003/186963 A1, US 20030186963 A1, US 20030186963A1, US 2003186963 A1, US 2003186963A1, US-A1-20030186963, US-A1-2003186963, US2003/0186963A1, US2003/186963A1, US20030186963 A1, US20030186963A1, US2003186963 A1, US2003186963A1
InventorsFlorencio Dorwald
Original AssigneeDorwald Florencio Zaragoza
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Central nervous system disorders; cardiovascular disorders
US 20030186963 A1
Abstract
A novel class of substituted piperidines, pharmaceutical compositions comprising them and use thereof in the treatment and/or prevention of diseases and disorders related to the histamine H3 receptor. More particularly, the compounds are useful for the treatment and/or prevention of diseases and disorders in which an interaction with the histamine H3 receptor is beneficial.
Images(35)
Previous page
Next page
Claims(37)
1. A compound of the general formula (I):
wherein
m is 0, or, 2,
R1 is
C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, C1-6-alkoxy and hydroxy,
C3-8-cycloalkyl, C5-8-cycloalkenyl, C3-8-cycloalkyl-C1-6-alkyl, di(C3-8-cycloalkyl)-C1-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C5-8-cycloalkenyl-C1-6-alkyl, C5-8-cycloalkenyl-C2-6-alkenyl, C5-8-cycloalkenyl-C2-6-alkynyl,
wherein the cyclic moieties may optionally be substituted with one or more substituents selected from C1-6-alkyl, halogen, trifluoromethyl and 2,2,2-trifluoroethyl,
R2 is C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl or C3-8-cycloalkyl-C1-6alkyl,
X is —CH2—(CH2)n—, —(CH2)n—CH═CH—(CH2)p—, —CH2—(CH2)n—O—(CH2)p—, —CH2—(CH2)n—C(═O)—(CH2)p 13 , —CH2—(CH2)n—S—(CH2)p—, —CH2—(CH2)n—S(═O)—(CH2)p— or —CH2—(CH2)n—S(═O)2—(CH2)p—,
n and p are independently 0, 1, 2, 3 or 4,
R3 and R4 are independently hydrogen, methyl or trifluoromethyl,
Y is
(a) aryl or heteroaryl, which may optionally be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, oxo, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR5R6 and —O(C═O)NR5R6,
wherein R5 and R6 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,
or wherein two substituents in adjacent positions form a radical —O—(CH2)1-3—O—,
aryl, aryloxy, aryl-C1-6-alkyl and aryl-C1-6-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluorom ethyl, trifluorom ethoxy, —NR7R8 and —O(C═O)NR7R8,
wherein R7 and R8 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R7 and R8 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,
or wherein two substituents in adjacent positions form a radical —O—(CH2)1-3—O—
(b) C3-8-cycloalkyl or C5-8-cycloalkenyl, which may optionally be substituted with one or more substituents selected from
C1-6-alkyl, C1-6-alkoxy, C1-6-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, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR9R10 and —O(C═O)NR9R10,
wherein R9 and R10 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,
(c) C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, which may optionally be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR11R12 and —O(C═O)NR11R12,
wherein R11 and R12 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R11 and R12 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,
aryl, aryl-C1-6-alkyl and aryl-C1-6-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR13R14 and —O(C═O)NR13R14,
wherein R13 and R14 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R13 and R14 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,
or wherein two substituents in adjacent positions form a radical —O—(CH2)1-3—O—
with the proviso that the compound must not be
as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein m is 1.
3. A compound according to claim 2, wherein R3 and R4 are both hydrogen.
4. A compound according to claim 1, wherein R1 is C1-6-alkyl which may optionally be substituted with one or more substituents selected from halogen, C1-6-alkoxy and hydroxy.
5. A compound according to claim 4, wherein R1 is C1-6-alkyl.
6. A compound according to claim 1, wherein R1 is di(C3-8-cycloalkyl)-C1-6-alkyl, wherein the cyclic moieties may optionally be substituted with one or more substituents selected from C1-6-alkyl, halogen, trifluorom ethyl and 2,2,2-trifluoroethyl.
7. A compound according to claim 6, wherein R1 is dicyclopropylmethyl.
8. A compound according to claim 1, wherein R2 is C1-6-alkyl.
9. A compound according to claim 1, wherein X is —CH2—(CH2)n—, —(CH2)n—CH═CH—(CH2)p—, —CH2—(CH2)n—O—(CH2)p—, —CH2—(CH2)n—C(═O)—(CH2)p, —CH2—(CH2)n—S—(CH2)p—, wherein n and p are as defined in claim 1.
10. A compound according to claim 1, wherein X is —CH2—(CH2)n—, —CH═CH—, —CH2—(CH2)n—O—, —CH2—(CH2)n—C(═O)—, or —CH2—S—(CH2)p—, wherein n is 0, 1, 2 or 3, and p is 0 or 1.
11. A compound according to claim 10, wherein X is —CH2—, —(CH2)2—, —(CH2)3—, —(CH2)4—, —CH═CH—,—CH2—O—, —(CH2)3—O—, —(CH2)2—C(═O)—, —CH2—S—CH2— or —CH2—S—.
12. A compound according to claim 11, wherein X is —CH2—.
13. A compound according to claim 1, wherein Y is C1-6-alkyl, C3-8-cycloalkyl, aryl or heteroaryl, which may optionally be substituted as defined in claim 1.
14. A compound according to claim 1, wherein Y is C1-6-alkyl, cyclohexyl, phenyl, naphthyl, pyridyl, benzoxazolyl or benzothiophenyl, which may optionally be substituted as defined in claim 1.
15. A compound according to claim 14, wherein Y is phenyl or naphthyl which may optionally be substituted with one or more substituents selected from trifluoromethyl, trifluoromethoxy, halogen, C1-6-alkyl, —NR5R6, —O(C═O)NR5R6 and C1-7-alkanoyl, wherein R5 and R6 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, aryl-C1-6-alkoxy, aryloxy, aryl-C1-6-alkyl and aryl, which may optionally be substituted with halogen or C1-6-alkyl,
or wherein two substituents in adjacent positions form a radical —O—(CH2)1-3—O—.
16. A compound according to claim 15, wherein Y is phenyl or naphthyl which may optionally be substituted with one or more substituents selected from
trifluoromethyl, trifluoromethoxy, halogen, C1-6-alkyl, —NR5R6, —O(C═O)NR5R6 and C1-7-alkanoyl, wherein R5 and R6 independently are hydrogen or C1-6-alkyl,
phenyl-C1-6-alkoxy, phenyl-C1-6-alkyl, phenyloxy and phenyl, which may optionally be substituted with halogen or C1-6-alkyl,
or wherein two substituents in adjacent positions form a radical —O—(CH2)1-3—O—.
17. A compound according to claim 16, wherein Y is phenyl, which is substituted with phenyl.
18. Use of a compound according to any one of the preceding claims 1 to 17 as a pharmaceutical composition.
19. A composition comprising, as an active ingredient, at least one compound according to claim 1 together with one or more pharmaceutically acceptable carriers or excipients.
20. A composition according to claim 19 in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound according to any one of the claims 1 to 17.
21. Use of a compound of the general formula (I′):
wherein
m is 0, or, 2,
R1 is
C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, C1-6-alkoxy and hydroxy,
C3-8-cycloalkyl, C5-8-cycloalkenyl, C3-8-cycloalkyl-C1-6-alkyl, di(C3-8-cycloalkyl)-C1-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C5-8-cycloalkenyl-C1-6-alkyl, C5-8-cycloalkenyl-C2-6-alkenyl, C5-8-cycloalkenyl-C2-6-alkynyl,
wherein the cyclic moieties may optionally be substituted with one or more substituents selected from C1-6-alkyl, halogen, trifluoromethyl and 2,2,2-trifluoroethyl,
R2 is C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl or C3-8-cycloalkyl-C1-6alkyl,
X is —CH2—(CH2)n—, —(CH2)n—CH═CH—(CH2)p—, —CH2—(CH2)n—O—(CH2)p—, —CH2—(CH2)n—C(═O)—(CH2)p 13 , —CH2—(CH2)n—S—(CH2)p—, —CH2—(CH2)n—S(═O)—(CH2)p— or —CH2—(CH2)n—S(═O)2—(CH2)p—,
n and p are independently 0, 1, 2, 3 or 4,
R3 and R4 are independently hydrogen, methyl or trifluoromethyl,
Y is
(a) aryl or heteroaryl, which may optionally be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, oxo, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR5R6 and —O(C═O)NR5R6,
wherein R5 and R6 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,
or wherein two substituents in adjacent positions form a radical —O—(CH2)1-3—O—,
aryl, aryloxy, aryl-C1-6-alkyl and aryl-C1-6-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluorom ethyl, trifluorom ethoxy, —NR7R8 and —O(C═O)NR7R8,
wherein R7 and R8 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R7 and R8 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,
or wherein two substituents in adjacent positions form a radical —O—(CH2)1-3—O—
(b) C3-8-cycloalkyl or C5-8-cycloalkenyl, which may optionally be substituted with one or more substituents selected from
C1-6-alkyl, C1-6-alkoxy, C1-6-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, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR9R10 and —O(C═O)NR9R10,
wherein R9 and R10 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,
(c) C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, which may optionally be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR11R12 and —O(C═O)NR11R12,
wherein R11 and R12 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R11 and R12 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,
aryl, aryl-C1-6-alkyl and aryl-C1-6-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR13R14 and —O(C═O)NR13R14,
wherein R13 and R14 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R13 and R14 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,
or wherein two substituents in adjacent positions form a radical —O—(CH2)1-3—O—
as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment and/or prevention of disorders and diseases related to the histamine H3 receptor.
22. Use of a compound as defined in claim 21 for the preparation of a pharmaceutical composition for the treatment and/or prevention of diseases and disorders in which an inhibition of the H3 histamine receptor has a beneficial effect.
23. Use of a compound as defined in claim 21 for the preparation of a pharmaceutical composition having histamine H3 antagonistic activity or histamine H3 inverse agonistic activity.
24. Use of a compound as defined in claim 21 for the preparation of a pharmaceutical composition for the reduction of weight.
25. Use of a compound as defined in claim 21 for the preparation of a pharmaceutical composition for the treatment and/or prevention of overweight or obesity.
26. Use of a compound as defined in claim 21 for the preparation of a pharmaceutical composition for the suppression of appetite or for satiety induction.
27. Use of a compound as defined in claim 21 for the preparation of a pharmaceutical composition for the prevention and/or treatment of disorders and diseases related to overweight or obesity.
28. Use of a compound as defined in claim 21 for the preparation of a pharmaceutical composition for the prevention and/or treatment of eating disorders such as bulimia and binge eating.
29. Use of a compound as defined in claim 21 for the preparation of a pharmaceutical composition for the treatment and/or prevention of IGT.
30. Use of a compound as defined in claim 21 for the preparation of a pharmaceutical composition for the treatment and/or prevention of Type 2 diabetes.
31. Use of a compound as defined in claim 21 for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to Type 2 diabetes.
32. Use of a compound as defined in claim 21 for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes.
33. Use of a compound as defined in claim 21 for the preparation of a pharmaceutical composition for the treatment and/or prevention of diseases and disorders in which a stimulation of the H3 histamine receptor has a beneficial effect.
34. Use of a compound as defined in claim 21 for the preparation of a pharmaceutical composition having histamine H3 agonistic activity.
35. Use of a compound as defined in claim 21 for the preparation of a pharmaceutical composition for the treatment and/or prevention of allergic rhinitis, ulcer or anorexia.
36. A method for the treatment of treatment and/or prevention of disorders or diseases related to the H3 histamine receptor the method comprising administering to a subject in need thereof an effective amount of a compound as defined in claim 21.
37. The method according to claim 36 wherein the effective amount of the compound is in the range of from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg and especially preferred from about 0.5 mg to about 500 mg per day.
Description
CROSS REFERENCE TO RELATED APPLCIATIONS

