The invention relates to substituted cyclohexane derivatives that have an affinity to the μ-opioid receptor and the ORL 1-receptor, methods for their production, medications containing these compounds and the use of these compounds for the production of medications.
Cyclohexane derivatives that have an affinity to the μ-opioid receptor and the ORL 1-receptor are known in the prior art. In this context, reference can be made, for example, to the following documents in their full scope WO2002/090317, WO2002/90330, WO2003/008370, WO2003/008731, WO2003/080557, WO2004/043899, WO2004/043900, WO2004/043902, WO2004/043909, WO2004/043949, WO2004/043967, WO2005/063769, WO2005/066183, WO2005/110970, WO2005/110971, WO2005/110973, WO2005/110974, WO2005/110975, WO2005/110976, WO2005/110977, WO2006/018184, WO2006/108565, WO2007/079927, WO2007/079928, WO2007/079930, WO2007/079931, WO2007/124903, WO2008/009415 and WO2008/009416.
However, the known compounds are not satisfactory in every respect and there is a need for further compounds with comparable or better properties.
Thus, in appropriate binding assays the known compounds occasionally exhibit a certain affinity to the hERG ion channel, the L-type calcium ion channel (phenylalkylamine, benzothiazepine, dihydropyridine binding sites) or to the sodium channel in the BTX assay (batrachotoxin), which can be respectively interpreted as an indication of cardiovascular side-effects. Moreover, many of the known compounds exhibit only a slight solubility in aqueous media, which can adversely affect the bioavailability, inter alia. In addition, the chemical stability of the known compounds is often merely inadequate. Thus, the compounds occasionally do not exhibit an adequate pH, UV or oxidation stability, which can adversely affect the storage stability and also the oral bioavailability, inter alia. Moreover, the known compounds have an unfavourable PK/PD (pharmacokinetic/pharmacodynamic) profile in some instances, which can be displayed, for example, in too long a duration of effect.
The metabolic stability of the known compounds also appears to be in need of improvement. An improved metabolic stability can point to an increased bioavailability. A weak or absent interaction with transporter molecules that participate in the absorption and excretion of medicinal substances should be considered an indication of an improved bioavailability and possibly low interactions of medications. Moreover, the interactions with the enzymes involved in the breakdown and excretion of medicinal substances should also be as low as possible, since such test results also indicate that low interactions of medications or none at all are possibly to be expected.
Moreover, the known compounds at times exhibit only a low selectivity with respect to the kappa-opioid receptor, which is responsible for side-effects such as e.g. dysphoria, sedation, diuresis. In addition, the known compounds at times exhibit a very high affinity to the μ-opioid receptor, which appears to be associated with other side-effects, in particular respiratory depression, constipation and addiction dependence.
WO 01/87838 discloses NK-1-receptor antagonists.
J. Med. Chem. 1996, 9, 911-920; J. Am. Chem. Soc. 1950, 72, 2411-2417; and Tetrahedron 2006, 62, 5536-5548 respectively disclose, inter alia, geminally substituted cyclohexyl-1,4-diamines, in which the amino groups are, however, substituted with hydrogen atoms throughout.
DE 28 39 891 A1 discloses, inter alia, 4-(dimethylamino)-1-methyl-4-p-tolyl cyclohexyl acetate.
The object forming the basis of the invention is to provide compounds that are suitable for pharmaceutical purposes and have advantages over the compounds of the prior art.
This object is achieved by the compounds described hereinbelow.
It has been surprisingly found that substituted cyclohexane derivatives can be produced that have an affinity to the μ-opioid receptor and the ORL 1-receptor.
The invention relates to compounds of the general formula (1),
Y1, Y1′, Y2, Y2′, Y3, Y3′, Y4 and Y4′ are respectively selected independently of one another from the group comprising —H, —F, —Cl, —Br, —I, —CN, —NO2, —CHO, —R0, —C(═O)R0, —C(═O)H, —C(═O)—OH, —C(═O)OR0, —C(═O)NH2, —C(═O)NHR0, —C(═O)N(R0)2, —OH, —OR0, —OC(═O)H, —OC(═O)R0, —OC(═O)OR0, —OC(═O)NHR0, —OC(═O)N(R0)2, —SH, —SR0, —SO3H, —S(═O)1-2—R0, —S(═O)1-2NH2, —NH2, —NHR0, —N(R0)2, —N+(R0)3, —N+(R0)2O−, —NHC(═O)R0, —NHC(═O)OR0, —NHC(═O)NH2, —NHC(═O)NHR0 and —NHC(═O)N(R0)2; preferably respectively selected independently of one another from the group comprising —H, —F, —Cl, —CN and —C1-8-aliphatic; or Y1 and Y1′, or Y2 and Y2′, or Y3 and Y3′, or Y4 and Y4′ jointly stand for ═O;
Q stands for —R0, —C(═O)—R0, —C(═O)OR0, —C(═O)NHR0, —C(═O)N(R0)2 or —C(═NH)—R0;
R0 respectively independently stands for —C1-8-aliphatic, —C3-12-cycloaliphatic, -aryl, -heteroaryl, —C1-8-aliphatic-C3-12-cycloaliphatic, —C1-8-aliphatic-aryl, —C1-8-aliphatic-heteroaryl, —C3-8-cycloaliphatic-C1-8-aliphatic, —C3-8-cycloaliphatic-aryl or —C3-8-cycloaliphatic-heteroaryl;
R1 and R2, independently of one another, stand for —H or —R0; or R1 and R2 jointly form a ring and stand for —CH2CH2OCH2CH2—, —CH2CH2NR4CH2CH2— or —(CH2)3-6—; on condition that R1 and R2 preferably do not both simultaneously stand for —H;
R3 stands for —R0;
R4 respectively independently stands for —H, —R0 or —C(═O)R0;
n stands for a whole number from 0 to 12, preferably for 0;
X stands for —O—, —S— or —NRA—, preferably for —NRA—;
RA stands for —H, —R0, —S(═O)0-2R0, —C(═O)R0, —C(═O)OR0, —C(═O)NH2, —C(═O)NHR0 or —C(═O)N(R0)2;
RB stands for —H, —R0, —C(═O)H, —C(═O)R0, —C(═O)OH, —C(═O)OR0, —C(═O)NH2, —C(═O)NHR0, —C(═O)N(R0)2, —S(═O)1-2—R0, —S(═O)1-2—OR0, —S(═O)1-2—NH2, —S(═O)1-2—NHR0 or —S(═O)1-2—N(R0)2; or RA and RB jointly form a ring and stand for —(CH2)2-5—, —CH2CH2OCH2CH2— or —CH2CH2NR4CH2CH2—; on condition that when X stands for —O— and at the same time n stands for 0, RB does not stand for —H;