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Title:
HISTAMINE H3 ANTAGONIST STEROIDAL CARBOXAMIDES
Document Type and Number:
WIPO Patent Application WO/2013/027073
Kind Code:
A1
Abstract:
The present invention relates to new histamine-3 (H3) receptor subtype preferring ligands of formula (I) (as defined in the claims) and/or geometric isomers and/or stereoisomers and/or diastereoisomers and/or salts and/or hydrates and/or solvates thereof. The invention further relates to pharmaceutical compositions comprising such compounds and the use of these compounds in methods for treating or preventing of conditions which require modulation of histamine-3 (H3) receptors. The invention also provides a method for manufacturing medicaments useful in the treatment or prevention of such conditions.˙

Inventors:
SCHMIDT EVA (HU)
KISS BELA (HU)
MAHO SANDOR (HU)
LEDNECZKI ISTVAN (HU)
GABOR ESZTER (HU)
TAPOLCSANYI PAL (HU)
BALAZS OTTILIA (HU)
Application Number:
PCT/HU2012/000075
Publication Date:
February 28, 2013
Filing Date:
August 17, 2012
Export Citation:
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Assignee:
RICHTER GEDEON NYRT (HU)
SCHMIDT EVA (HU)
KISS BELA (HU)
MAHO SANDOR (HU)
LEDNECZKI ISTVAN (HU)
GABOR ESZTER (HU)
TAPOLCSANYI PAL (HU)
BALAZS OTTILIA (HU)
International Classes:
C07J41/00; A61K31/566
Foreign References:
US20060074060A12006-04-06
US20020143002A12002-10-03
US20040198711A12004-10-07
FR1338308A1963-09-27
US20050182038A12005-08-18
US20050227953A12005-10-13
Other References:
MICHIELS P J A ET AL: "Ligand-based NMR spectra demonstrate an additional phytoestrogen binding site for 17beta-hydroxysteroid dehydrogenase type 1", JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, ELSEVIER SCIENCE LTD., OXFORD, GB, vol. 117, no. 4-5, 1 November 2009 (2009-11-01), pages 93 - 98, XP026719207, ISSN: 0960-0760, [retrieved on 20090723], DOI: 10.1016/J.JSBMB.2009.07.004
CHEN ZHAO ET AL: "The Alkaloid Conessine and Analogues as Potent Histamine H3 Receptor Antagonists", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 51, no. 17, 11 March 2008 (2008-03-11), pages 5423 - 5430, XP008145593, ISSN: 0022-2623, DOI: 10.1021/JM8003625
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Attorney, Agent or Firm:
RICHTER GEDEON NYRT. (Budapest, HU)
Download PDF:
Claims:
CLAIMS

1. Compounds of formula (I)

(I)

wherein,

R ,R2, R3 ,R4 represent independently from each other:

hydrogen atom

or

C-I-C6 alkyl-group or C3-C7 cycloalkyl-group

or

R1 and R2 or R3 and R4 with the adjacent nitrogen atom form a 4- 10-membered, 1 or 2 ringed, saturated, heterocyclic group, which optionally contain one or two heteroatoms selected from O or S, selected independently from each other

and

optionally substituted by one or two oxo groups, one or two halogen atoms or one or two C C-6 alkyl groups, R5 and R6 collectively represent

oxo group

or

R5 is hydrogen atom and R6 is hydrogen atom or OR7, wherein R7 group is hydrogen atom or C1-C6 alkyl group

n is 0, 1 or 2,

m is 0 or 1.

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof.

2. Acid addition salts of the compounds of formula (I) according to Claim 1 formed with organic or inorganic acids.

3. Compounds of formula (I) according to Claim 1 characterized by that the carboxamide side chain containing the -NR3R4 group is bonded to the C15 carbon atom of the steroid structure. The meaning of the other substituents, n and m is as described above for formula (I) in Claim 1.

4. Compounds of formula (I) according to any of Claims 1-3, wherein R and R2 with the adjacent nitrogen atom form a 5-membered, optionally substituted heterocyclic group and n=1. The meaning of R3, R4, R5 ,R6 substituents and m is as described above for formula (I) in Claim 1.

5. Compounds of formula (I) according to any of Claims 1-4, wherein R1 and R2 with the adjacent nitrogen atom form a 5-membered heterocyclic group, which contains a methyl group at its 2nd position and n=1. The meaning of R3, R4, R5 ,R6 substituents and m is as described for formula (I) in Claim 1.

6. Compounds of formula (I) according to any of Claims 1-5, wherein R1 and R2 with the adjacent nitrogen atom form a 5-membered heterocyclic group, which contains a methyl group at its 2nd position and the configuration of the carbon atom at the 2nd position of the heterocyclic ring is R and n=1. The meaning of R3, R4, R5 ,R6 substituents and m is as described for formula (I) in Claim 1. 7. Compounds of formula (I) according to any of Claims 1-2, wherein R3 and R4 with the adjacent nitrogen atom form a 5-membered heterocyclic group and m=0. The meaning of R1, R2, R5 ,R6 substituents and n is as described for formula (I) in Claim 1. 8. Compounds of formula (I) according to any of Claims 1-2, wherein R3 represents hydrogen and R4 represents methyl or ethyl and m=0. The meaning of R1, R2, R5 ,R6 substituents and n is as described for formula (I) in Claim 1.

9. Compounds of formula (I) according to any of Claims 1 -5 or 7-8, wherein

R1 and R2 with the adjacent nitrogen atom form a 5-membered heterocyclic group, which contains a methyl group at its 2nd position;

R3 and R4 with the adjacent nitrogen atom form a 5-membered heterocyclic group or R3 represents hydrogen and R4 represents methyl or ethyl;

m=0, n=1.

The meaning of R5 and R6 substituents is as described for formula (I) in Claim

1.

10. Compounds of formula (I) according to any of Claims 1 -5 or 7 or 9, wherein

R1 and R2 with the adjacent nitrogen atom form a 5-membered heterocyclic group, which contains a methyl group at its 2nd position;

R3 and R4 with the adjacent nitrogen atom form a 5-membered heterocyclic group;

R5 and R6 collectively represent oxo group;

m=0, n=1.

11. Compounds of formula (I) according to any of Claims 1-5 or 8-9, wherein

R and R2 with the adjacent nitrogen atom form a 5-membered heterocyclic group, which contains a methyl group at its 2nd position;

R3 represents hydrogen,

R4 represents ethyl;

R5 represents hydrogen and R6 represents -OCH3;

m=0, n=1.

12. Compounds of formula (I) according to any of Claims 1-5 or 8-9, wherein

R1 and R2 with the adjacent nitrogen atom form a 5-membered heterocyclic group, which contains a methyl group at its 2nd position;

R3 represents hydrogen;

R4 represents ethyl;

R5 and R6 collectively represent oxo group;

m=0, n=1.

13. Compounds of formula (I) according to any of Claims 1 -5 or 8-9, wherein

R1 and R2 with the adjacent nitrogen atom form a 5-membered heterocyclic group, which contains a methyl group at its 2nd position;

R3 represents hydrogen;

R4 represents methyl;

R5 and R6 collectively represent oxo group;

14. Compounds of formula (I) according to any of Claims 1-5 or 8-9, wherein

R1 and R2 with the adjacent nitrogen atom form a 5-membered heterocyclic group, which contains a methyl group at its 2nd position;

R3 represents hydrogen;

R4 represents ethyl;

R5 and R6 collectively represent a hydrogen atom;

m=0, n=1.

15. A compound of formula (I) as in any of Claims 1-5 or 8-14 characterized by that R and R2 with the adjacent nitrogen atom form a 5-membered heterocyclic group, which contains a methyl group at its 2nd position and the configuration of the carbon atom at the 2nd position of the heterocyclic ring is R and

the carboxamide side chain containing the -NR3R4 group is bonded to the C15 carbon atom of the steroid structure.

16. A compound of any of Claims 1 -2 selected from the group of

(15a)-3-{3-[(2f?)-2-methylpyrrolidin-1 -yl]propoxy}-15-( pyrrol id in-1 -ylcarbonyl)estra

1 ,3,5(10)-trien-17-on;

(15a, 17p)-A/-ethyl-3-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}-17-methoxyestra- 1 ,3,5(10)-triene-15-carboxamide;

(15a)-A/-ethyl-3-{3-[(2S)-2-methylpyrrolidin-1 -yl]propoxy}-17-oxoestra-1 ,3,5(10)- triene-15-carboxamide; (15a)-/V-ethyl-3-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}-17-oxoestra-1 ,3,5(10)- triene-15-carboxamide;

(15oc)-3-[3-(1 ,4-dioxa-8-azaspiro[4.5]dec-8-yl)propoxy]-A/-ethyl-17-oxoestra-1 ,3,5(10)- triene-15-carboxamide;

(15a)-/V-ethyl-3-{3-[(3R)-3-fluoropyrrolidin-1 -yl]propoxy}-17-oxoestra-1 ,3,5(10)-triene- 15-carboxamide;

(15a)-/V-ethyl-3-[3-(4-fluoropiperidine-1-yl)propoxy]- 7-oxoestra-1 ,3,5(10)-triene- 5- carboxamide;

(15a)-/V-ethyl-3-[3-(4,4-difluoropiperidine-1-yl)propoxy]-17-oxoestra-1 , 3,5(10)-triene- 15-carboxamide;

(15a)-/V-ethyl-3-{2-[(2 )-2-methylpyrrolidin-1-yl]etoxy}-17-oxoestra-1 ,3,5(10)-triene- 5-carboxamide;

(15a)-A/-ethyl-3-{4-[(2R)-2-methylpyrrolidin-1 -yl]butoxy}-17-oxoestra-1 ,3,5(10)-triene- 15-carboxamide;

(15a)-A/-methyl-3-{3-[(2f?)-2-methylpyrrolidin-1-yl]propoxy}-17-oxoestra-1 ,3,5(10)- triene-15-carboxamide;

(15p)-A/-ethyl-3-{3-[(2f?)-2-methylpyrrolidin-1-yl]propoxy}-17-oxoestra-1 , 3,5(10)- triene-15-carboxamide;

(15a)-/V-ethyl-3-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}estra- ,3,5( 0)-triene-15- carboxamide;

(15a)-/V-cyclopropyl-3-{3-[(2R)-2-methylpyrrolidin-1 -yl]propoxy}estra-1 ,3,5(10)-triene- 15-carboxamide;

(15a)-/V-cyclobutyl-3-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}estra-1 , 3,5(10)-triene- 15-carboxamide;

(16a,17p)-A/-methyl-3-{3-[(2R)-2-methylpyrrolidin-1 -yl]propoxy}-17-methoxyestra- 1 ,3,5( 0)-triene-16-carboxamide;

(16β,17 )-/V-methyl-3-{3-[(2R)-2-methylpyrrolidin-1 -yl]propoxy}-17-methoxyestra- 1 ,3,5(10)-triene-16-carboxamide;

(15a)-3-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}-17-oxoestra-1 ,3,5(10)-triene-15- carboxamide;

(15a,17p)-3-{3-[(2R)-2-methylpyrrolidin-1 -yl]propoxy}-15-(pyrrolidin-1 - ylcarbonyl)estra-1 ,3,5(10)-trien-17-ol; (15 ,17 )-/V-ethyl-3-[3-(4-fluoropiperidin-1-yl)propoxy]-17-hydroxyestra-1 ,3,5(10)- triene-15-carboxamide;

(15a)-A/,A/-diethyl-3-{3-[(2R)-2-methylpyrrolidin-1 -yl]propoxy}-17-oxoestra-1 ,3,5(10)- triene-15-carboxamide hydrochloride;

(15a)-A/-ethyl-3-{3-[(3R)-3-fluoropyrrolidinium-1 -yl]propoxy}-17-oxoestra-1 ,3,5(10)- triene-15-carboxamide (2E)-3-carboxyprop-2-enoate;

(15a)-3-[3-(3, 3-d ifluoropyrrolidinium-1-yl)propoxy]-/\/-ethyl-17-oxoestra-1 ,3,5(10)- triene-15-carboxamide chloride;

(15a)-A/-ethyl-3-[3-(4-fluoropiperidinium-1-yl)propoxy]-17-oxoestra-1 ,3,5(10)-triene- 15-carboxamide bromide;

(15a)-3-[3-(4,4-difluoropiperidinium-1-yl)propoxy]-/V-ethyl-17-oxoestra-1 ,3,5(10)- triene-15-carboxamide 3,4-dicarboxy-3-hydroxybutanoate;

(15a, 17β)-15-[2-(ethylamino)-2-oxoethyl]-17-methoxy-3-{3-[(2R)-2-methylpyrrolidin-1 - yl]propoxy}estra-1 ,3,5(10)-triene chloride.

17. Compounds of formula (II),

(II)

wherein

R8 represents hydrogen atom or benzyl or C2-C haloalkyl;

Y represents hydroxyl or -NR3R4 group.

The meaning of R3, R4, R5 ,R6 substituents and m is as described for formula (I) in Claim 1.

18. Compounds of formula (II) according to Claim 17, wherein

R8 represents benzyl;

Y represents hydroxyl; The meaning of R5 ,R6 substituents and m is as described for formula (I) in Claim 1.

19. Compounds of formula (II) according to Claim 17, wherein

R8 represents benzyl;

Y represents NR3R4;

The meaning of R3, R4, R5 ,R6 substituents and m is as described for formula (I) in Claim 1. 20. Compounds of formula (II) according to Claim 17, wherein

R8 represents hydrogen atom;

Y represents NR3R4;

The meaning of R3, R4, R5 ,R6 substituents and m is as described for formula (I) in Claim 1.