[0001] This application claims priority under 35 U.S.C. 119 of Danish application no. PA 2001 01344 filed Sep. 14, 2001 and U.S. provisional application No. 60/323,004 filed Sep. 18, 2001, the contents of which are fully incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to novel substituted piperidines, 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 and/or prevention of diseases and disorders related to the histamine H3 receptor.

BACKGROUND OF THE INVENTION

[0003] 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, H.; Schlicker, E.; Schunack, W., Drugs Fut. 1996, 21, 507-520; Leurs, R.; Timmerman, H.; Vollinga, R. C., Progress in Drug Research 1995, 45, 107-165). Recently, the human histamine H3 receptor has been cloned, cf Lovenberg, T. W. 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 show 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.

[0004] Piperidines similar to the compounds of the present invention have previously been prepared, and their biological properties have been investigated, cf U.S. Pat. No. 3,577,440, WO 01/44191, J. Comb. Chemical (2000), 2(3), 266-275, WO 96/29307, WO 95/00512 and GB 2000136.

[0005] However, these references neither disclose nor suggest that these substituted piperidines may have a histamine H3 receptor antagonistic or agonistic activity.

[0006] 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 rat histamine H3 receptor have been described. Thus, 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), Kalindjian et al. (WO 99/42458), Schwartz et al. (EP 0 978 512), and Ludwig et al. (WO 97/17345) disclose cyclic amines having rat histamine H3 receptor agonistic or antagonistic activity. However, the structures of these amines are quite different from that of the present compounds. Thus, none of the amines disclosed in these publications contain a piperidine structure, as is the case in the present compounds.

[0007] 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 substituted piperidines has a high and specific affinity to the histamine H3 receptor.

[0008] Due to their interaction with the histamine H3 receptor, the present compounds are useful in the treatment and/or prevention 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.

DEFINITIONS

[0009] In the structural formulae given herein and throughout the present specification, the following terms have the indicated meaning:

[0010] The term “halogen” means F, Cl, Br or I.

[0011] The term “C1-6-alkyl” as used herein represent a branched or straight hydrocarbon group having from 1 to 6 carbon atoms. Typical C1-6-alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.

[0012] The term “C2-6-alkenyl” as used herein represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, allyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl and the like.

[0013] The term “C2-6-alkynyl” as used herein represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl and the like.

[0014] The term “C1-6-alkoxy” as used herein, alone or in combination, refers to the radical —O—C1-6-alkyl wherein C1-6-alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.

[0015] The term “C1-6-alkylthio” as used herein, alone or in combination, refers to the radical —S—C1-6-alkyl wherein C1-6-alkyl is as defined above. Representative examples are methylthio, ethylthio, isopropylthio, n-propylthio, butylthio, pentylthio and the like.

[0016] The term “C1-6-alkylsulfonyl” as used herein, alone or in combination, refers to the radical —S(═O)2—C1-6-alkyl wherein C1-6-alkyl is as defined above. Representative examples are methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-propylsulfonyl, butylsulfonyl, pentylsulfonyl and the like.

[0017] The term “C1-7-alkanoyl” as used herein, alone or in combination, refers to the radical —C(═O)H or —C(═O)C1-6-alkyl wherein C1-6-alkyl is as defined above. Representative examples are formyl, acetyl, propionyl, butanoyl, pentanoyl, hexanoyl, heptanoyl and the like.

[0018] The term “C3-8-cycloalkyl” as used herein represents a monocyclic, carbocyclic group having from from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

[0019] The term “C5-8-cycloalkenyl” as used herein represents a monocyclic, carbocyclic, non-aromatic group having from 5 to 8 carbon atoms and at least one double bond. Representative examples are cyclopentenyl, cyclohexenyl, cyclohepentyl, cyclooctenyl, and the like.

[0020] The term “aryl” as used herein is intended to include carbocyclic aromatic ring systems such as phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like.

[0021] The term “aryloxy” as used herein refers to the radical —O-aryl where aryl is as defined above. Non-limiting examples are phenoxy, naphthoxy, anthracenyloxy, phenantrenyloxy, fluorenyloxy, indenyloxy and the like.

[0022] The term “heteroaryl” as used herein is intended to include heterocyclic aromatic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.

