N-METHYLBENZIMIDAZOLES AS MIDH1 INHIBITORS
20180170882 · 2018-06-21
Assignee
Inventors
- Sven Ring (Jena, DE)
- Olaf Panknin (Berlin, DE)
- Katja ZIMMERMANN (Düsseldorf, DE)
- Judith GÜNTHER (Berlin, DE)
- Lars BÄRFACKER (Düsseldorf, DE)
Cpc classification
C07C229/42
CHEMISTRY; METALLURGY
A61K45/06
HUMAN NECESSITIES
A61K31/4184
HUMAN NECESSITIES
C07C229/60
CHEMISTRY; METALLURGY
C07D235/24
CHEMISTRY; METALLURGY
C07D235/30
CHEMISTRY; METALLURGY
A61P35/00
HUMAN NECESSITIES
International classification
C07D235/30
CHEMISTRY; METALLURGY
A61K31/4184
HUMAN NECESSITIES
Abstract
The present invention relates to benzimidazol-2-amines of general formula (I), in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients.
##STR00001##
Claims
1. A compound of formula (I) ##STR00081## in which: R.sup.1 represents a halogen atom or a group selected from: C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-cycloalkyloxy, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-haloalkoxy, cyano, (C.sub.1-C.sub.6-alkyl)-S, (C.sub.1-C.sub.6-alkyl)-S(O), (C.sub.1-C.sub.6-alkyl)-S(O).sub.2, (C.sub.1-C.sub.6-haloalkyl)-S, (C.sub.1-C.sub.6-haloalkyl)-S(O), (C.sub.1-C.sub.6-haloalkyl)-S(O).sub.2, C(O)OR.sup.9, C(O)N(R.sup.10)R.sup.11 and N(R.sup.10)R.sup.11; R.sup.2 represents a hydrogen atom; R.sup.3 represents a hydrogen atom; R.sup.4 represents a hydrogen atom or a halogen atom; R.sup.5 represents a group selected from: C(O)OR.sup.9, R.sup.9OC(O)(C.sub.1-C.sub.6-alkyl)-, R.sup.9OC(O)(C.sub.2-C.sub.6-alkenyl)-, R.sup.9OC(O)(C.sub.1-C.sub.6-alkoxy)-, C(O)N(R.sup.10)R.sup.11, R.sup.10(R.sup.11)NC(O)(C.sub.1-C.sub.6-alkyl)-, R.sup.10(R.sup.1)NC(O)(C.sub.2-C.sub.6-alkenyl)- and R.sup.10(R.sup.11)NC(O)(C.sub.1-C.sub.6-alkoxy)-; R.sup.6 represents a hydrogen atom or a halogen atom or a group selected from: C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyloxy, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-haloalkoxy and cyano; R.sup.7 represents a hydrogen atom; R.sup.8 represents a hydrogen atom; R.sup.9 represents a hydrogen atom or a group selected from: C.sub.1-C.sub.6-alkyl and C.sub.3-C.sub.6-cycloalkyl; R.sup.10 and R.sup.11 are independently of each other selected from: hydrogen and C.sub.1-C.sub.6-alkyl; or R.sup.10 and R.sup.11 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyl; said 4- to 6-membered heterocycloalkyl being optionally substituted with one substituent selected from: C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.3-haloalkoxy, amino, hydroxy, halogen and cyano; or said 4- to 6-membered heterocycloalkyl being optionally substituted with two halogen atoms; or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
2. The compound according to claim 1, wherein: R.sup.1 represents a halogen atom or a group selected from: C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-cycloalkyloxy, C.sub.1-C.sub.6-haloalkyl and C.sub.1-C.sub.6-haloalkoxy; R.sup.2 represents a hydrogen atom; R.sup.3 represents a hydrogen atom; R.sup.4 represents a hydrogen atom or a halogen atom; R.sup.5 represents a group selected from: C(O)OR.sup.9 and R.sup.9OC(O)(C.sub.1-C.sub.6-alkyl)-; R.sup.6 represents a hydrogen atom or a halogen atom or a group selected from: C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyloxy, C.sub.1-C.sub.6-haloalkyl and C.sub.1-C.sub.6-haloalkoxy; R.sup.7 represents a hydrogen atom; R.sup.8 represents a hydrogen atom; R.sup.9 represents a hydrogen atom or a C.sub.1-C.sub.6-alkyl group; or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
3. The compound according to claim 1, wherein: R.sup.1 represents a halogen atom or a group selected from: C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyloxy, C.sub.1-C.sub.3-haloalkyl and C.sub.1-C.sub.3-haloalkoxy; R.sup.2 represents a hydrogen atom; R.sup.3 represents a hydrogen atom; R.sup.4 represents a hydrogen atom or a halogen atom; R.sup.5 represents a group selected from: C(O)OR.sup.9 and R.sup.9OC(O)(C.sub.1-C.sub.3-alkyl)-; R.sup.6 represents a hydrogen atom or a halogen atom or a group selected from: C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyloxy, C.sub.1-C.sub.3-haloalkyl and C.sub.1-C.sub.3-haloalkoxy; R.sup.7 represents a hydrogen atom; R.sup.8 represents a hydrogen atom; R.sup.9 represents a hydrogen atom or a C.sub.1-C.sub.3-alkyl group; or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
4. The compound according to claim 1, wherein: R.sup.1 represents a group selected from: C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy and C.sub.1-C.sub.3-haloalkoxy; R.sup.2 represents a hydrogen atom; R.sup.3 represents a hydrogen atom; R.sup.4 represents a hydrogen atom; R.sup.5 represents a group selected from: C(O)OR.sup.9 and R.sup.9OC(O)(C.sub.1-C.sub.2-alkyl)-; R.sup.6 represents a hydrogen atom or a group selected from: C.sub.1-C.sub.3-alkyl and C.sub.1-C.sub.3-alkoxy, R.sup.7 represents a hydrogen atom; R.sup.8 represents a hydrogen atom; R.sup.9 represents a hydrogen atom or a C.sub.1-C.sub.3-alkyl group; or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
