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Substituted 4-aminocyclohexane derivatives


Title: Substituted 4-aminocyclohexane derivatives.
Abstract: The invention relates to compounds 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 treatment of pain and other conditions. ...



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USPTO Applicaton #: #20090247530 - Class: 514241 (USPTO) - 10/01/09 - Class 514 
Inventors: Bert Nolte, Wolfgang Schroder, Klaus Linz, Werner Englberger, Hans Schick, Heinz Graubaum, Birgit Roloff, Sigrid Ozegowski, Jozsef Balint, Helmut Sonnenschein

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The Patent Description & Claims data below is from USPTO Patent Application 20090247530, Substituted 4-aminocyclohexane derivatives.

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),

wherein
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;
wherein
“aliphatic” respectively is a branched or unbranched, saturated or a mono- or polyunsaturated, unsubstituted or mono- or polysubstituted, aliphatic hydrocarbon residue;
“cycloaliphatic” respectively is a saturated or a mono- or polyunsaturated, unsubstituted or mono- or polysubstituted, alicyclic, mono- or multicyclic hydrocarbon residue, the number of ring-carbon atoms of which preferably lies in the specified range (i.e. “C3-8-cycloaliphatic” preferably has 3, 4, 5, 6, 7 or 8 ring-carbon atoms);
wherein with respect to “aliphatic” and “cycloaliphatic”, “mono- or polysubstituted” is understood to mean the mono- or polysubstitution, e.g. the mono-, di-, tri- or complete substitution, of one or more hydrogen atoms by substituents selected independently of one another from the group comprising aus —F, —Cl, —Br, —I, —CN, —NO2, —CHO, ═O, —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, —NH—C(═O)N(R0)2, —Si(R0)3, —PO(OR0)2;
“aryl”, respectively independently, stands for a carbocyclic ring system with at least one aromatic ring, but without heteroatoms in this ring, wherein, if necessary, the aryl residues can be condensed with further saturated, (partially) unsaturated or aromatic ring systems, and each aryl residue can be present in unsubstituted or mono- or polysubstituted form, wherein the aryl substituents can be the same or different and in any desired and possible position of the aryl;
“heteroaryl” stands for a 5-, 6- or 7-membered cyclic aromatic residue, which contains 1, 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms, the same or different, are nitrogen, oxygen or sulphur, and the heterocycle can be unsubstituted or mono- or polysubstituted; wherein in the case of the substitution on the heterocycle the substituents can be the same or different and can be in any desired and possible position of the heteroaryl; and wherein the heterocycle can also be part of a bi- or polycyclic system;
wherein with respect to “aryl” and “heteroaryl”, “mono- or polysubstituted” is understood to mean the mono- or polysubstitution of one or more hydrogen atoms of the ring system by substituents selected from the group comprising —F, —Cl, —Br, —I, —CN, —NO2, —CHO, ═O, —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, —O(CH2)1-2O—, —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, —NH—C(═O)NH2, —NHC(═O)NHR0, —NHC(═O)N(R0)2, —Si(R0)3, —PO(OR0)2; wherein any N-ring atoms present can be respectively oxidised (N-oxide);
in the form of a single stereoisomer or mixture thereof, the free compounds and/or their physiologically compatible salts and/or solvates, wherein 4-(dimethylamino)-1-methyl-4-p-tolyl cyclohexyl acetate and its salts are preferably excepted.

In the combination of different residues, e.g. Y1, Y1′, Y2, Y2′, Y3, Y3′, Y4 and Y4′, and also the combination of residues at substituents thereof such as e.g. —OR0, —OC(═O)R0, —OC(═O)NHR0, a substituent, e.g. R0, can assume different meanings within a substance for two or more residues, e.g. —OR0, —OC(═O)R0, —OC(═O)NHR0.

The compounds according to the invention exhibit favourable binding to the ORL 1-receptor and the μ-opioid receptor.