21. Compounds of formula (II) according to Claim 17, wherein

R8 represents C2-C4 haloalkyl;

Y represents NR3R4;

The meaning of R3, R4, R5 ,R6 substituents and m is as described for formula (I) in Claim 1.

22. A compound of Claim 17 selected from the group of

( 15a)-3-( benzyloxy)- 17-oxoestra- 1 ,3,5(10)-triene- 15-ca rboxyl ic acid ;

(15a, 17P)-3-(benzyloxy)-17-methoxyestra-1 ,3,5(10)-triene-15-carboxylic acid;

(153)-3-(benzyloxy)-17-oxoestra-1 ,3,5(10)-triene-15-carboxylic acid;

(15a)-3-(benzyloxy)estra-1 ,3,5(10)-triene- 5-carboxylic acid;

[(17 )-3-(benzyloxy)-17-methoxyestra-1 ,3,5(10)-trien-15-yl]-acetic acid;

(17 )-3-(benzyloxy)-17-methoxyestra-1 ,3,5(10)-triene-16-carboxylic acid;

(15a)-3-(benzyloxy)-15-( pyrrol id in-1 -ylcarbonyl)estra-1 ,3,5(10)-trien- 7-on;

(15a, 17P)-3-(benzyloxy)-A/-ethyl-17-methoxyestra- ,3,5(10)-triene-15-carboxamide;

(15a)-3-(benzyloxy)-/V,/V-diethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide;

(15a)-3-(benzyloxy)-/\/-ethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide; (15a)-3-(benzyloxy)-/V-methyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide;

(15p)-3-(benzyloxy)-/V-ethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide;

(15a)-3-(benzyloxy)-A/-ethylestra-1 ,3,5(10)-triene-15-carboxamide;

(15a)-3-(benzyloxy)-/V-cyclopropylestra-1 ,3,5(10)-triene-15-carboxamide;

(15a)-/V-cyclobutyl-3-hydroxyestra-1 ,3,5(10)-triene-15-carboxamide;

(15a, 17 )-3-(benzyloxy)-15-[2-(ethylamino)-2-oxoethyl]-17-methoxyestra-1 ,3,5(10)- triene;

(16a,17 )-3-(benzyloxy)-/V-methyl-17-methoxyestra-1 ,3,5(10)-triene-16-carboxamide;

(16 ,17p)-3-(benzyloxy)-A/-methyl-17-methoxyestra-1 ,3,5(10)-triene-16-carboxamide; (15a)-3-(benzyloxy)-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide;

(15a)-3-hydroxy-15-(pyrrolidin-1 -ylcarbonyl)estra-1 ,3,5(10)-trien-17-on;

(15a, 17 )-A/-ethyl-3-hydroxy-17-methoxyestra-1 ,3,5(10)-triene-15-carboxamide;

(15a)-/V,/V-diethyl-3-hydroxy-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide;

(15a)-/V-ethyl-3-hydroxy- 7-oxoestra-1 ,3,5( 0)-triene- 5-carboxamide;

(15a)-3-hydroxy-A/-methyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide;

(15p)-/V-ethyl-3-hydroxy-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide;

(15a)-/V-ethyl-3-hydroxyestra-1 ,3,5(10)-triene-15-carboxamide;

(15a)-/V-cyclopropyl-3-hydroxyestra-1 ,3,5(10)-triene-15-carboxamide;

(15a)-/V-cyclobutyl-3-hydroxyestra-1 ,3,5(10)-triene-15-carboxamide;

( 5α,17β)- 5-[2-(ethylamino)-2-oxoethyl]-3-hydroxy-17-methoxyestra-1 ,3,5(10)-trien-

3-ol;

(16a, 17 )-3-hydroxy-A/-methyl-17-methoxyestra-1 ,3,5(10)-triene-16-ca rboxamide; (16 ,17P)-3-hydroxy-A/-methyl-17-methoxyestra-1 ,3,5(10)-triene-16-carboxamide; (15a)-3-hydroxy-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide;

(15a)-3-(3-bromopropoxy)-15-(pyrrolidin-1 -ylcarbonyl)estra-1 ,3,5(10)-trien-17-on; (15a, 17 )-3-(3-bromopropoxy)-A/-ethyl-17-methoxyestra-1 ,3,5(10)-triene-15- carboxamide;

(15a)-3-(3-bromopropoxy)-/V,/V-diethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide; (15a)-3-(3-bromopropoxy)-A/-ethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide; (15a) 3-(2-bromoethoxy)-A/-ethyl-17-oxoestra-1 , 3, 5(10)-triene-15-carboxamide;

(15a)-3-(4-bromobutoxi)-A/-ethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide;

(15a)-3-(3-bromopropoxy)-/V-methyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide; (15p)-3-(3-bromopropoxy)-/V-ethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide; (15a)-3-(3-bromopropoxy)-/V-ethylestra-1 ,3,5(10)-triene-15-carboxamide;

(15a)-3-(3-bromopropoxy)-/V-cyclopropylestra-1 ,3,5(10)-triene-15-carboxamide;

(15a)-3-(3-bromopropoxy)-A/-cyclobutylestra-1 ,3,5(10)-triene-15-carboxamide;

(15a,17P)-3-(3-bromopropoxy)-15-[2-(ethylamino)-2-oxoethyl]-17-methoxyestra- 1 ,3,5(10)-triene;

(16a, 7 )-3-(3-bromopropoxy)-/V-methyl- 7-methoxyestra-1 ,3,5(10)-triene-16- carboxamide;

(16β, 17p)-3-(3-bromopropoxy)-/V-methyl- 7-methoxyestra- ,3,5(10)-triene- 6- carboxamide;

(15oc)-3-(3-bromopropoxy)-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide.

23. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as claimed in any of Claims 1 -16 and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof as active ingredients and pharmaceutically acceptable auxiliary materials.

24. Pharmaceutical composition according to claim 23 for the treatment and/or prevention of conditions which require modulation of histamine H3 receptor functions.

25. Pharmaceutical composition according to claim 24, characterized by that the composition contains a compound of formula (I) which has histamine H3 receptor antagonist or inverse agonist effect.

26. The pharmaceutical composition according to any of Claims 23-25 for the treatment and/or prevention of cognitive disorders associated with neurodegenerative diseases (e.g. Alzheimer's disease) or age-associated learning and mental disorders or other cognitive disorders due to general medical conditions (e.g. attention-deficit hyperactivity disorder (ADHD) or Huntington disease), psychotic disorders (e.g. schizoaffective disorders or schizophrenia), sleep disorders (e.g. narcolepsy, EDS, somnolence or hypersomnia), eating disorders, obesity, obesity related metabolic disorders (e.g. hyperlipidemia, diabetes), dizziness, epilepsy, anxiety disorders (e.g. generalized anxiety disorder, panic disorder, post traumatic stress disorder (PTSD), or social anxiety disorder), mood adjustment disorders (e.g. depressed mood, mixed anxiety with depressed mood), disturbances of the central nervous system (e.g. agitation or depression), other central nervous system (CNS) disorders (such as schizophrenia), allergy, congestion (e.g. nasal congestion), hypotension, cardiovascular diseases, inflammatory pain, other pain induced disorders (e.g. neuropathic pain), drug (e.g. alcohol, cocaine, nicotine, opioids) abuse, irritable bowel syndrome and osteoarthritis.

27. The use of a compound of formula (I) as claimed in any of claims 1-16 and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof in the manufacture of a medicament.

28. The use according to Claim 27 characterized by manufacturing of a medicament for the treatment and/or prevention of conditions which require modulation of histamine H3 receptor functions. 29. The use according to any of Claims 27-28 in the manufacture of a medicament for the treatment and/or prevention of cognitive disorders associated with neurodegenerative diseases (e.g. Alzheimer's disease) or age-associated learning and mental disorders or other cognitive disorders due to general medical conditions (e.g. attention-deficit hyperactivity disorder (ADHD) or Huntington disease), psychotic disorders (e.g. schizoaffective disorders or schizophrenia), sleep disorders (e.g. narcolepsy, EDS, somnolence or hypersomnia), eating disorders, obesity, obesity related metabolic disorders (e.g. hyperlipidemia, diabetes), dizziness, epilepsy, anxiety disorders (e.g. generalized anxiety disorder, panic disorder, post traumatic stress disorder (PTSD), or social anxiety disorder), mood adjustment disorders (e.g. depressed mood, mixed anxiety with depressed mood), disturbances of the central nervous system (e.g. agitation or depression), other central nervous system (CNS) disorders (such as schizophrenia), allergy, congestion (e.g. nasal congestion), hypotension, cardiovascular diseases, inflammatory pain, other pain induced disorders (e.g. neuropathic pain), drug {e.g. alcohol, cocaine, nicotine, opioids) abuse, irritable bowel syndrome and osteoarthritis. 30. Method of treating and/or preventing of a condition which requires modulation of histamine H3 receptor characterized by administering an effective amount of a compound of formula (I) as claimed in any of Claims 1 -16 and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof to the mammal to be treated.

31. Method in accordance with claim 30 for the treatment and/or prevention of cognitive disorders associated with neurodegenerative diseases (e.g. Alzheimer's disease) or age-associated learning and mental disorders or other cognitive disorders due to general medical conditions (e.g. attention-deficit hyperactivity disorder (ADHD) or Huntington disease), psychotic disorders (e.g. schizoaffective disorders or schizophrenia), sleep disorders (e.g. narcolepsy, EDS, somnolence or hypersomnia), eating disorders, obesity, obesity related metabolic disorders (e.g. hyperlipidemia, diabetes), dizziness, epilepsy, anxiety disorders (e.g. generalized anxiety disorder, panic disorder, post traumatic stress disorder (PTSD), or social anxiety disorder), mood adjustment disorders (e.g. depressed mood, mixed anxiety with depressed mood), disturbances of the central nervous system (e.g. agitation or depression), other central nervous system (CNS) disorders (such as schizophrenia), allergy, congestion (e.g. nasal congestion), hypotension, cardiovascular diseases, inflammatory pain, other pain induced disorders (e.g. neuropathic pain), drug (e.g. alcohol, cocaine, nicotine, opioids) abuse, irritable bowel syndrome and osteoarthritis.

Description:
Histamine H 3 antagonist steroidal carboxamides

FIELD OF THE INVENTION

The present invention relates to new histamine-3 (H 3 ) receptor subtype preferring ligands of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereoisomers and /or salts and/or hydrates and/or solvates thereof. The invention further relates to pharmaceutical compositions comprising such compounds and the use of these compounds in methods for treating or preventing of conditions which require modulation of histamine-3 (H 3 ) receptors. The invention also provides a method for manufacturing medicaments useful in the treatment or prevention of such conditions.

BACKGROUND OF THE INVENTION

Histamine has long been known to trigger allergic reactions and gastric acid secretion. However, it was later discovered that, in the brain, histamine has neurotransmitter roles and regulates basic homeostatic and higher functions, including cognition, arousal, circadian rhythms and feeding behaviour. The sole source of brain histamine are the neurons localized in the hypothalamic tuberomamillary nuclei. These neurons sending axons to several parts of the brain are organized into functionally distinct circuits influencing different brain regions and exert selective control mechanisms.

Histamine is an important biogenic amine that modulates many physiological responses in humans. Its biological actions are mediated via four histamine receptors named H^ H 2 , H3 and H 4 , a classification based on their sequence, their link to differential intracellular signalling mechanisms and their unique pharmacological profile (Haas and Panula, Nat Rev Neurosci (2003) 4:121-130; Leurs et al., Nat Rev Drug Discov (2005) 4:107-120; Esbenshade et al., Br J Pharmacol (2008) 154(6):1 166-1 181 ).

The Hi and H 2 receptors are druggable targets as indicated by the efficacy of their antagonists in the treatment of allergy and ulcers, respectively. The role of the H 4 receptors is unclear at the present time, although preclinical evidence suggests a potential role in inflammation and pain processes. The histamine H3 receptor acts as both an autoreceptor controlling the synthesis and release of the endogenous agonist, histamine (Arrang et al., Nature (1983) 302: 832-837), and importantly, can also function as a heteroreceptor which regulates the release of other key neurotransmitters such as acetylcholine, norepinephrine, serotonin and dopamine. These latter neurotransmitters also play critical roles in cognitive processes (Schlicker et al., Naunyn Schmiedeberg's Arch Pharmacol (1988) 337:588-590, Schlicker et al., J. Neural Transm Gen Sect (1993) 93:1-10, Schlicker et al., Naunyn Schmiedeberg's Arch Pharmacol (1989) 340:633- 638, Clapham and Kilpatrick, Br. J. Pharmacol.(1992) 107:919-923, Blandina et al., Br. J. Pharmacol. (1996) 1 19: 1656-1664).

Histamine H 3 receptors are also implicated in regulation of feeding behaviour. Selective antagonists/inverse agonists of histamine H 3 receptors have been found to influence food consumption and body weight control (Passani et al., J Pharmacol Exp Ther (2011 ) 336, 24-29).