5. The compound according to claim 1, wherein: R.sup.1 represents a group selected from: isopropyl, isopropoxy and trifluoromethoxy; R.sup.2 represents a hydrogen atom; R.sup.3 represents a hydrogen atom; R.sup.4 represents a hydrogen atom; R.sup.5 represents a group selected from: C(O)OR.sup.9 and R.sup.9OC(O)(C.sub.1-C.sub.2-alkyl)-; R.sup.6 represents a hydrogen atom or a group selected from: methyl and methoxy, R.sup.7 represents a hydrogen atom; R.sup.8 represents a hydrogen atom; R.sup.9 represents a hydrogen atom or a methyl group; or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
6. The compound according to claim 1, having a structural formula (I-a) ##STR00082## in which: R.sup.1 represents a group selected from: C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy and C.sub.1-C.sub.3-haloalkoxy; R.sup.2 represents a hydrogen atom; R.sup.3 represents a hydrogen atom; R.sup.4 represents a hydrogen atom; R.sup.5 represents a group selected from: C(O)OR.sup.9 and R.sup.9OC(O)(C.sub.1-C.sub.2-alkyl)-; R.sup.6 represents a hydrogen atom or a group selected from: C.sub.1-C.sub.3-alkyl and C.sub.1-C.sub.3-alkoxy, R.sup.7 represents a hydrogen atom; R.sup.8 represents a hydrogen atom; R.sup.9 represents a hydrogen atom or a C.sub.1-C.sub.3-alkyl group; or an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
7. The compound according to claim 6, wherein: R.sup.1 represents a group selected from: isopropyl, isopropoxy and trifluoromethoxy; R.sup.2 represents a hydrogen atom; R.sup.3 represents a hydrogen atom; R.sup.4 represents a hydrogen atom; R.sup.5 represents a group selected from: C(O)OR.sup.9 and R.sup.9OC(O)(C.sub.1-C.sub.2-alkyl)-; R.sup.6 represents a hydrogen atom or a group selected from: methyl and methoxy, R.sup.7 represents a hydrogen atom; R.sup.8 represents a hydrogen atom; R.sup.9 represents a hydrogen atom or a methyl group; or an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
8. The compound according to claim 1, which is selected from the group consisting of: methyl 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-{[4-(trifluoromethoxy)-phenyl]amino}-1H-benzimidazole-5-carboxylate; methyl 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-1H-benzimidazole-5-carboxylate; methyl 2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-1H-benzimidazole-5-carboxylate; methyl 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxylate; methyl 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-6-methyl-1H-benzimidazole-5-carboxylate; methyl 2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methyl-1H-benzimidazole-5-carboxylate; methyl 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxylate; methyl 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-6-methoxy-1H-benzimidazole-5-carboxylate; methyl 2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-1H-benzimidazole-5-carboxylate; methyl (1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)acetate; methyl {1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-1H-benzimidazol-5-yl})acetate; methyl {2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-1H-benzimidazol-5-yl}acetate; methyl (1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)acetate; methyl {1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-6-methyl-1H-benzimidazol-5-yl}acetate; methyl {2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methyl-1H-benzimidazol-5-yl}acetate; methyl (1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)acetate; methyl {1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-6-methoxy-1H-benzimidazol-5-yl}acetate; methyl {2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-1H-benzimidazol-5-yl}acetate; methyl 3-(1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoate; methyl 3-{1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-1H-benzimidazol-5-yl}propanoate; methyl 3-{2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-1H-benzimidazol-5-yl}propanoate; 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxylic acid; 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-1H-benzimidazole-5-carboxylic acid; 2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-1H benzimidazole-5-carboxylic acid; 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxylic acid; 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-6-methyl-1H-benzimidazole-5-carboxylic acid; 2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methyl-1H-benzimidazole-5-carboxylic acid; 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxylic acid; 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-6-methoxy-1H-benzimidazole-5-carboxylic