[0023] As used herein, the phrase “4 to 7 membered, saturated or unsaturated heterocyclic ring” is intended to include heterocyclic rings which are saturated or contain one or two double bonds.

[0024] Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.

[0025] The term “optionally substituted” as used herein means that the group in question is either unsubstituted or substituted with one or more of the substituents specified. When the group in question is substituted with more than one substituent the substituents may be the same or different.

[0026] “Aryl-C1-6-alkyl”, “aryl-C1-6-alkoxy” etc. mean C1-6-alkyl or C1-6-alkoxy as defined above, substituted by aryl as defined above, for example:

SUMMARY OF THE INVENTION

[0027] The invention relates to a compound of the general formula (I):

[0028] wherein

[0029] m is 0, or, 2,

[0030] R1 is

[0031] C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl,

[0032] which may optionally be substituted with one or more substituents selected from halogen, C1-6-alkoxy and hydroxy,

[0033] C3-8-cycloalkyl, C5-8-cycloalkenyl, C3-8-cycloalkyl-C1-6-alkyl, di(C3-8-cycloalkyl)-C1-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C5-8-cycloalkenyl-C1-6-alkyl, C5-8-cycloalkenyl-C2-6-alkenyl, C5-8-cycloalkenyl-C2-6-alkynyl,

[0034] wherein the cyclic moieties may optionally be substituted with one or more substituents selected from C1-6-alkyl, halogen, trifluoromethyl and 2,2,2-trifluoroethyl,

[0035] R2 is C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl or C3-8-cycloalkyl-C1-6alkyl,

[0036] X is —CH2—(CH2)n—, —(CH2)n—CH═CH—(CH2)p—, —CH2—(CH2)n—O—(CH2)p—, —CH2—(CH2)n—C(═O)—(CH2)p 13 , —CH2—(CH2)n—S—(CH2)p—, —CH2—(CH2)n—S(═O)—(CH2)p— or —CH2—(CH2)n—S(═O)2—(CH2)p—,

[0037] n and p are independently 0, 1, 2, 3 or 4,

[0038] R3 and R4 are independently hydrogen, methyl or trifluoromethyl,

[0039] Y is

[0040] (a) aryl or heteroaryl, which may optionally be substituted with one or more substituents selected from

[0041] halogen, nitro, cyano, hydroxy, oxo, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR5R6 and —O(C═O)NR5R6,

[0042] wherein R5 and R6 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

[0043] or wherein two substituents in adjacent positions form a radical —O—(CH2)1-3—O—,

[0044] aryl, aryloxy, aryl-C1-6-alkyl and aryl-C1-6-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from

[0045] halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR7R8 and —O(C═O)NR7R8,

[0046] wherein R7 and R8 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R7 and R8 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

[0047] or wherein two substituents in adjacent positions form a radical —O—(CH2)1-3—O—

[0048] (b) C3-8-cycloalkyl or C5-8-cycloalkenyl, which may optionally be substituted with one or more substituents selected from

[0049] C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, cyano, trifluoromethyl, trifluoromethoxy and halogen,

[0050] aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from

[0051] halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR9R10 and —O(C═O)NR9R10,

[0052] wherein R9 and R10 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

[0053] (c) C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, which may optionally be substituted with one or more substituents selected from

[0054] halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR11R12 and —O(C═O)NR11R12,

[0055] wherein R11 and R12 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R11 and R12 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

[0056] aryl, aryl-C1-6-alkyl and aryl-C1-6-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from

[0057] halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR13R14 and —O(C═O)NR13R14,

[0058] wherein R13 and R14 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R13 and R14 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

[0059] or wherein two substituents in adjacent positions form a radical —O—(CH2)1-3—O—

[0060] with the proviso that the compound must not be

[0061] as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.

[0062] In one embodiment of the invention Y is

[0063] (a) aryl or heteroaryl, which may optionally be substituted with one or more substituents selected from

[0064] halogen, nitro, cyano, hydroxy, oxo, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR5R6 and —O(C═O)NR5R6,

[0065] wherein R5 and R6 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

[0066] or wherein two substituents in adjacent positions form a radical —O—(CH2)1-3—O—,

[0067] aryl, aryl-C1-6-alkyl and aryl-C1-6-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from

[0068] halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR7R8 and —O(C═O)NR7R8,

[0069] wherein R7 and R8 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R7 and R8 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

[0070] or wherein two substituents in adjacent positions form a radical —O—(CH2)1-3—O—

[0071] (b) C3-8-cycloalkyl or C5-8-cycloalkenyl, which may optionally be substituted with one or more substituents selected from

[0072] C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, cyano, trifluoromethyl, trifluoromethoxy and halogen,

[0073] aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from

[0074] halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR9R10 and —O(C═O)NR9R10,

[0075] wherein R9 and R10 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

[0076] (c) C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, which may optionally be substituted with one or more substituents selected from

[0077] halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR11R12 and —O(C═O)NR11R12,

[0078] wherein R11 and R12 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R11 and R12 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

[0079] aryl, aryl-C1-6-alkyl and aryl-C1-6-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from

[0080] halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR13R14 and —O(C═O)N13R14,

[0081] wherein R13 and R14 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R13 and R14 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

[0082] or wherein two substituents in adjacent positions form a radical —O—(CH2)1-3—O—

[0083] In another embodiment of the invention m is 1.

[0084] In another embodiment of the invention R3 and R4 are both hydrogen.

[0085] In yet another embodiment of the invention R1 is C1-6-alkyl which may optionally be substituted with one or more substituents selected from halogen, C1-6-alkoxy and hydroxy.

[0086] In an embodiment thereof R1 is C1-6-alkyl such as isopropyl, tert-butyl or 2-methyl-2-butyl.

[0087] In still another embodiment of the invention R1 is di(C3-8-cycloalkyl)-C1-6-alkyl, wherein the cyclic moieties may optionally be substituted with one or more substituents selected from C1-6-alkyl, halogen, trifluoromethyl and 2,2,2-trifluoroethyl.

[0088] In an embodiment thereof R1 is dicyclopropylmethyl.

[0089] In a further embodiment of the invention R2 is C1-6-alkyl.

[0090] In still a further embodiment of the invention X is —CH2—(CH2)n—, —(CH2)n—CH═CH—(CH2)p—, —CH2—(CH2)n—O—(CH2)p—, —CH2—(CH2)n—C(═O)—(CH2)p—, —CH2—(CH2)n—S—(CH2)p—, wherein n and p are as defined for formula (I).

[0091] In an embodiment thereof X is —CH2—(CH2)n—, —CH═CH—, —CH2—(CH2)n—O—, —CH2—(CH2)n—C(═O)—, —CH2—S—(CH2)p—, wherein n is 0, 1, 2 or 3, and p is 0 or 1.

[0092] In yet an embodiment thereof X is —CH2—, —(CH2)2—, —(CH2)3—, —(CH2)4—, —CH═CH—, —CH2—O—, —(CH2)3—O—, —(CH2)2—C(═O)—, —CH2—S—CH2— or —CH2—S—, such as —CH2—.

[0093] In another embodiment of the invention Y is C1-6-alkyl, C3-8-cycloalkyl, aryl or heteroaryl, which may optionally be substituted as defined for formula (I).

[0094] In an embodiment thereof Y is C1-6-alkyl, cyclohexyl, phenyl, naphthyl, pyridyl, benzoxazolyl or benzothiophenyl, which may optionally be substituted as defined for formula (I).

[0095] In yet an embodiment thereof Y is phenyl or naphthyl which may optionally be substituted with one or more substituents selected from

[0096] trifluoromethyl, trifluoromethoxy, halogen, C1-6-alkyl, —NR5R6 and —O(C═O)NR5R6, C1-7-alkanoyl, wherein R5 and R6 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

[0097] aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryloxy, and aryl, which may optionally be substituted with halogen or C1-6-alkyl,

[0098] or wherein two substituents in adjacent positions form a radical —O—(CH2)1-3—O—.