In a preferred embodiment, the compounds according to the invention have an affinity ratio of ORL1/μ of at least 0.1. The ORL1/μ ratio is defined as 1/[Ki(ORL1)/Ki(μ)]. It is particularly preferred if the ORL1/μ ratio amounts to at least 0.2 or at least 0.5, more preferred at least 1.0 or at least 2.0, further preferred at least 3.0 or at least 4.0, most preferred at least 5.0 or at least 7.5 and in particular at least 10 or at least 15. In a preferred embodiment the ORL1/μ ratio lies in the range of 0.1 to 30, more preferred 0.1 to 25.

In another preferred embodiment, the compounds according to the invention have an ORL1/μ affinity ratio of more than 30, more preferred at least 50, further preferred at least 100, most preferred at least 200 and in particular at least 300.

The compounds according to the invention preferably have a Ki value on the μ-opioid receptor of at maximum 500 nM, more preferred at maximum 100 nM, further preferred at maximum 50 nM, most preferred at maximum 10 nM and in particular at maximum 1.0 nM.

Methods for determining the Ki value on the μ-opioid receptor are known to the person skilled in the art. The determination is preferably conducted as described in association with the examples.

It has surprisingly been shown that compounds with affinity to the ORL 1- and μ-opioid receptor, in which the ratio of ORL 1 to μ defined by 1/[Ki(ORL1)/Ki(μ)] lies in the range of 0.1 to 30, preferably 0.1 to 25, have a pharmacological profile that has significant advantages compared to the other opioid receptor ligand: 1. The compounds according to the invention exhibit an efficacy in acute pain models that is at times comparable with the usual stage-3 opioids. However, they are distinguished at the same time by a significantly better compatibility compared to classic μ-opioids. 2. In contrast to common stage-3 opioids, the compounds according to the invention exhibit a significantly higher efficacy in mono- and polyneuropathic pain models, which is attributable to a synergy of ORL 1- and μ-opioid components. 3. In contrast to common stage-3 opioids, the compounds according to the invention exhibit in neuropathic animals a substantial, preferably a complete, separation of antiallodynic or antihyperalgesic effect and antinociceptive effect. 4. In contrast to common stage-3 opioids, in animal models the compounds according to the invention exhibit a significant increase in efficacy for chronic inflammatory pain (carageenan- or CFA-induced hyperalgesia, visceral inflammatory pain, amongst others) compared to acute pain. 5. In contrast to common stage-3 opioids, side-effects typical of μ-opioids (respiratory depression, opioid-induced hyperalgesia, physical dependence/withdrawal, psychic dependence/addiction, among others) are significantly reduced or preferably not observed with the compounds according to the invention in the therapeutically effective dose range.

In view of the reduced μ-opioid side-effects, on the one hand, and the increased efficacy in chronic, preferably neuropathic pain, on the other hand, the mixed ORL 1/μ agonists are thus distinguished by significantly increased safety margins compared to pure μ-opioids. This results in a significantly increased “therapeutic window” in the treatment of pain conditions, preferably chronic pain, more preferred neuropathic pain.

