HK1138183B

HK1138183B - Inhibitors of the task-1 and task-3 ion channel

Info

Publication number: HK1138183B
Application number: HK10103417.7A
Authority: HK
Inventors: Joachim Brendel; Heinz Goegelein; Klaus Wirth; Walter Kamm
Original assignee: 塞诺菲-安万特德国有限公司
Priority date: 2006-04-27
Filing date: 2007-04-13
Publication date: 2012-09-28

Description

Inhibitors of the TASK-1 and TASK-3 ion channels

The invention relates to compounds of formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih and/or Ij

And/or physiologically compatible salts thereof, in the manufacture of a medicament for the treatment or prevention of respiratory disorders, sleep-related respiratory disorders, central and obstructive sleep apneas, upper airway resistance syndrome, Cheyne-Stokes respiration, snoring, impaired central respiratory drive, sudden child death, postoperative hypoxia and apnea, muscle-related respiratory disorders, respiratory disorders after prolonged ventilation, respiratory disorders during adaptation in high mountains, acute and chronic lung disorders with hypoxia and hypercapnia, neurodegenerative disorders, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, cancerous disorders, breast cancer, lung cancer, colon cancer and prostate cancer.

Compounds of the formulae Ia to Ij and/or their physiologically compatible salts inhibit the so-called TASK potassium channels, in particular the TASK-1 and/or TASK-3 subtypes.

Potassium channels are a broad range of membrane proteins that play an important role in many physiological processes due to their effect on cellular membrane potential. Within each class of potassium channels, the difference depends on their molecular structure between three major classes, which are characterized by the number of transmembrane domains (2, 4 or 6). The potassium channel type with 4 transmembrane segments differs from the other two in that it represents two pore domains each, which is why these channels are also called K_2PThe reason for the channels [ Coetzee w.j. et al; molecular diversity of K + channels; Ann.New York Acad.Sci.1999(868), 233-]. In functional terms, K_2PChannels are characterized by so-called "leakage" or "background" currents flowing through them, while they play an important role in resting membrane potential and thus in nerve or muscle cell excitability.

At K_2PA family of channels of particular interest is the family of TASK channels, which were not discovered until the end of the last 90 th century and of which 5 representative TASK-1, TASK-2, TASK-3, TASK-4 and TASK-5 are presently described. Other terms used in the literature for potential genes are KCNK3 or K2P3.1(═ TASK-1), KCNK5 or K2P5.1(═ TASK-2), KCNK9 or K2P9.1(═ TASK-3), KCNK15 or K2P15.1(═ TASK-5), and KCNK17 or K2P17.1(═ TASK-4, TALK-2). The greatest homology within this family is that the TASK-1 and TASK-3 channels have more than 50% amino acid identity. K_2PDimeric structure of channelsA functional potassium channel with a total of 4-well units was formed. The flow through these channels is referred to in the literature as IKso flow. For example, in addition to homodimerization of two TASK-1 or two TASK-3 proteins, heterodimerization of TASK-1 and TASK-3 is also possible in context [ Berg a.p., Talley e.M., Manger J.p., Bayliss D.a.; motoneurons express heterocyclic TWIK-related acid-sensitive K + (TASK) channels relating TASK-1(KCNK3) and TASK-3(KCNK9) subbunits; neuroscience 2004(24), 6693-]。

The TASK channel is of particular interest because it is very strongly dependent on the extracellular physiological range of pH. The channel is inhibited at acidic pH and activated at basic pH. Because of this pH dependence, the physiological function of sensors that translate small changes in extracellular pH that correspond to cellular signals is attributed to the TASK channel [ Duprat f., Lesage f., Fink m., Reyes r., Heurteaux c., Lazdunski m.; TASK, a human background K + channel sense external pH variations near physiological pH; EMBO.J 1997(16), 5464-5471; patel a.j., Honore e.; properties and modulation of mammalian 2P domains K + channels; trends neurosci.2001(24), 339-346 ].

TASK-1is expressed in the brain and also in the spinal ganglia and certain peripheral tissues, such as the pancreas, placenta, uterus, lungs, heart, kidneys, small intestine and stomach. Furthermore, TASK-1 was detected in chemosensitive cells of the brainstem and carotid body and also in motor neurons of the hypoglossal nerve.

TASK-3 is expressed primarily in the cerebellum [ Medhurst a.d., Rennie g., Chapman c.g., Meadows h., Duckworth m.d., Kelsell r.e., Glober i.i., Pangalos m.n.; distribution analysis of human two-hole domain channels of the central nervous system and period; brain Res.2001(86), 101-.

TASK-1 potassium channel was detected in motor neurons of the hypoglossal nerve (motor cranial nerves with the most important function of maintaining the upper respiratory tract) and in the locus coeruleusThe current generated by the track. The TASK-1 channel has been found to be involved in respiratory regulation in the respiratory neurons of the brainstem, the motor neurons of the carotid body and the hypoglossal nerve, and in the epithelial cells of the pulmonary nerve. Due to CO₂In case of elevated concentrations and acidosis or insufficient respiration (hypoxia, respiratory obstruction) by acidic metabolites (lactate) and physiological stress, there is a pH drop and thus a pH-dependent block of the TASK-1 channel. This depolarizes the cell, resulting in neuronal activation involving respiratory regulation [ Buckler k.j., Williams b.a., Honore e; an oxidative, acid-and anaerobic-reactive TASK-like background channel in a rat electrochemical cells; j. Physiol 2000(525), 135-142; bayliss d.a., Talley e.m., Sirois j.e., Lei q.; TASK-1is a highlymodified pH-sensitive 'leak' K + channel expressed in filtered responses neurones; reproduction Physiology 2001(129), 159-174]。

Motor neuron activation of chemosensitive neurons and hypoglossal nerves can stimulate respiration and at the same time stabilize the upper respiratory tract and prevent their failure and obstruction by blocking the increase in activity of the TASK channels. In addition, snoring can be inhibited by stabilizing the upper airway mechanism. Blocking the TASK-1 ion channel can thus be applied to the treatment of respiratory disorders, such as sleep apnea.

Obstructive sleep apnea is produced by a reduction in inspiratory pressure produced by the diaphragm and pectoral muscles during inhalation into the upper airway in the presence of upper airway constriction. Anatomical conditions of narrowing of the upper respiratory tract are present in cases of obesity (fat gain) and anatomically predisposed body mass (e.g. maxilla). In persons predisposed to the disease, the extensional muscular structure tension of the upper respiratory muscular structure must always be increased compared to healthy persons to prevent failure. The genioglossus muscle (the muscle on the base of the tongue) is the most important of the upper respiratory tract dilating muscles; it is innervated by the hypoglossal nerve. Although the muscle tone in the upper respiratory tract is still high enough to prevent breathing disorders in the awake state, it drops significantly in sleep, so that it is too low relative to the decrease in inspiratory pressure. This inconsistency leads to upper airway failure (obstructive apnea) during inhalation. With high upper airway constriction and correspondingly high tissue pressures, failure can occur even during exhalation, i.e. without decompression. The increase of the muscle tone in the upper respiratory tract by the Kv1.5 inhibitors of the invention can thus prevent obstructive apneas.

Snoring results from flow-related vibrations in the upper respiratory tract. It is generated in the following cases: the upper respiratory tract is excessively narrowed, while the muscle tone of the upper respiratory tract is insufficient, and thus has a close pathophysiological correlation with obstructive sleep apnea. Snoring can thus be considered to some extent a precursor to obstructive apnea. Snoring and sleep apnea can thus be prevented by the Kv1.5 inhibitor of the present invention increasing the muscle tone of the upper respiratory tract.

Central sleep apnea is caused by a collapse of the respiratory regulatory center. The respiratory stimulating effect of the Kv1.5 inhibitors of the invention prevents them simultaneously (effect on minute quantities).

The TASK-1 channel is also present in mesenteric and pulmonary artery smooth muscle cells. In the latter, it may be the case that they are involved in acidosis-induced pulmonary vasoconstriction [ Gurney a.m., osiphenkoo.n., MacMillan d., McFarlane k.m., Tate r.j., kempsilol f.e.; two-poredomain K channel, TASK-1, in pulmony array smooth muscle cells; circ. Res.2003(93), 957-.

It has also been described that the TASK channels are involved in the secretion of adrenal hormones in the bulbar ligaments of the adrenal cortex [ Czirjak g., Fischer t., A.，Lesage F.，Enyedi P.；TASK(TWIK-related acid-sensitive K+channel)is expressed in glomerulosa cellsof rat adrenal cortex and inhibited by angiotensin II；MolecularEndocrinology 2000(14)，863-874]。

in cultured cerebellar granule cells, it has been demonstrated that genetic inactivation of the TASK channel causes neuroprotection [ Lauritzen i., Zanzouri m., Honor é e., Duprat f., ehrengrubber m.u., Lazdunski m., Patel a.j.; k + -dependent cerebellar grain neuronopathy-Role of Task leave K + channels; j.biol.chem.2003(278), 32068-. It was also demonstrated that the TASK-1 channel leads to programmed cell death (apoptosis) in granulosa cells and that cell death can be prevented by blocking TASK-3. It is therefore postulated that The development of specific inhibitors of The TASK-1/3 channel may imply a pharmacological strategy for The treatment of neurodegenerative disorders [ Patel a.j., Lazdunski m., The 2P-domain K + channels: roll in apoptosis and tomogenesis, Pfleger Arch.2004(448), 261-.

The TASK-3 gene is amplified and overexpressed in various human Cancer tissues, such as breast, lung, colon and metastatic prostate cancers [ Mu D, Chen L, Zhang X, et al, genomic and oncogenic properties of the KCNK9 porous gene, Cancer Cell 2003(3), 297-302 ]. It has been found that point mutations in TASK-3 cut off the channel function and at the same time abrogate the tumor-forming function. Thus, it is expected that TASK-3 antagonists may reduce the growth of various human cancers and constitute a new family of anticancer drugs [ Pei l., Wiser o., slave a., Mu d., Powers s., Jan l.y., Hoey t.; genetic potential of TASK3(Kcnk9) depends on K + channel function; proc. Natl. Acad. Sci. USA 2003(100), 7803- & 7807 ].

Despite the great physiological importance of the TASK channels, only very small amounts of pharmacological modulators of these channels are known so far in the literature. Activation of the TASK-1 channel by therapeutic concentrations of the inhalation anesthetics halothane and isoflurane is described [ Patel a.j., Honor é e., lesagef., Fink m., Romey g., Lazdunski m; inhalational and reactive to the pore-domain background K + channels; nature Neurosci.1999(2), 422-426]. The only known direct blockers of TASK-1 are arachidonamides Androgram (an endogenous ligand for the cannabinoid receptor) and its methanandamide homologue, which for its part describes an IC of 0.7 μm₅₀Values [ Maigret F., Patel A.J., Lazdunski M.,Honoré E.；The endocannabinoid anandamide is a direct and selective blocker of thebackground K+channel TASK-1；EMBO J.2001(20)，47-54]and also doxorquine, which is used for the treatment of respiratory disorders and for which an IC of 0.4 μm is described₅₀Values [ Cotten j.f., Keshavaprasad b., last m.j., Eger e.i., Yost c.s.; the vehicle stimulus Doxapram inhibition TASK derived Port (K)_2P)Potassium Channel Function but Does Not Affect minimum AlveolarAnesthetic Concentration；Anesth.Analg.2006(102)779-785]。

It has now been found that compounds of formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ij are potent blockers of the TASK channels, particularly the subtypes TASK-1 and TASK-3. These compounds have hitherto only been referred to as Kv1.5 channel blockers, the Kv1.5 channel belonging to the potassium channel with 6 transmembrane domains and 1 pore domain (WO01/00573, WO01/025189, WO02/044137, WO02/046162, WO02/048131, WO02/087568, WO02/088073, WO 02/100825). Given the large structural differences between Kv1.5 channels and TASK channels, the effect of these compounds, known as Kv1.5 blockers, on TASK-1 and TASK-3 channels was surprising.

In view of the inhibitory properties of TASK-1 and/or TASK-3, the compounds of the formulae Ia to Ij and/or their pharmaceutically compatible salts are suitable for the prevention and treatment of disorders caused by TASK-1 and/or TASK-3 activated or activated by TASK-1 and/or TASK-3, and also disorders having TASK-1 and/or TASK-3 associated damage as a secondary cause.

Compounds of formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ij and/or physiologically compatible salts thereof may also be useful in the treatment and prevention of disorders in which TASK-1 and/or TASK-3 is only partially inhibited, for example by using lower doses.