acid; 2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-1H-benzimidazole-5-carboxylic acid; (1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)acetic acid; {1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-1H benzimidazol-5-yl}acetic acid; {2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-1H-benzimidazol-5-yl}acetic acid; (1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)acetic acid; {1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-6-methyl-1H-benzimidazol-5-yl}acetic acid; {2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6- methyl-1H-benzimidazol-5-yl}acetic acid; (1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)acetic acid; {1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-6-methoxy-1H-benzimidazol-5-yl}acetic acid; {2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6 methoxy-1H-benzimidazol-5-yl}acetic acid; 3-(1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoic acid; 3-{1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-1H-benzimidazol-5-yl}propanoic acid; 3-{2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 1H-benzimidazol-5-yl}propanoic acid; methyl 3-(1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoate; methyl 3-{2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-1H-benzimidazol-5-yl}propanoate; methyl 3-{1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)-amino]-6-methoxy-1H-benzimidazol-5-yl}propanoate; 3-(1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoic acid; 3-{2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 6-methoxy-1H-benzimidazol-5-yl}propanoic acid; and 3-{1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-6 -methoxy-1H-benzimidazol-5-yl}propanoic acid; or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
9. A method of preparing a compound of general formula (I) according to claim 1, said method comprising the step of allowing an intermediate compound of general formula (III): ##STR00083## in which R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are as defined for the compounds of general formula (I), to react with a compound of general formula (IV): ##STR00084## in which R.sup.1, R.sup.2 and R.sup.3 are as defined for the compounds of general formula (I), thereby giving a compound of general formula (I): ##STR00085## in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as defined for the compounds of general formula (I).
10. A method of preparing a compound of general formula (I) according to claim 1, said method comprising the step of allowing an intermediate compound of general formula (V): ##STR00086## in which R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are as defined for the compounds of general formula (I), to react with a compound of general formula (VI): ##STR00087## in which R.sup.1, R.sup.2, R.sup.3 and R.sup.8 are as defined for the compounds of general formula (I), thereby giving a compound of general formula (I): ##STR00088## in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as defined for the compounds of general formula (I).
11. A compound of general formula (I), or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to claim 1, for use in the treatment or prophylaxis of a disease.
12. A pharmaceutical composition comprising a compound of general formula (I), or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to claim 1, and a pharmaceutically acceptable diluent or carrier.
13. A pharmaceutical combination comprising: one or more first active ingredients selected from a compound of general formula (I) according to claim 1, and one or more second active ingredients selected from chemotherapeutic anti-cancer agents.
14. Use of a compound of general formula (I), or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to claim 1, for the prophylaxis or treatment of a disease.
15. Use of a compound of general formula (I), or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to claim 1, for the preparation of a medicament for the prophylaxis or treatment of a disease.
16. Use according to claim 11, wherein said disease is a disease of uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, particularly in which the disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is a haematological tumour, a solid tumour and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
17. Use of a compound of general formula (III): ##STR00089## in which R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are as defined for the compounds of general formula (I) according to claim 1, for the preparation of a compound of general formula (I).
18. Use of a compound of general formula (V): ##STR00090## in which R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are as defined for the compounds of general formula (I) according to claim 1, for the preparation of a compound of general formula (I).