It is preferred if 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, —NH2, —NH—C1-6-aliphatic, —NH—C3-8-cycloaliphatic, —NH—C1-6-aliphatic-OH, —N(C1-6-aliphatic)2, —N(C3-8-cycloaliphatic)2, —N(C1-6-aliphatic-OH)2, —NO2, —NH—C1-6-aliphatic-C3-8-cycloaliphatic, —NH—C1-6-aliphatic-aryl, —NH—C1-6-aliphatic-heteroaryl, —NH-aryl, —NH-heteroaryl, —SH, —S—C1-6-aliphatic, —S—C3-8-cycloaliphatic, —S—C1-6-aliphatic-C3-8-cycloaliphatic, —S—C1-6-aliphatic-aryl, —S—C1-6-aliphatic-heteroaryl, —S-aryl, —S-heteroaryl, —OH, —O—C1-6-aliphatic, —O—C3-8-cycloaliphatic, —O—C1-6-aliphatic-OH, —O—C1-6-aliphatic-C3-8-cycloaliphatic, —O—C1-6-aliphatic-aryl, —O—C1-6-aliphatic-heretoaryl, —O-aryl, —O-heteroaryl, —O—C(═O)C1-6-aliphatic, —O—C(═O)C3-8-cycloaliphatic, —O—C(═O)C1-6-aliphatic-OH, —O—C(═O)C1-6-aliphatic-C3-8-cycloaliphatic, —O—C(═O)C1-6-aliphatic-aryl, —O—C(═O)C1-6-aliphatic-heretoaryl, —O—C(═O)aryl, —O—C(═O)heteroaryl, —C1-6-aliphatic, —C3-8-cycloaliphatic, —C1-6-aliphatic-C3-8-cycloaliphatic, —C1-6-aliphatic-aryl, —C1-6-aliphatic-heteroaryl, -aryl, -heteroaryl, —C(═O)C1-6-aliphatic, —C(═O)C3-8-cycloaliphatic, —C(═O)C1-6-aliphatic-C3-8-cycloaliphatic, —C(═O)C1-6-aliphatic-aryl, —C(═O)C1-6-aliphatic-heteroaryl, —C(═O)aryl, —C(═O)heteroaryl, —CO2H, —CO2—C1-6-aliphatic, —CO2—C3-8-cycloaliphatic, —CO2—C1-6-aliphatic-C3-8-cycloaliphatic, —CO2—C1-6-aliphatic-aryl, —CO2—C1-6-aliphatic-heteroaryl, —CO2-aryl, —CO2-heteroaryl; or Y1 and Y1′, or Y2 and Y2′, or Y3 and Y3′, or Y4 and Y4′ jointly stand for ═O. It is preferred if 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, —NH2 and —OH.

In a preferred embodiment one of the residues Y1, Y1′, Y2, Y2′, Y3, Y3′, Y4 and Y4′ differs from —H and the remaining residues stand for —H.

It is particularly preferred if Y1, Y1′, Y2, Y2′, Y3, Y3′, Y4 and Y4′ respectively stand for —H.

Q preferably stands for —R0, —C(═O)Ro or —C(═NH)Ro. It is particularly preferred if Q stands for —C1-8-aliphatic, -aryl, -heteroaryl, —C1-8-aliphatic-aryl, —C1-8-aliphatic-deteroaryl, —C(═O)—C1-8-aliphatic, —C(═O)-aryl, —C(═O)-heteroaryl, —C(═O)—C1-8-aliphatic-aryl, —C(═O)—C1-8-aliphatic-heteroaryl, —C(═NH)—C1-8-aliphatic, —C(═NH)-aryl, —C(═NH)-heteroaryl, —C(═NH)—C1-8-aliphatic-aryl, or —C(═NH)—C1-8-aliphatic-heteroaryl.

It is particularly preferred if Q stands for —C1-8-aliphatic, -aryl, -heteroaryl, —C1-8-aliphatic-aryl, —C(═O)-heteroaryl or —C(═NH)-heteroaryl.

In this case, -aryl and -heteroaryl can respectively be unsubstituted or mono- or polysubstituted, preferably with substituents that are selected independently of one another from the group comprising —C1-8-aliphatic, —OH, —OC1-8-aliphatic, —C1-8-aliphatic-O—C1-8-aliphatic (e.g. —CH2—O—CH3), —CF3, —F, —Cl, —Br, —NO2, —CN, -heteroaryl, —C1-8-aliphatic-aryl and —C1-8-aliphatic-heteroaryl.

In a preferred embodiment Q is selected from the group comprising —C1-8-alkyl, -phenyl, -benzyl, -pyrrolyl, -furyl, -thienyl, pyridyl, -indolyl, -benzofuryl and -benzothienyl, wherein these can respectively be unsubstituted or mono- or polysubstituted, preferably with substituents that are selected independently of one another from the group comprising —C1-8-aliphatic, —OH, —OC1-8-aliphatic, —C1-8-aliphatic-O—C1-8-aliphatic, —CF3, —F, —Cl, —Br, —NO2, —CN, -heteroaryl, —C1-8-aliphatic-aryl and —C1-8-aliphatic-heteroaryl (e.g. -ethyl-4-pyridyl). It is particularly preferred if Q is selected from the group comprising:

R0, respectively independently, preferably stands for —C1-8-aliphatic, —C3-12-cycloaliphatic, -aryl, -heteroaryl, —C1-8-aliphatic-C3-12-cycloaliphatic, —C1-8-aliphatic-aryl or —C1-8-aliphatic-heteroaryl. In this case —C1-8-aliphatic-C3-12-cycloaliphatic, —C1-8-aliphatic-aryl or —C1-8-aliphatic-heteroaryl mean that the residues —C3-12-cycloaliphatic, -aryl or -heteroaryl are respectively bonded via a bivalent bridge —C1-8-aliphatic-. Preferred examples of —C1-8-aliphatic-aryl are —CH2—C6H5, —CH2CH2—C6H5, and —CH═CH—C6H5.

R1 and R2, independently of one another, preferably stand for —H; —C1-6-aliphatic; —C3-8-cyclo-aliphatic, —C1-6-aliphatic-aryl, —C1-6-aliphatic-C3-8-cycloaliphatic or —C1-6-aliphatic-heteroaryl; or the residues R1 and R2 together form a ring and represent —CH2CH2OCH2CH2—, —CH2CH2NR4CH2CH2— or —(CH2)3-6—, on condition that R1 and R2 preferably do not both stand for —H at the same time. It is more preferred if R1 and R2, independently of one another, stand for —H; —C1-5-aliphatic; or the residues R1 and R2 together form a ring and represent —CH2CH2OCH2CH2—, —CH2CH2NR4—CH2CH2— or —(CH2)3-6—, wherein R4 preferably represents —H or —C1-5-aliphatic, on condition that R1 and R2 preferably do not both stand for —H at the same time. Particularly preferred are those compounds, in which R1 and R2, independently of one another, stand for —CH3 or —H, wherein R1 and R2 do not simultaneously represent —H; or R1 and R2 form a ring and represent —(CH2)3-4—. Compounds, in which R1 and R2 stand for —CH3 or in which R1 stands for —H and R2 stands for —CH3, are most particularly preferred.

It is particularly preferred if R1 and R2 together with the nitrogen atom, to which they are bonded, form one of the following functional groups:

R3 preferably stands for —C1-8-aliphatic, —C3-8-cycloaliphatic, -aryl, -heteroaryl; or for -aryl, -heteroaryl or —C3-8-cycloaliphatic respectively bonded via a —C1-3-aliphatic group.

It is particularly preferred if R3 stands for -ethyl, -propyl, -butyl, -pentyl, -hexyl, -heptyl, -cyclopentyl, -cyclohexyl, -phenyl, -benzyl, -naphthyl, -anthracenyl, -thiophenyl, -benzothio-phenyl, -furyl, -benzofuranyl, -benzodioxolanyl, -indolyl, -indanyl, -benzodioxanyl, -pyrrolyl, -pyridyl, -pyrimidyl or -pyrazinyl, respectively unsubstituted or mono- or polysubstituted; —C5-6-cycloaliphatic, -phenyl, -naphthyl, -anthracenyl, -thiophenyl, -benzothiophenyl, -pyridyl, -furyl, -benzofuranyl, -benzodioxolanyl, -indolyl, -indanyl, -benzodioxanyl, -pyrrolyl, -pyrimidyl, -triazolyl or -pyrazinyl, respectively unsubstituted or mono- or polysubstituted, bonded via a saturated, unbranched —C1-3-aliphatic group.

It is more preferred if R3 stands for -propyl, -butyl, -pentyl, -hexyl, -phenyl, -furyl, -thiophenyl, -naphthyl, -benzyl, -benzofuranyl, -indolyl, -indanyl, -benzodioxanyl, -benzodioxolanyl, -pyridyl, -pyrimidyl, -pyrazinyl, -triazolyl or -benzothiophenyl, respectively unsubstituted or mono- or polysubstituted; -phenyl, -furyl or -thiophenyl, respectively unsubstituted or mono- or polysubstituted, bonded via a saturated, unbranched —C1-3-aliphatic group.