Antagonists/inverse agonists of the histamine H3 receptors increase synthesis and release of cerebral histamine and, through this mechanism, that of other monoamines. Histamine H 3 antagonists promote waking, improve cognitive function and they induce the normalization of vestibular reflexes. Histamine H 3 receptor antagonists/inverse agonists, through disinhibition of H 3 autoreceptors, enhance synaptic histamine release that in turn activates postsynaptic Hi receptors and promotes waking. The wake-promoting property of H 3 receptor antagonists/inverse agonists most likely depends on H 3 autoreceptor-mediated modulation of histaminergic neurotransmission. Procognitive activity of H 3 antagonists/inverse agonists seems to involve effects at not only histaminergic but also other (e.g. cholinergic, noradrenergic, dopaminergic, glutamatergic) neurotransmitter systems which also play important roles in cognition. (Khateb et al., Neuroscience (1995) 69(2):495-506; Lin et al., J Neurosci (1996) 16(4): 1523-1537; Passani et al., Trends Pharmacol Sci (2004) 25:618-625; Jones, Trends Pharmacol Sci (2005) 26:578-586; Bonaventure et al., Biochem Pharmacol (2007) 73:1084-1096; Ligneau et al., Biochem Pharmacol (2007) 73:1215-1224; Parmentier et al., Biochem Pharmacol (2007) 73:1157-1 171 ; Haas et al., Physiol Rev (2008) 88:1 183-1241 ). The naturally occurring steroid-based alkaloid, conessine was discovered to bind to both rat and human H 3 receptors with high affinity and selectivity compared with other (e.g. Hi, H 2 and H 4 ) histamine receptors (C. Zhao, M. Sun, M.D. Cowart, Y.L. Bennani Azacyclosteroid Histamine-3 receptor ligands, US2005/0227953 A1 , et al., J. Med. Chem. (2008), 51 :5423-5430). On the other hand, its relatively high affinity for human alpha 2c adrenergic receptors has also been described (Zhao et al., J. Med. Chem. (2008), 51 :5423-5430). Since alpha 2c adrenergic receptors are involved in blood pressure regulation such affinity may cause side effects (Li et al., Hypertension (2006) 47:1140-1146; De Luca et al., Pharmacol Res (2005) 51(4):381- 384).

Modification based on introducing diversity at position 3 with amide formation resulted analogues, which displayed decreased adrenergic receptor binding, although this affinity can not be eliminated. Furthermore, some synthetic conessine analogue showed strong affinity to muscarinic (Mi) receptors (Zhao et al., J Med Chem (2008) 51 -.5423-5430).

Elimination of the above unfavourable properties from the molecule is a challenging synthetic task considering the complicated structure of conessine (Stork et al., J Am Chem Soc (1962) 84:2018-2020). The invention

Our aim was to synthetize steroid-based structures as potential H3 antagonists or inverse agonists, which are more simple and easy to be modified than conessine and also possess higher chemical flexibility and display highly selective binding to histamine H3 receptors.

Surprisingly, it has been found that in contrast to the compounds described above, the compounds we synthetized exhibited no affinity to different steroidal, muscarinic or adrenergic receptors, however showed high affinity and selectivity for histamine H 3 receptors.

Due to the high histamine H3 receptor affinity and selectivity the pharmacological effects and expected side effect profile of these compounds might be more favourable. A number of diseases may be treated with histamine-^ receptor ligands wherein the H3 ligand may be an antagonist or inverse agonist.

The histamine H 3 receptor antagonists/inverse agonists of the present invention are useful for treating age-associated learning and mental disorders, including Alzheimer's disease, or other cognitive disorders due to general medical conditions (e.g. attention-deficit hyperactivity disorder (ADHD) or Huntington disease), psychotic disorders (e.g. schizoaffective disorders or schizophrenia), sleep disorders (e.g. narcolepsy, excessive day time sleeping in Parkinson's disease, somnolence or hypersomnia), eating disorders, obesity, obesity related metabolic disorders (e.g. hyperlipidemia, diabetes), dizziness and epilepsy.

The histamine H3 receptor antagonists/inverse agonists of the present invention are useful for treating anxiety disorders (e.g. generalized anxiety disorder, panic disorder, post traumatic stress disorder (PTSD), or social anxiety disorder), mood adjustment disorders (e.g. depressed mood, mixed anxiety with depressed mood), disturbances of the central nervous system (e.g. agitation or depression), and other central nervous system (CNS) disorders (such as schizophrenia).

The histamine H3 receptor antagonists/inverse agonists of the present invention are useful for treating, for example allergy, congestion (e.g. nasal congestion), hypotension, cardiovascular disease, inflammatory pain, other pain induced disorders (e.g. neuropathic pain), drug (e.g. alcohol, cocaine, nicotine, opioids) abuse, irritable bowel syndrome and osteoarthritis.

The histamine-H3 receptor antagonist/inverse agonist compounds of the present invention useful for treating the conditions listed in the preceding paragraphs are highly selective for the H 3 receptor (vs. other histamine receptors, H-i , H 2 and H 4 ).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the compounds of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof,

wherein,

R 1 ,R 2 , R 3 ,R 4 represent independently from each other:

hydrogen atom

or

C1-C6 alkyl-group or C3-C7 cycloalkyl-group

or

R 1 and R 2 or R 3 and R 4 with the adjacent nitrogen atom form a 4- 10-membered, 1 or 2 ringed, saturated, heterocyclic group, which optionally contain one or two heteroatoms selected from O or S, selected independently from each other

and

optionally substituted by one or two oxo groups, one or two halogen atoms or one or two C1-C6 alkyl groups, R 5 and R 6 collectively represent

oxo group

or

R 5 is hydrogen atom and R 6 is hydrogen atom or OR 7 , wherein R 7 group is hydrogen atom or C1-C6 alkyl group

n is 0, 1 or 2,

m is 0 or 1. The term "C-1-C6 alkyl" as used herein refers to branched or straight chain alkyl groups comprising one to six carbon atoms.

The term "C3-C7 cycloalkyl" as used herein refers to carbocyclic groups of 3 to 7 carbons, respectively; for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "halogen" or "halo" as used herein alone or as a part of another group refers to chlorine, bromine, fluorine and iodine.

Both organic and inorganic acids can be used for the formation of acid addition salts. Suitable inorganic acids include, but are not limited to, hydrochloric acid, sulphuric acid, nitric acid and phosphoric acid. Representatives of monovalent organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, and different butyric acids, valeric acids and capric acids. Representatives of bivalent organic acids include, but are not limited to, oxalic acid, malonic acid, maleic acid, fumaric acid and succinic acid. Other organic acids can also be used, such as hydroxy acids, for example, citric acid, tartaric acid, or aromatic carboxylic acids, for example, benzoic acid or salicylic acid, as well as aliphatic and aromatic sulfonic acids, for example, methanesulfonic acid, naphtalenesulfonic acid and p- toluenesulfonic acid.

A preferred group of acid addition salts are those in which the acid component itself is pharmaceutically acceptable and does not have a therapeutic effect in the applied dose and/or it does not have unfavourable influence on the effect of the active ingredient. These acid addition salts are pharmaceutically acceptable acid addition salts. Acid addition salts which are not pharmaceutically acceptable acid addition salts can be advantageous in the purification and isolation of the desired compounds of formula (I), and are therefore also included within the scope of the present invention.

Solvates and/or hydrates of compounds of formula (I), as well as solvates and/or hydrates of salts of compounds of formula (I) are also included within the scope of the present invention. Included within the scope of the present invention are all stereoisomers, geometric isome a (I)

- wherein the meaning of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n and m is as described above for the formula (I) - including also compounds exhibiting more than one type of isomerism and mixtures of one or more thereof.

Preferred compounds of the invention are those compounds of formula (I), wherein the carboxamide side chain containing the -NR 3 R 4 group is bonded to the C15 carbon atom of the steroid structure. The meaning of the other substituents, n and m is as described above for the formula (I).

Preferred compounds of the invention are those compounds of formula (I), wherein R 1 and R 2 with the adjacent nitrogen atom form a 5-membered, optionally substituted heterocyclic group and n=1. The meaning of R 3 , R 4 , R 5 ,R 6 substituents and m is as described above for the formula (I).

Further preferred compounds of the invention are those compounds of formula (I), wherein R 1 and R 2 with the adjacent nitrogen atom form a 5-membered heterocyclic group, which contains a methyl group at its 2nd position and n=1. The meaning of R 3 , R 4 , R 5 ,R 6 substituents and m is as described above for the formula (I). Further preferred compounds of the invention are those compounds of formula

(I), wherein R 1 and R 2 with the adjacent nitrogen atom form a 5-membered heterocyclic group, which contains a methyl group at its 2nd position and the configuration of the carbon atom at the 2nd position of the heterocyclic ring is R and n=1. The meaning of R 3 , R 4 , R 5 ,R 6 substituents and m is as described above for the formula (I).

Preferred compounds of the invention are those compounds of formula (I), wherein R 3 and R 4 with the adjacent nitrogen atom form a 5-membered heterocyclic group and m=0. The meaning of R 1 , R 2 , R 5 ,R 6 substituents and n is as described above for the formula (I).

Further preferred compounds of the invention are those compounds of formula (I), wherein R 3 represents hydrogen and R 4 represents methyl or ethyl and m=0. The meaning of R 1 , R 2 , R 5 ,R 6 substituents and n is as described above for the formula

(I)-

Another preferred compounds of the invention are those compounds of formula (I), wherein

R 1 and R 2 with the adjacent nitrogen atom form a 5-membered heterocyclic group, which contains a methyl group at its 2nd position;

R 3 and R 4 with the adjacent nitrogen atom form a 5-membered heterocyclic group or R 3 represents hydrogen and R 4 represents methyl or ethyl;

m=0, n=1.

The meaning of R 5 and R 6 substituents is as described above for the formula

(I)-

Another preferred compounds of the invention are those compounds of formula (I), wherein

R 1 and R 2 with the adjacent nitrogen atom form a 5-membered heterocyclic group, which contains a methyl group at its 2nd position;

R 3 and R 4 with the adjacent nitrogen atom form a 5-membered heterocyclic group;

R 5 and R 6 collectively represent oxo group;

m=0, n=1. Particularly preferred compounds of the invention are those compounds of formula (I), wherein

R 1 and R 2 with the adjacent nitrogen atom form a 5-membered heterocyclic group, which contains a methyl group at its 2nd position;

R 3 represents hydrogen, R 4 represents ethyl, R 5 represents hydrogen and R 6 represents -OCH3;

Further particularly preferred compounds of the invention are those compounds of formula (I), wherein

R 1 and R 2 with the adjacent nitrogen atom form a 5-membered heterocyclic group, which contains a methyl group at its 2nd position;

R 3 represents hydrogen, R 4 represents ethyl;

R 5 and R 6 collectively represent oxo group;

m=0, n=1.

Further particularly preferred compounds of the invention are those compounds of formula (I), wherein

R 1 and R 2 with the adjacent nitrogen atom form a 5-membered heterocyclic group, which contains a methyl group at its 2nd position;

R 3 represents hydrogen, R 4 represents methyl;

R 5 and R 6 collectively represent oxo group;

m=0, n=1.

Further particularly preferred compounds of the invention are those compounds of formula (I), wherein

R 1 and R 2 with the adjacent nitrogen atom form a 5-membered heterocyclic group, which contains a methyl group at its 2nd position;

R 3 represents hydrogen, R 4 represents ethyl;

R 5 and R 6 collectively represent a hydrogen atom; Further particularly preferred compounds of the invention are those compounds of formula (I), wherein

R 1 and R 2 with the adjacent nitrogen atom form a 5-membered heterocyclic group, which contains a methyl group at its 2nd position and the configuration of the carbon atom at the 2nd position of the heterocyclic ring is R;

the carboxamide side chain containing the -NR 3 R 4 group is bonded to the C15 carbon atom of the steroid structure.

The meaning of the other substituents, n and m is as described above for the formula (I).

The present invention relates to the compounds and salts of formulas I-A and l-B according to formula (I) depending on the position of the carboxamide side chain - wherein the meaning of R 1 , R 2 , R 3 , R 4 , R 5 ,R 6 substituents, n and m is as described above for the formula (I).

As a further aspect of the present invention there is provided the synthesis of compounds of formula (I).

I-A l-B

Compounds in accordance with the present invention were synthetized with the synthetic routes and schemes described in the following paragraphs. Accordingly, the compounds of formulas l-A and l-B of the invention can be synthetized by the following methods (the meaning of groups, substituents and other markers is as described above for the formula (I), Hal represents halogen atom):

(II-;

(I)

Reaction stage„e": salt formation Reaction stage„a"

Reacting the intermediates of formula ll-a with organic or inorganic acid halids (e.g. oxalyl chloride) in the presence of catalytic amounts of /V,A/-dimethylformamide in an inert solvent (preferably in dichloromethane) under water-free conditions; reacting the obtained carboxylic acid halide intermediate compounds with amines or optionally with amines in situ released from amine salts.

Reaction stage„b"

Reductive debenzylation of the intermediates of formula ll-b in alcoholic solvent in the presence of catalyst with hydrogen or a reagent capable of releasing hydrogen atom. Reaction stage„c"

Reacting the intermediates of formula ll-c in an inert solvent (preferably in tetrahydrofuran) in the presence of alkali hydroxide with α,ω-dihalo-alkanes. Reaction stage„d"

Reacting the intermediates of formula ll-d in an inert solvent (preferably in tetrahydrofurane or ethanol) with an amine, obtaining the compound after chromatographic purification. In case an oxo group is bonded to the C17 carbon atom, then a reducing agent - preferably sodium tetrahydridoborate - can transform it to the 17-hydroxy compound.

Reaction stage„e": salt formation Dissolving the compounds of formula (I) obtained in reaction stage„d" in a polar solvent, adding equimolar amounts of acid and removing the solvent by evaporation. The present invention also relates to the compounds of formula (II),

(ID

wherein

R 8 represents hydrogen atom or benzyl or C2-C 4 haloalkyl;

Y represents hydroxyl or -NR 3 R 4 group.