[0099] In an embodiment thereof Y is phenyl or naphthyl which may optionally be substituted with one or more substituents selected from

[0100] trifluoromethyl, trifluoromethoxy, halogen, C1-6-alkyl, —NR5R6 and —O(C═O)NR5R6 and C1-7-alkanoyl, wherein R5 and R6 independently are hydrogen or C1-6-alkyl,

[0101] phenyl-C1-6-alkoxy, phenyl-C1-6-alkyl, phenyloxy and phenyl, which may optionally be substituted with halogen or C1-6-alkyl,

[0102] or wherein two substituents in adjacent positions form a radical —O—(CH2)1-3—O—.

[0103] In yet an embodiment thereof Y is phenyl, which is substituted with phenyl.

[0104] The compounds of the present invention may be chiral, and it is intended that any enantiomers, as separated, pure or partially purified enantiomers or racemic mixtures thereof are included within the scope of the invention.

[0105] Furthermore, when a double bond or a fully or partially saturated ring system or more than one center of asymmetry or a bond with restricted rotatability is present in the molecule diastereomers may be formed. It is intended that any diastereomers, as separated, pure or partially purified diastereomers or mixtures thereof are included within the scope of the invention.

[0106] Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms, which the compounds are able to form, are included within the scope of the present invention.

[0107] The present invention also encompasses pharmaceutically acceptable salts of the present compounds. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.

[0108] Also intended as pharmaceutically acceptable acid addition salts are the hydrates, which the present compounds are able to form.

[0109] 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.

[0110] The compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such solvates are also contemplated as being within the scope of the present invention.

[0111] The invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

[0112] The invention also encompasses active metabolites of the present compounds.

[0113] The compounds of the present invention interact with the histamine H3 receptor and are accordingly useful for the treatment and/or prevention of a wide variety of conditions and disorders in which histamine H3 receptor interactions are beneficial.

[0114] Accordingly, in another aspect the present invention relates to a compound of the general formula (I) as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for use as a pharmaceutical composition.

[0115] The invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the formula (I) or any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents.

[0116] Furthermore, the invention relates to the use of a compound of the general formula (I′):

[0117] wherein

[0118] m is 0, or, 2,

[0119] R1 is

[0120] C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl,

[0121] which may optionally be substituted with one or more substituents selected from halogen, C1-6-alkoxy and hydroxy,

[0122] C3-8-cycloalkyl, C5-8-cycloalkenyl, C3-8-cycloalkyl-C1-6-alkyl, di(C3-8-cycloalkyl)-C1-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C5-8-cycloalkenyl-C1-6-alkyl, C5-8-cycloalkenyl-C2-6-alkenyl, C5-8-cycloalkenyl-C2-6-alkynyl,

[0123] wherein the cyclic moieties may optionally be substituted with one or more substituents selected from C1-6-alkyl, halogen, trifluoromethyl and 2,2,2-trifluoroethyl,

[0124] R2 is C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl or C3-8-cycloalkyl-C1-6alkyl,

[0125] X is —CH2—(CH2)n—, —(CH2)n—CH═CH—(CH2)p—, —CH2—(CH2)n—O—(CH2)p—, —CH2—(CH2)n—C(═O)—(CH2)p 13 , —CH2—(CH2)n—S—(CH2)p—, —CH2—(CH2)n—S(═O)—(CH2)p— or —CH2—(CH2)n—S(═O)2—(CH2)p—,

[0126] n and p are independently 0, 1, 2, 3 or 4,

[0127] R3 and R4 are independently hydrogen, methyl or trifluoromethyl,

[0128] Y is

[0129] (a) aryl or heteroaryl, which may optionally be substituted with one or more substituents selected from

[0130] halogen, nitro, cyano, hydroxy, oxo, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR5R6 and —O(C═O)NR5R6,

[0131] wherein R5 and R6 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

[0132] or wherein two substituents in adjacent positions form a radical —O—(CH2)1-3—O—,

[0133] aryl, aryloxy, aryl-C1-6-alkyl and aryl-C1-6-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from

[0134] halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR7R8 and —O(C═O)NR7R8,

[0135] wherein R7 and R8 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R7 and R8 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

[0136] or wherein two substituents in adjacent positions form a radical —O—(CH2)1-3—O—

[0137] (b) C3-8-cycloalkyl or C5-8-cycloalkenyl, which may optionally be substituted with one or more substituents selected from

[0138] C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, cyano, trifluoromethyl, trifluoromethoxy and halogen,

[0139] aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from

[0140] halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR9R10 and —O(C═O)NR9R10,

[0141] wherein R9 and R10 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

[0142] (c) C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, which may optionally be substituted with one or more substituents selected from

[0143] halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR11R12 and —O(C═O)NR11R12,

[0144] wherein R11 and R12 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R11 and R12 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

[0145] aryl, aryl-C1-6-alkyl and aryl-C1-6-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from

[0146] halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR13R14 and —O(C═O)NR13R14,

[0147] wherein R13 and R14 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-7-alkanoyl or aryl, or R13 and R14 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

[0148] or wherein two substituents in adjacent positions form a radical —O—(CH2)1-3—O—

[0149] as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment and/or prevention of disorders and diseases related to the histamine H3 receptor.

[0150] In still another aspect, the invention relates to a method for the treatment and/or prevention of diseases and disorders related to the histamine H3 receptor the method comprising administering to a subject in need thereof an effective amount of a compound of the formula (I′) or any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.

DETAILED DESCRIPTION OF THE INVENTION

[0151] In one aspect the invention relates to compounds with histamine H3 receptor antagonistic activity or inverse agonistic activity which may accordingly be useful in the treatment of a wide range of conditions and disorders in which histamine H3 receptor blockade is beneficial.

[0152] In another aspect the invention relates to compounds with histamine H3 receptor agonistic activity and which may accordingly be useful in the treatment of a wide range of conditions and disorders in which histamine H3 receptor activation is beneficial.

[0153] In a preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the reduction of weight.

[0154] In a preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of over-weight or obesity.

[0155] In another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the suppression of appetite or satiety induction.

[0156] In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the prevention and/or treatment of disorders and diseases related to overweight or obesity such as atherosclerosis, hypertension, IGT (impaired glucose tolerance), diabetes, especially Type 2 diabetes (NIDDM (non-insulin dependent diabetes mellitus)), dyslipidaemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancer such as endometrial, breast, prostate and colon cancers.

[0157] In yet a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the prevention and/or treatment of eating disorders such as bulimia and binge eating.

[0158] In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of IGT.

[0159] In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of Type 2 diabetes.

[0160] In another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to Type 2 diabetes.

[0161] In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes.

[0162] The compounds of the present invention may also be used for the treatment of airway disorders such as asthma, as anti-diarrhoeals and for the modulation of gastric acid secretion.

[0163] Furthermore, the compounds of the present invention may be used for the treatment of diseases associated with the regulation of sleep and wakefulness and for the treatment of narcolepsy and attention deficit disorders.

[0164] Moreover, the compounds of the invention may be used as CNS stimulants or as sedatives.

[0165] The present compounds may also be used for the treatment of conditions associated with epilepsy. Additionally, the present compounds may be used for the treatment of motion sickness and vertigo. Furthermore, they may be useful as regulators of hypothalamohypophyseal secretion, antidepressants, modulators of cerebral circulation, and in the treatment of irritable bowel syndrome.

[0166] Further, the compounds of the present invention may be used for the treatment of dementia and Alzheimer's disease.

[0167] The compounds of the present invention may also be useful for the treatment of allergic rhinitis, ulcer or anorexia.

[0168] The compounds of the present invention may furthermore be useful for the treatment of migraine, see R. L. McLeod et al., The Journal of Pharmacology and Experimental Therapeutics 287 (1998), 43-50, and for the treatment of myocardial infarction, see C. J. Mackins and R. Levi, Expert Opinion on Investigational Drugs 9 (2000), 2537-2542.

[0169] In a further aspect of the invention the present compounds are combined with diet and/or exercise.

[0170] In a further aspect of the invention the present compounds may be administered in combination with one or more further pharmacologically active substances in any suitable ratios. Such further active agents may be selected from antiobesity agents, antidiabetics, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.

[0171] Thus, in a further aspect of the invention the present compounds may be administered in combination with one or more antiobesity agents or appetite regulating agents.