It is further preferred if R3 stands for -propyl, -butyl, -pentyl, -hexyl, -phenyl, -phenethyl, -thiophenyl, -pyridyl, -triazolyl, -benzothiophenyl or -benzyl, respectively substituted or unsubstituted, particularly preferred for -propyl, -3-methoxypropyl, -butyl, -pentyl, -hexyl, -phenyl, -3-methylphenyl, -3-fluorophenyl, -benzo[1,3]-dioxolyl, -thienyl, -benzothiophenyl, -4-chlorobenzyl, -benzyl, -3-chlorobenzyl, -4-methylbenzyl, -2-chlorobenzyl, -4-fluorobenzyl, -3-methylbenzyl, -2-methylbenzyl, -3-fluorobenzyl, -2-fluorobenzyl, -1-methyl-1,2,4-triazolyl or -phenethyl.

It is especially preferred if R3 stands for -butyl, -ethyl, -3-methoxypropyl, -benzothiophenyl, -phenyl, -3-methylphenyl, -3-fluorophenyl, -benzo[1,3]-dioxolyl, -benzyl, -1-methyl-1,2,4-triazolyl, -thienyl or -phenethyl.

It is most preferred if R3 stands for -phenyl, -benzyl or -phenethyl, respectively unsubstituted or mono- or polysubstituted on the ring; —C1-5-aliphatic, —C4-6-cycloaliphatic, -pyridyl, -thienyl, -thiazolyl, -imidazolyl, -1,2,4 triazolyl or -benzimidazolyl, unsubstituted or mono- or polysubstituted.

It is particularly preferred if R3 stands for -phenyl, -benzyl, -phenethyl, -thienyl, -pyridyl, -thiazolyl, -imidazolyl, -1,2,4 triazolyl, -benzimidazolyl or -benzyl, unsubstituted or mono- or polysubstituted with —F, —Cl, —Br, —CN, —CH3, —C2H5, —NH2, —NO2, —SH, —CF3, —OH, —OCH3, —OC2H5 or —N(CH3)2; -ethyl, -n-propyl, -2-propyl, -allyl, -n-butyl, -iso-butyl, -sec-butyl, -tert-butyl, -n-pentyl, -iso-pentyl, -neo-pentyl, -n-hexyl, -cyclopentyl or -cyclohexyl, respectively unsubstituted or mono- or polysubstituent with —OH, —OCH3 or —OC2H5, wherein -thienyl, -pyridyl, -thiazolyl, -imidazolyl, -1,2,4-triazolyl and -benzimidazolyl are preferably unsubstituted.

It is particularly preferred if R3 stands for -phenyl, unsubstituted or mono-substituted with —F, —Cl, —CN, —CH3; -thienyl; -ethyl, -n-propyl or -n-butyl, unsubstituted or mono- or polysubstituted with —OCH3, —OH or —OC2H5, in particular with —OCH3.

R4 preferably stands for —H, —C1-5-aliphatic, —C3-8-cycloaliphatic, -aryl, -heteroaryl, —C1-6-aliphatic-aryl, —C1-6-aliphatic-C3-8-cycloaliphatic, —C1-6-aliphatic-heteroaryl, —C(═O)aryl, —C(═O)heteroaryl, or —C(═O)C1-6-aliphatic, more preferred for —H or —C1-5-aliphatic.



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Crystalline forms of [(1r), 2s]-2-aminopropionic acid 2-[4-(4-fluoro-2-methyl-1h-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methylethyl ester
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stats Patent Info
Application #
US 20090247530 A1
Publish Date
10/01/2009
Document #
12410801
File Date
03/25/2009
USPTO Class
514241
Other USPTO Classes
544216, 548509, 514415
International Class
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Drawings
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Grunenthal Gmbh

Browse recent Grunenthal Gmbh patents

Drug, Bio-affecting And Body Treating Compositions   Designated Organic Active Ingredient Containing (doai)   Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai   Hetero Ring Is Six-membered Consisting Of Three Nitrogens And Three Carbon Atoms