The meaning of R 3 , R 4 , R 5 ,R 6 substituents and m is as described above for the formula (I).

A smaller group of the compounds of formula (II) of the present invention is represented by the compounds of formula ll-a. The meaning of R 5 ,R 6 substituents and m is as described above for formula (I). Another smaller group of the compounds of formula (II) of the present invention is represented by the compounds of formula ll-b. The meaning of R 3 , R 4 , R 5 ,R 6 substituents and m is as described above for formula (I).

A further smaller group of the compounds of formula (II) of the present invention is represented by the compounds of formula ll-c. The meaning of R 3 , R 4 , R 5 ,R 6 substituents and m is as described above for formula (I).

Another smaller group of the compounds of formula (II) of the present invention is represented by the compounds of formula ll-d. The meaning of R 3 , R 4 , R 5 ,R 6 substituents and m is as described above for formula (I). For use in medicine, the compounds of formula (I) of the present invention and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof are usually administered as a standard pharmaceutical composition. The present invention therefore provides in a further aspect pharmaceutical compositions comprising a new compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof and one or more pharmaceutically acceptable carrier(s).

The present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a new compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof and one or more pharmaceutically acceptable carrier(s) for the treatment and/or prevention of conditions which require the modulation histamine H 3 receptors.

The pharmaceutical compositions of the present invention most preferably contain compounds with H 3 receptor antagonist or inverse agonist effect of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof.

The present invention also provides in a further aspect pharmaceutical compositions containing a new compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof, which would be effective in the treatment and/or prevention of age-associated cognitive dysfunction, learning and mental disorders (e.g. Alzheimer's disease) or other cognitive disorders due to general medical conditions (e.g. attention-deficit hyperactivity disorder (ADHD) or Huntington disease), psychotic disorders (e.g. schizoaffective disorders or schizophrenia), sleep disorders (e.g. narcolepsy, excessive day time sleeping in Parkinson's disease (EDS), somnolence or hypersomnia), eating disorders, obesity, obesity related metabolic disorders (e.g. hyperlipidemia, diabetes), dizziness, epilepsy, anxiety disorders (e.g. generalized anxiety disorder, panic disorder, post traumatic stress disorder (PTSD), or social anxiety disorder), mood adjustment disorders (e.g. depressed mood, mixed anxiety with depressed mood), disturbances of the central nervous system (e.g. agitation or depression), other central nervous system (CNS) disorders (such as schizophrenia), allergy, congestion (e.g. nasal congestion), hypotension, cardiovascular diseases, inflammatory pain, other pain induced disorders (e.g. neuropathic pain), drug (e.g. alcohol, cocaine, nicotine, opioids) abuse, irritable bowel syndrome and osteoarthritis.

In a further aspect the present invention also relates to the use of a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof in the manufacture of a medicament.

The present invention also provides the use of a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof in the manufacture of a medicament for the treatment and or prevention of conditions which require modulation of histamine H 3 receptor functions.

In a further aspect the present invention also provides the use of a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof in the manufacture of a medicament for the treatment and/ or prevention of age-associated cognitive dysfunctions, learning and mental disorders (e.g. Alzheimer's disease) or other cognitive disorders due to general medical conditions (e.g. attention-deficit hyperactivity disorder (ADHD) or Huntington disease), psychotic disorders (e.g. schizoaffective disorders or schizophrenia), sleep disorders (e.g. narcolepsy, excessive day time sleeping in Parkinson's disease (EDS), somnolence or hypersomnia), eating disorders, obesity, obesity related metabolic disorders (e.g. hyperlipidemia, diabetes), dizziness, epilepsy, anxiety disorders (e.g. generalized anxiety disorder, panic disorder, post traumatic stress disorder (PTSD), or social anxiety disorder), mood adjustment disorders (e.g. depressed mood, mixed anxiety with depressed mood), disturbances of the central nervous system (e.g. agitation or depression), other central nervous system (CNS) disorders (such as schizophrenia), allergy, congestion (e.g. nasal congestion), hypotension, cardiovascular diseases, inflammatory pain, other pain induced disorders (e.g. neuropathic pain), drug (e.g. alcohol, cocaine, nicotine, opioids) abuse, irritable bowel syndrome and osteoarthritis. The present invention also provides a method of treating and/or preventing conditions which require modulation of histamine H3 receptor functions comprising the administration to the mammal - including human - to be treated an effective amount of a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof as such or combined with pharmaceutically acceptable auxiliary materials like usually applied in pharmaceuticals.

In a further aspect, the present invention also provides a method of treating and/or preventing conditions which require modulation of histamine H3 receptor functions such as, but not limited to age-associated cognitive dysfunctions, learning and mental disorders (e.g. Alzheimer's disease) or other cognitive disorders due to general medical conditions (e.g. attention-deficit hyperactivity disorder (ADHD) or Huntington disease), psychotic disorders (e.g. schizoaffective disorders or schizophrenia), sleep disorders (e.g. narcolepsy, excessive day time sleeping in Parkinson's disease (EDS), somnolence or hypersomnia), eating disorders, obesity, obesity related metabolic disorders (e.g. hyperlipidemia, diabetes), dizziness, epilepsy, anxiety disorders (e.g. generalized anxiety disorder, panic disorder, post traumatic stress disorder (PTSD), or social anxiety disorder), mood adjustment disorders (e.g. depressed mood, mixed anxiety with depressed mood), disturbances of the central nervous system (e.g. agitation or depression), other central nervous system (CNS) disorders (such as schizophrenia), allergy, congestion (e.g. nasal congestion), hypotension, cardiovascular diseases, inflammatory pain, other pain induced disorders (e.g. neuropathic pain), drug (e.g. alcohol, cocaine, nicotine, opioids) abuse, irritable bowel syndrome and osteoarthritis, comprising the administration of an effective amount of a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof as such or combined with pharmaceutically acceptable auxiliary materials like usually applied in pharmaceuticals to the subject in need thereof.

The compounds of formula (I) of the present invention and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof may be administered by any convenient method, for example by oral, parental, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.

The compounds of formula (I) of the present invention and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, film-tablets, dragees, capsules and lozenges.

A liquid formulation of the compounds of formula (I) of the present invention and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof generally consists of a suspension or solution of the compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically salts and/or hydrates and/or solvates thereof in suitable liquid carrier(s), for example an aqueous solvent, such as water, ethanol or glycerol, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain one or more suspending agent, preservative, flavouring or colouring agent, or combinations thereof.

A composition in the solid form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose, cellulose, etc.

A composition in the solid form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatine capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatine capsule.

Parenteral compositions are typically a solution or suspension of the compound of formula (I) of the present invention and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

Compositions of the present invention for nasal administration containing a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof may conveniently be formulated as aerosols, drops, gels and powders. Compositions of the present invention containing a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier, such as sugar and acacia, tragacanth, or gelatine and glycerol etc.

Compositions of the present invention containing a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter.

Compositions of the present invention containing a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof for transdermal administration include ointments, gels and patches.

The above described ingredients and different routes of manufacture are merely representative. Other materials as well as processing techniques and the like well known in the art can also be used.

The pharmaceutically acceptable compounds of formula (I) of the present invention - wherein the meaning of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n and m is as described above for the formula (I)- and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof can normally be administered in a daily dosage regimen (for an adult patient) 1 to 4 times per day in case of all type of compositions, wherein each dosage unit may contain 0.05 to 2000 mg of a compound of formula (I) calculated as the free base. The compounds of the present invention can suitably be administered for a period of continuous therapy, for example for a week or more.

The present invention will be now illustrated by the following not limiting examples. The structures of all intermediates and end products were elucidated by N MR and MS spectroscopy.

Example 1

(15a)-3-(benzyloxy)-17-oxoestra-1 ,3,5(10)-triene-15-carboxylic acid

5.83 g (14.34 mmol) of (15a,17 )-3-(benzyloxy)-17-hydroxyestra-1 ,3,5(10)-triene-15- carboxylic acid (Labaree et al., J Med Chem, (2003) 46:1886-1904) was suspended in 120 ml of acetone, it was cooled down to 0°C, and approximately during 15 minutes 5 ml of Jones reagent was added. Afterwards, the dark green suspension was diluted with 45 ml of acetone. After cooling, the reaction mixture was stirred for an hour, then 10 ml of isopropyl alcohol was added and the mixture was stirred for 20 minutes. 200 ml of water and 150 ml of ethyl acetate were added, mixed, and the phases were separated. The aqueous phase was extracted with 2x100 ml of ethyl acetate, the combined organic layer was washed with 4x200 ml of water. The obtained solution was dried over anhydrous sodium sulfate and evaporated resulting in 4.90 g (84%) of crystalline title compound. Mp.: 205.8-206.4°C.

HNMR (800 MHz, CDCI 3 ): 0.97 s (3H, H 3 -18); 2.97 m (1 H, H-15); 5.02 s (2H, 3- OCHgPh); 6.70 d (1 H, H-4), 6.79 dd (1 H, H-2); 7.20 d (1 H, H-1 ); 10.43 br (COOH) 13 CNMR (200 MHz, CDCI 3 ): 14.9 (C-18); 40.9 (C-15); 69.9 (3-OCH 2 Ph); 112.6 (C-2); 1 14.7 (C-4); 126.6 (C-1 ); 156.9 (C-3); 181.4 (15-COOH); 216.1 (C-17);

MS: M + =404

Example 2

(15a,17P)-3-(benzyloxy)-17-methoxyestra-1 ,3,5(10)-triene-15-carboxylic acid

5.17 g (12.71 mmol) of (15a,17p)-3-(benzyloxy)-17-hydroxyestra-1 ,3,5(10)-triene-15- carboxylic acid (Labaree et al., J Med Chem, (2003) 46:1886-1904) was dissolved in 55 ml of A/,A/-dimethylformamide and while cooling 2.03 g (50.85 mmol) of sodium hydride (60% dispersion in mineral oil) was added at 20°C, under an inert atmosphere and the dense suspension was diluted with 25 ml of N,N- dimethylformamide. At +17°C 8.87 ml (142.5 mmol) of methyl iodide was added and the reaction mixture was stirred for 1.5 hours at room temperature. The mixture was diluted with 150 ml of dichloromethane and applying continuous stirring and cooling keeping the temperature at 20°C 300 ml of 5% hydrochloric acid was poured to it. After 10 minutes of stirring the phases were separated, the organic phase was washed until neutral with 4x250 ml of water. The solution was dried over anhydrous sodium sulfate and evaporated.

The methyl substituted derivative of the title compound was obtained by column chromatography using silica gel as adsorbent and cyclohexane : ethyl acetate = 8:1 as eluent. The fractions containing the title compound were evaporated to yield 5.1 g (92 %) of methyl [(15a, 17 )-3-(benzyloxy)-17-metoxyestra-1 , 3,5(10)- triene-15-carboxylate]. Mp.: 148-150°C.

HNMR (500 MHz, CDCI 3 ): 0.82 s (3H, H 3 -18); 3.37 s (3H, 17-OCH 3 ); 3.48 t (1 H, H- 17); 3.70 s (3H, 15-COOCH 3 ); 5.02 s (2H, 3-OCH 2 Ph);

13 CNMR (125 MHz, CDCI 3 ): 12.3 (C-18); 51.9 (15-COOCH 3 ); 58.0 (17-OCH 3 ); 69.9 (3-OCH 2 Ph); 88.9 (C-17); 178.1 (15-COOCH 3 );

MS: M + =434 The previously synthetised methyl [(15a,17P)-3-(benzyloxy)-17-methoxyestra- 1 ,3,5(10)-triene-15-carboxylate was converted to the title compound as follows:

4.94 g (11.37 mmol) of methyl [(15 a,17P)-3-(benzyloxy)-17-methoxyestra-1 ,3,5(10)- triene-15-carboxylate was suspended in 400 ml of ethanol and a solution of 12.92 g (230.26 mmol) of potassium hydroxide in 46 ml of water was added. After 7 hours of reflux, the reaction mixture was evaporated. The residue was dissolved in a mixture of 100 ml of water and 50 ml of 10% sodium hydroxide, and extracted with 100 ml of ethyl acetate. Afterwards, the aqueous phase was acidified with 82 ml of 10% hydrochloric acid solution and extracted with 1x350 ml and 2x150 ml of ethyl acetate. The combined organic phase was washed until neutral with 4x200 ml of water. After drying over anhydrous sodium sulfate, the solution was evaporated and crystallized from diisopropyl ether to yield 4.20 g (88%) of the title compound as white crystalline material. Mp.: 194-195°C. 1 HNMR (500 MHz, CDCI 3 ): 0.83 s (3H, H 3 -18); 2.67 m (1 H, H-15); 3.38 s (3H, 17- OCH 2 ); 5.02 s (2H, 3-OCH 2 Ph); 10.91 br (COOH);

13 CNMR (125 MHz, CDCI 3 ): 12.3 (C-18); 42.0 (C-15); 58.1 (17-OCH 3 ); 69.9 (3- OCH 2 Ph); 183.3 (15-COOH);

MS: M + =420

Example 3

(15P)-3-(benzyloxy)-17-oxoestra-1 ,3,5(10)-triene-15-carboxylic acid

10 g (27.90 mmol) of 3-(benzyloxy)estra-1 ,3,5(10),15-tetraene-17-one (Labaree et al., J Med Chem, (2003) 46:1886-1904) was dissolved in 200 ml of dimethyl sulfoxide and 16 ml (295.4 mmol) of nitromethane was added to the solution. Under an inert atmosphere, 9.0 g (65.1 mmol) of potassium carbonate was added and stirred at 40 °C for one hour. Then the mixture was poured into 1000 ml of 1 % hydrochloric acid solution at 0 °C. The precipitate was collected by filtration, washed with water until neutral and dried to yield 10.2 g (87%) of (15 )-3-(benzyloxy)-15- (nitromethyl)estra-l ,3,5(10)-trien-17-one.