[0172] Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, MC3 (melanocortin 3) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, β3 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors such as fluoxetine, seroxat or citalopram, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth factors such as prolactin or placental lactogen, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR (peroxisome proliferator-activated receptor) modulators, RXR (retinoid X receptor) modulators, TR β agonists, AGRP (Agouti related protein) inhibitors, opioid antagonists (such as naltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor.

[0173] In one embodiment of the invention the antiobesity agent is leptin.

[0174] In another embodiment the antiobesity agent is dexamphetamine or amphetamine.

[0175] In another embodiment the antiobesity agent is fenfluramine or dexfenfluramine.

[0176] In still another embodiment the antiobesity agent is sibutramine.

[0177] In a further embodiment the antiobesity agent is orlistat.

[0178] In another embodiment the antiobesity agent is mazindol or phentermine.

[0179] In still another embodiment the antiobesity agent is phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate or ecopipam.

[0180] Suitable antidiabetic agents comprise insulin, insulin analogues and derivatives such as those disclosed in EP 792 290 (Novo Nordisk A/S), eg NεB29-tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705 275 (Novo Nordisk A/S), eg AspB28 human insulin, U.S. Pat. No. 5,504,188 (Eli Lilly), eg LysB28 ProB29 human insulin, EP 368 187 (Aventis), eg Lantus, which are all incorporated herein by reference, GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S), which is incorporated herein by reference, as well as orally active hypoglycaemic agents.

[0181] The orally active hypoglycaemic agents preferably comprise imidazolines, sulphonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitizers, α-glucosidase inhibitors, agents acting on the ATP-dependent potassium channel of the β-cells eg potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S) which are incorporated herein by reference, or mitiglinide, or a potassium channel blocker, such as BTS-67582, nateglinide, glucagon antagonists such as those disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference, GLP-1 agonists such as those disclosed in WO 00/42026 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase (protein tyrosine phosphatase) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, GSK-3 (glycogen synthase kinase-3) inhibitors, compounds modifying the lipid metabolism such as antilipidemic agents, compounds lowering food intake, PPAR (peroxisome proliferator-activated receptor) and RXR (retinoid X receptor) agonists, such as ALRT-268, LG-1268 or LG-1069.

[0182] In one embodiment of the invention the present compounds are administered in combination with insulin.

[0183] In a further embodiment of the invention the present compounds are administered in combination with a sulphonylurea eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride, glicazide or glyburide.

[0184] In another embodiment of the invention the present compounds are administered in combination with a biguanide eg metformin.

[0185] In yet another embodiment of the invention the present compounds are administered in combination with a meglitinide eg repaglinide or nateglinide.

[0186] In still another embodiment of the invention the present compounds are administered in combination with a thiazolidinedione insulin sensitizer eg troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/Cl-1037 or T 174 or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), which are incorporated herein by reference.

[0187] In still another embodiment of the invention the present compounds may be administered in combination with an insulin sensitizer eg such as GI 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 (Dr. Reddy's Research Foundation) and WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190 and WO 00/63189 (Novo Nordisk A/S), which are incorporated herein by reference.

[0188] In a further embodiment of the invention the present compounds are administered in combination with an α-glucosidase inhibitor eg voglibose, emiglitate, miglitol or acarbose.

[0189] In another embodiment of the invention the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the β-cells eg tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide.

[0190] In yet another embodiment of the invention the present compounds may be administered in combination with nateglinide.

[0191] In still another embodiment of the invention the present compounds are administered in combination with an antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.

[0192] In another aspect of the invention, the present compounds are administered in combination with more than one of the above-mentioned compounds eg in combination with metformin and a sulphonylurea such as glyburide; a sulphonylurea and acarbose; nateglinide and metformin; acarbose and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin and lovastatin; etc.

[0193] Furthermore, the present compounds may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are β-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ram ipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and α-blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

[0194] It should be understood that any suitable combination of the compounds according to the invention with diet and/or exercise, one or more of the above-mentioned compounds and optionally one or more other active substances are considered to be within the scope of the present invention.

[0195] Pharmaceutical Compositions

[0196] The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

[0197] The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.

[0198] Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.

[0199] Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

[0200] Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.

[0201] Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.

[0202] A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.

[0203] The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain of from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.

[0204] For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for oral administration.

[0205] The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of a free base. When a compound of the formula (I) contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the formula (I) with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids. Representative examples are mentioned above. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.

[0206] For parenteral administration, solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.

[0207] Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water. 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 pharmaceutical compositions formed by combining the novel compounds of the formula (I) and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.

[0208] Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.

[0209] If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

[0210] A typical tablet, which may be prepared by conventional tabletting techniques, may contain:

Core:
Active compound (as free compound or salt thereof) 5.0 mg
Lactosum Ph. Eur. 67.8 mg
Cellulose, microcryst. (Avicel) 31.4 mg
Amberlite ® IRP88* 1.0 mg
Magnesii stearas Ph. Eur. q.s.
Coating:
Hydroxypropyl methylcellulose approx. 9 mg
Mywacett 9-40 T** approx. 0.9 mg

[0211] If desired, the pharmaceutical composition of the invention may comprise the compound of the formula (I) in combination with further pharmacologically active substances such as those described in the foregoing.

EXAMPLES

[0212] The preparation of the compounds of this invention can be realized in many different ways. The compounds of the present invention were prepared using standard synthetic procedures, well-known by those skilled in the art, as described, for instance, in Houben Weyl. Methoden der Organischen Chemie, Thieme Verlag, Stuttgart.

[0213] The amides were prepared either in solution or with the aid of an insoluble nitrophenol from the corresponding amines and carboxylic acids, using standard methodology (see eg J. J. Parlow, J. E. Normansell, Mol. Diversity 1996, 1, 266-269; R. Kalir, M. Fridkin, A. Patchornik, Eur. J. Biochem. 1974, 42,151-156; B. J. Cohen, H. Karoly-Hafeli, A. Patchornik, J. Org. Chem. 1984, 49, 922-924). In solution the carboxylic acid was activated by treatment with carbonyl diimidazole or di-(N-succinimidyl)carbonate and then treated with the amine. The carbamates were prepared by activating an alcohol with phosgene or 4-nitrophenyl chloroformate, and treating the resulting chloroformate or 4-nitrophenyl carbonate with an amine. The ureas were prepared by treating an amine with a suitable isocyanate or carbamoyl chloride.

[0214] In the examples the following terms are intended to have the following, general meanings:

[0215] DCM: dichloromethane, methylenechloride

[0216] DIC: diisopropylcarbodiimide

[0217] DMF: N,N-dimethyl formamide

[0218] DMSO: dimethyl sulphoxide

[0219] THF: tetrahydrofuran

[0220] PS: Polystyrene

[0221] NMR spectra were recorded on Bruker 300 MHz and 400 MHz instruments. HPLC-MS was performed on a Perkin Elmer instrument (API 100).

[0222] HPLC-systems from Merck-Hitachi (Hibar™ RT 250-4, Lichrosorb™ RP 18, 5.0 μm, 4.0×250 mm, gradient elution, 20% to 80% acetonitrile in water within 30 min, 1.0 ml/min, detection at 254 nm) and Waters (Symmetry™, C18, 3.5 μm, 3.0×150 mm, gradient elution, 5% to 90% acetonitrile in water within 15 min, 1.0 ml/min, detection at 214 nm) were used.

[0223] Furthermore, where stated the following HPLC method h8 was used:

[0224] The reverse phase analysis was performed using UV detections at 214, 254, 276 and 301 nm on a 218TP54 4.6 mm×150 mm C-18 silica column, which was eluted at 1 ml/min at 42° C. The column was equilibrated with 5% acetonitrile, 85% water and 10% of a solution of 0.5% trifluoroacetic acid in water and eluted by a linear gradient from 5% acetonitrile, 85% water and 10% of a solution of 0.5% trifluoroacetic acid to 90% acetonitrile and 10% of a solution of 0.5% trifluoroacetic acid over 15 min.