Description
EXPERIMENTAL SECTION
[0310] The following table 1 lists the abbreviations used in this paragraph and in the Intermediate Examples and Examples section as far as they are not explained within the text body. NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered. Chemical names were generated using the ICS naming tool of ACD labs. In some cases generally accepted names of commercially available reagents were used in place of ICS naming tool generated names.
TABLE-US-00001 TABLE 1 Abbreviations Abbreviation Meaning br. broad signal in NMR br. s. broad singlet d doublet dd doublet of doublets DMSO dimethyl sulfoxide EDC N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride ESI electrospray ionization h hour(s) HClO.sub.4 perchloric acid HPLC, LC high performance liquid chromatography m multiplet m.sub.c centered multiplet min minute(s) MS mass spectroscopy NMR nuclear magnetic resonance R.sub.t retention time rt room temperature s singlet sept septet t triplet UPLC ultra performance liquid chromatography
[0311] Other abbreviations have their meanings customary per se to the skilled person. The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way.
Syntheses of Compounds (Overview)
[0312] The following schemes and general procedures illustrate general synthetic routes to the compounds of general formula (I) of the invention and are not intended to be limiting. It is obvious to the person skilled in the art that the order of transformations as exemplified in Schemes 1 and 2 can be modified in various ways. The order of transformations exemplified in Schemes 1 and 2 is therefore not intended to be limiting. In addition, interconversion of substituents, for example of residues R.sup.1, R.sup.4, R.sup.5 and R.sup.6 can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999).
##STR00011##
in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as defined supra, and X represents a halogen atom.
[0313] Nitroanilines of general formula 3 can be obtained from nitroarenes of general formula 1 by nucleophilic substitution with amines of general formula 2 in a suitable solvent such as for example tetrahydrofurane or acetonitrile and in the presence of a suitable base such as for example potassium carbonate or triethylamine at temperatures between room temperature and the boiling point of the solvent, typically at 50-90 C. Instead of using amines of general formula 2 their corresponding ammonium salts can be used as well. Nitroarenes 1 and amines 2 or their corresponding ammonium salts are either commercially available, known compounds or may be formed from known compounds by known methods by a person skilled in the art.
[0314] Diamines of general formula (III) in turn may be obtained from nitroanilines of general formula 3 by reduction. For reduction, all processes that are known to the person skilled in the art may be applied. Nitroanilines 3 may be hydrogenated under an atmosphere of hydrogen at pressures between 1 bar and 100 bar in a suitable solvent such as for example ethyl acetate, tetrahydrofurane, methanol or ethanol or mixtures thereof and in the presence of a metal catalyst such as for example palladium on charcoal at temperatures between 0 C. and the boiling point of the solvent, typically at room temperature. The addition of a suitable acid such as for example hydrochloric acid or acetic acid may be necessary. Alternatively, nitroanilines of general formula 3 may be reduced with iron/ammonium chloride or tin(II) chloride in a suitable solvent such as for example water, methanol or ethanol or mixtures thereof at temperatures between room temperature and the boiling point of the solvent, typically at 70 C.
[0315] Suitably functionalized diamines of formula (III) may be reacted with thioisocyanates of general formula (IV) in a suitable solvent such as for example tetrahydrofurane and in the presence of a carbodiimide such as for example diisopropylcarbodiimide or EDC at temperatures between 0 C. and the boiling point of the solvent, typically at 70 C. Thioisocyanates (IV) are either commercially available, known compounds or may be formed from known compounds by known methods by a person skilled in the art.
##STR00012##
in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as defined supra.
[0316] Alternatively, compounds of general formula (I) may be obtained from chlorobenzimidazoles (V) according to Scheme 2. Suitably functionalized chlorobenzimidazoles (V) may be reacted with anilines of general formula (VI) in a suitable solvent such as for example NMP at temperatures between room temperature and the boiling point of the solvent, typically at 110 C. Anilines (VI) are either commercially available, known compounds or may be formed from known compounds by known methods by a person skilled in the art.
[0317] Chlorobenzimidazoles (V) in turn can be obtained from benzimidazolones of general formula 4 by reaction with chlorinating agents such as for example phosphoric trichloride at temperatures between room temperature and the boiling point of the reagent, typically at 105 C. Benzimidazolones of general formula 4 may be synthesized from suitably functionalized diamines of general formula (III) by reaction with carbonic acid equivalents such as for example CDI, phosgene or phosgene derivatives in a suitable solvent such as for example DMF or tetrahydrofurane at temperatures between room temperature and the boiling point of the solvent, typically at 50 C.