1 HNMR (800 MHz, CDCI 3 ): 0.98 s (3H, H 3 -18); 3.23 m (1 H, H-15); 4.51 t (15- CH 2 NO 2 ); 4.58 dd (I 5-CH 2 NO 2 ), 5.04 s (2H, S-OCHgPh);

13 CNMR (200 MHz, CDCI 3 ): 17.2 (C-18); 33.3 (C-15); 41.0 (C-16); 69.9 (3-OCH 2 Ph); 77.4 (15-CH 2 N0 2 ); 217.3 (C-17);

MS: M+H=420

10 g (23.8 mmol) of (15 )-3-(benzyloxy)-15-(nitromethyl)estra-1 ,3,5(10)-trien-17-one was dissolved in 390 ml of A/,A/-dimethylformamide and 20.8 g (301 .4 mmol) of sodium nitrite was added. While stirring, 60 ml of acetic acid was added dropwise and the solution was stirred at 40 °C for another 10 hours. The reaction mixture was poured to 750 ml of 3.5% hydrochloric acid. The acidic mixture was extracted twice with 1000 ml of ethyl acetate. The combined organic phase was washed with 700 ml of 5% sodium hydrogen carbonate solution and 700 ml of brine, dried over anhydrous sodium sulfate, and evaporated. The raw product was purified by column chromatography using silica gel as adsorbent and cyclohexane : ethyl acetate : acetic acid = 5:1 :0.1 as eluent. The fractions containing the title compound were evaporated, crystallized from cyclohexane and dried to yield 5.0 g (52%) of the title compound. Mp.: 208-21 1 °C

1 HNMR (800 MHz, CDCI 3 ): 0.93 s (3H, H 3 -18); 3.30 m (1 H, H-15); 5.04 s (2H, 3- 0¾Ph); 1 1.35 br (COOH)

3CNMR (200 MHz, CDCI 3 ): 15.0 (C-18); 38.8 (C-15); 70.0 (3-OCH 2 Ph); 179.6 (15- COOH); 218.1 (C-17);

MS: M+H=405

Example 4

(15a)-3-(benzyloxy)estra-1 ,3,5(10)-triene-15-carboxylic acid

3.3 g (8.16 mmol) of (15a)-3-(benzyloxy)-17-oxoestra-1 ,3,5(10)-triene-15-carboxylic acid (Example 1 ), 2.91 g (51.9 mmol) of potassium hydroxide, 3.05 ml (49 mmol) hydrazin hydrate and 37 ml of triethylene glycol were weighed into a flask and the reaction mixture was heated at 110-130°C for 2 hours. Then a still head was mounted to the flask and the water and hydrazine were slowly distilled off. The flask was heated up to 200°C, kept at this temperature for 4 hours and then cooled down to room temperature. The cooled reaction mixture was diluted with 37 ml of water and added to 37 ml of 20% hydrochloric acid solution while stirring. The precipitated product was collected by filtration, washed with water until neutral and dried. The white, solid product was purified by column chromatography using silica gel as adsorbent and cyclohexane : ethyl acetate = 1 :1 as eluent. The fractions containing the title compound were evaporated, crystallized from methanol and dried to yield 2.43 g (76%) of the title product. Mp.: 51-153.5°C.

HNMR (500 MHz, CDCI 3 ): 0.81 s (3H, H 3 -18); 1.43-1.55 m (5H, H x -7, H-8, H x -11 , H x - 12, H x -17); 1.58 m (1 H, H y -17); 2.62 m (1 H, H-15); 5.03 s (2H, 3-OCH2Ph); 11.31 br (15-COOH);

13 CNMR (125 MHz, CDCI 3 ): 18.2 (C-18); 39.9 (C-17); 44.1 (C-15); 69.9 (3-OCH 2 Ph); 184.3 (15-COOH);

MS: M + =390 Example 5

[(17p)-3-(benzyloxy)-17-methoxyestra-1 ,3,5(10)-trien-15-yl]acetic acid

The methyl {[(17 )-3-(benzyloxy)-17-methoxyestra-1 ,3,5(10)-trien-15-yl]acetate} intermediate was synthetised from [(17p)-3-(benzyloxy)-17-hydroxyestra-1 ,3,5(10)- trien-15-yl]acetic acid (Labaree et al., J Med Chem, (2003) 46:1886-1904) according to Example 2.

MS: M + =448

The title compound was synthetised from methyl {[(17p)-3-(benzyloxy)-17- methoxyestra-1 ,3,5(10)-trien-15-yl]acetate} according to Example 2.

MS: M + =434

Example 6

(17p)-3-(benzyloxy)-17-methoxyestra-1 ,3,5(10)-triene-16-carboxylic acid

2.10 g (5 mmol) of methyl [(17 )-3-(benzyloxy)-17-hydroxyestra-1 ,3,5(10)-triene-16- carboxylate (Allan et al., J Med Chem, (2006) 49: 1325-1345) was dissolved in 30 ml of /V,A/-dimethylformamide under an inert atmosphere. While cooling with ice, 0.40 g (10 mmol) of sodium hydride (60% dispersion in mineral oil) was added, and at room temperature, 1.55 ml (25 mmol) of methyl iodide was added dropwise to the mixture. The mixture was stirred for 4 hours at room temperature. While cooling with ice, the reagent residue was decomposed by careful dropwise addition of water and the mixture was poured to 150 ml of 5% hydrochloric acid solution. The solution was extracted with 3x100 ml of ethyl acetate, the organic phase was washed with 2x100 ml of water and 100 ml of brine, then dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography using silica gel as adsorbent and dichloromethane as eluent resulting in 1.22 g of methyl [(17β)-3- (benzyloxy)-l 7-methoxyestra- ,3,5(10)-triene-16-carboxylate] as a mixture of 16β and 16a epimers.

Beta-isomer:

1HNMR (500 MHz, CDCI 3 ): 0.92 s (3H, H 3 -18) ; 3.44 s (3H, 17-OCHs); 3.50 d (1 H, H- 17); 3.70 s (3H, 16-COOCI½); 5.02 s (2H, 3-OCH 2 Ph); 13 CNMR (125 MHz, CDCI 3 ): 1 1 .8 (C-18); 51 .6 (16-COOCH 3 ); 59.8 (17-OCH 3 ); 70.0 (3-OCH 2 Ph); 92.0 (C-17);

Alpha-isomer:

1HNMR (500 MHz, CDCI 3 ): 0.82 s (3H, H 3 -18) ; 3.40 s (3H, 17-OCHs); 3.61 d (1 H, H- 17); 3.73 s (3H, 6-COOCH 3 ); 5.02 s (2H, S-OCHgPh);

13 CNMR (125 MHz, CDCI 3 ): 12.2 (C-18); 52.3 (16-COOCH 3 ); 58.8 (17-OCH 3 ); 70.0 (3-OCH 2 Ph); 93.6 (C-17);

MS: M + =434

The title compound was synthetised from methyl [(17p)-3-(benzyloxy)-1 7- methoxyestra-1 ,3,5(10)-triene-16-carboxylate] as follows.

1 .87 g (4.31 mmol) of methyl [(17 )-3-(benzyloxy)-17-methoxyestra-1 ,3,5(10)-triene- 16-carboxylate] was dissolved in 25 ml of dioxane. 1 .72 g of sodium hydroxide dissolved in 2.5 ml of water was added to the solution and refluxed for 4 hours. Then 150 ml of ice water was added and acidified with 37% hydrochloric acid solution adjusting the pH to 1 -2 while cooling with ice. The mixture was stirred in an ice bath for 1 hour. The precipitate was collected by filtration, washed with water until neutral, dried and purified by column chromatography using silica gel as adsorbent and acetone : dichloromethane = 5:95 as eluent resulting in 0.51 g of (16β,17β)-3- (benzyloxy)-l 7-methoxyestra-1 ,3,5(10)-triene-16-carboxylic acid and 0.53 g of the more polar ( 6a,17p)-3-(benzyloxy)-17-methoxyestra- ,3,5( 0)-triene-16-carboxylic acid. (16β,17p)-3-(benzyloxy)-17-methoxyestra-1 ,3,5(10)-triene-16-carboxylic acid

Mp.: 166-168 °C; MS: M+H=421

1 HNMR (500 MHz, CDCI 3 ): 0.81 s (3H, H 3 -18) ; 3.18 m (1 H, H-16); 3.44 s (3H, 17- OCH 3 ); 3.50 d (1 H, H-17); 5.03 s (2H, 3-Ο¾ΡΙι); 10.71 br (16-COOH);

1 3 CNMR (125 MHz, CDCI 3 ): 1 1 .4 (C-18); 42.6 (C-16); 60.2 (17-OCH 3 ); 70.0 (3- OCH 2 Ph); 91 .4 (C-17); (16α, 17 )-3-(benzyloxy)-17-methoxyestra-1 ,3,5(10)-triene-16-carboxylic acid Mp.: 171 -173 °C; MS: M+H=421

1 HNMR (500 MHz, CDCI 3 ): 0.83 s (3H, H 3 -18) ; 2.81 m (1 H, H-16); 3.46 s (3H, 17- OCH 3 ); 3.62 d (1 H, H-17); 5.03 s (2H, S-OCHgPh); 10.45 br (16-COOH);

1 3 CNMR (125 MHz, CDCI 3 ): 1 1.9 (C-18); 46.9 (C-16); 58.9 (17-OCH 3 ); 70.0 (3- OCH 2 Ph); 93.5 (C-17);

Reaction stage„a"

Example a-1

(15a)-3-(benzyloxy)-15-(pyrrolidine-1 -ylcarbonyl)estra-1 ,3,5(10)-trien-17-one

3.43 g (8.48 mmol) of (15a)-3-(benzyloxy)-17-oxoestra-1 ,3,5(10)-triene-15-carboxylic acid was dissolved in 195 ml of dichloromethane. Under an inert atmosphere and while cooling, 2.10 ml (24.07 mmol) of oxalyl chloride and 0.1 ml of N,N- dimethylformamide were added to the solution, which was then stirred for 12 hours at room temperature. Afterwards, the reaction mixture was evaporated to dryness, the dichloromethane was distilled off and the obtained acid chloride was dissolved in 200 ml of dichloromethane. To this solution, the solution of 2.10 ml of (25.39 mmol) pyrrolidine in 12 ml of dichloromethane was added at 0 °C under an inert atmosphere and stirring. Afterwards, the reaction mixture was stirred at room temperature for another 2.5 hours. The reaction mixture was washed in the following order with 3x100 ml of 5% sodium hydroxide solution, 1x90 ml of water, 2x80 ml of 10% hydrochloric acid and 4x 90 ml of water until neutral. The obtained solution was dried over anhydrous sodium sulfate, evaporated and crystallized from ether resulting in 3.46 g (89%) of the crystalline title compound. Mp.: 208-213°C.

1HNMR (500 MHz, CDCI 3 ): 0.98 s (3H, H 3 -18); 1 .89-1.98 m (3H, H x -12, H 2 - 3'(pyrrolidinyl)*); 2.02 m (2H, H 2 -4'(pyrrolidinyl)*); 2.98 m (1 H, H-15); 3.44-3.65 m (4H, H 2 -2',H 2 -5'(pyrrolidinyl)); 5.03 s (2H, S-OCH^Ph);

1 3 CNMR (125 MHz, CDCI3): 15.3 (C-18); 24.4 (C-3'(pyrrolidinyl)) * ; 26.2 (C- 4'(pyrrolidinyl)) * ; 40.2 (C-15); 46.3 (C-2'(pyrrolidinyl)) ** ; 47.0 (C-5'(pyrrolidinyl))**; 70.0 (3-OCH 2 Ph); (*, * * : interchangeable assignation)

MS: M + =457 Example a-2

(15a,17p)-3-(benzyloxy)-/V-ethy 1-17-methoxyestra-1 ,3,5(10)-triene-15- carboxamide

1.15 g (2.73 mmol) of (15a,17 )-3-(benzyloxy)-17-methoxyestra-1 ,3,5(10)-triene-15- carboxylic acid was dissolved in 93 ml of dichloromethane. Under an inert atmosphere and cooling, 0.64 ml (7.34 mmol) of oxalyl chloride and 0.04 ml of N,N- dimethylformamide were added to the solution, then stirred for 12 hours at room temperature. Afterwards, the reaction mixture was evaporated to dryness, dichloromethane was distilled off from the dry residue and the obtained acid chloride was dissolved in 90 ml of dichloromethane. Then, approximately during 50 minutes, this solution was added to the mixture of 0.68 g (8.34 mmol) of ethylamine hydrochloride and 1.90 ml (13.63 mmol) of triethylamine in 34 ml of dichloromethane at 0 °C under an inert atmosphere and stirring. Afterwards, the reaction mixture was stirred at room temperature for further 2.5 hours, then diluted with 50 ml of dichloromethane and washed with 100 ml of 5% hydrochloric acid solution. The acidic washing of the organic phase is repeated twice more and further washings were carried out in the following order with 100 ml of water, 5% sodium hydroxide solution and finally 4x100 ml of water. The obtained solution was dried over anhydrous sodium sulfate, evaporated and crystallized from ether resulting in 1.04 g (85%) of the title compound as drab coloured crystalline substance. Mp.: 187-189°C. 1 HNMR (400 MHz, CDCI 3 ): 0.82 s (3H, H 3 -18); 1 .15 t (3H, 15-CONHCH 2 CH 3 ); 3.32 m (2H, I 5-CONHCH 2 CH 3 ); 3.36 s (3H, I 7-OCH 3 ); 5.02 s (2H, 3-OCH 2 Ph); 5.51 t (1 H, NH);