The compounds of formulae Ia-Ij are particularly useful for the treatment or prophylaxis of respiratory disorders, sleep-related respiratory disorders, central and obstructive sleep apneas, cheyne-stokes respiration, snoring, impaired central respiratory drive, sudden child death, post-operative hypoxia and apnea, muscle-related respiratory disorders, respiratory disorders after prolonged ventilation, respiratory disorders during adaptation in high mountains, acute and chronic lung disorders with hypoxia and hypercapnia, neurodegenerative disorders, dementia, alzheimer's disease, parkinson's disease, huntington's chorea, cancerous disorders, breast cancer, lung cancer, colon cancer and prostate cancer.

In addition to the described blockade of TASK channels, the inhibition of other potassium channels, for example Kv channels, may also relate to the use of the compounds of the formulae Ia to Ij according to the invention for the treatment or prophylaxis of respiratory disorders, sleep-related respiratory disorders, central and obstructive sleep apneas, upper airway resistance syndrome, cheynes' breathing, snoring, impaired central respiratory drive, sudden child death, postoperative hypoxia and apnea, muscle-related respiratory disorders, respiratory disorders after long-term ventilation, respiratory disorders during adaptation in mountains, acute and chronic lung disorders with hypoxia and hypercapnia.

The invention relates to the use of Kv1.5 inhibitors for the production of a medicament for the treatment or prevention of respiratory disorders, sleep-related respiratory disorders, central and obstructive sleep apneas, upper airway resistance syndrome, Cheyne-Stokes respiration, snoring, impaired central respiratory drive, sudden child death, postoperative hypoxia and apnea, muscle-related respiratory disorders, respiratory disorders after prolonged ventilation, respiratory disorders during adaptation in high mountains, acute and chronic lung disorders with hypoxia and hypercapnia, neurodegenerative disorders, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, cancer disorders, breast cancer, lung cancer, colon cancer and prostate cancer.

The present invention relates to compounds of formula Ia

Wherein R (8) is 1-indanyl of formula II or 2-indanyl of formula III

And wherein:

r (1) and R (2)

Each independently of the other is R (20) -C_rH_2r

Wherein C is_rH_2rOne CH of the radicals₂The radicals may be substituted by-O-, -CH-, -C-, -CO-O-, -O-CO-, -S-, -SO-, -SO₂a-NR (21) -or-CONR (21) substitution;

r (21) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

r (20) is H, CH₃、CH₂F、CHF₂、CF₃、C₂F₅、C₃F₇Cycloalkyl having 3, 4, 5, 6, 7 OR 8 carbon atoms, NR (22) R (23), -CONR (22) R (23), -OR (24), -COOR (24), phenyl OR an N-containing heterocycle having 1, 2, 3, 4, 5, 6, 7, 8 OR 9 carbon atoms,

wherein the phenyl and the N-containing heterocycle are unsubstituted or substituted by one or two substituents selected from the group consisting of F, Cl, Br, I, CF₃、NO₂、CN、NH₂OH, methyl, ethyl, hydroxymethyl, hydroxyethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; r (22) and R (23)

Each independently hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or

R (22) and R (23)

Together being a chain of 4 or 5 methylene groups, one CH of which₂The groups may be replaced by-O-, -S-, -NH-, -N (methyl) -or-N (benzyl) -;

r (24) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

r is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

or

R (1) and R (2)

r (3), R (4), R (5) and R (6)

Each independently of the others hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, CN, CF₃、NO₂OR (25) OR NR (26) R (27);

r (25) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, formula-C_xH_2xCF_yH_3-yA fluorinated alkyl group or a phenyl group of (a),

unsubstituted or substituted by one or two substituents selected from F, Cl, Br, I, CF₃、NO₂、CN、NH₂OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino;

x is 0, 1, 2 or 3;

y is 1, 2 or 3;

r (26) and R (27)

Each independently hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

or

R (26) and R (27)

r (7) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

r (9) is hydrogen, OR (28) OR OCOR (28);

r (28) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

r (10) and R (11)

Each independently hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

r (12), R (13), R (14) and R (15)

Each independently of the others hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, -CN, -CF₃、-C₂F₅、-C₃F₇、-N₃、-NO₂、-Y-C_sH_2s-R (29), phenyl, thienyl, furyl or an N-containing heterocycle having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,

wherein the phenyl, thienyl, furyl and N-containing heterocycles are unsubstituted or substituted by one or two substituents selected from the group consisting of F, Cl, Br, I, CF₃、NO₂、CN、NH₂OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino;

y is-O-, -CO-O-, -O-CO-, -S-, -SO₂-、-O-SO₂-、-SO₂NR (30) -, -CONR (30) -, or-NR (30) CO-, wherein the bond to the base structure is in each case via the atom on the left;

r (30) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

s is 0, 1, 2, 3, 4, 5 or 6;

r (29) is hydrogen, methyl, CF₃、C₂H₅、C₃F₇Cycloalkyl having 3, 4, 5, 6, 7 OR 8 carbon atoms, -OR (31), -COOR (31), -NR (32) R (33), -CONR (32) R (33), phenyl OR an N-containing heterocycle having 1, 2, 3, 4, 5, 6, 7, 8 OR 9 carbon atoms;

wherein phenyl and containsThe N-heterocyclic ring being unsubstituted or substituted by one or two substituents selected from F, Cl, Br, I, CF₃、NO₂、CN、NH₂OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino;

r (31) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

r (32) and R (33)

Each independently hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

or

R (32) and R (33)

Together being a chain of 4 or 5 methylene groups, one CH of which₂The radicals being possibly substituted by-O-, -S-, -NH-, -N (CH)₃) -or-N (benzyl) -substitution;

and/or compounds of the formula Ib

Wherein:

r (1) is C (O) OR (9), SO₂R (10), COR (11), C (O) NR (12) R (13) or C (S) NR (12) R (13);

r (9) is C_xH_2x-R(14)；

x is 0, 1, 2, 3 or 4,

wherein R (14) is OR (15) OR SO₂Me, x cannot be zero;

r (14) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF₃、C₂F₅、C₃F₇、CH₂F、CHF₂、OR(15)、SO₂Me, phenyl, naphthyl, biphenyl, furyl, thienyl or have 1, 2, 3, 4, 5, 6, 7A N-containing heteroaromatic group of 8 carbon atoms,

wherein the phenyl, naphthyl, biphenyl, furyl, thienyl and N-containing heteroaromatic radicals are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (15) is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF₃Or phenyl

Which is unsubstituted or substituted by 1, 2 or 3 substituents selected from F, Cl, Br, I, CF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (10), R (11) and R (12)

Each independently is as defined for R (9);

r (13) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF₃；

R (2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF₃；

R (3) is C_yH_2y-R(16)；

y is 0, 1, 2, 3 or 4,

wherein R (16) is OR (17) OR SO₂Me, y cannot be 0;

r (16) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF₃、C₂F₅、C₃F₇、CH₂F、CHF₂、OR(17)、SO₂Me, phenyl, naphthyl, furyl, thienyl or N-containing heteroaromatic radicals having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,

wherein the phenyl, naphthyl, furyl, thienyl and N-containing heteroaromatic radicals are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (17) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF₃Phenyl or 2, 3 or 4-pyridyl, wherein phenyl or 2, 3 or 4-pyridyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

or

R (3) is CHR (18) R (19);

r (18) is hydrogen or C_zH_2z-R (16), wherein R (16) is as defined above;

z is 0, 1, 2 or 3;

r (19) is COOH, CONH₂、CONR(20)R(21)、COOR(22)、CH₂OH；

R (20) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, C_vH_2v-CF₃Or C_wH_2w-a phenyl group,

wherein the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

v is 0, 1, 2 or 3;

w is 0, 1, 2 or 3;

r (21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;

r (22) is an alkyl group having 1, 2, 3, 4, or 5 carbon atoms;

r (4) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF₃；

Or

R (3) and R (4)

A chain of 4 or 5 methylene groups together, one of which may be replaced by-O-, -S-, -NH-, -N (methyl) -or-N (benzyl) -;

r (5), R (6), R (7) and R (8)

Each independently hydrogen, F, Cl, Br, I, CF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;

r (30) and R (31)

Each independently hydrogen or alkyl having 1, 2 or 3 carbon atoms;

or

R (30) and R (31)

Together a chain of 2 methylene groups;

and/or compounds of formula Ic

Wherein:

a1, A2, A3, A4, A5, A6, A7 and A8

Each independently is nitrogen, CH or CR5, wherein at least 4 of these groups are CH;

r (9), R (10), R (11) and R (12)

Each independently is C_xH_2x-R(14)；

x is 0, 1, 2, 3 or 4;

wherein R (14) is OR (15) OR SO₂Me, x cannot be 0;

r (14) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF₃、C₂F₅、C₃F₇、CH₂F、CHF₂、OR(15)、SO₂Me, phenyl, naphthyl, biphenyl, furyl, thienyl or N-containing heteroaromatic radicals having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,

r (13) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF₃；

R (2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF₃；

R (3) is C_yH_2y-R(16)；

y is 0, 1, 2, 3 or 4,

wherein R (16) is OR (17) OR SO₂Me, y cannot be 0;

r (16) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF₃、C₂F₅、C₃F₇、CH₂F、CHF₂、OR(17)、SO₂Me, phenyl, naphthyl, furyl, thienyl or a N-containing heteroaromatic radical having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the phenyl, naphthyl, furyl, thienyl and N-containing heteroaromatic radicals are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino,

R(17) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF₃Phenyl or 2, 3 or 4-pyridyl, wherein phenyl or 2, 3 or 4-pyridyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

or

R (3) is CHR (18) R (19);

r (18) is hydrogen or C_zH_2z-R (16), wherein R (16) is as defined above;

z is 0, 1, 2 or 3;

r (19) is COOH, CONH₂CONR (20) R (21), COOR (22) or CH₂OH；

R (20) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, C_vH_2v-CF₃Or C_wH_2w-phenyl radical

Wherein the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

v is 0, 1, 2 or 3;

w is 0, 1, 2 or 3;

r (21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;

r (22) is an alkyl group having 1, 2, 3, 4, or 5 carbon atoms;

r (4) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF₃；

Or

R (3) and R (4)

r (5) is F, Cl, Br, I, CF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino, wherein the R (5) groups are each independently defined for the case where the majority of the A1-A8 groups are defined as CR (5);

r (30) and R (31)

Each independently hydrogen or alkyl having 1, 2 or 3 carbon atoms;

or

R (30) and R (31)

Together a chain of 2 methylene groups;

and/or compounds of formula Id

Wherein:

a1, a2, A3, a4, a5, a6, a7, and A8 are each independently nitrogen, CH, or CR (5), wherein at least one of these groups is nitrogen and at least 4 of these groups are CH;

r (9), R (10), R (11) and R (12)

Each independently is C_xH_2x-R(14)；

x is 0, 1, 2, 3 or 4;

wherein R (14) is OR (15) OR SO₂Me, x cannot be 0;

r (14) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF₃、C₂F₅、C₃F₇、CH₂F、CHF₂、OR(15)、SO₂Me, phenyl, naphthyl, biphenyl, furyl, thienyl or N-containing heteroaromatic radicals having 1, 2, 3, 4, 5, 6, 7 or 9 carbon atoms,

r (15) is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF₃Or phenyl, unsubstituted or substituted by 1, 2 or 3 substituents selected from F, Cl, Br, I, CF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (13) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF₃；

R (2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF 3;

R(3)is C_yH_2y-R(16)；

y is 0, 1, 2, 3 or 4,

wherein R (16) is OR (17) OR SO₂Me, y cannot be 0;

or

R (3) is CHR (18) R (19);

r (18) is hydrogen or C_zH_2z-R (16), wherein R (16) is as defined above;

z is 0, 1, 2 or 3;

r (19) is COOH, CONH₂CONR (20) R (21), COOR (22) or CH₂OH；

v is 0, 1, 2 or 3;

w is 0, 1, 2 or 3;

r (21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;

r (22) is an alkyl group having 1, 2, 3, 4, or 5 carbon atoms;

r (4) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF₃；

Or

R (3) and R (4)

r (5) is each independently F, Cl, Br, I, CF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino, wherein the R (5) groups are each independently defined for the case where the majority of the a1-A8 groups are defined as CR (5);

r (30) and R (31)

Each independently hydrogen or alkyl having 1, 2 or 3 carbon atoms;

or

R (30) and R (31)

A chain of oxygen or 2 methylene groups together;

and/or a compound of formula Ie or If

Wherein:

x is oxygen or sulfur;

r (9), R (10), R (11) and R (12)