[0318] In accordance with one embodiment, the present invention also relates to a method of preparing a compound of general formula (I) as defined supra, said method comprising the step of allowing an intermediate compound of general formula (III):
##STR00013##
in which R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are as defined for the compounds of general formula (I) supra,
to react with a compound of general formula (IV):
##STR00014##
in which R.sup.1, R.sup.2 and R.sup.3 are as defined for the compounds of general formula (I), supra,
thereby giving a compound of general formula (I):
##STR00015##
in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as defined for the compounds of general formula (I) supra.
[0319] In accordance with another embodiment, the present invention also relates to a method of preparing a compound of general formula (I-a) as defined supra, said method comprising the step of allowing an intermediate compound of general formula (III-a):
##STR00016##
in which R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are as defined for the compounds of general formula (I) supra,
to react with a compound of general formula (IV):
##STR00017##
in which R.sup.1, R.sup.2 and R.sup.3 are as defined as for the compounds of general formula (I), supra,
thereby giving a compound of general formula (I-a):
##STR00018##
in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as defined for the compounds of general formula (I) supra.
[0320] In accordance with another embodiment, the present invention also relates to a method of preparing a compound of general formula (I) as defined supra, said method comprising the step of allowing an intermediate compound of general formula (V):
##STR00019##
in which R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are as defined for the compound of general formula (I) supra,
to react with a compound of general formula (VI):
##STR00020##
in which R.sup.1, R.sup.2, R.sup.3 and R.sup.8 are as defined as for the compounds of general formula (I), supra,
thereby giving a compound of general formula (I):
##STR00021##
in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as defined for the compounds of general formula (I) supra.
[0321] In accordance with another embodiment, the present invention also relates to a method of preparing a compound of general formula (I-a) as defined supra, said method comprising the step of allowing an intermediate compound of general formula (V-a):
##STR00022##
in which R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are as defined for the compounds of general formula (I) supra,
to react with a compound of general formula (VI):
##STR00023##
in which R.sup.1, R.sup.2, R.sup.3 and R.sup.8 are as defined as for the compounds of general formula (I), supra,
thereby giving a compound of general formula (I-a):
##STR00024##
in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as defined for the compounds of general formula (I) supra.
General Part
[0322] All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.
[0323] The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP-Sil or KP-NH in combination with a Biotage autopurifier system (SP4 or Isolera Four) and eluents such as gradients of hexane/ethyl acetate or dichloromethane/methanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
[0324] In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
UPLC-MS Standard Procedures
[0325] Analytical UPLC-MS was performed as described below. The masses (m/z) are reported from the positive mode electrospray ionisation unless the negative mode is indicated (ES).
[0326] In most of the cases method A is used. If not, it is indicated.
UPLC-MS Method A
[0327] Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 502.1 mm; Eluent A: water+0.1% formic acid, Eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL/min; Temperature: 60 C.; Injection: 2 L; DAD scan: 210-400 nm.
UPLC-MS Method B
[0328] Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 502.1 mm; Eluent A: water+0.2% ammonia, Eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL/min; Temperature: 60 C.; Injection: 2 L; DAD scan: 210-400 nm; ELSD.
UPLC-MS Method C
[0329] Instrument: Waters Acquity UPLC-MS ZQ4000; Column: Acquity UPLC BEH C18 1.7 502.1 mm; Eluent A: water+0.05% formic acid, Eluent B: acetonitrile+0.05% formic acid; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL/min; Temperature: 60 C.; Injection: 2 L; DAD scan: 210-400 nm.
UPLC-MS Method D
[0330] Instrument: Waters Acquity UPLC-MS ZQ4000; Column: Acquity UPLC BEH C18 1.7 502.1 mm; Eluent A: water+0.2% ammonia, Eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL/min; Temperature: 60 C.; Injection: 2 L; DAD scan: 210-400 nm; ELSD.
UPLC-MS Method E
[0331] Instrument: Waters Acquity UPLC-MS ZQ2000; Column: Acquity UPLC BEH C18 1.7 502.1 mm; Eluent A: water+0.1% formic acid, Eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL/min; Temperature: 60 C.; Injection: 1 L; DAD scan: 210-400 nm; ELSD.