[0225] General Procedures for the Preparation of Compounds of the General Formula (I):

[0226] An insoluble nitrophenol was prepared by acylating commercially available aminomethyl polystyrene (1% cross-linked with divinyl benzene, 0.8 mmol/g) with 4-hydroxy-3-nitrobenzoic acid. The resulting support was acylated with a carboxylic acid (DCM/DMF, DIC, 2 hours, room temperature), filtered and washed with three times with DCM and then treated with less than one equivalent of an amine (DCM/acetonitrile, room temperature, overnight). Filtration and concentration yielded the pure products, which were either tested directly, or further purified by recrystallization or column chromatography. The products were analyzed by 1H NMR and HPLC-MS.

[0227] Most of the 4-aminopiperidines required for the preparation of the compounds of the present invention were commercially available. The preparation of those amines which were not commercially available is described below.

[0228] 1-Isopropyl-4-methylaminopiperidine

[0229] To a stirred mixture of methylamine hydrochloride (2.62 g, 38.8 mmol), THF (30 ml), ethanol (15 ml), N-isopropyl-4-piperidinone (3.0 ml, 20.2 mmol), and acetic acid (3.60 ml) was added sodium cyanoborohydride (30 ml, 1 molar solution in THF, 30 mmol), and the mixture was stirred at 60° C. for 6 hours and then at room temperature overnight. The mixture was concentrated under reduced pressure, water (50 ml) and potassium carbonate (47.0 g) were added, and the mixture was extracted with ethyl acetate (6×50 ml). The combined extracts were dried over magnesium sulphate and concentrated, to yield 3.78 g (quant.) of the title compound as an oil, which was used without further purification.

[0230] Typical Procedure

Example 11

[0231] 2-Biphenyl-4-yl-N-methyl-N-(1-methylpiperidin-4-yl)acetamide hydrochloride

[0232] To the polymeric nitrophenol (1.5 g, approx. 1 mmol) was added a filtered solution of 4-biphenylylacetic acid (1.10 g, 5.18 mmol) in a mixture of 1,2-dichloropropane (18 ml) and DMF (2 ml), followed by the addition of a solution of DIC (0.63 g, 4.99 mmol) in 1,2-dichloropropane (5 ml). The mixture was shaken at room temperature for 15 hours, filtered, and the polymer was extensively washed with DCM, DMF, and 1,2-dichloropropane. To the polymer was added 1,2-dichloropropane (5 ml) and a solution of 1-methyl-4-methylaminopiperidine (0.10 g, 0.78 mmol) in 1,2-dichloropropane (10 ml). The resulting mixture was shaken at room temperature for 21 hours and then at 60° C. for one hour, filtered, and the polymer was carefully washed with DCM and methanol. The combined filtrates were concentrated to yield the crude product, which was purified by column chromatography (silicagel, gradient elution with DCM/methanol). The amine was mixed with ethanol and 1 molar aqueous hydrochloric acid, concentrated, and the residual hydrochloride was recrystallized from acetone. 120 mg (42%) of the title compound was obtained.

[0233]1H NMR (400 MHz, DMSO, mixture of rotamers): δ1.64 (m, 2H), 2.05 (m, 2H), 2.71 (m, 4H), 2.87 (s, 2H), 3.06 (m, 2H), 3.41 (m, 2H), 3.75 and 3.83 (2×s, 2H), 4.13 (m, 0.5H), 4.54 (m, 0.5H), 7.27-7.38 (m, 3H), 7.45 (t, J=8 Hz, 2H), 7.58-7.66 (m, 4H), 10.25 (m, 1H); HPLC-MS: m/z 323 (MH+); Rt: 4.1 min.

[0234] Using this methodology the following compounds were prepared:

Found
Example Structure Name MH+
1 3-[4-(4-Fluorobenzyloxy)phenyl]-N- methyl-N-(1-methylpiperidin-4-yl)- acrylamide 383
2 3-(4-Chlorophenyl)-N-methyl-N-(1- methylpiperidin-4-yl)propionamide 295
3 2-Biphenyl-4-yl-N-cyclopropyl-N-(1- propylpiperidin-4-yl)acetamide 377
4 N-Methyl-N-(1-methylpiperidin-4-yl)-3- (4-trifluoromethylphenyl)propionamide 329
5 2-Biphenyl-4-yl-N-(1-isopropyl- piperidin-4-yl)-N-methylacetamide 351
6 2-(2-Methoxyphenoxy)-N-methyl-N- (1-methylpiperidin-4-yl)acetamide 293
7 3-(2-Methoxyphenyl)-N-methyl-N-(1- methylpiperidin-4-yl)acrylamide 289
8 2-(2-Chlorophenoxy)-N-methyl-N-(1- methylpiperidin-4-yl)acetamide 297
9 N-Methyl-N-(1-methylpiperidin-4-yl)-3- naphthalen-1-ylacrylamide 309
10 3-(5-Bromo-2-ethoxyphenyl)-N- methyl-N-(1-methylpiperidin-4-yl)- acrylamide 381
11 2-Biphenyl-4-yl-N-methyl-N-(1- methylpiperidin-4-yl)acetamide 323
12 3-(3-Methoxyphenyl)-N-methyl-N-(1- methylpiperidin-4-yl)acrylamide 289
13 4-(4-Methoxyphenyl)-N-methyl-N-(1- methylpiperidin-4-yl)butyramide 305
14 2-(2,4-Dichloro-5-methylphenyl- sulfanyl)-N-methyl-N-(1-methyl- piperidin-4-yl)acetamide 362
15 4-(3-Fluoro-4-methoxyphenyl)-N- methyl-N-(1-methylpiperidin-4-yl)-4- oxobutyramide 337
16 3-(4-Dimethylaminophenyl)-N-methyl- N-(1-methylpiperidin-4-yl)acrylamide 302
17 2-(2-Benzyloxyphenyl)-N-methyl-N- (1-methylpiperidin-4-yl)acetamide 353
18 3-(3,4-Dimethoxyphenyl)-N-methyl-N- (1-methylpiperidin-4-yl)propionamide 321
19 4-(2,4-Dichlorophenoxy)-N-methyl-N- (1-methylpiperidin-4-yl)butyramide 360
20 3-(2-Methoxyphenyl)-N-methyl-N-(1- methylpiperidin-4-yl)propionamide 391
21 4-(4-Chloro-2-methylphenoxy)-N- methyl-N-(1-methylpiperidin-4-yl)- butyramide 339
22 2-(4-Fluorophenylsulfanyl)-N-methyl- N-(1-methylpiperidin-4-yl)acetamide 297
23 3-(4-Fluoro-3-trifluoromethylphenyl)- N-methyl-N-(1-methylpiperidin-4-yl)- acrylamide 345
24 N-Methyl-N-(1-methylpiperidin-4-yl)-2- (3-trifluoromethoxyphenyl)acetamide 331
25 2-(4-Fluorophenoxy)-N-methyl-N-(1- methylpiperidin-4-yl)acetamide 281
26 2-(2,3-Dichlorophenoxy)-N-methyl-N- (1-methylpiperidin-4-yl)acetamide 332
27 2-(4-Methoxyphenoxy)-N-methyl-N- (1-methylpiperidin-4-yl)acetamide 293
28 N-Methyl-N-(1-methylpiperidin-4-yl)-2- (4-trifluoromethoxyphenyl)acetamide 331
29 3-Benzo[1,3]dioxol-5-yl-N-methyl-N- (1-methylpiperidin-4-yl)propionamide 305
30 N-Methyl-N-(1-methylpiperidin-4-yl)-2- (naphthalen-2-yloxy)acetamide 313
31 N-Methyl-N-(1-methylpiperidin-4-yl)-3- (3,4,5-trimethoxyphenyl)propionamide 351
32 3-(2,4-Dimethoxyphenyl)-N-methyl-N- (1-methylpiperidin-4-yl)acrylamide 319
33 4-Biphenyl-4-yl-N-methyl-N-(1- methylpiperidin-4-yl)-4-oxobutyramide 365
34 N-Methyl-N-(1-methylpiperidin-4-yl)-2- (naphthalen-2-ylsulfanyl)acetamide 329
35 3-(3,5-Dimethoxyphenyl)-N-methyl-N- (1-methylpiperidin-4-yl)acrylamide 319
36 3-(2,3-Dimethoxyphenyl)-N-methyl-N- (1-methylpiperidin-4-yl)acrylamide 319
37 4-(3,4-Dimethoxyphenyl)-N-methyl-N- (1-methylpiperidin-4-yl)butyramide 335
38 2-(2,3-Dimethylphenoxy)-N-methyl-N- (1-methylpiperidin-4-yl)acetamide 291
39 2-(8-Chloronaphthalen-1-ylsulfanyl)- N-methyl-N-(1-methylpiperidin-4-yl)- acetamide 363
40 N-Methyl-N-(1-methylpiperidin-4-yl)-2- (naphthalen-1-yloxy)acetamide 313
41 2-(4-Acetylphenoxy)-N-methyl-N-(1- methylpiperidin-4-yl)acetamide 305
42 3-(3-Methoxyphenyl)-N-methyl-N-(1- methylpiperidin-4-yl)propionamide 291
43 N-Methyl-N-(1-methylpiperidin-4-yl)-3- pyridin-3-ylpropionamide 262
44 3-(4-Benzyloxy-3-methoxyphenyl)-N- methyl-N-(1-methylpiperidin-4-yl)- acrylamide 395
45 3-(5-Bromo-2-ethoxyphenyl)-N- methyl-N-(1-methylpiperidin-4-yl)- acrylamide 382
46 4-(3,4-Dihydro-2H-benzo[b][1,4]- dioxepin-7-yl)-N-methyl-N-(1-methyl- piperidin-4-yl)-4-oxobutyramide 361
47 3-(2-Chloro-3,4-dimethoxyphenyl)-N- methyl-N-(1-methylpiperidin-4-yl)- acrylamide 353
48 2-(2-Chloro-4-fluorophenylsulfanyl)-N- methyl-N-(1-methylpiperidin-4-yl)- acetamide 331
49 N-Methyl-N-(1-methylpiperidin-4-yl)-2- (naphthalen-1-ylmethylsulfanyl)- acetamide 343
50 N-Methyl-N-(1-methylpiperidin-4-yl)-3- (2-oxo-benzooxazol-3-yl)propionamide 318
51 5-Cyclohexylpentanoic acid methyl- (1-methylpiperidin-4-yl)amide 295
52 3-(4-Methoxyphenyl)-N-methyl-N-(1- methylpiperidin-4-yl)propionamide 291
53 N-Methyl-N-(1-methylpiperidin-4-yl)-2- (4-trifluoromethoxyphenoxy)acetamide 247
54 2-(2-Acetylphenoxy)-N-methyl-N-(1- methylpiperidin-4-yl)acetamide 305
55 Dimethylcarbamic acid 4-{2-[methyl- (1-methylpiperidin-4-yl)carbamoyl]- ethyl}-phenyl ester 348
56 2-(5-Chloro-3-methyl-benzo[b]thio- phen-2-yl)-N-methyl-N-(1-methyl- piperidin-4-yl)acetamide 351