Each independently is C_xH_2x-R(14)；

x is 0, 1, 2, 3 or 4;

wherein R (14) is OR (15) OR SO₂Me, x cannot be 0;

r (13) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF₃；

R (2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF₃；

R (3) is C_yH_2y-R(16)；

y is 0, 1, 2, 3 or 4,

wherein R (16) is OR (17) OR SO₂Me, y cannot be 0;

r (16) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF₃、C₂F₅、C₃F₇、CH₂F、CHF₂、OR(17)、SO₂Me, phenyl, naphthyl, furyl, thienyl or a N-containing heteroaromatic radical having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the phenyl, naphthyl, furyl, thienyl and N-containing heteroaromatic radicals are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, having 1, 2, 3 or 4 carbonsAn alkyl group of atoms, an alkoxy group having 1, 2, 3 or 4 carbon atoms, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group and a methylsulfonylamino group,

or

R (3) is CHR (18) R (19);

r (18) is hydrogen or C_zH_2z-R (16), wherein R (16) is as defined above;

z is 0, 1, 2 or 3;

r (19) is COOH, CONH₂CONR (20) R (21), COOR (22) or CH₂OH；

v is 0, 1, 2 or 3;

w is 0, 1, 2 or 3;

r (21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;

r (22) is an alkyl group having 1, 2, 3, 4, or 5 carbon atoms;

r (4) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF₃；

Or

R (3) and R (4)

r (5), R (6) and R (7)

Each independently of the others being hydrogen, F, Cl, Br, I, CF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;

r (30) and R (31)

Each independently hydrogen or alkyl having 1, 2 or 3 carbon atoms;

or

R (30) and R (31)

A chain of oxygen or 2 methylene groups together;

and/or a compound of formula Ig

Wherein

R (1) is (CH)₂)_x-R(8)

x is 0, 1, 2, 3, 4 or 5,

r (8) is phenyl, thienyl or furyl,

wherein the phenyl, thienyl and furyl groups are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (2) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

r (3) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

r (4) is alkyl having 3, 4, 5, 6 or 7 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, phenyl, naphthyl or heteroaryl,

wherein the phenyl and heteroaryl groups are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃、NO₂、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, methylsulfonyl and methylsulfonylamino;

r (5), R (6) and R (7)

Each independently is F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

and/or a compound of formula Ih

Wherein:

or

A is-C_nH_2n-；

n is 0, 1, 2, 3, 4 or 5;

o is oxygen;

d is a bond or oxygen;

e is-C_mH_2m-；

m is 0, 1, 2, 3, 4 or 5;

r (8) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or C_pH_2p-R(14)；

p is 0, 1, 2, 3, 4 or 5;

r (14) is cycloalkyl having 3, 4, 5 or 6 carbon atoms, aryl or heteroaryl, wherein aryl and heteroaryl are each unsubstituted or substituted with 1, 2 or 3 substituents selected from F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (9) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;

r (10) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl, aryl or heteroaryl having 3, 4, 5 or 6 carbon atoms,

wherein aryl and heteroaryl are each unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (11) is cycloalkyl having 3, 4, 5 or 6 carbon atoms, phenyl, naphthyl, thienyl, furyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl,

wherein phenyl, naphthyl, thienyl, furyl, pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl are each unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (12) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, aryl or heteroaryl,

r (13) is C_pH_2p-R(14’)；

P is 0, 1, 2, 3, 4 or 5;

r (14') is cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, aryl or heteroaryl having 3, 4, 5 or 6 carbon atoms,

r (15) is cycloalkyl having 3, 4, 5, 6, 7, or 8 carbon atoms;

r (2) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

r (3) is alkyl having 3, 4, 5, 6 or 7 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, phenyl or naphthyl,

wherein phenyl or naphthyl is each unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (4), R (5), R (6) and R (7)

Each independently hydrogen, F, Cl, Br, I, CF₃、OCF₃、OCHF₂、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

and/or compounds of formula Ij

Wherein:

or

A is-C_nH_2n-；

n is 0, 1, 2, 3, 4 or 5;

d is a bond or-O-;

e is-C_m2_2m-；

m is 0, 1, 2, 3, 4 or 5;

r (8) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or C_pH_2p-R(14)；

p is 0, 1, 2, 3, 4 or 5;

r (14) is phenyl, naphthyl or heteroaryl,

wherein phenyl, naphthyl and heteroaryl are each unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (9) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;

r (10) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, phenyl, naphthyl or heteroaryl,

wherein phenyl, naphthyl and heteroaryl are each unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylsulfamoylA group;

r (11) is cycloalkyl having 3, 4, 5 or 6 carbon atoms, phenyl, naphthyl, thienyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl or cinnolinyl, wherein phenyl, naphthyl, thienyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl or cinnolinyl are each unsubstituted or substituted by 1, 2 or 3 substituents selected from F, Cl, Br, I, CF, Cl, Br, I₃、OCF₃、NO₂、CN、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (12) is alkyl having 1, 2, 3 or 4 carbon atoms, alkynyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, phenyl, naphthyl or heteroaryl,

r (13) is C_pH_2p-R(14)；

p is 0, 1, 2, 3, 4 or 5;

r (15) is cycloalkyl having 3, 4, 5, 6, 7, or 8 carbon atoms;

r (2) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

r (3) is a heteroaryl group,

wherein the heteroaryl is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (4), R (5), R (6) and R (7)

Each independently hydrogen, F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

and/or physiologically compatible salts of compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ij, for the manufacture of a medicament for the treatment or prophylaxis of respiratory disorders, sleep-related respiratory disorders, central and obstructive sleep apneas, upper airway resistance syndrome, Cheyne-Stokes respiration, snoring, impaired central respiratory drive, sudden child death, postoperative hypoxia and apnea, muscle-related respiratory disorders, respiratory disorders after long-term ventilation, respiratory disorders during adaptation in mountains, acute and chronic lung disorders with hypoxia and hypercapnia, neurodegenerative disorders, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, cancer disorders, breast cancer, lung cancer, colon cancer and prostate cancer.

Preferably of the formulae Ia to Ij and/or physiologically compatible salts thereof, for the production of a medicament for the treatment or prophylaxis of respiratory disorders, in particular sleep apnoea and cancerous disorders.

The use of compounds of the formulae Ia to Ij and/or their physiologically compatible salts for the production of medicaments for the treatment or prophylaxis of respiratory disorders, in particular sleep-related respiratory disorders such as central and obstructive sleep apneas, upper airway resistance syndrome, Cheyne-Stokes respiration, snoring, impaired central respiratory drive (sudden childhood death, postoperative hypoxia and apnea), muscle-related respiratory disorders, respiratory disorders after prolonged ventilation, respiratory disorders during adaptation in mountains, acute and chronic lung disorders with hypoxia and hypercapnia.

A further use of the compounds of the formulae Ia to Ij and/or their physiologically compatible salts is for the production of medicaments for the treatment or prophylaxis of respiratory disorders, in particular sleep-related respiratory disorders such as central and obstructive sleep apnea, cheyne-stokes respiration, snoring, impaired central respiratory drive (sudden childhood death, postoperative hypoxia and apnea), muscle-related respiratory disorders, respiratory disorders after prolonged ventilation, respiratory disorders during adaptation in high mountains, acute and chronic lung disorders with hypoxia and hypercapnia.

Preferred uses of the compounds of formulae Ia to Ij and/or physiologically compatible salts thereof are in the manufacture of medicaments for the treatment or prevention of sleep-related respiratory disorders, such as central and obstructive sleep apnea, upper airway resistance syndrome and snoring.

Another preferred use of the compounds of the formulae Ia to Ij and/or their physiologically compatible salts is the production of medicaments for the treatment or prophylaxis of sleep apneas, for example central and obstructive sleep apneas and snoring.

Another use of the compounds of the formulae Ia to Ij and/or their physiologically compatible salts is for the production of medicaments for the treatment or prophylaxis of neurodegenerative disorders, such as dementia, Alzheimer's disease, Parkinson's disease, Huntington's chorea.

Another use of a compound of formulae Ia-Ij and/or physiologically compatible salts thereof is in the manufacture of a medicament for the treatment or prevention of cancerous disorders, such as breast, lung, colon and prostate cancer.

In one embodiment, the compounds of the formulae Ia to Ij are used for the production of medicaments for intravenous administration, in particular for the production of medicaments for intravenous administration for the treatment or prophylaxis of respiratory disorders, preferably sleep-related respiratory disorders such as central and obstructive sleep apneas, upper airway resistance syndrome and snoring, for example sleep-related respiratory disorders such as central and obstructive sleep apneas and snoring.

In another embodiment, the compounds of formulae Ia-Ij are used for the manufacture of medicaments for oral administration, in particular for the manufacture of medicaments for oral administration for the treatment or prophylaxis of respiratory disorders, preferably sleep-related respiratory disorders such as central and obstructive sleep apneas, upper airway resistance syndrome and snoring, for example sleep-related respiratory disorders such as central and obstructive sleep apneas and snoring.

In another embodiment, the compounds of formulae Ia-Ij are used for the manufacture of a medicament for nasal administration, in particular for the manufacture of a medicament for nasal administration for the treatment or prophylaxis of respiratory disorders, preferably sleep-related respiratory disorders such as obstructive sleep apnea, upper airway resistance syndrome and snoring, for example sleep-related respiratory disorders such as obstructive sleep apnea and snoring.

In one embodiment, compounds of formula Ia are used, wherein:

r (1) is hydrogen;

r (2) is R (20) -C_rH_2r；

R (20) is CH₃、CH₂F、CHF₂、CF₃Cycloalkyl having 3, 4, 5, 6, 7 OR 8 carbon atoms, -CONR (22) R (23), -OR (24), -COOR (24) OR phenyl which is unsubstituted OR substituted by 1 OR 2 substituents selected from F, Cl, Br, CF₃、NO₂CN, OH, methyl, ethyl, hydroxymethyl, hydroxyethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino;

r (22) and R (23)

Each independently hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

or

R (22) and (R (23)

r (24) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

r is 0, 1, 2, 3, 4 or 5;

r (3), R (4), R (5) and R (6)

Each independently of the others hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, CN, CF₃、NO₂OR OR (25);

r (25) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, formula-C_xH_2xCF_yH_3-yUnsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, CF₃、NO₂CN, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino;

x is 0, 1, 2 or 3;

y is 1, 2 or 3;

r (7) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

r (8) is 1-indanyl of formula II;

r (9) is hydrogen OR OR (28);

r (28) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

r (10) and R (11)

Each independently hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

r (12), R (13), R (14) and R (15)

Each independently of the others hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, CN, CF₃、-NO₂or-Y-C_sH_2s-R(29)；

r (30) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

s is 0, 1, 2, 3, 4 or 5;

r (29) is hydrogen, methyl, CF₃-OR (31), -COOR (31), -NR (32) R (33), -CONR (32) R (33) OR phenyl,

unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, CF₃、NO₂CN, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino;

r (31) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

r (32) and R (33)

Each independently hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

or

R (32) and R (33)

and/or a compound of formula Ib, wherein:

r (1) is C (O) OR (9), SO₂R (10), COR (11) or C (O) NR (12) R (13);

r (9) is C_xH_2x-R(14)；

x is 0, 1, 2, 3 or 4,

wherein when R (14) is OR (15), x cannot be 0;

r (14) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃、C₂F₅OR (15), phenyl, furyl, thienyl OR a N-containing heteroaromatic radical having 1, 2, 3, 4, 5, 6, 7, 8 OR 9 carbon atoms,

wherein the phenyl, furyl, thienyl and N-containing heteroaromatic radical are each unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

Which is unsubstituted or substituted by 1, 2 or 3 substituents selected from F, Cl, Br, CF₃、NO₂、CN、COOMe、CONH₂COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (10), R (11) and R (12)

Each independently is as defined for R (9);

r (13) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF₃；

R (2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF₃；

R (3) is C_yH_2y-R(16)；

y is 0, 1, 2, 3 or 4,

wherein when R (16) is OR (17), y cannot be 0;

r (16) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃、C₂F₅OR (17), phenyl, furyl, thienyl OR a N-containing heteroaromatic radical having 1, 2, 3, 4, 5, 6, 7, 8 OR 9 carbon atoms,

r (17) is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF₃Phenyl or 2, 3 or 4-pyridyl, wherein phenyl or 2, 3 or 4-pyridyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

or

R (3) is CHR (18) R (19);

r (18) is hydrogen or C_zH_2z-R (16), wherein R (16) is as defined above

z is 0, 1, 2 or 3;

r (19) is CONH₂、CONR(20)R(21)、COOR(22)、CH₂OH；

wherein the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from F, Cl, Br, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

v is 0, 1, 2 or 3;

w is 0, 1, 2 or 3;

r (21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;

r (22) is an alkyl group having 1, 2, 3, 4, or 5 carbon atoms;

r (4) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF₃；

R (5), R (6), R (7) and R (8)

Each independently hydrogen, F, Cl, Br, CF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;

r (30) and R (31)

Each independently hydrogen or alkyl having 1, 2 or 3 carbon atoms;

or

R (30) and R (31)

Together a chain of 2 methylene groups;

and/or a compound of formula Ic, wherein:

a1, A2, A3, A4, A5, A6, A7 and A8

Each independently is nitrogen, CH or CR (5), wherein no more than one of these groups is nitrogen and at least 5 of these groups are CH;

r (1) is C (O) OR (9), SO₂R (10), COR (11) or C (O) NR (12) R (13);

r (9), R (10), R (11) and R (12)