UPLC-MS Method F
[0332] Instrument: Waters Acquity UPLC-MS ZQ2000; Column: Acquity UPLC BEH C18 1.7 502.1 mm; Eluent A: water+0.2% ammonia, Eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL/min; Temperature: 60 C.; Injection: 1 L; DAD scan: 210-400 nm; ELSD.
[0333] NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.
[0334] The obtained benzimidazoles of general formula (I) may be chiral and may be separated into their diastereomers and/or enantiomers by chiral HPLC.
Intermediates
Intermediate 1-1
methyl 3-amino-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}benzoate
[0335] ##STR00025##
Step 1: methyl 4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-3-nitrobenzoate
[0336] 770 mg (3.86 mmol) Methyl-4-fluoro-3-nitrobenzoate (commercially available) and 600 mg (3.86 mmol) (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexan-1-amine (CAS 2216-54-8) were given in 46 mL tetrahydrofurane. After addition of 587 mg (4.25 mmol) potassium carbonate the reaction mixture was heated at 50 C. overnight. The solids were filtered off via a glass fibre filter, washed with ethyl acetate and discarded. The filtrate was diluted with water (50 mL) and ethyl acetate (80 mL). After vigorous stirring for 15 min the organic phase was separated. The organic phase was washed with brine and dried with magnesium sulfate. After evaporation the product was obtained in quantitative yield and was used without further purification in the next step.
[0337] UPLC-MS (ESI+): [M+H].sup.+=335; R.sub.t=1.67 min (Method D).
Step 2: methyl 3-amino-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-benzoate
[0338] 1.35 g (4.04 mmol) Methyl 4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-3-nitrobenzoate from step 1 were dissolved in a mixture of methanol (17 ml) and tetrahydrofurane (40 ml). After addition of 0.35 g (0.40 mmol) Pd/C (10% Pd) the reaction mixture was stirred under a hydrogen atmosphere for 2 hours at room temperature. The catalyst was filtered off via a glass fibre filter and washed with ethyl acetate. After evaporation of the solvent 1.2 g (97%) of methyl 3-amino-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}benzoate were obtained.
[0339] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=0.66 (d, 3H), 0.84-0.92 (m, 6H), 1.03-1.16 (m, 1H), 1.28-1.38 (m, 1H), 1.42-1.56 (m, 1H), 1.62-1.78 (m, 2H), 1.94-2.01 (m, 1H), 2.10-2.20 (m, 1H), 3.71 (s., 3H), 4.85 (m.sub.c, 2H), 6.49 (d, 1H), 7.13-7.21 (m, 2H).
Intermediate 1-2
methyl 5-amino-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-2-methyl-benzoate
[0340] ##STR00026##
[0341] The title compound was prepared in analogy to intermediate 1-1 from methyl 4-fluoro-2-methyl-5-nitrobenzoate (CAS 1163287-01-1) and (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexan-1-amine (CAS 2216-54-8) according to step 1 and 2 of intermediate 1-1.
[0342] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=0.66 (d, 3H), 0.83-0.91 (m, 6H), 1.02-1.15 (m, 1H), 1.24-1.35 (m, 1H), 1.41-1.57 (m, 1H), 1.61-1.75 (m, 2H), 1.92-2.00 (m, 1H), 2.07-2.19 (m, 1H), 2.38 (s, 3H), 3.68 (s., 3H), 4.52 (me, 2H), 4.75 (d, 1H), 6.30 (s, 1H), 7.14 (s, 1H).
[0343] UPLC-MS (ESI+): [M+H].sup.+=319; R.sub.t=1.56 min (Method F).
Intermediate 1-3
methyl 5-amino-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-2-methoxybenzoate
[0344] ##STR00027##
[0345] The title compound was prepared in analogy to intermediate 1-1 from methyl 4-fluoro-2-methoxy-5-nitrobenzoate (CAS 151793-17-8) and (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexan-1-amine (CAS 2216-54-8) according to step 1 and 2 of intermediate 1-1.
[0346] UPLC-MS (ESI+): [M+H].sup.+=335; R.sub.t=1.42 min (Method F).