13 CNMR (100 MHz, CDCI 3 ): 12.6 (C-18); 14.7 (15-CONHCH 2 CH 3 ); 34.5 (15- CONHCH 2 CH 3 ); 44.7 (C-15); 58.0 (17-OCH 3 ); 70.0 (3-OCH 2 Ph); 176.2 (15- CONHCH 2 CH 3 );

MS: M + =447 Example a-3

(15a)-3-(benzyloxy)-A ,/V-diethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide

The (15a)-3-(benzyloxy)-17-oxoestra-1 ,3,5(10)-triene-15-carboxylic acid compound obtained in Example 1 is converted to the title compound according to Example a-1 . Diethylamine is used as amine. Mp.: 133-134 °C; MS: M + =459

Example a -4

(15a)-3-(benzy loxy)-A/-ethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide

The (15a)-3-(benzyloxy)-17-oxoestra-1 ,3,5(10)-triene-15-carboxylic acid compound obtained in Example 1 is converted to the title compound according to Example a-2. Mp.: 212-216 °C; MS: M + =431

Example a-5

(15a)-3-(benzy loxy)-/V-methyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide

The (15a)-3-(benzyloxy)-17-oxoestra-1 ,3,5(10)-triene-15-carboxylic acid compound obtained in Example 1 is converted to the title compound according to Example a-2. Methylamine hydrochloride is used as amine. Mp.: 194-196 °C

MS: M + =417 Example a-6

(15p)-3-(benzyloxy)-/V-ethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide

The (15 )-3-(benzyloxy)-17-oxoestra-1 ,3,5(10)-triene-15-carboxylic acid compound obtained in Example 3 is converted to the title compound according to Example a-2. Mp.: 210-21 1 °C; MS: M+H=432

Example a-7

(15cc)-3-(benzyloxy)-W-ethylestra-1 ,3,5(10)-triene-15-carboxamide

The (15a)-3-(benzyloxy)estra-1 ,3,5(10)-triene-15-carboxylic acid compound obtained in Example 4 is converted to the title compound according to Example a-2.

Mp.: 199-201 °C; MS: M + =417 Example a-8

(15a)-3-(benzy loxy)-A/-cyclopropylestra-1 ,3,5(10)-triene-15-carboxamide

The (15 )-3-(benzyloxy)estra-1 ,3,5(10)-triene-15-carboxylic acid compound obtained in Example 4 is converted to the title compound according to Example a-1.

Cyclopropylamine is used as amine. Mp.: 187-189 °C; MS: M+H=430

Example a-9

(15oc)-/V-cyclobutyl-3-hydroxyestra-1 ,3,5(10)-triene-15-carboxamide

The (15a)-3-(benzyloxy)estra-1 , 3, 5(10)-triene-15-carboxylic acid compound obtained in Example 4 is converted to the title compound according to Example a-1.

Cyclobutylamine is used as amine. Mp.: 210-21 1 °C;MS: M+H=444

Example a-10

(15a,17p)-3-(benzyloxy)-15-[2-(ethylamino)-2-oxoethyl]-17-me thoxyestra- 1 , 3,5(10)-trlene

The [(17p)-3-(benzyloxy)-17-methoxyestra-1 ,3,5(10)-trien-15-yl]acetic acid compound obtained in Example 5 is converted to the title compound according to Example a-2. MS: M + =461 Example a-11

(16cc,17p)-3-(benzyloxy)-N-metriyl-17-methoxyestra-1 ,3,5(10)-triene-16- carboxamide

The (16a,17 )-3-(benzyloxy)-17-methoxyestra-1 ,3,5(10)-triene-16-carboxylic acid compound obtained in Example 6 is converted to the title compound according to Example a-2. Methylamine hydrochloride is used as amine.

MS: M+H=434 Example a-12

(16β, 17p)-3-(benzyloxy)-/V-methyl-17-methoxyestra-1 ,3,5(10)-triene-16- carboxamide

The (16β,17p)-3-(benzyloxy)-17-methoxyestra-1 ,3,5(10)-triene-16-carboxylic acid compound obtained in Example 6 is converted to the title compound according to Example a-2. Methylamine hydrochloride is used as amine. Mp.: 174-177 °C

MS: M+H=434.

Example a-13

(15a)-3-(benzyloxy)-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide

7.0 g (17.31 mmol) of (15a)-3-(benzyloxy)-17-oxoestra-1 ,3,5(10)-triene-15-carboxylic acid was suspended in 2 0 ml of toluene under an inert atmosphere. While cooling, 4.2 ml (48.14 mmol) of oxalyl chloride and 0.07 ml of /V,A/-dimethylformamide were added, and the mixture was stirred for 1.5 hours at room temperature. Then the reaction mixture was concentrated to its half volume and added to 25% ammonium hydroxide solution dropwise at 0-5 °C. The precipitate was collected by filtration, washed until neutral and dried to yield 6.38g (91 %) of the title compound as a white solid.

Mp.: 268-272°C; MS: M+H=404

Reaction stage„b" Example b-1

(15a)-3-hydroxy-15-(pyrrolidyn-1 -ylcarbony l)estra-1 ,3,5(10)-trien-17-on

1.22 g (2.67 mmol) of (15a)-3-(benzyloxy)-15-(pyrrolidyn-1 -ylcarbonyl)estra- 1 ,3,5(10)-trien-17-one was suspended in 100 ml of ethanol. To the mixture 2.5 ml of cyclohexene and 0.25 g of 10% Pd/C catalyst were added under an inert atmosphere. The reaction mixture was refluxed for 3 hours, then the catalyst was filtered off. The filtrate was concentrated and the precipitate was suspended in diethyl ether and collected to yield 0.85 g (87%) of the title compound as crystalline substance. Mp.: 305-307°C. 1 HNMR (500 MHz, CDCI 3 ): 0.98 s (3H, H 3 -18); 1.89-1 .98 m (3H, H x -12, H 2 - 3'(pyrrolidinyl)*); 2.03 m (2H, H 2 -4'(pyrrolidinyl)*); 3.01 m (1 H, H-15); 3.43-3.67 m (4H, H-2', H-5'(pyrrolidinyl)); 8.34 br (1 H, OH);

13 CNMR (125 MHz, CDCI 3 ): 15.4 (C-18); 24.7 (C-3'(pyrrolidinyl))*; 26.4 (C- 4'(pyrrolidinyl))*; 46.4 (C-2'(pyrrolidinyl)) ** ; 47.0 (C-5'(pyrrolidinyl)) * *; 126.4 (C-1 ); *, **: interchangeable assignation

MS: M + =367

Example b-2

(15a,17P)-/V-ethyl-3-hydroxy-17-methoxyestra-1 ,3,5(10)-triene-15-carboxamide

The (15a, 17β)-3-(benzyloxy)-Λ/-ethyl-17-methoxyestra-1 ,3,5(10)-triene-15-carbox- amide compound obtained in Example a-2 is converted to the title compound according to Example b-1.

MS: M + =357

Example b-3

(15a)-3-hydroxy-/V,W-diethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide

The (15a)-3-(benzyloxy)-/V,/V-diethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example a-3 is converted to the title compound according to Example b-1 .

MS: M + =371

Example b-4

(15a)-/V-ethyl-3-hydroxy-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide

The (15a)-3-(benzyloxy)-A/-ethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example a-4 is converted to the title compound according to Example b-1.

MS: M + =341 . Example b-5

(15a)-3-hydroxy-A -methyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide

The (15a)-3-(benzyloxy)-/V-methyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example a-5 is converted to the title compound according to Example b-1.

MS: M+H=328

Example b-6

(15p)-/V-ethyl-3-hydroxy-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide

The (15p)-3-(benzyloxy)-/V-ethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example a-6 is converted to the title compound according to Example b- .

Mp.: 254-258 °C

MS: M+H=342

Example b-7

(15a)-W-ethyl-3-hydroxyestra-1 ,3,5(10)-triene-15-carboxamide

The (15a)-3-(benzyloxy)-A/-ethylestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example a-7 is converted to the title compound according to Example b- 1. Mp.: 121-131 °C

MS: M + =327

Example b-8

(15a)- A/-cyclopropyl-3-hydroxyestra-1 , 3,5(10)-triene-15-carboxamide

The (15a)-3-(benzyloxy)-A/-cyclopropylestra- ,3,5(10)-triene-15-carboxamide compound obtained in Example a-8 is converted to the title compound according to Example b-1 . Mp.: 132-136 °C

MS: M + =339 Example b-9

(15a)-/V-cyclobutyl-3-hydroxyestra-1 ,3,5(10)-triene-15-carboxamide

The (15a)-3-(benzyloxy)-/\/-cyclobutylestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example a-9 is converted to the title compound according to Example b-1. Mp.: 140.5-144.5 °C

MS: M + =353

Example b-10

(15α,17β)-15-[2-(ethylamino)-2-oxoethyl]-17-methoxyestra-1 ,3,5(10)-trien-3-ol The (15a, 17P)-3-(benzyloxy)-15-[2-(ethylamino)-2-oxoethyl]-17-methoxy estra-

1 , 3,5(10)-triene compound obtained in Example a-10 is converted to the title compound according to Example b-1.

MS: M + =371 Example b-11

(16a,17P)-3-hydroxy-/V-methyl-17-methoxyestra-1 ,3,5(10)-triene-16-carboxamide

The (16a, 17 )-3-(benzyloxy)-/V-methyl-17-methoxyestra-1 ,3,5(10)-triene-16- carboxamide compound obtained in Example a-1 1 is converted to the title compound according to Example b- .

MS : M+H=344.

Example b-12

(16β,17p)-3-hydroxy-/V-methy 1-17-methoxyestra-1 ,3,5(10)-triene-16-carboxamide

The (16β, 17 )-3-(benzyloxy)-A/-methyl-17-methoxyestra-1 ,3,5(10)-triene-16- carboxamide compound obtained in Example a-12 is converted to the title compound according to Example b-1.

MS : M+H=344. Example b-13

(15a)-3-hydroxy-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide

The (15a)-3-(benzyloxy)-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example a-13 is converted to the title compound according to Example b- 1 . Mp.: 314-318 °C. MS : M+H=314.

Reaction stage„c" Example c-1

(15a)-3-(3-bromopropoxy)-15-(pyrrolidin-1 -ylcarbony l)estra-1 ,3,5(10)-trien-17- one

To the refluxing mixture of 16 ml of tetrahydrofuran and 2 ml of (19.70 mmol) 1 ,3- dibromopropane, the suspension prepared with 15 ml of tetrahydrofuran from 0.74 g (2 mmol) of (15a)-3-hydroxy-15-(pyrrolidin-1-ylcarbonyl)estra-1 ,3,5(10)-trien-17-one obtained in Example b-1 and a solution of 0.34 g (6.06 mmol) of potassium hydroxide in 1.2 ml of water were parallelly added during 45 minutes.

After the addition, the reaction mixture was refluxed for further 1 hour and 45 minutes. After cooling, 50 ml of dichloromethane and 65 ml of water were added, mixed and separated. The aqueous phase was washed with 2x40 ml of dichloromethane, the combined organic layers were washed with 5x50 ml of water until neutral, dried over anhydrous sodium sulfate and evaporated. The residual 1 ,3- dibromopropane was removed in vacuo at 70 °C.

The raw product was purified by column chromatography using silica gel as adsorbent and cyclohexane : ethyl acetate = 1 :1 as eluent. The fractions containing the title compound were concentrated to yield 0.82 g (84%) of the title compound. Mp.: 33-136 °C

1 HNMR (500 MHz, CDCI 3 ): 0.97 s (3H, H 3 -18); 1.93 m (2H, H 2 -3'(pyrrolidinyl)*); 2.03 m (2H, H 2 -4'(pyrrolidinyl) * ); 2.30 m (2H, 3-OCH 2 CH 2 CH 2 Br); 3.44-3.65 m (4H, H 2 -2\ H 2 -5'(pyrrolidinyl)); 3.60 1 (2H, 3-OCH 2 CH 2 CH 2 Br); 4.07 1 (2H, 3-OCH 2 CH 2 CH 2 Br); 13 CNMR (125 MHz, CDCI 3 ): 15.3 (C-18); 24.4 (C-3'(pyrrolidinyl))*; 26.0 (C- 4'(pyrrolidinyl))*; 30.1 (3-OCH 2 CH 2 CH 2 Br); 32.4 (3-OCH 2 CH 2 CH 2 Br); 46.2 (C- 2'(pirrolidinil))**; 46.9 (C-5'(pyrrolidinyl))**; 51 .8 (C-14); 65.1 (3-OCH 2 CH 2 CH 2 Br); 172.7 (15-CON-); 217.4 (C-17);

*, **: interchangeable assignation

MS: M + =487.

Example c-2

(15a,17 )-3-(3-bromopropoxy)-A/-ethyl-17-methoxyestra-1 ,3,5(10)-triene-15- carboxamide

The (15a,17p)-A/-ethyl-3-hydroxy-17-methoxyestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example b-2 is converted to the title compound according to Example c-1 .

MS: M + =477.