Each independently is C_xH_2x-R(14)；

x is 0, 1, 2, 3 or 4;

R(14)

is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃Phenyl, naphthyl, biphenyl, furyl, thienyl or N-containing heteroaromatic radicals having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,

wherein the phenyl, naphthyl, biphenyl, furyl, thienyl and N-containing heteroaromatic radicals are each unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (13) is hydrogen;

r (2) is hydrogen or methyl;

r (3) is C_yH_2y-R(16)；

y is 0, 1, 2, 3 or 4;

wherein when R (16) is OR (17), y cannot be 0;

r (16) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃、OR(17)、SO₂Me, phenyl, naphthyl, furyl, thienyl or N-containing heteroaromatic radicals having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,

wherein the phenyl, naphthyl, furyl, thienyl and the N-containing heteroaromatic radical are each unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、NO₂、OCF₃、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (17) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF₃Phenyl or 2, 3 or 4-pyridyl, wherein phenyl or 2, 3 or 4-pyridyl are each unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (4) is hydrogen, alkyl having 1 or 2 carbon atoms;

r (5) is F, Cl, Br, I, CF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;

r (30) and R (31)

Each independently is hydrogen or methyl;

and/or a compound of formula (Id) wherein:

a1, a2, A3, a4, a5, a6, a7 and A8 are each independently nitrogen, CH or CR (5), wherein at least one of these groups and at most two of these groups are nitrogen and at least 4 of these groups are CH;

r (1) is C (O) OR (9), SO₂R (10), COR (11) or C (O) NR (12) R (13) R (9), R (10), R (11) and R (12)

Each independently is C_xH_2x-R(14)；

x is 0, 1, 2, 3 or 4;

wherein when R (14) is OR (15), x cannot be 0;

r (14) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃OR (15), phenyl, naphthyl, biphenyl, furyl, thienyl OR a N-containing heteroaromatic radical having 1, 2, 3, 4, 5, 6, 7, 8 OR 9 carbon atoms,

wherein the phenyl, naphthyl, biphenyl, furyl, thienyl and the N-containing heteroaromatic radical are each unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (15) is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF₃Or phenyl, unsubstituted or substituted by 1, 2 or 3 substituents selected from F, Cl, Br, I, CF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, diMethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino;

r (13) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF₃；

R (2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF₃；

R (3) is C_yH_2y-R(16)；

y is 0, 1, 2, 3 or 4,

wherein R (16) is OR (17) OR SO₂When M, y cannot be 0;

wherein the phenyl, naphthyl, furyl, thienyl and the N-containing heteroaromatic radical are each unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (17) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF₃Phenyl or 2, 3 or 4-pyridyl, wherein phenyl or 2, 3 or 4-pyridyl are each unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylAn alkylsulfonylamino group;

or

R (3) is CHR (18) R (19);

r (18) is hydrogen or C_zH_2z-R (16), wherein R (16) is as defined above;

z is 0, 1, 2 or 3;

r (19) is CONH₂CONR (20) R (21), COOR (22) or CH₂OH；

v is 0, 1, 2 or 3;

w is 0, 1, 2 or 3;

r (21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;

r (22) is an alkyl group having 1, 2, 3, 4, or 5 carbon atoms;

r (4) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF₃；

R (5) is each independently F, Cl, Br, I, CF₃、NO₂、CN、COOMe、CONH₂、COMe、NH₂OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;

r (30) and R (31)

Each independently hydrogen or alkyl having 1, 2 or 3 carbon atoms;

or

R (30) and R (31)

Is a chain of 2 methylene groups;

and/or a compound of formula Ie or If, wherein:

x is oxygen or sulfur;

r (1) is C (O) OR (9) OR COR (11);

r (9) and R (11)

Each independently is C_xH_2x-R(14)；

x is 0, 1, 2 or 3;

r (14) is cycloalkyl having 5 or 6 carbon atoms or phenyl

Wherein the phenyl group is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF₃、OCF₃OH, alkyl having 1, 2 or 3 carbon atoms or alkoxy having 1 or 2 carbon atoms;

r (2) is hydrogen;

r (3) is C_yH_2y-R(16)；

y is 0, 1 or 2;

r (16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, phenyl or pyridyl,

wherein phenyl and pyridyl are each unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, CF₃Alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbon atoms;

r (4) is hydrogen;

r (5), R (6) and R (7)

Each independently hydrogen, F, Cl, alkyl having 1, 2, or 3 carbon atoms, or alkoxy having 1 or 2 carbon atoms;

r (30) and R (31)

Each is hydrogen;

and/or a compound of formula Ig, wherein:

r (1) is (CH)₂)_x-R(8)

x is 1 or 2;

r (8) is phenyl, thienyl or furyl,

wherein phenyl, thienyl and furyl are each unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF₃、OCF₃、CN、COOMe、CONH₂COMe, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1, 2 or 3 carbon atoms, sulfamoyl, methylsulfonyl and methylsulfonyl hydride;

r (2) is hydrogen or alkyl having 1 or 2 carbon atoms;

r (3) is hydrogen;

r (4) is phenyl

Wherein the phenyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF₃、OCF₃COMe, alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1, 2 or 3 carbon atoms;

r (5), R (6) and R (7)

Each independently of the others being F, Cl, Br, CF₃、OCF₃、CN、COOMe、CONH₂COMe, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

and/or a compound of formula Ih, wherein:

r (1) isOr

A is-C_nH_2n-；

n is 0, 1, 2 or 3;

o is oxygen;

d is a bond or oxygen;

e is-C_mH_2m-；

m is 0, 1, 2 or 3;

r (8) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

r (9) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;

r (10) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4 or 5 carbon atoms,

r (11) is cycloalkyl having 3, 4, 5 or 6 carbon atoms, phenyl or pyridyl,

wherein phenyl and pyridyl are each unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF₃、OCF₃、NO₂CN, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (12) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4 or 5 carbon atoms, aryl or heteroaryl,

wherein aryl and heteroaryl are each unsubstituted or substituted by 1, 2 or 3 substituents selected from F, Cl, Br, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂COMe, OH, having 1, 2,Alkyl of 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (13) is C_pH_2p-R(14’)；

p is 0, 1, 2, 3, 4 or 5;

wherein aryl and heteroaryl are each unsubstituted or substituted by 1, 2 or 3 substituents selected from F, Cl, Br, CF₃、OCF₃、NO₂、CN、COOMe、CONH₂COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (2) is hydrogen or alkyl having 1 or 2 carbon atoms;

r (3) is an alkyl group having 3, 4 or 5 carbon atoms or a phenyl group;

wherein the phenyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF₃、OCF₃、NO₂、COOMe、CONH₂COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r (4), R (5), R (6) and R (7)

Each independently hydrogen, F, Cl, Br, CF₃、OCF₃、OCHF₂、NO₂、CN、COOMe、CONH₂COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

and/or a compound of formula Ij, wherein:

r (1) isOr

A is-C_nH_2n-；

n is 0, 1, 2, 3, 4 or 5;

d is a bond or-O-;

e is-C_mH_2m-；

m is 0, 1, 2, 3, 4 or 5;

r (8) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or C_pH_2p-R(14)；

p is 0, 1, 2, 3, 4 or 5;

r (14) is phenyl, naphthyl or heteroaryl,

r (9) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;

r (13) is C_pH_2p-R(14)；

p is 0, 1, 2, 3, 4 or 5;

r (15) is cycloalkyl having 3, 4, 5, 6, 7, or 8 carbon atoms;

r (2) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

r (3) is heteroaryl

r (4), R (5), R (6) and R (7)

and/or physiologically compatible salts of compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ij.

In another embodiment, compounds of formula Ia are used.

In another embodiment, compounds of formula Ib are used.

In another embodiment, compounds of formula Ic are used.

In another embodiment, compounds of formula Id are used.

In another embodiment, compounds of formula Ie are used.

In another embodiment, compounds of formula If are used.

In another embodiment, a compound of formula Ig is used.

In another embodiment, compounds of formula Ih are used.

In another embodiment, compounds of formula Ij are used.

Particular preference is given to the use of compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ih and Ij.

In one embodiment, preference is given to compounds of the formula Ia in which R (8) is a 1-indanyl group of the formula II, for example a 1-indanyl group of the formula II in which R9, R10, R11, R12, R13, R14 and R15 are each hydrogen.

In another embodiment, preference is given to compounds of the formula Ia in which R (1) is hydrogen.

In another embodiment, preference is given to compounds of the formula Ia in which R (2) is R (20) -C_rH_2rWherein R (20) is CH₃、CH₂F、CHF₂、CF₃Cycloalkyl having 3, 4, 5, 6, 7 OR 8 carbon atoms, -CONR (22) R (23), -OR (24), -COOR (24) OR phenyl, unsubstituted OR substituted with 1 OR 2 substituents selected from F, Cl, Br, CF₃、NO₂CN, OH, methyl, ethyl, hydroxymethyl, hydroxyethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino and r is 0, 1, 2, 3, 4, or 5; particular preference is given to compounds of the formula Ia in which R (2) is R (20) -C_rH_2rWherein R (20) is CH₃And r is 4.

In another embodiment, preference is given to compounds of the formula Ia in which R (3), R (4), R (5) and R (6) are each independently of the other hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, CN, CF₃、NO₂OR OR (25); particular preference is given to compounds of the formula Ia in which R (3), R (4), R (5) and R (6) are each independently of the other hydrogen or alkyl having 1, 2 or 3 carbon atoms, for example methyl; particular preference is given to compounds of the formula Ia in which R (3), R (4) and R (5) are each hydrogen and R (6) is methyl.

In another embodiment, preference is given to compounds of the formula Ia in which R (7) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, for example hydrogen.

In one embodiment, preference is given to compounds of the formula Ib in which R (1) is C (O) OR (9) OR COR (11), in which R (9) and R (11) are each C_xH_2x-R (14), wherein x is 0, 1, 2 or 3 and R (14) is cycloalkyl having 5 or 6 carbon atoms or phenyl, wherein phenyl is unsubstituted or substituted with 1 or 2 substituents selected from F, Cl, CF₃、OCF₃Alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbon atoms; particular preference is given to compounds of the formula Ib in which R (1) is C (O) OR (9) OR COR (11), in which R (9) and R (11) are each C_xH_2x-R (14), wherein x is 1 or 2 and R (14) is phenyl, wherein phenyl is unsubstituted or substituted by one substituent selected from alkoxy having 1 or 2 carbon atoms, such as methoxy.

In another embodiment, preference is given to compounds of the formula Ib in which R (2) is hydrogen.

In another embodiment, preference is given to compounds of the formula Ib in which R (3) is C_yH_2y-R (16) wherein y is 0, 1, 2 or 3 and R (16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, CF₃OR17, phenyl OR pyridyl, wherein R17 is hydrogen and wherein phenyl and pyridyl are each unsubstituted OR substituted with 1 OR 2 substituents selected from F, Cl, CF₃、OCF₃Alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbon atoms; particular preference is given to compounds of the formula Ib wherein R (3) is C_yH_2y-R (16), wherein y is 1, 2 OR 3 and R (16) is OR17, phenyl OR pyridyl, wherein R17 is hydrogen and wherein phenyl and pyridyl are each unsubstituted OR substituted with 2 substituents selected from F and Cl, e.g. F.

In another embodiment, preference is given to compounds of the formula Ib in which R (4) is hydrogen or alkyl having 1 or 2 carbon atoms, for example hydrogen or methyl.

In another embodiment, preference is given to compounds of the formula Ib in which R (5), R (6), R (7) and R (8) are each independently of the other hydrogen, F, Cl, CF₃Alkyl having 1, 2 or 3 carbon atoms or alkoxy having 1 or 2 carbon atoms; particular preference is given to compounds of the formula Ib in which R (5) is hydrogen or Cl and R (6), R (7) and R (8) are each hydrogen.

In another embodiment, preference is given to compounds of the formula Ib in which R (30) and R (31) are each hydrogen.

In one embodiment, preference is given to compounds of the formula Ic in which a1, a2, A3, a4, a5, a6, a7 and A8 are each independently of the other nitrogen, CH or CR (5), where at most one of these radicals is nitrogen and at least 5 of these radicals are CH; particular preference is given to compounds of the formula Ic in which A1 is CR (5) in which R (5) is alkyl having 1, 2 or 3 carbon atoms, for example methyl, and A2, A3, A4, A5, A6, A7 and A8 are each CH.