[0235] Spectral Data for Selected Examples

Example 2

[0236] 3-(4-Chlorophenyl)-N-methyl-N-(1-methylpiperidin-4-yl)propionamide hydrochloride

[0237]1H NMR (400 MHz, DMSO, mixture of rotamers): δ1.55-1.76 (m, 2H), 2.05 (m, 2H), 2.56-2.83 (m, 9H), 3.05 (m, 2H), 3.39 (m, 2H), 3.95 (m, 1H), 4.52 (m, 1H), 7.30 (m, 4H), 10.36 (br s, 1H); HPLC-MS: m/z295 (MH+); Rt: 4.1 min.

Example 3

[0238] 2-Biphenyl-4-yl-N-cyclopropyl-N-(1-propylpiperidin-4-yl)acetamide hydrochloride

[0239]1H NMR (400 MHz, DMSO, mixture of rotamers): δ0.89 (m, 7H), 1.68 (m, 2H), 1.82 (m, 2H), 2.38 (m, 2H), 2.63 (m, 1H), 2.93 (m, 4H), 3.46 (m, 2H), 3.91 (s, 2H), 4.03 (m, 1H), 7.29-7.38 (m, 3H), 7.46 (t, J=8 Hz, 2H), 7.58-7.68 (m, 4H), 9.84 (br s, 1H); HPLC-MS: m/z 377 (MH30 ); Rt: 5.0 min.

Example 5

[0240] 2-Biphenyl-4-yl-N-(1-isopropylpiperidin-4-yl)-N-methylacetamide hydrochloride

[0241]1H NMR (400 MHz, DMSO, mixture of rotamers): δ1.18-1.30 (m, 6H), 1.66 (m, 2H), 2.10-2.32 (m, 3H), 2.82 and 2.89 (2×s, 3H), 3.08 (m, 3H), 3.76 and 3.82 (2×s, 2H), 4.25 (m, 1H), 4.61 (m, 1H), 7.28-7.39 (m, 3H), 7.46 (t, J=8 Hz, 2H), 7.58-7.68 (m, 4H), 10.1 (br s, 1H);

[0242] HPLC-MS: m/z 351 (MH+); Rt: 4.5 min.

[0243] Pharmacological Methods

[0244] The ability of the compounds to interact with the histamine H3 receptor can be determined by the following in vitro binding assays.

[0245] Binding Assay (I)

[0246] Rat cerebral cortex is homogenized in ice cold K-Hepes, 5 mM MgCl2 pH 7.1 buffer. After two differential centrifugations the last pellet is resuspended in fresh Hepes buffer containing 1 mg/ml bacitracin. Aliquots of the membrane suspension (400 μg/ml) are incubated for 60 min at 25° C. with 30 pM [125I]-iodoproxifan, a known histamine H3 receptor antagonist, and the test compound at various concentrations. The incubation is stopped by dilution with ice-cold medium, followed by rapid filtration through Whatman GF/B filters pretreated for 1 hour with 0.5% polyethyleneimine. The radioactivity retained on the filters is counted using a Cobra II auto gamma counter. The radioactivity of the filters is indirectly proportional to the binding affinity of the tested compound. The results are analyzed by nonlinear regression analysis.

[0247] Binding Assay (II)

[0248] The H3-receptor agonist ligand R-α-methyl[3H]histamine (RAMHA) is incubated with isolated rat cortex cell-membranes at 25° C. for 1 hour, followed by a filtration of the incubate through Whatman GF/B filters. Radioactivity retained on the filters is measured using a beta counter.

[0249] Male Wistar rats (150-200 g) are decapitated and cerebral cortex is quickly dissected out and frozen immediately on dry ice. Tissue is kept at −80° C. until membrane preparation. During the membrane preparation the tissue is kept on ice all the time. Rat cerebral cortex is homogenized in 10 volumes (w/w) ice-cold Hepes buffer (20 mM Hepes, 5 mM MgCl2 pH 7.1 (KOH)+1 mg/ml bacitracin) using an Ultra-Turrax homogenizer for 30 seconds. The homogenate is centrifuged at 140 g in 10 min. The supernatant is transferred to a new test tube and centrifuged for 30 min at 23000 g. Pellet is resuspended in 5-10 ml Hepes buffer, homogenized and centrifuged for 10 min at 23000 g. This short centrifugation step is repeated twice. After the last centrifugation the pellet is resuspended in 2-4 ml Hepes buffer and the protein concentration is determined. The membranes are diluted to a protein concentration of 5 mg/ml using Hepes buffer, aliquoted and stored at −80° C. until use.

[0250] 50 μl test-compound, 100 μl membrane (200 μg/ml), 300 μl Hepes buffer and 50 μl R-α-methyl[3H]histamine (1 nM) are mixed in a test tube. The compounds to be tested are dissolved in DMSO and further diluted in H2O to the desired concentrations. Radioligand and membranes are diluted in Hepes buffer+1 mg/ml bacitracin. The mixture is incubated for 60 min at 25° C. Incubation is terminated by adding 5 ml ice-cold 0.9% NaCl, followed by rapid filtration through Whatman GF/B filters pre-treated for 1 hour with 0.5% polyethyleneimine. The filters are washed with 2×5 ml ice-cold NaCl. To each filter a 3 ml scintillation cocktail is added and the radioactivity retained is measured with a Packard Tri-Carb beta counter.