Example c-3

(15a)-3-(3-bromopropoxy)-A/,A/-diethyl-17-oxoestra-1 ,3,5(10)-triene-15- carboxamide

The (15a)-/V,/\/-diethyl-3-hydroxy-17-oxoestra- ,3,5(10)-triene-15-carboxamide compound obtained in Example b-3 is converted to the title compound according to Example c-1 .

MS: M + =489.

Example c-41

(15a)-3-(3-bromopropoxy)-A/-ethyl-17-oxoestra-1 , 3,5(10)-triene-15-carboxamide

The (15a)-A/-ethyl-3-hydroxy-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide

compound obtained in Example b-4 is converted to the title compound according to Example c-1 .

Mp.: 174-176 °C

MS: M + =461 . Example c-47

(15a)-3-(2-bromoethoxy)-W-ethy 1-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide

The (15a)-A/-ethyl-3-hydroxy-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide

compound obtained in Example b-4 is converted to the title compound according to Example c-1 applying ,2-dibromoethane.

Mp.: 207-210 °C

MS: M + =447.

Example c-48

(15a)-3-(4-bromobutoxy)-/V-ethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide

The (15a)-A/-ethyl-3-hydroxy-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide

compound obtained in Example b-4 is converted to the title compound according to Example c-1 applying 1 ,2-dibromobutane.

Mp.: 153-154 °C

MS: M + =475.

Example c-5

(15a)-3-(3-bromopropoxy)-A -methy 1-17-oxoestra-1 ,3,5(10)-triene-15- carboxamide

The (15a)-3-hydroxy-AV-methyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example b-5 is converted to the title compound according to Example c-1.

Mp.: 139-140 °C

MS: M + =447.

Example c-6

(15p)-3-(3-bromopropoxy)-W-ethyl-17-oxoestra-1 , 3,5(10)-triene-15-carboxamide

The (15p)-A7-ethyl-3-hydroxy-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example b-6 is converted to the title compound according to Example c-1. Mp.: 200-202 °C

MS: M+H=462 Example c-7

(15a)-3-(3-bromopropoxy)-W-ethylestra-1 , 3, 5(10)-triene~15-carboxamide

The (15a)-/V-ethyl-3-hydroxyestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example b-7 is converted to the title compound according to Example c- 1 . Mp.:146-147 °C

MS: M + =447.

Example c-8

(15a)-3-(3-bromopropoxy)-A/-cyclopropylestra-1 ,3,5(10)-triene-15-carboxamide The (15a)-A/-cyclopropyl-3-hydroxyestra- ,3,5(10)-triene-15-carboxamide compound obtained in Example b-8 is converted to the title compound according to

Example c-1 . MS: M + =459.

Example c-9

(15a)-3-(3-bromopropoxy)-/V-cyclobutylestra-1 ,3,5(10)-triene-15-carboxamide

The (15a)-A/-cyclobutyl-3-hydroxyestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example b-9 is converted to the title compound according to

Example c-1.

MS: M + =473.

Example c-10

(15a,17P)-3-(3-bromopropoxy)-15-[2-(ethylamino)-2-oxoethyl]- 17-methoxyestra- 1 , 3,5(10)-triene

The (15a, 17p)- 5-[2-(ethylamino)-2-oxoethyl]-17-methoxyestra- ,3,5(10)-trien-3-ol compound obtained in Example b-10 is converted to the title compound according to Example c-1.

MS: M + =491. Example c-11

(16a,17p)-3-(3-bromopropoxy)-A -methy 1-17-methoxyestra-1 ,3,5(10)-triene-16- carboxamide

The (16a,17 )-3-hydroxy-A/-methyl-17-methoxyestra-1 ,3,5(10)-triene-16- carboxamide compound obtained in Example b-11 is converted to the title compound according to Example c-1.

MS: M+H=464.

Example c-12

(16β,17 )-3-(3-bromopropoxy)-W-methy 1-17-methoxyestra-1 ,3,5(10)-trlene-16- carboxamide

The (16β,17p)-3-hydroxy-/V-methyl-17-methoxy- estra-1 ,3,5(10)-triene-16- carboxamide compound obtained in Example b-12 is converted to the title compound according to Example c-1.

MS: M+H=464

Example c-13

(15a)-3-(3-bromopropoxy)-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide

The (15a)-3-hydroxy-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example b-13 is converted to the title compound according to Example c-1 .

MS : M+H=434.

Reaction stage„d" Example d-1

(15a)-3-{3-[(2 ?)-2-methylpyrrolidin-1 -yl]propoxy}-15-(pyrrolidin-1 - ylcarbonyl)estra-1 ,3,5(10)-trien-17-one

0.5 g (1 .02 mmol) of (15a)-3-(3-bromopropoxy)-15-(pyrrolidin-1-ylcarbonyl)estra- 1 ,3,5(10)-trien-17-one compound obtained in Example c-1 was dissolved in 28 ml of tetrahydrofuran. 0.40 ml (3.99 mmol) of (R)-(-)-2-methylpyrrolidine was added and the reaction mixture was heated under reflux for 5 hours. 50 ml of dichloromethane and 30 ml of 3.3% sodium hydroxide solution was added to the cooled reaction mixture. After agitation, the phases were separated. The aqueous phase was extracted with 2x10 ml of dichloromethane. The combined organic phase was washed with 2x30 ml of 3.3% sodium hydroxide solution and 8x50 ml of water. The solution was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography using silica gel as adsorbent and dichloromethane : methanol = 15:1 as eluent. The fractions containing the title compound were concentrated to yield 0.32 g (64%) of the foam-like title compound. 1 HNMR (800 MHz, CDCI 3 ): 0.97 s (3H, H 3 -18); 1.22 br d (3H, 2'- CH^(methylpyrrolidinyl)); 1.91 m (2H, H 2 -3'(pyrrolidinyl)*); 2.03 m (2H, H 2 - 4'(pyrrolidinyl)*); 2.08 br m (2H, 3-OCH2CH2CH2N-); 3.06 br m (1 H, 3- OCH 2 CH 2 CH 2 N-); 3.34 br m (1 H, H x -5'(methylpyrrolidinyl)); 3.44-3.65 m (4H, H 2 -2', H 2 -5'(pyrrolidinyl)); 3.98 m (1 H, 3-OCH 2 CH 2 CH 2 N-); 4.03 m (1 H, 3-OCH 2 CH 2 CH 2 N-); 3CNMR (200 MHz, CDCI 3 ): 15.3 (C-18); 18.0 (2'-CH 3 (methylpyrrolidinyl)); 21.5 (C- 4'(methylpyrrolidinyl)); 24.3 (C-3'(pyrrolidinyl))*; 26.1 (C-4'(pyrrolidinyl))*; 27.8 (3- OCH 2 CH 2 CH 2 N-); 32.3 (C-3'(methylpyrrolidinyl)); 46.2 (C-2'(pyrrolidinyl))**; 46.9 (C- 5'(pyrrolidinyl) * *; 50.8 (3-OCH 2 CH 2 CH 2 N-); 53.7 (C-5'(methylpirrolidine)); 61 .1 (C- 2'(methylpyrrolidinyl)); 66.0 (3-OCH 2 CH 2 CH 2 N-); 172.7 (15-CON-); 217.4 (C-17); * , * * : interchangeable assignation

MS: M + =492.

Example d-2

(15a,17p)-/V-ethyl-3-{3-[(2f?)-2-methylpyrrolidin-1-yl]propo xy}17-methoxyestra- 1 ,3,5(10)-triene-15-carboxamide

The (15a,17p)-3-(3-bromopropoxy)-/V-ethyl-17-methoxyestra-1 ,3,5(10)-triene-15- carboxamide compound obtained in Example c-2 is converted to the title compound according to Example d-1.

MS: M + =482. Example d-41

(15a)-W-ethyl-3-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}-17 -oxoestra-1 ,3,5(10)- triene-15-carboxamide

The (15a)-3-(3-bromopropoxy)-/V-ethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example c-41 is converted to the title compound according to Example d-1.

(S)-(+)-2-methylpyrrolidine is used as amine.

MS : M+H=467. Example d-42

(15 )-A -ethyl-3-{3-[(2/?)-2-methylpyrrolidin-1-yl]propoxyi}-17-oxoe stra-1 ,3,5(10)= triene-15-carboxamide

The (15a)-3-(3-bromopropoxy)-A/-ethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example c-41 is converted to the title compound according to Example d-1.

MS : M + =466.

Example d-43

(15oc)-3-[3-(1 ,4-dioxa-8-azaspiro[4.5]dec-8-yl)propoxy]-W-ethyl-17-oxoestr a- 1 ,3,5(10)-triene-15-carboxamide

The (15a)-3-(3-bromopropoxy)-/V-ethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example c-41 is converted to the title compound according to Example d-1. 1 ,4-dioxa-8-azaspiro[4.5]decane is used as amine.

MS: M + =524.

Example d-44

(15 )-W-ethyl-3-{3-[(3 ?)-3-fluoropyrrolidin-1-yl]propoxy}-17-oxoestra-1 ,3,5(10)- triene-15-carboxamide

The (15a)-3-(3-bromopropoxy)-A/-ethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example c-41 is converted to the title compound according to Example d-1. 3-(3R)-3-fluoropyrrolidine is used as amine.

MS: M+H=471 Example d-45

(15a)-/V-ethy l-3-[3-(4-fluoropiperidin-1 -yl)propoxy]-17-oxoestra-1 ,3,5(10)-triene- 15-carboxamide

The (15a)-3-(3-bromopropoxy)-/V-ethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example c-41 is converted to the title compound according to Example d-1. 4-fluoropiperidine is used as amine.

MS: M+H=485

Example d-46

(15a)-W-ethyl-3-[3-(4,4-difluoropiperidin-1-yl)propoxy]-1 7-oxoestra-1 , 3,5(10)- triene-15-carboxamide

The (15a)-3-(3-bromopropoxy)-/V-ethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example c-41 is converted to the title compound according to Example d-1. 4,4-difluoropiperidine is used as amine.

MS: M+H=503

Example d-47

(15a)- V-ethyl-3-{2-[(2 ?)-2-methylpyrrolidin-1-yl]etoxy}-17-oxoestra-1 , 3,5(10)- triene-15-carboxamide

The (15a)-A/-ethyl-3-(2-bromoethoxy)-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example c-47 is converted to the title compound according to Example d-1 .

MS: M + =452. Example d-48

(15a)-W-ethyl-3-{4-[(2 ?)-2-methylpyrrolidin-1-yl]butoxy}-17-oxoestra-1 ,3,5(10)- triene-15-carboxamide

The (15a)-3-(4-bromobutoxy)-/V-ethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example c-48 is converted to the title compound according to Example d-1 .

MS: M+H=481 . Example d-5

(15a)- V-methyl-3-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}-17-oxoe stra- 1 ,3,5(10)-triene-15-carboxamide

The (15a)-3-(3-bromopropoxy)-A/-methyl-17-oxoestra-1 ,3,5(10)-triene-15- carboxamide compound obtained in Example c-5 is converted to the title compound according to Example d-1.

MS: M + =452.

Example d-6

(15p)-/V-ethyl-3-{3-[(2 ?)-2-methylpyrrolidin-1-yl]propoxy}-17-oxoestra-1 ,3,5(10)- triene-15-carboxamide

The (15 )-3-(3-bromopropoxy)-/V-ethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example c-6 is converted to the title compound according to Example d-1.

MS: M+H=467

Example d-7

(15a)-/V-ethyl-3-{3-[(2/?)-2-methylpyrrolidin-1-yl]propoxy}e stra-1 ,3,5(10)-triene- 15-carboxamide

The (15a)-3-(3-bromopropoxy)-/V-ethylestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example c-7 is converted to the title compound according to Example d-1 .

MS: M + =452. Example d-8

(15a)-W-cyclopropyl-3-{3-[(2R)-2-methylpyrrolidin-1 -yl]propoxy}estra-1 ,3,5(10)- triene-15-carboxamide

The (15a)-3-(3-bromopropoxy)-/V-cyclopropylestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example c-8 is converted to the title compound according to Example d-1 .

MS: M + =464. Example d-9

(15a)-W-cyclobutyl-3-{3-[(2 ?)-2-methylpyrrolidin-1 -yl]propoxy}estra-1 ,3,5(10)- triene-15-carboxamide

The (15 )-3-(3-bromopropoxy)-A/-cyclobutylestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example c-9 is converted to the title compound according to Example d-1.

MS: M+H=479.

Example d-11

(16a,17p)- V-methyl-3-{3-[(2 ?)-2-methylpyrrolidin-1 -yl]propoxy}-17- methoxyestra-1 ,3,5(10)-triene-16-carboxamide

The (16a, 17P)-3-(3-bromopropoxy)-/\/-methyl-17-methoxyestra-1 ,3,5(10)-triene-16- carboxamide compound obtained in Example c-1 1 is converted to the title compound according to Example d-1.

MS: M+H=469.

Example d-12

(16p,17p)-W-methyl-3-{3-[(2 ?)-2-methylpyrrolidin-1-yl]propoxy}-17- methoxyestra-1 ,3,5(10)-triene-16-carboxamide

The (16β,17p)-3-(3-bromopropoxy)-/V-methyl-17-methoxyestra-1 ,3,5(10)-triene-16- carboxamide compound obtained in Example c-12 is converted to the title compound according to Example d-1.

MS : M+H=469. Example d-13

(15a)-3-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}-17-oxoestr a-1 ,3,5(10)-triene- 15-carboxamide

The (15a)-3-(3-bromopropoxy)-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example c-13 is converted to the title compound according to Example d-1.