In another embodiment, preference is given to compounds of the formula Ic in which R (1) is C (O) OR (9) OR COR (11), in which R (9) and R (11) are each independently of the other C_xH_2x-R (14), wherein x is 0, 1, 2 or 3 and R (14) is cycloalkyl having 5 or 6 carbon atoms or phenyl, wherein phenyl is unsubstituted or substituted with 1 or 2 substituents selected from F, Cl, Br, I, CF₃、OCF₃OH, alkyl having 1, 2 or 3 carbon atoms or alkoxy having 1 or 2 carbon atoms; particular preference is given to compounds of the formula Ic in which R (1) is COR (11) in which R (11) is C_xH_2x-R (14), wherein x is 2 and R (14) is phenyl, wherein phenyl is substituted with one substituent selected from alkoxy having 1 or 2 carbon atoms, such as methoxy.

In another embodiment, preference is given to compounds of the formula Ic in which R (2) is hydrogen.

In another embodiment, preference is given to compounds of the formula Ic in which R (3) is C_yH_2y-R (16), wherein y is 0, 1, 2, 3 or 4 and R (16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, phenyl or pyridyl, wherein phenyl and pyridyl are each unsubstituted or substituted with 1, 2 substituents selected from F, Cl, CF₃、OCF₃Alkyl having 1, 2 or 3 carbon atoms or alkoxy having 1 or 2 carbon atoms; particular preference is given to compounds of the formula Ic in which R (3) is C_yH_2y-R (16), wherein y is 4 and R (16) is an alkyl group having 1, 2 or 3 carbon atoms, such as methyl.

In another embodiment, preference is given to compounds of the formula Ic in which R (4) is hydrogen.

In another embodiment, preference is given to compounds of the formula Ic in which R (30) and R (31) are each hydrogen.

In one embodiment, preference is given to compounds of the formula Id in which one of a1, a4 and a7 is nitrogen and in each case the other of a1, a4 and a7 and a2, A3, a5, a6 and A8 are each independently CH or CR (5), where at least 5 of these radicals are CH; particular preference is given to compounds of the formula Id in which one of a1, a4 and a7 is nitrogen and in each case the other of a1, a4 and a7 and a2, A3, a5, a6 and A8 are each CH.

In another embodiment, preference is given to compounds of the formula Id in which R (1) is C (O) OR (9) OR COR (11), in which R (9) and R (11) are each independently of the other C_xH_2x-R (14), wherein x is 0, 1, 2 or 3 and R (14) is cycloalkyl having 5 or 6 carbon atoms or phenyl, wherein phenyl is unsubstituted or substituted with 1 or 2 substituents selected from F, Cl, Br, I, CF₃、OCF₃OH, alkyl having 1, 2 or 3 carbon atoms or alkoxy having 1 or 2 carbon atoms; particular preference is given to compounds of the formula Id in which R (1) is C (O) OR (9) OR COR (11), in which R (9) and R (11) are each independently of the other C_xH_2x-R (14), wherein x is 1, 2 or 3 and R (14) is phenyl.

In another embodiment, preference is given to compounds of the formula Id in which R (2) is hydrogen.

In another embodiment, preference is given to compounds of the formula Id in which R (3) is C_yH_2y-R (16), wherein y is 0, 1, 2, 3 or 4 and R (16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, phenyl or pyridyl, wherein phenyl and pyridyl are each unsubstituted or substituted with 1 or 2 substituents selected from F, Cl, CF and the like₃Alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbon atoms; particular preference is given to compounds of the formula Id in which R (3) is C_yH_2y-R (16), wherein y is 1, 2 or 4 and R (16) is alkyl having 1, 2 or 3 carbon atoms, such as methyl, cycloalkyl having 3 carbon atoms, phenyl or pyridyl, wherein phenyl and pyridyl are each unsubstituted or substituted with 2 substituents selected from F or Cl, such as F.

In another embodiment, preference is given to compounds of the formula Id in which R (4) is hydrogen.

In another embodiment, preference is given to compounds of the formula Id in which R (30) and R (31) are each hydrogen.

In another embodiment, preference is given to compounds of the formula Ie in which X is oxygen or sulfur, for example sulfur.

In another embodiment, preference is given to compounds of the formula Ie in which R (1) is C (O) OR (9) OR COR (11), in which R (9) and R (11) are each independently of the other C_xH_2x-R (14), wherein x is 0, 1, 2, 3 or 4 and R (14) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 5 or 6 carbon atoms or phenyl, wherein the phenyl is unsubstituted or substituted with 1 or 2 substituents selected from F, Cl, Br, I, CF₃、OCF₃OH, alkyl having 1, 2 or 3 carbon atoms or alkoxy having 1 or 2 carbon atoms; particular preference is given to compounds of the formula Ie in which R (1) is COR (11) and in which R (11) is C_xH_2x-R (14), wherein x is 1 and R (14) is phenyl,wherein the phenyl group is substituted with one substituent selected from alkoxy groups having 1 or 2 carbon atoms, such as methoxy.

In another embodiment, preference is given to compounds of the formula Ie in which R (2) is hydrogen.

In another embodiment, preference is given to compounds of the formula Ie in which R (3) is C_yH_2y-R (16), wherein y is 0, 1 or 2 and R (16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, phenyl or pyridyl, wherein phenyl and pyridyl are each unsubstituted or substituted with 1, 2 or 3 substituents selected from F, Cl, CF₃An alkyl group having 1, 2 or 3 carbon atoms or an alkoxy group having 1 or 2 carbon atoms; particular preference is given to compounds of the formula Ie in which R (3) is C_yH_2y-R (16), wherein y is 1 and R (16) is phenyl, wherein phenyl is substituted with 2 substituents selected from F and Cl, e.g. F.

In another embodiment, preference is given to compounds of the formula Ie in which R (4) is hydrogen.

In another embodiment, preference is given to compounds of the formula Ie in which R (5), R (6) and R (7) are each hydrogen.

In another embodiment, preference is given to compounds of the formula Ie in which R (30) and R (31) are each hydrogen.

In another embodiment, preference is given to compounds of the formula If in which X is oxygen or sulfur.

In another embodiment, preference is given to compounds of the formula If in which R (1) is C (O) OR (9) OR COR (11), in which R (9) and R (11) are each independently of the other C_xH_2x-R (14), wherein x is 0, 1, 2, 3 or 4 and R (14) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 5 or 6 carbon atoms or phenyl, wherein the phenyl is unsubstituted or substituted with 1 or 2 substituents selected from F, Cl, Br, I, CF₃、OCF₃OH, alkyl having 1, 2 or 3 carbon atomsOr alkoxy having 1 or 2 carbon atoms; particular preference is given to compounds of the formula If in which R (1) is COR (11) in which R (11) is C_xH_2x-R (14), wherein x is 1 and R (14) is phenyl, wherein phenyl is substituted with 1 substituent selected from alkoxy having 1 or 2 carbon atoms, such as methoxy.

In another embodiment, preference is given to compounds of the formula If in which R (2) is hydrogen.

In another embodiment, preference is given to compounds of the formula If in which R (3) is C_yH_2y-R (16), wherein y is 0, 1, 2, 3 or 4 and R (16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, phenyl or pyridyl, wherein phenyl and pyridyl are each unsubstituted or substituted with 1, 2 or 3 substituents selected from F, Cl, CF₃An alkyl group having 1, 2 or 3 carbon atoms or an alkoxy group having 1 or 2 carbon atoms; particular preference is given to compounds of the formula If in which R (3) is C_yH_2y-R (16) wherein y is 1 or 4 and R (16) is an alkyl group having 1, 2 or 3 carbon atoms, such as methyl, or phenyl, wherein phenyl is substituted with 2 substituents selected from F and Cl, such as F.

In another embodiment, preference is given to compounds of the formula If in which R (4) is hydrogen.

In another embodiment, preference is given to compounds of the formula If in which R (5), R (6) and R (7) are each hydrogen.

In another embodiment, preference is given to compounds of the formula If in which R (30) and R (31) are each hydrogen.

In another embodiment, preference is given to compounds of the formula Ih in which R (1) isWherein A is-C_nH_2n-, where n is 0, 1 or 2, D is a bond or oxygen, E is-C_mH_2m-, where m is 0 or1, R (8) is hydrogen or has 1, 2, 3 or 4 carbon atomsR (9) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, R (12) is alkyl having 1, 2, 3 or 4 carbon atoms or cyclopropyl and R (11) is phenyl or pyridyl, wherein phenyl and pyridyl are each unsubstituted or substituted with 1, 2 or 3 substituents selected from F, Cl, CF, and₃、OCF₃CN, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; particular preference is given to compounds of the formula Ih in which R (1) isWherein A is-C_nH_2n-, where n is 0, D is a bond, E is-C_mH_2m-, wherein m is 0, R (8) and R (9) are each hydrogen, R (12) is an alkyl group having 1, 2 or 3 carbon atoms, such as ethyl, and R (11) is phenyl or pyridyl, wherein phenyl and pyridyl are each unsubstituted or substituted by 1 substituent selected from alkoxy groups having 1 or 2 carbon atoms, such as methoxy.

In another embodiment, preference is given to compounds of the formula Ih in which R (2) is hydrogen.

In another embodiment, preference is given to compounds of the formula Ih in which R (3) is alkyl having 3, 4 or 5 carbon atoms or phenyl, wherein the phenyl is unsubstituted or substituted by 1, 2 or 3 substituents selected from F, Cl, CF₃、OCF₃、COOMe、CONH₂COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; particular preference is given to compounds of the formula Ih in which R (3) is alkyl having 3, 4 or 5 carbon atoms, for example 4 carbon atoms, or phenyl, wherein phenyl is substituted by 1 substituent selected from alkoxy having 1 or 2 carbon atoms, for example methoxy.

In another embodiment, preference is given to compounds of the formula Ih in which R (5) is hydrogen or methoxy and R (4), R (6) and R (7) are each hydrogen.

In another embodiment, preference is given to compounds of the formula Ij, in which R (1) is

Wherein A is-C_nH_2n-, where n is 0 or1, D is a bond or-O-, E is-C_mH_2m-, where m is 0 or1, R (8) is hydrogen or alkyl having 1, 2 or 3 carbon atoms, R (9) is hydrogen, ethyl or methyl, R (11) is phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl or cinnolinyl, where phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl or cinnolinyl are each unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF₃、OCF₃CN, COMe, methoxy, ethoxy, dimethylamino, sulfamoyl and methylsulfonyl, and R (12) is alkyl having 1, 2 or 3 carbon atoms, ethynyl, cyclopropyl, phenyl, naphthyl or heteroaryl, wherein phenyl, naphthyl and heteroaryl are each unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, CF₃、OCF₃CN, COMe, ethoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; particular preference is given to compounds of the formula Ih in which R (1) isWherein A is-C_nH_2n-, where n is 0, D is a bond, E is-C_mH_2m-, where m is 0, R (8) is hydrogen, R (9) is hydrogen, R (11) is unsubstituted phenyl and R (12) is alkyl having 1, 2 or 3 carbon atoms, for example ethyl.

In another embodiment, preference is given to compounds of the formula Ij, wherein R (2) is hydrogen.

In addition toIn one embodiment, preference is given to compounds of the formula Ij wherein R (3) is heteroaryl, wherein heteroaryl is unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, CF₃、OCF₃CN, COMe, methyl, methoxy, ethoxy, dimethylamino, sulfamoyl and methylsulfonyl; particular preference is given to compounds of the formula Ih in which R (3) is furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, for example quinolinyl.

In another embodiment, preference is given to compounds of the formula Ij in which R (5) is hydrogen or F, for example F, and R (4), R (6) and R (7) are each hydrogen.

In the compounds of formula Ih and Ij R (1) is linked to the carbonyl residue in the compounds of formula Ih and Ij through a nitrogen atom on the residue R (1).

Particular preference is given to the use of a compound selected from the group consisting of:

2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide,

2- (butyl-1-sulfonylamino) -N- [1(S) - (6-methoxypyridin-3-yl) propyl ] benzamide,

n- (2-pyridin-3-ylethyl) -2' - { [2- (4-methoxyphenyl) acetylamino ] methyl } biphenyl-2-carboxamide,

(S) -5-fluoro-2- (quinoline-8-sulfonylamino-N- (1-phenylpropyl) benzamide,

(S) -5-methoxy-2- (4-methoxybenzenesulphonylamino) -N- (1-phenylpropyl) benzamide,

n- (2- (R) -hydroxypropyl) -2' - (alpha- (S) -methylbenzyloxycarbonylaminomethyl) biphenyl-2-carboxamide,

n- (2, 4-difluorobenzyl) -5-chloro-2' - { [2- (4-methoxyphenyl) acetylamino ] methyl } biphenyl-2-carboxamide,

{ 2' - [ methyl (2-pyridin-2-ylethyl) carbamoyl ] biphenyl-2-ylmethyl } carbamic acid benzyl ester,

n- (2, 4-difluorobenzyl) -3- (2- { [2- (4-methoxyphenyl) acetylamino ] methyl } phenyl) thiophene-2-carboxamide,

n- (2, 4-difluorobenzyl) -5- (2- { [2- (4-methoxyphenyl) acetylamino ] methyl } phenyl) furan-2-carboxamide,

n- (3-methylbutyl) -2- (2- { [2- (4-methoxyphenyl) acetylamino ] methyl } phenyl) furan-3-carboxamide,

n- (2, 4-difluorobenzyl) -2- (2- { [2- (4-methoxyphenyl) acetylamino ] methyl } phenyl) thiophene-3-carboxamide,

{2- [2- (2-pyridin-2-ylethylcarbamoyl) pyridin-3-yl ] benzyl } carbamic acid (S) -1-phenylethyl ester,

n-cyclopropylmethyl-3- {2- [ ((R) -3-phenylbutylamino) methyl ] phenyl } pyridine-2-carboxamide,

{ benzyl 2- [3- (2, 4-difluorobenzylcarbamoyl) pyridin-2-yl ] benzyl } carbamate,

{4- [3- (3-methylbutylcarbamoyl) phenyl ] pyridin-3-ylmethyl } carbamic acid benzyl ester,

n- (3-methylbutyl) -2' - { [3- (4-methoxyphenyl) propionylamino ] methyl } -6-methylbiphenyl-3-carboxamide,

and N-indan-1-yl-2-methyl-5- (3-methylbutylsulfamoyl) benzamide and/or a physiologically compatible salt thereof.