[0251] IC50 values are calculated by non-linear regression analysis of binding curves (6 points minimum) using the windows program GraphPad Prism, GraphPad software, USA.

[0252] Binding Assay (III)

[0253] The human H3 receptor is cloned by PCR and subcloned into the pcDNA3 expression vector. Cells stably expressing the H3 receptor are generated by transfecting the H3-expression vectors into HEK 293 cells and using G418 to select for H3 clones. The human H3-HEK 293 clones are cultured in DMEM (GIBCO-BRL) with glutamax, 10% foetal calf serum, 1% penicillin/streptavidin and 1 mg/ml G 418 at 37° C. and 5% CO2. Before harvesting, the confluent cells are rinsed with PBS and incubated with Versene (proteinase, GIBCO-BRL) for approximately 5 min. The cells are flushed with PBS and DMEM and the cellsuspension collected in a tube and centrifuged for 5-10 min at 1500 rpm in a Heraeus Sepatech Megafuge 1.0. The pellet is resuspended in 10-20 vol. Hepes buffer (20 mM Hepes, 5 mM MgCl2, pH 7.1 (KOH)) and homogenized for 10-20 seconds using an Ultra-Turrax homogenizer. The homogenate is centrifuged for 30 min at 23 000 g. The pellet is resuspended in 5-10 ml Hepes buffer, homogenized 5-10 seconds with the Ultra-Turrax and centrifuged for 10 min at 23 000 g. Following this centrifugation step, the membrane pellet is resuspended in 2-4 ml Hepes buffer, homogenized with a syringe or teflonhomogenizer, and the protein concentration determined. The membranes are diluted to a protein concentration of 1-5 mg/ml in Hepes buffer, aliquoted and kept at −80° C. until use.

[0254] Aliquots of the membrane suspension are incubated for 60 min at 25° C. with 30 pM [125I]-iodoproxifan, a known compound with high affinity for the H3 receptor, and the test compound at various concentrations. The incubation is stopped by dilution with ice-cold medium, followed by rapid filtration through Whatman GF/B filters pretreated for 1 hour with 0.5% polyethyleneimine. The radioactivity retained on the filters is counted using a Cobra II auto gamma counter. The radioactivity of the filters is indirectly proportional to the binding affinity of the tested compound. The results are analysed by nonlinear regression analysis.

[0255] When tested, the present compounds of the formula (I) generally show a high binding affinity to the histamine H3 receptor.

[0256] Preferably, the compounds according to the invention have an IC50 value as determined by one or more of the assays of less than 10 μM, more preferred of less than 1 μM, and even more preferred of less than 500 nM, such as of less than 100 nM.

[0257] Functional Assay (I)

[0258] The ability of the compounds to interact with the histamine H3 receptor as agonists, inverse agonists and/or antagonists, is determined by an in vitro functional assay utilizing membranes from HEK 293 cell expressing the human H3 receptors.

[0259] The H3 receptor is cloned by PCR and subcloned into the pcDNA3 expression vector. Cells stably expressing the H3 receptor are generated by transfecting the H3-expression vectors into HEK 293 cells and using G418 to select for H3 clones. The human H3-HEK 293 clones are cultured in DMEM with glutamax, 10% foetal calf serum, 1% penicillin/streptavidin and 1 mg/ml G 418 at 37° C. and 5% CO2.

[0260] The H3 receptor expressing cells are washed once with phosphate buffered saline (PBS) and harvested using versene (GIBCO-BRL). PBS is added and the cells are centrifuged for 5 min at 188 g. The cell pellet is resuspended in stimulation buffer to a concentration of 1×106 cells/mi. cAMP accumulation is measured using the Flash Plate® cAMP assay (NEN™ Life Science Products). The assay is generally performed as described by the manufacturer. Briefly, 50 μl cell suspension is added to each well of the Flashplate which also contained 25 μl 40 μM isoprenaline, to stimulate cAMP generation, and 25 μl of test compound (either agonists or inverse agonists alone, or agonist and antagonist in combination). The assay can be run in “agonist-mode” which means that the test compound is added, in increasing concentration, on its own, to the cells, and cAMP is measured. If cAMP goes up, it is an inverse agonist; if cAMP does not change, it is a neutral antagonist, and if cAMP goes down, it is an agonist. The assay can also be run in the “antagonist-m ode” which means that a test compound is added, in increasing concentrations, together with increasing concentrations of a known H3 agonist (eg RAMHA). If the compound is an antagonist, increasing concentrations of it cause a right-ward shift in the H3-agonist's dose-response curves. The final volume in each well is 100 μl. Test compounds are dissolved in DMSO and diluted in H2O. The mixture is shaken for 5 min, and allowed to stand for 25 min at room temperature. The reaction is stopped with 100 μl “Detection Mix” per well. The plates are then sealed with plastic, shaken for 30 min, allowed to stand overnight, and finally the radioactivity is counted in the Cobra II auto gamma topcounter. EC50 values are calculated by non-linear regression analysis of dose response curves (6 points minimum) using GraphPad Prism. Kb values are calculated by Schild plot analysis.

[0261] The Open Cage Schedule-Fed Rat Model

[0262] The ability of the present compounds to reduce weight is determined using the in vivo open cage Schedule-fed rat model.

[0263] Sprague-Dawley (SD) male rats of an age of about 1½ to 2 months and a weight of about 200-250 g are purchased from Mlleg{dot over (a)}rd Breeding and Research Centre A/S (Denmark). On arrival they are allowed some days of acclimatisation before being placed in individual open plastic cages. They are habituated to the presence of food (Altromin pelleted rat chow) in their home cage only during 7 hours in the morning from 07.30 to 14.30 h all days a week. Water is present ad libitum. As the consumption of food has stabilised after 7 to 9 days, the animals are ready for use.

[0264] Each animal is used only once to avoid carry-over effects between treatments. During the test sessions, the test compound is administered intraperitoneally or orally 30 min before the start of the sessions. One group of animals is administered the test compound at different doses and a control group of animals is given a vehicle. Food and water intake are monitored at 1, 2 and 3 hours post administration.

[0265] Any side effects may rapidly be discovered (barrel-rolling, bushy fur etc.) since the animals are kept in transparent plastic cages to enable continuous monitoring.

[0266] The invention described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed, since these embodiments are intended as illustrations of several aspects of the invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

[0267] Various references are cited herein, the disclosure of which are incorporated by reference in their entireties.

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US8124605Jul 7, 2008Feb 28, 2012Kinex Pharmaceuticals, LlcCompositions and methods for modulating a kinase cascade
WO2008127727A1 *Apr 14, 2008Oct 23, 2008Kinex Pharmaceuticals LlcBiaryl compositions and methods for modulating a kinase cascade
Classifications
U.S. Classification514/217.03, 514/217.11, 540/596, 514/422, 540/605, 546/207, 548/557, 548/517, 514/326, 546/223, 514/317, 514/426, 514/316, 546/186
International ClassificationA61K31/4523, C07D413/12, C07D211/56, C07D401/12, A61K31/40, C07D405/12, C07D211/58, A61K31/445, C07D409/12, C07D207/14
Cooperative ClassificationC04B35/632, C07D211/56, C07D409/12, C07D401/12, C07D413/12, A61K31/40, A61K31/445, C07D207/14, C07D211/58, C07D405/12, A61K31/4523
European ClassificationA61K31/445, A61K31/40, C07D211/56, A61K31/4523, C07D207/14, C07D211/58, C07D409/12, C07D401/12, C07D413/12, C07D405/12, C04B35/632
Legal Events
DateCodeEventDescription
Feb 21, 2008ASAssignment
Owner name: NOVO NORDISK A/S, DENMARK
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BOEHRINGER INGELHEIM INTERNATIONAL, GMBH;REEL/FRAME:020541/0001
Effective date: 20080207
Dec 9, 2002ASAssignment
Owner name: BOEHRINGER INGELHEIM INTERNATIONAL GMBH, GERMANY
Owner name: NOVO NORDISK A/S A, DENMARK
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:DORWALD, FLORENCIO ZARAGOZA;REEL/FRAME:013559/0489
Effective date: 20021123