MS : M+H=439. Example d-14

(15a,17p)-3-{3-[(2 ?)-2-methylpyrrolidin-1-yl]propoxy}-15-(pyrrolidin-1- ylcarbonyl)estra-1 ,3,5(10)-trien-17-ol

0.40 g (0.81 mmol) of (15a)-3-{3-[(2f?)-2-methylpyrrolidin-1-yl]propoxy}-15-(pyrro lidin- 1 -ylcarbonyl)estra-1 ,3,5(10)-trien-17-one obtained in Example d-1 was dissolved in a mixture of 5 ml of dichloromethane and 5 ml of methanol. While cooling 46 mg (1.22 mmol) of sodium borohydride was added and the reaction mixture was stirred for 3 hours at room temperature. After the addition of 20ml of dichloromethane and 20 ml of water the phases were agitated and separated. The organic phase was washed with 4x30 ml of water until neutral, dried over anhydrous sodium sulfate, filtered and evaporated.

The obtained oil was purified by column chromatography using silica gel as adsorbent and dichloromethane : methanol : cc. ammonium hydroxide = 5:2:0.1 as eluent. The fractions containing the title compound were concentrated to yield 0.29 g (73%) of the foam-like title compound.

MS : M+H=495

Example d-15

(15a,17 )-/V-ethyl-3-[3-(4-fluoropiperidin-1 -yl)propoxy]-17- ydroxyestra- 1 ,3,5(10)-triene-15-carboxamide

The (15a)-A/-ethyl-3-[3-(4-fluoropiperidin-1 -yl)propoxy]-17-oxoestra-1 ,3,5(10)-triene- 15-carboxamide compound obtained in Example d-45 is converted to the title compound according to Example d-14.

MS : M+H=487.

Salt formation Example e-1

(15a)-/V,/V-diethyl-3-{3-[(2 ?)-2-methylpyrrolidin-1 -yl]propoxy}-17-oxoestra- 1 ,3,5(10)-triene-15-carboxamide hydrochloride The (15a)-3-(3-bromopropoxy)-/V,/\/-diethyl-17-oxoestra-1 ,3,5(10)-triene-15- carboxamide compound obtained in Example c-3 was reacted with R)-(-)-2- methylpyrrolidine. To its ethanolic solution an equimolar amount of hydrochloric acid was added and the solution was evaporated resulting in a foam-like, solid compound as the title compound.

H NMR (800 MHz, DMSO-d 6 ): 0.95 s (3H, H 3 -18); 1.03 t (3H, 15-CON(CH 2 CH 3 ) 2 ); 1.16 t (3H, 15-CON(CH 2 CH 3 ) 2 ); 1.39 d (3H, 2'-CH^(methylpyrrolidinyl)); 1.94 m (2H, H 2 -4'(methylpyrrolidinyl)); 2.13 m (2H, S-OCHzChbC^N); 2.22 td (1 H, H-9); 3.04 m (1 H, 3-OCH 2 CH 2 CH 2 N); 3.07 m (1 H, H x -5'(methylpyrrolidinyl)); 3.22 m (1 H, 15- CON(CH2CH 3 ) 2 ); 3.39 m (1 H, H-2'(methylpyrrolidinyl)); 3.40 m (2H, 15- CON(CH 2 CH 3 ) 2 , 3-OCH 2 CH 2 CH 2 N); 3.46 m (1 H, 15-CON(CH 2 CH 3 ) 2 ); 3.49 m (1 H, 15-CON(CH 2 CH 3 ) 2 ); 3.59 m (1 H, H y -5'(methylpyrrolidinyl)); 4.01 m (2H, 3- OCH 2 CH 2 CH 2 N); 10.34 br (1 H, NH + ) ppm.

13 C NMR (200 MHz, DMSO-cfe): 12.6 (15-CON(CH 2 CH 3 ) 2 ); 14.9 (C-18); 15.1 (15- CONiCHzCHsk); 15.4 (2'-CH 3 (methylpyrrolidinyl)); 20.9 (C-4'(methylpyrrolidinyl)); 25.0 (3-OCH 2 CH 2 CH 2 N); 30.9 (C-3'(methylpyrrolidinyl)); 36.5 (C-15); 40.2 (15- CON(CH 2 CH 3 ) 2 ); 41.6 (15-CON(CH 2 CH 3 ) 2 ); 52.4 (C-5'(methylpyrrolidinyl)); 63.5 (C- 2'(methylpyrrolidinyl)); 64.7 (3-OCH 2 CH 2 CH 2 N); 173.1 (15-CON(CH 2 CH 3 ) 2 ); 217.0 (C-17) ppm.

MS: M + =494.

Example e-2

(15a)-W-ethyl-3-{3-[(3 ?)-3-fluoropyrrolidinium-1-yl]propoxy}-17-oxoestra- 1 ,3,5(10)-triene-15-carboxamide (2£)-3-carboxy prop-2-enoate

The salt formation was carried out from the compound obtained in Example d-44 with fumaric acid according to Example e-1.

MS: M b ase=471

Example e-3

(15a)-3-[3-(3,3-difluoropyrrolidinium-1 -yl)propoxy]-W-ethyl-17-oxoestra- 1 ,3,5(10)-triene-15-carboxamide chloride The (15a)-3-(3-bromopropoxy)-/V-ethyl-17-oxoestra-1 ,3,5(10)-triene-15-carboxamide compound obtained in Example c-41 was reacted with 3,3-difluoropyrrolidine according to Example d-1. To its ethanolic solution an equimolar amount of hydrochloric acid was added and the solution was evaporated resulting in a foam- like, solid compound as the title compound.

MS : M b ase=489

Example e-4

(15a)-W-ethyl-3-[3-(4-fluoropiperidinium-1-yl)propoxy]-17-ox oestra-1,3,5(10)- triene-15-carboxamide bromide

The salt formation was carried out from the (15a)-/V-ethyl-3-[3-(4-fluoropiperidin-1- yl)propoxy]-17-oxoestra-1 ,3,5( 0)-triene-15-carboxamide compound obtained in Example d-45 with aqueous hydrogen bromide solution according to Example e-1. MS: M b ase=485

Example e-5

(15a)-3-[3-(4,4-difluoropiperidinlum-1-yl)propoxy]-/V-ethyl- 17-oxoestra-1 ,3,5(10)- triene-15-carboxamide 3,4-dicarboxy-3-hydroxybutanoate

The salt formation was carried out from the (15a)-A/-ethyl-3-[3-(4,4-difluoropiperidin- 1-yl)propoxy]-17-oxoestra-1 , 3, 5(10)-triene-15-carboxamide compound obtained in Example d-46 with citric acid according to Example e-1.

MS: M b ase=503

Example e-6

(15a,17P)-15-[2-(ethylamino)-2-oxoethyl]-3-{3-[(2R)-2-met hylpyrrolidinium-1- yl]propoxy}-17-methoxyestra-1 ,3,5(10)-triene chloride

The (15a, 17β)-3-(3-bromopropoxy)-15-[2-(ethylamino)-2-oxoethyl]-17-m ethoxyestra- 1 ,3,5(10)-triene compound obtained in Example c-10 was reacted with (R)-(-)-2- methylpyrrolidine according to Example d-1. To its ethanolic solution an equimolar amount of hydrochloric acid was added and the solution was evaporated resulting in a foam-like, solid compound as the title compound.

MS: M b ase=496 Biological evaluation

The in vitro affinity of the compounds in the present invention for recombinant human histamine H 3 receptors can be determined according to the following procedure.

Membrane preparation

The membrane was prepared from hH 3 -A2 cells (expressed in CHO-K1 cells) according to the Euroscreen Technical Data Sheet ( Cat. No.: ES-392/F). Cells were dissociated in Ca 2+ -and Mg 2+ -free phosphate buffered saline (PBS) and centrifuged (1500 rpm, 3 min, 4 °C). The pellet was resuspended in buffer A ( 5 mM Tris-HCI pH 7.5, 2mM MgC , 0.3 mM EDTA, 1 mM EGTA) and homogenized in a glass homogenizer. The crude membrane fraction was collected by two consecutive centrifugation steps at 40.000 g for 25 min at 4 °C, separated by a washing step in above described buffer. The final pellet was resuspended in buffer B (75 mM Tris-HCI pH 7.5, 12.5 mM MgCI 2 , 0.3 mM EDTA, 1 mM EGTA, 250 mM sucrose), divided into aliquots, flash frozen and stored at -80°C until use. Protein content was determined by the Lowry method with bovine serum albumin (BSA) as a standard.

In vitro binding assay conditions

Assays were performed in duplicate in at least two independent experiments (with at least 5 concentrations each) containing the binding buffer (50 mM Tris HCI pH 7.4, 5 mM MgCI 2 ), hh membrane (14 pg protein/tube), N-a-[Methyl- 3 H]methylhistamine dihydrochloride (1 nM) as radioligand. Non-specific binding was determined in the presence of 10 μΜ thioperamide. The samples were incubated in a final volume of 0.25 ml for 30 min at 25 °C. Binding reactions were terminated by rapid filtration through UniFilter® GF/B™ fiber glass filters, presoaked for at least 2 h in 0.5 % polyethylene imine (PEI). The filterplates were washed nine times 0.5 ml of ice-cold washing buffer (same composition as the binding buffer containing 0.5 M NaCI) using Brandel harvester. The filterplates were dried at 50°C for 45 minutes and 40 μΙ Microscint20 (Packard) scintillation cocktail was added to each well. Filters radioactivity was determined by TopCount (Packard) scintillation counter. Data analyses

The ligand displacement by the compounds was determined in duplicate. The specific radioligand binding was defined as the difference between total binding and the non-specific binding determined in the presence of excess of unlabelled ligand or other compounds used to specifically displace of radioligand. Results were expressed as a percent inhibition of specific binding obtained in the presence of tested compounds.

IC 50 values (i.e. concentration of compound giving 50% inhibition of specific binding) were calculated from concentration-displacement curves by sigmoidal fitting using GraphPad Prism Software 4.0. K, values (i.e. inhibition constants) were calculated using the Cheng-Prusoff equation(Cheng YC and Prusoff WH (1973) Biochem Pharmacol 22:3099-3108).

Ki values

The in vitro affinity at human H3 histamine receptors of the compounds of the present invention can be seen in the following table.



++ Ki is between 10 and 50 nM

The compounds of d-2, d-42, d-7, d-8, d-9, e-6 and d-12 structures - with their K, values below 10nM - show outstanding affinity , whereas the compounds of d-1 , e-1 , d-41 , d-5, d-6, and d-11 structures - with their K, values between 10 and 50 nM - show moderate affinity for recombinant human H 3 receptors.

Preparation of pharmaceutical compositions

The following formulation examples illustrate representative pharmaceutical compositions of this invention. The present invention however not limited to the following pharmaceutical compositions. The concentration of mixtures are expressed in weight percent.

Examples

a) Tablets

0.01-50 % of active ingredient of formula (I), 15-50 % of lactose, 15-50 % of potato starch, 5-15 % of polyvinyl pyrrolidone, 1-5 % of talc, 0.01-3 % of magnesium stearate, 1-3 % of colloid silicon dioxide and 2-7 % of ultraamylopectin were mixed, then granulated by wet granulation and pressed to tablets.

b) Draqees, filmcoated tablets

The tablets made according to the method described above were coated by a layer consisting of entero- or gastrosolvent film, or of sugar and talc. The dragees were polished by a mixture of beeswax and carnuba wax. c) Capsules

0.01-50 % of active ingredient of formula (I), 1-5 % of sodium lauryl sulfate, 15-50 % of starch, 15-50 % of lactose, 1-3 % of colloid silicon dioxide and 0.01-3 % of magnesium stearate were thoroughly mixed, the mixture was passed through a sieve and filled in hard gelatin capsules.

d) Suspensions

Ingredients: 0.01- 5 % of active ingredient of formula (I), 0.1-2 % of sodium hydroxide, 0.1-3 % of citric acid, 0.05-0.2 % of nipagin (sodium methyl 4- hydroxybenzoate), 0.005-0.02 % of nipasol, 0.01-0.5 % of carbopol (polyacrilic acid), 0.1-5 % of 96 % ethanol, 0.1-1 % of flavoring agent, 20-70 % of sorbitol (70 % aqueous solution) and 30-50 % of distilled water.

To solution of nipagin and citric acid in 20 ml of distilled water, carbopol was added in small portions under vigorous stirring, and the solution was left to stand for 10-12 h. Then the sodium hydroxide in 1 ml of distilled water, the aqueous solution of sorbitol and finally the ethanolic raspberry flavor were added with stirring. To this carrier the active ingredient was added in small portions and suspended with an immersing homogenizator. Finally the suspension was filled up to the desired final volume with distilled water and the suspension syrup was passed through a colloid milling equipment. e) Suppositories

For each suppository 0.01-15% of active ingredient of formula (I) and 1-20% of lactose were thoroughly mixed, then 50-95% of adeps pro suppository (for example Witepsol 4) was melted, cooled to 35 °C and the mixture of active ingredient and lactose was mixed in it with homogenizator. The obtained mixture was mould in cooled forms. f) Lyophilized powder ampoule compositions

A 5 % solution of mannitol or lactose was made with bidistilled water for injection use, and the solution was filtered so as to have sterile solution. A 0.01-5 % solution of the active ingredient of formula (I) was also made with bidistilled water for injection use, and this solution was filtered so as to have sterile solution. These two solutions were mixed under aseptic conditions, filled in 1 ml portions into ampoules, the content of the ampoules was lyophilized, and the ampoules were sealed under nitrogen. The contents of the ampoules were dissolved in sterile water or 0.9 % (physiological) sterile aqueous sodium chloride solution before administration.

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.