If any of the radicals, substituents, ring members, numbers or other features in the compounds of the formulae I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ij, such as, for example, R14, alkyl etc., occur several times, they can each, independently of one another, have any of the meanings indicated and can in each case be identical to or different from one another.

The alkyl and alkylene groups may be straight or branched. It is also applicable to formula C_rH_2r、C_xH_2x、C_sH_2s、C_yH_2y、C_zH_2z、C_vH_2v、C_wH_2w、C_nH_2n、C_mH_2m、C_pH_2pAnd (CH)₂)_xAn alkylene group of (a). Alkyl and alkylene groups may also be straight or branched when they are substituted or present on other groups, such as fluoroalkyl or alkoxy groups. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl (═ 1-methylethyl), n-butyl, isobutyl (═ 2-methylpropyl), sec-butyl (═ 1-methylpropyl), tert-butyl (═ 1, 1-dimethylethyl), n-pentyl, isopentyl, tert-pentyl, neopentyl, hexyl and heptyl. Divalent groups derived from these groups, such as methylene, 1-ethylene, 1, 2-ethylene, 1-propylene, 1, 2-propylene, and the like, are examples of alkylene groups. Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl. In alkyl, one or more, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, hydrogen atoms may be substituted by fluorine atoms. Examples of such fluoroalkyl groups are trifluoromethyl, 2, 2, 2-trifluoroethyl and pentafluoroethyl. The substituted alkyl group may be substituted at any position.

The alkynyl group may be linear or branched. This is also the case when they have substituents, for example in fluoroalkynyl. Alkynyl groups may be unsaturated at various positions and may also be polyunsaturated. Examples of alkynyl groups are ethynyl, n-prop-1-ynyl, n-prop-2-ynyl, n-but-1-ynyl, n-but-2-ynyl, n-but-3-ynyl, n-but-1, 3-diynyl and sec-but-2-ynyl (═ 1-methylprop-2-ynyl). In alkynyl, one or more, for example 1, 2, 3, 4, 5, 6 or 7, hydrogen atoms may be substituted by fluorine atoms. Substituted alkynyl groups may be substituted at any position.

Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and cycloundecyl. In cycloalkyl, one or more, for example 1, 2, 3, 4, 5, 6, 7 or 8, hydrogen atoms may be substituted by fluorine atoms. Substituted cycloalkyl groups may be substituted at any position.

Aryl is, for example, phenyl and 2-or 3-naphthyl.

The phenyl radicals may be unsubstituted or mono-or polysubstituted, for example mono-, di-or trisubstituted, by identical or different radicals. When the phenyl group is substituted, it preferably has one or two substituents which may be the same or different. It is likewise applicable to phenyl substituted on a radical such as, for example, phenylalkyl or phenoxy. In monosubstituted phenyl, the substituent may be present in the 2-, 3-or 4-position. The disubstituted phenyl groups may be substituted in the 2, 3-position, 2, 4-position, 2, 5-position, 2, 6-position, 3, 4-position or 3, 5-position. In trisubstituted phenyl, the substituents may be present in the 2, 3, 4-position, 2, 3, 5-position, 2, 4, 6-position, 2, 3, 6-position or 3, 4, 5-position.

Heteroaryl groups may be aromatic ring compounds in which one or more ring atoms are an oxygen atom, a sulfur atom, or a nitrogen atom, for example 1, 2, or 3 nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, or a combination of different heteroatoms. Heteroaryl groups may be attached through all positions, for example through the 1-position, 2-position, 3-position, 4-position, 5-position, 6-position, 7-position or 8-position. The heteroaryl group may be unsubstituted or mono-or polysubstituted, for example mono-, di-or trisubstituted, by identical or different groups. It applies equally to heteroaryl groups, such as, for example, on heteroarylalkyl. Heteroaryl is, for example, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl and cinnolinyl. Heteroaryl is in particular 2 or 3-thienyl, 2 or 3-furyl, 1, 2 or 3-pyrrolyl, 1, 2, 4 or 5-imidazolyl, 1, 3, 4 or 5-pyrazolyl, 1, 2, 3-triazol-1-, -4-or-5-yl, 1, 2, 4-triazol-1-, -3-or-5-yl, 1 or 5-tetrazolyl, 2, 4 or 5-oxazolyl, 3, 4 or 5-isoxazolyl, 1, 2, 3-oxadiazol-4-or-5-yl, 1, 2, 4-oxadiazol-3-or-5-yl, 1, 3, 5-oxadiazol-2-yl or-5-yl, 2-pyrrolyl, 1, 2, 5-oxadiazol-2-yl or-5-yl, 4 or 5-thiazolyl, 3, 4 or 5-isothiazolyl, 1, 3, 4-thiadiazol-2-or-5-yl, 1, 2, 4-thiadiazol-3-or-5-yl, 1, 2, 3-thiadiazol-4-or-5-yl, 2, 3 or 4-pyridyl, 2, 4, 5 or 6-pyrimidinyl, 3 or 4-pyridazinyl, pyrazinyl, 1, 2, 3, 4, 5, 6 or 7-indolyl, 1, 2, 4 or 5-benzimidazolyl, 1, 3, 4, 5, 6 or 7-indazolyl, 2, 3, 4, 5, 6, 7 or 8-quinolinyl, 1, 3, 4, 5, 6, 7 or 8-isoquinolinyl, 2, 4, 5, 6, 7 or 8-quinazolinyl, 3. 4, 5, 6, 7 or 8-cinnolinyl, 2, 3, 5, 6, 7 or 8-quinoxalinyl, 1, 4, 5, 6, 7 or 8-phthalazinyl. Also included are the corresponding N-oxides of these compounds, i.e., for example, 1-oxo-2-, -3-or-4-pyridyl.

Particular preference is given to the heteroaromatic radicals 2 or 3-thienyl, 2 or 3-furyl, 1, 2 or 3-pyrrolyl, 1, 2, 4 or 5-imidazolyl, 2, 3, 4, 5, 6, 7 or 8-quinolyl, 1, 3, 4 or 5-pyrazolyl, 2, 3 or 4-pyridyl, 2 or 3-pyrazinyl, 2, 4, 5 or 6-pyrimidinyl and 3 or 4-pyridazinyl.

N-containing heterocycles are ring compounds in which one or more ring atoms is a nitrogen atom, for example 1, 2 or 3 nitrogen atoms. The N-containing heterocycle may be attached through all positions, for example through the 1-position, 2-position, 3-position, 4-position, 5-position, 6-position, 7-position or 8-position. The N-containing heterocyclic ring may be unsubstituted or mono-or polysubstituted, for example mono-, di-or trisubstituted, by identical or different radicals. N-containing heterocycles having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms are in particular the aromatic system 1, 2 or 3-pyrrolyl, 1, 2, 4 or 5-imidazolyl, 1, 3, 4 or 5-pyrazolyl, 1, 2, 3-triazol-1-, -4-or-5-yl, 1, 2, 4-triazol-1-, -3-or-5-yl, 1 or 5-tetrazolyl, 2, 4 or 5-oxazolyl, 3, 4-or 5-isoxazolyl, 1, 2, 3-oxadiazol-4-or-5-yl, 1, 2, 4-oxadiazol-3-or-5-yl, 1, 3, 4-oxadiazol-2-yl or-5-yl, 2. 4 or 5-thiazolyl, 3, 4 or 5-isothiazolyl, 1, 3, 4-thiadiazol-2-or-5-yl, 1, 2, 4-thiadiazol-3-or-5-yl, 1, 2, 3-thiadiazol-4-or-5-yl, 2, 3 or-4-pyridyl, 2, 4, 5 or 6-pyrimidinyl, 3 or 4-pyridazinyl, pyrazinyl, 1, 2, 3, 4, 5, 6 or 7-indolyl, 1, 2, 4 or 5-benzimidazolyl, 1, 3, 4, 5, 6 or 7-indazolyl, 2, 3, 4, 5, 6, 7 or 8-quinolinyl, 1, 3, 4, 5, 6, 7 or 8-isoquinolinyl, 2, 4, 5, 6, 7 or 8-quinazolinyl, 3. 4, 5, 6, 7 or 8-cinnolinyl, 2, 3, 5, 6, 7 or 8-quinoxalinyl, 1, 4, 5, 6, 7 or 8-phthalazinyl.

Particular preference is given to N-containing heterocyclic pyrrolyl, imidazolyl, quinolinyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.

The N-containing heteroaromatic compound is an aromatic ring compound in which one or more ring atoms are nitrogen atoms, for example 1, 2 or 3 nitrogen atoms. The N-containing heteroaromatic group may be attached through all positions, for example through the 1-position, 2-position, 3-position, 4-position, 5-position, 6-position, 7-position or 8-position. The N-containing heteroaromatic groups may be unsubstituted or mono-or polysubstituted, for example mono-, di-or trisubstituted, by identical or different groups. N-containing heteroaromatic radicals having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms are in particular the aromatic system 1, 2 or 3-pyrrolyl, 1, 2, 4 or 5-imidazolyl, 1, 3, 4 or 5-pyrazolyl, 1, 2, 3-triazol-1-, -4-or-5-yl, 1, 2, 4-triazol-1-, -3-or-5-yl, 1-or 5-tetrazolyl, 2, 4 or 5-oxazolyl, 3, 4 or 5-isoxazolyl, 1, 2, 3-oxadiazol-4-or-5-yl, 1, 2, 4-oxadiazol-3-or-5-yl, 1, 3, 4-oxadiazol-2-yl or-5-yl, 2. 4 or 5-thiazolyl, 3, 4 or 5-isothiazolyl, 1, 3, 4-thiadiazol-2-or-5-yl, 1, 2, 4-thiadiazol-3-or-5-yl, 1, 2, 3-thiadiazol-4-or-5-yl, 2, 3 or-4-pyridyl, 2, 4, 5-or 6-pyrimidinyl, 3 or 4-pyridazinyl, pyrazinyl, 1, 2, 3, 4, 5, 6 or 7-indolyl, 1, 2, 4 or 5-benzimidazolyl, 1, 3, 4, 5, 6 or 7-indazolyl, 2, 3, 4, 5, 6, 7 or 8-quinolyl, 1, 3, 4, 5, 6, 7 or 8-isoquinolyl, 2, 4, 5, 6, 7 or 8-quinazolinyl, 3, 4, 5, 6, 7 or 8-cinnolinyl, 2, 3, 5, 6, 7 or 8-quinoxalinyl, 1, 4, 5, 6, 7 or 8-phthalazinyl. Also included are the corresponding N-oxides of these compounds, i.e., for example, 1-oxo-2-, -3-or-4-pyridyl.

The pyridyl group is a2, 3 or 4-pyridyl group. Thienyl is 2 or 3-thienyl. Furyl is 2 or 3-furyl.

With respect to the di-or polysubstitution of the radicals, the substituents may be identical or different.

When the compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ij contain one or more acidic or basic groups or one or more basic heterocycles, the invention also comprises the corresponding physiologically or toxicologically compatible salts, in particular the pharmaceutically useful salts. For example, the compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ij can be deprotonated at the sulfonamide group and used, for example, as alkali metal salts, preferably sodium or potassium salts, or as ammonium salts, for example with ammonia or organic amines or amino acids. The compounds of the formulae Ia or Ib which contain pyridine or quinoline substituents can also be used in the form of their physiologically compatible acid addition salts with inorganic or organic acids, for example as hydrochlorides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malates, gluconates and the like. The compounds of formula Ia or Ib may also be present as trifluoroacetate salts.

The compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ij may, where appropriate substituted, be present in stereoisomeric forms. When the compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ij comprise one or more asymmetric centers, they may each independently have S configuration or R configuration. The present invention includes all possible stereoisomers, such as enantiomers or diastereomers and mixtures of two or more stereoisomeric forms, such as enantiomers and/or diastereomers, in any ratio. For example, the enantiomers are thus included in the invention in enantiomerically pure form, as the levorotatory and dextrorotatory enantiomers, and also in the form of mixtures of the two enantiomers in different ratios or in the form of racemates. If desired, the individual stereoisomers can be prepared by separating the mixtures by customary methods, or, for example, by using isomerically pure synthesis units.

The invention includes all tautomeric forms of the compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ij.

Compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ij may be prepared according to the preparation methods described in WO01/00573, WO01/025189, WO02/044137, WO02/046162, WO02/048131, WO02/087568, WO02/088073, WO 02/100825.

According to the invention, the compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ij can be used individually, in mixtures with one another or in pharmaceutical preparations, for the treatment or prophylaxis of respiratory disorders, sleep-related respiratory disorders, central and obstructive sleep apneas, upper airway resistance syndrome, Cheyne-Stokes respiration, snoring, impaired central respiratory drive, sudden child death, postoperative hypoxia and apnea, muscle-related respiratory disorders, respiratory disorders after long-term ventilation, respiratory disorders during adaptation in mountains, acute and chronic lung disorders with hypoxia and hypercapnia, neurodegenerative disorders, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, cancerous disorders, breast cancer, lung cancer, colon cancer and prostate cancer in humans or animals.

Pharmaceutical formulations comprise the active ingredient, i.e. an effective dose of at least one compound of formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih and/or Ij and/or physiologically compatible salts thereof, together with conventional pharmaceutically non-objectionable carriers and auxiliaries and optionally also one or more further pharmacologically active components. Pharmaceutical preparations generally contain 0.1 to 90% by weight of a compound of the formulae Ia to Ij and/or physiologically compatible salts thereof.

The pharmaceutical preparations can be produced in a manner known per se. To this end, the active ingredients and/or their physiologically compatible salts are converted with one or more solid or liquid pharmaceutical carriers and/or auxiliaries into a suitable administration form or dosage form, which can then be used as medicaments in human or veterinary medicine.

Medicaments comprising the compounds of the formulae Ia to Ij according to the invention and/or their pharmaceutically compatible salts can be administered, for example, orally, parenterally, intravenously, rectally, nasally, by inhalation or topically, in particular orally, intravenously or nasally, the preferred administration depending on the particular situation.

Excipients suitable for the desired pharmaceutical formulation are well known to those skilled in the art based on their expert knowledge. In addition to solvents, gel formers, suppository bases, tablet excipients and other active ingredient carriers, it is also possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavorings, preservatives, solubilizers, agents for achieving a long-lasting effect, buffer substances or colorants.

For oral administration, the active compounds are mixed with additives suitable for the purpose, such as carriers, stabilizers or inert diluents, and converted by customary methods into suitable dosage forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic or oily solutions. Examples of useful inert carriers include acacia, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. The formulation may be in dry granular form or wet granular form. Examples of useful oil carriers or useful solvents are vegetable or animal oils, such as sunflower oil or cod liver oil. Useful solvents for the aqueous or alcoholic solution include, for example, water, ethanol or sugar solutions or mixtures thereof. Additional adjuvants which are also used in other application forms are, for example, polyethylene glycols and polypropylene glycols.

For subcutaneous, intramuscular or intravenous administration, the active compounds used together with substances customary for this purpose, such as solubilizers, emulsifiers or additional excipients, are converted, if desired, into solutions, suspensions or emulsions. Examples of useful solvents are: water, physiological saline or alcohols, for example ethanol, propanol, glycerol and additionally sugar solutions, such as glucose or mannitol solutions, or just mixtures of the different solvents mentioned.

Examples of suitable pharmaceutical preparations for administration in the form of aerosols or sprays, for example for nasal administration, are solutions, suspensions, emulsions or capsular and micellar pharmaceutical forms of the active ingredient or of a physiologically compatible salt thereof in water or a pharmaceutically unconventionally water-miscible or oil solvent or a mixture of such solvents. Furthermore, aerosols or sprays suitable, for example, for nasal administration are in the form of powders of the active ingredient or of physiologically compatible salts thereof. All formulations may also contain other pharmaceutically acceptable excipients, such as isotonic additives, surfactants, emulsifiers and stabilizers and also propellant gases, if desired. The formulations mentioned may also be in the form of freeze-dried products. These formulations contain the active ingredient in a typical concentration of about 0.001 to about 10% by weight, particularly about 0.05 to about 5% by weight.

The dose of the active compounds or physiologically compatible salts thereof to be administered according to the invention depends on the individual case and, in order to achieve optimum action, should be adjusted to the circumstances of the individual case as usual. For example, it depends of course on the frequency of administration and on the efficacy and duration of action of the compounds used in each case of therapy or prophylaxis, but also on the nature and severity of the disease to be treated and on the sex, age, weight and individual responsiveness of the human or animal to be treated and whether acute therapy or chronic therapy or prophylaxis is carried out.

The dosage of the compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and/or Ij may generally vary from 1mg to 1g per day and per person (at about 75kg body weight), preferably from 5 to 750mg per day and per person. However, higher doses may also be suitable. The daily dose of the active ingredient may be administered once or it may be divided into a plurality of administrations, for example 2, 3 or 4 administrations.

Experimental part

Abbreviation list

EDAC N-ethyl-N' - (3-dimethylaminopropyl) carbodiimide hydrochloride

EMG electromyogram

DMSO dimethyl sulfoxide

HOBT 1-hydroxy-1H-benzotriazole

n.s. not significant

PEG polyethylene glycol

THF tetrahydrofuran

Standard error of SEM

vs. and

example 1: 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide and 2- (butyl-1-sulfonylamino) -N- [1(S) - (6-methoxypyridin-3-yl) propyl ] benzamide

a)2- (butyl-1-sulfonylamino) benzoic acid

20g (188mmol) of sodium carbonate are added to a suspension of 20g (146mmol) of 2-aminobenzoic acid in 250ml of water. 11.4g (72.8mmol) of butylsulfonyl chloride are subsequently added dropwise and the reaction mixture is stirred at room temperature for 2 days. The mixture was acidified with hydrochloric acid and stirred at room temperature for 3 hours, and the precipitated product was filtered off by suction. Drying under reduced pressure gave 9.6g of 2- (butyl-1-sulfonylamino) benzoic acid.

b)1- (6-methoxypyridin-3-yl) propylamines

3ml (23.2mmol) of 5-bromo-2-methoxypyridine are added at-70 ℃ to a solution of 10.2ml of butyllithium (2.5M in hexane; 25.5mmol) in 50ml of diethyl ether. After 10 minutes, 1.4ml (19.5mmol) of propionitrile were added. After 2 hours at-70 ℃, the reaction mixture was slowly brought to room temperature. Then 2.2g of sodium sulphate decahydrate were added and the mixture was kept stirring for 1 hour. After the subsequent addition of 5g of magnesium sulfate and brief stirring, the salt was filtered off and the filtrate was concentrated. The residue is dissolved in 70ml of methanol and 1.1g (28mmol) of sodium borohydride are added at 0 ℃. After stirring overnight, the reaction mixture was adjusted to pH2 using concentrated hydrochloric acid and concentrated with a rotary evaporator. The residue was mixed with 10ml of water and extracted once with diethyl ether. Subsequently, the aqueous phase was extracted with sodium bicarbonate and concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate extract was dried and concentrated to give 1.4g of racemic 1- (6-methoxypyridin-3-yl) propylamine.

c)2- (butyl-2-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide

4.4g (32.7mmol) of 1-hydroxy-1H-benzotriazole and 6.3g (32.7mmol) of N-ethyl-N' - (3-dimethylaminopropyl) carbodiimide hydrochloride are added to a solution of 8.0g (31.1mmol) of 2- (butyl-1-sulfonylamino) benzoic acid in 250ml of tetrahydrofuran and the reaction mixture is stirred for 90 minutes. A solution of 5.4g (32.7mmol) of racemic 1- (6-methoxypyridin-3-yl) propylamine in 20ml of tetrahydrofuran was then added dropwise and the mixture was stirred overnight. The reaction mixture was mixed with 250ml of water and extracted with 300ml of ethyl acetate. The organic phase is extracted 5 times with saturated sodium bicarbonate solution, 100ml each time, and then dried over magnesium sulfate. This procedure gave 9.0g of 2- (butyl-1-sulfonylamino) -N- [1- (6-methoxypyridin-3-yl) propyl ] benzamide.

The enantiomers were separated by preparative HPLC using a Chiralpak ADH column (250 × 4.6 mm); eluent heptane/ethanol/methanol 10:1: 1; temperature: 30 ℃; flow rate: 1 ml/min, 4.0g of 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide were first eluted at a retention time of 5.9 minutes. After mixing the fractions, 3.0g of 2- (butyl-1-sulfonylamino) -N- [1(S) - (6-methoxypyridin-3-yl) propyl ] benzamide were obtained at a retention time of 7.2 minutes.

2g of 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide was dissolved in 9ml of isopropanol by heating, then 8ml of warm water was added and the reaction mixture was allowed to cool slowly overnight. Filtration by suction at 0 ℃ gave 1.5g of 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide as colorless needle crystals; melting point 97 ℃.

Example 2: n- (2-pyridin-3-ylethyl) -2' - { [2- (4-methoxyphenyl) acetylamino ] methyl } biphenyl-2-carboxamide

15.5g (0.115mol) HOBT and 21.9g (0.115mol) EDAC were added to a solution of 37.8g (0.11mol) 2' - (tert-butoxycarbonylaminomethyl) biphenyl-2-carboxylic acid (Brandmeier, V.; Sauer, W.H.B.; Feigel, M.; Helv.Chim.acta 1994, 77(1), 70-85) in 550ml THF, and the reaction mixture was stirred at room temperature for 45 minutes. 14.0g (0.115mol) of 3- (2-aminoethyl) pyridine are subsequently added and the mixture is stirred at RT overnight. After addition of 400ml of water and 500ml of ethyl acetate and vigorous stirring, the phases are separated. The organic phase is washed once with 400ml of saturated sodium chloride solution and twice with 400ml of saturated sodium bicarbonate solution each time. After drying over magnesium sulfate in the presence of activated carbon, the mixture was filtered and concentrated with a rotary evaporator.

The resulting intermediate (40.7g) was dissolved in 600ml of dichloromethane and then 100ml of trifluoroacetic acid was slowly added dropwise. After stirring overnight, the reaction mixture was concentrated under reduced pressure. The residue was mixed with 250ml of ethyl acetate and concentrated again in order to distill off excess trifluoroacetic acid. 72.8ml (530mmol) of triethylamine were added dropwise to the resulting crude product dissolved in 170ml of dichloromethane, and 1g of DMAP were added. Subsequently, 18.7g (100mmol) of 4-methoxyphenylacetyl chloride were added dropwise over 30 minutes at 5-10 ℃ and the mixture was stirred at room temperature overnight. After addition of 150ml of water and vigorous stirring, the phases are separated and the organic phase is washed once with 100ml of sodium chloride solution, once with 25ml of 1M hydrochloric acid and twice with 100ml of saturated sodium bicarbonate solution each time. After drying over magnesium sulfate and activated carbon, the mixture was concentrated under reduced pressure. The resulting oil was dissolved in hot acetonitrile and allowed to slowly crystallize out. 21.5g of N- (2-pyridin-3-ylethyl) -2' - { [2- (4-methoxyphenyl) acetylamino ] methyl } biphenyl-2-carboxamide are obtained, m.p. 116 ℃.

Example 3: (S) -5-fluoro-2- (quinoline-8-sulfonylamino) -N- (1-phenylpropyl) benzamide sodium salt

a) 5-fluoro-2- (quinoline-8-sulfonylamino) benzoic acid

A reaction mixture of 10.0g (64mmol) of 5-fluoro-2-aminobenzoic acid, 16.3g (193mmol) of sodium bicarbonate and 16.3g of 8-quinolinesulfonyl chloride in 325ml of water and 325ml of ethyl acetate was stirred at room temperature overnight. The aqueous phase was removed and extracted once with 50ml ethyl acetate. Subsequently, the aqueous phase was acidified with concentrated hydrochloric acid and stirred for 2 hours. The precipitated solid was filtered off by suction and dried under reduced pressure to give 19.5 g of 5-fluoro-2- (quinoline-8-sulfonylamino) benzoic acid.

b) (S) -5-fluoro-2- (quinoline-8-sulfonylamino) -N- (1-phenylpropyl) benzamide

5.5g (15.9mmol) of 5-fluoro-2- (quinoline-8-sulfonylamino) benzoic acid and 2.3g (16.7mmol) of (S) -phenylpropylamine are used for 5.7g of the title compound obtained according to the method of WO 02100825.

m.p.：163℃。

c) 2ml of a 30% sodium methoxide solution are added to a solution of 5g of (S) -5-fluoro-2- (quinoline-8-sulfonylamino) -N- (1-phenylpropyl) benzamide in 120ml of ethyl acetate. The precipitated sodium salt was filtered off by suction and recrystallized from 25ml of ethanol to give 3.3g of (S) -5-fluoro-2- (quinoline-8-sulfonylamino) -N- (1-phenylpropyl) benzamide sodium salt.

Example 4: (S) -5-methoxy-2- (4-methoxybenzenesulphonylamino) -N- (1-phenylpropyl) benzamide

This compound was obtained according to the synthesis method detailed in WO 02088073.

Example 5: n- (2- (R) -hydroxypropyl) -2' - (alpha- (S) -methylbenzyloxycarbonylaminomethyl) biphenyl-2-carboxamide

The compound was obtained according to the synthesis method detailed in WO 0125189.

Example 6: n- (2, 4-difluorobenzyl) -5-chloro-2' - { [2- (4-methoxyphenyl) acetylamino ] methyl } biphenyl-2-carboxamide

Example 7: { 2' - [ methyl- (2-pyridin-2-ylethyl) carbamoyl ] biphenyl-2-ylmethyl } carbamic acid benzyl ester

Example 8: n- (2, 4-difluorobenzyl) -3- (2- { [2- (4-methoxyphenyl) acetylamino ] methyl } phenyl) thiophene-2-carboxamide

The compound was obtained according to the synthesis method specified in WO 0248131.

Example 9: n- (2, 4-difluorobenzyl) -5- (2- { [2- (4-methoxyphenyl) acetylamino ] methyl } phenyl) furan-2-carboxamide

Example 10: n- (3-methylbutyl) -2- (2- { [2- (4-methoxyphenyl) acetylamino ] methyl } phenyl) furan-3-carboxamide

Example 11: n- (2, 4-difluorobenzyl) -2- (2- { [2- (4-methoxyphenyl) acetylamino ] methyl } phenyl) thiophene-3-carboxamide

Example 12: {2- [2- (2-pyridin-2-ylethylcarbamoyl) pyridin-3-yl ] benzyl } carbamic acid (S) -1-phenylethyl ester

The compound was obtained according to the synthesis method detailed in WO 0246162.

Example 13: n-cyclopropylmethyl-3- {2- [ ((R) -3-phenylbutylamino) methyl ] phenyl } pyridine-2-carboxamide

Example 14: {2- [3- (2, 4-difluorobenzylcarbamoyl) pyridin-2-yl ] benzyl } carbamic acid benzyl ester

Example 15: {4- [3- (3-methylbutylcarbamoyl) phenyl ] pyridin-3-ylmethyl } carbamic acid benzyl ester

Example 16: n- (3-methylbutyl) -2' - { [3- (4-methoxyphenyl) propionylamino ] methyl } -6-methylbiphenyl-3-carboxamide

The compound was obtained according to the synthesis method specified in WO 0244137.

Example 17: n-indan-1-yl-2-methyl-5- (3-methylbutylsulfamoyl) benzamide

This compound was obtained according to the synthesis method detailed in WO 0100573.

Pharmacological study

A) Determination of TASK-1 channel Activity in Xenopus oocytes

Mouse or human TASK-1 channels are expressed in Xenopus oocytes. For this purpose, oocytes are first isolated from Xenopus laevis (Xenopus levis) and the follicles (decapoliulated) are removed.RNA encoding TASK-1, synthesized in vitro, was then injected into these oocytes. After 2 days of TASK-1 protein expression, the TASK-1 current was measured on the oocytes using a two-microelectrode voltage clamp technique. In this assay, the TASK-1 channel is typically activated using a voltage ramp lasting 250ms to 40 mV. The tank was rinsed with a solution of the following composition: NaCI 96mM, KCl 2mM, CaCl₂ 1.8mM、MgCl₂1mM, HEPES 5mM (titrated to pH7.4 with NaOH). These experiments were performed at room temperature. For data acquisition and analysis, the following were used: geneclamp amplifiers (Axon Instruments, Foster City, USA) and MacLab D/A converters and software (ADInstructions, Castle Hill, Australia). The substances of the invention were tested by adding them to bath solutions of different concentrations. The effect of the substance was calculated as percent inhibition of the TASK-1 control current obtained when no substance was added to the solution. The data were then fitted to the hill equation to determine the median-maximum Inhibitory Concentration (IC) of a particular substance₅₀Value).

In this manner, the IC of the compounds listed below was determined₅₀The value:

compound (I)	IC₅₀(μmol) TASK1 (mouse)	IC₅₀(μmol) TASK1 (human)
			Example 1 (R-enantiomer)	0.15	0.10
Example 1 (S-enantiomer)	0.80
			Example 2	0.43	0.57

Example 3	0.82
		Example 4	0.65
Example 5	2.08
		Example 6	1.15
Example 7	1.06
		Example 8	0.55
Example 9	2.37
		Example 10	1.19
Example 11	0.35
		Example 12	3.36
Example 13	3.07
		Example 14	2.90
Example 15	1.83
		Example 16	2.77

B) Determination of activity on TASK-1 channels Using FLIPR technique

The inhibition of the human TASK-1 current produced by the compounds of the examples at a concentration of 10. mu. mol/l was determined by means of the FLIPR assay using CHO cells, in which the human TASK-1 channel was expressed. This procedure yielded the following inhibition values:

compound (I)	Inhibition at 10. mu. mol/l
		Example 1 (R-enantiomer)	81％
Example 1 (S-enantiomer)	58％
		Example 2	77％
Example 3	82％
		Example 5	88％
Example 6	68％
		Example 7	57％
Example 8	77％

Example 9	60％
		Example 10	61％
Example 11	88％
		Example 12	73％
Example 13	65％
		Example 14	50％
Example 15	70％

C) Determination of activity on the TASK-3 channel by patch-clamp studies

The inhibition of the human TASK-3 current generated by the compounds of the examples at a concentration of 10. mu. mol/l, in which the human TASK-3 channel is expressed, was determined using CHO cells with the aid of the patch clamp technique. To generate the TASK-3 cell line, human TASK-3 cDNA (Genbank, Access number 248241) was cloned into the eukaryotic expression vector p658, which has a DHFR (dihydrofolate reductase) resistance gene [ ref: gene 1994(149), 341-344, 1994 ]. CHO (Chinese hamster ovary) DHFR-negative cells were transfected with the TASK-3 expression construct using Fugene reagent (Roche Biochemicals) according to the manufacturer's instructions. Recombinant DHFR-positive cells were cultured in MEM (minimal essential medium) supplemented with 10% dialyzed calf serum. The resulting cell clones were analyzed for TASK-3 expression by means of a fluorescence-based activity assay in FlexStation (Molecular Devices) and using a membrane potential-sensitive Dye (Molecular Devices FMP Dye Kit). Functional expression of TASK-3, which corresponds to membrane potential depolarization, was confirmed by an increase in fluorescence signal following addition of 50mM KCl to the cells. The potassium current generated by the TASK-3-positive cell clones was subsequently analyzed using the patch-clamp technique. The cell clone CHO-244-8-1 was selected as a representative cell clone for subsequent studies.

To study the material, the cells were introduced into an assay chamber fixed on an inverted microscope. A micropipette pulled from borosilicate glass was carefully pressed against the visually observable cells. Slow aspiration creates a high impedance seal between the glass pipette and the cell. The brief suction opened the membrane patch and established a whole cell leak. The current was recorded in the voltage clamp by means of an electric patch clamp amplifier (Axopatch-1D) by applying a voltage ramp of-140 mV to +80 mV. The effect of the substance was recorded by adding an increasing concentration into the bath solution. Half-maximal Inhibitory Concentration (IC) of current was determined by fitting a curve to the mathematical Hill equation₅₀Value).

In this analysis, the following IC was determined₅₀The value:

compound (I)	IC₅₀(μmol/l) TASK3 (human)
		Example 1 (R-enantiomer)	1.0μM

D) Effect on rabbit respiration

Apnea was induced at rabbit values by infusion of the anesthetic propofol, 10 mg/kg/min. The vehicle for the compound of example 1(R enantiomer) was DMSO/PEG (0.2ml/1.8 ml). The time from the start of propofol infusion to apnea was recorded. In the control group, apnea was initiated after about 2.92 minutes; after administration of 10mg/kg i.v. of the compound of example 1 (R-enantiomer), the onset of apnea was delayed and not started until 5.63 minutes after the start of propofol infusion (table 1).

Table 1(p < 0.001; number n ═ 13):

	foundation	Media	Example 1 (R-enantiomer)
				Mean value of	2.87 minutes	2.92 minutes	5.63 minutes
Standard deviation of	0.69 minute	0.60 minute	2.08 minutes

The study demonstrates the effect of example 1 on central sleep apnea.

E) Study of the Effect of electromyographic Activity of the genioglossus muscle of rats and the respiratory airflow per minute

Investigation of the electromyographic activity of the genioglossus muscle of the compounds of example 1(R enantiomer) and example 2 and of a male with a body weight of 250-Respiratory stimulation in sexual urethane-aldochlorous-anesthetized vagotomy rats. For this purpose, the genioglossus muscle EMG activity is measured with EMG electrodes. The effect of stimulating respiration was studied by measuring the respiratory airflow per minute with a tracheal cannula. For the study, rats were administered 1, 3 and 10mg/kg of the compounds of example 1(R enantiomer) and example 2, continuously intravenously, with glycogen (50%) as vehicle, at 15 minute intervals. Introducing CO₂Used as a positive control for stimulating genioglossus muscle activity and respiratory airflow per minute.

Table 2. effect of example 1(R enantiomer) on EMG activity of genioglossus muscle in anesthetized rats (number n-8). EMG Activity in arbitrary units

Table 3. effect of example 1(R enantiomer) on respiration (minute respiratory volume in ml/min) of anesthetized rats (number n ═ 8)

Table 4: example 2 effect on EMG activity of the genioglossus muscle in anesthetized rats (number n-11). EMG Activity in arbitrary units

Table 5: example 2 effect on the respiration (respiratory airflow per minute in ml/min) of anesthetized rats (number n ═ 11)

The compounds of example 1(R enantiomer) and example 2 stimulate electromyographic activity of the genioglossus muscle (tables 2 and 4), which increases the muscle tone of the upper respiratory tract and significantly increases the respiratory airflow per minute (tables 3 and 5). The increase in muscle tone and respiratory stimulation may prevent respiratory disorders such as central or obstructive sleep apnea and snoring.

F) Study of rat compatibility

No side effects were observed with oral administration of 1000mg/kg of the compound of example 1(R enantiomer).

Claims

1. Use of a compound of formula Ib and/or a physiologically compatible salt of a compound of formula Ib for the manufacture of a medicament for the treatment or prevention of sleep-related breathing disorders, central and obstructive sleep apneas, upper airway resistance syndrome, snoring

Wherein:

r (1) is C (O) OR (9) OR COR (11);

r (9) is C_xH_2x-R(14)；

x is 0, 1, 2 or 3,

r (14) is cycloalkyl having 5 or 6 carbon atoms or phenyl,

wherein the phenyl group is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF₃、OCF₃An alkyl group having 1, 2 or 3 carbon atoms or an alkoxy group having 1 or 2 carbon atoms;

r (11) is as defined for R (9);

r (2) is hydrogen;

r (3) is C_yH_2y-R(16)；

y is 0, 1, 2 or 3,

wherein when R (16) is OR (17), y cannot be 0;

r (16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, CF₃OR (17), phenyl OR pyridyl,

wherein the phenyl or pyridyl is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF₃、OCF₃An alkyl group having 1, 2 or 3 carbon atoms or an alkoxy group having 1 or 2 carbon atoms;

r (17) is hydrogen;

r (4) is hydrogen or alkyl having 1 or 2 carbon atoms;

r (5), R (6), R (7) and R (8)

Each independently of the others being hydrogen, F, Cl, CF₃Or an alkyl group having 1, 2 or 3 carbon atoms;

r (30) and R (31) are hydrogen.

2. Use according to claim 1 for the manufacture of a medicament for the treatment or prevention of sleep-related breathing disorders, central and obstructive sleep apneas and snoring.

3. Use according to claim 1 or 2 for the manufacture of a medicament for the treatment or prevention of central and obstructive sleep apnea.

4. Use of a compound according to claim 1, selected from the group consisting of:

benzyl { 2' - [ methyl (2-pyridin-2-ylethyl) carbamoyl ] biphenyl-2-ylmethyl } carbamate and/or physiologically compatible salts thereof.

5. The use of claim 1, wherein the medicament is for intravenous administration.

6. The use of claim 1, wherein the medicament is for oral administration.

7. The use of claim 1, wherein the medicament is for nasal administration.