Intermediate 1-4
methyl (3-amino-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}phenyl)-acetate
[0347] ##STR00028##
Step 1: methyl (4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-3-nitro-phenyl)acetate
[0348] A solution of methyl 3-(4-fluoro-3-nitrophenyl)propanoate (823 mg, 3.8 mmol, CAS 226888-37-5) in 1,4-dioxane (21 mL) was treated with 600 mg (3.86 mmol) (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexan-1-amine (CAS 2216-54-8) and cesium carbonate (1.25 g, 3.8 mmol), warmed to 90 C. and stirred at this temperature for 72 h. Upon cooling to rt the precipitate was filtered off and washed with ethyl acetate. The combined filtrates were concentrated in vacuo and the obtained residue partitioned between water and ethyl acetate. The phases were separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with water (twice) and brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound (1.02 g, 75%) which was not further purified.
[0349] UPLC-MS (ESI+): [M+H].sup.+=349; R.sub.t=1.64 min (Method F).
Step 2: methyl (3-amino-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-phenyl)acetate
[0350] In analogy to step 2 of intermediate 1-1 the title compound was prepared from methyl (4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-3-nitrophenyl)acetate (product from step 1).
[0351] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=0.67 (d, 3H), 0.82-0.91 (m, 6H), 1.00-1.15 (m, 1H), 1.22-1.32 (m, 1H), 1.37-1.50 (m, 1H), 1.61-1.74 (m, 2H), 1.96-2.04 (m, 1H), 2.22-2.31 (m, 1H), 3.57 (s, 3H), 3.93 (me, 1H), 4.51 (me, 2H), 6.30-6.44 (m, 3H).
[0352] UPLC-MS (ESI+): [M+H].sup.+=319; R.sub.t=1.55 min (Method B).
Intermediate 1-5
methyl (5-amino-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-2-methylphenyl)acetate
[0353] ##STR00029##
Step 1: (4-fluoro-2-methyl-5-nitrophenyl)acetic acid
[0354] (4-Fluoro-2-methylphenyl)acetic acid (6 g, 35 mmol CAS 407640-40-8) was suspended in conc. sulfuric acid (36 ml) and cooled to 10 C. Then a mixture of nitric acid (1.8 mL, 90%) and sulfuric acid (2.6 mL, conc.) was added dropwise, the reaction mixture stirred at 10 C. for 1 h and poured on ice. The precipitate was filtered off and dried to give 6.46 g (84%) of the title compound.
[0355] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=2.31 (s, 3H), 3.75 (s, 2H), 7.45 (d, 1H), 8.05 (d, 1H).
Step 2: methyl (4-fluoro-2-methyl-5-nitrophenyl)acetate
[0356] A solution of (4-fluoro-2-methyl-5-nitrophenyl)acetic acid (9 g, 42 mmol) from step 1 in methanol (78 mL) was cooled in an ice-bath and dropwise treated with concentrated sulfuric acid (3.50 eq., 7.8 mL, 147 mmol). Upon addition the mixture was warmed to rt and stirred at this temperature for 24 h. The reaction mixture was concentrated to the half volume in vacuo, diluted with ethyl acetate and the organic layer washed with water, saturated sodium hydrogencarbonate solution and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the title compound (8.7 g 90%).
[0357] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=2.32 (s, 3H), 3.64 (s, 3H), 3.88 (s, 2H), 7.48 (d, 1H), 8.09 (d, 1H).
Step 3: methyl (5-amino-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-2-methylphenyl)acetate
[0358] The title compound was prepared from methyl (4-fluoro-2-methyl-5-nitrophenyl)acetate (product from step 2) and (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexan-1-amine in analogy to intermediate 1-4 (step 1) followed by hydrogenation in analogy to intermediate 1-1 (step 2).
[0359] UPLC-MS (ESI+): [M+H].sup.+=363; R.sub.t=1.66 min (Method F).
Intermediate 1-6
methyl (5-amino-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-2-methoxyphenyl)acetate
[0360] ##STR00030##
Step 1: (2,4-difluoro-5-nitrophenyl)acetic acid
[0361] (2,4-Difluorophenyl)acetic acid (commercially available) (6 g, 34 mmol) was suspended in conc. sulfuric acid (36 mL) and cooled to 0 C. Then a mixture of nitric acid (1.8 mL, 90%) and sulfuric acid (2.5 mL, conc.) was added dropwise, the reaction mixture stirred at 0 C. for 1 h and poured on ice. The precipitate was filtered off and dried to give 6.9 g (91%) of the title compound.
[0362] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=2.77 (s, 2H), 7.65-7.77 (m, 1H), 8.32 (t, 1H) 12.71 (s, 1H).
[0363] UPLC-MS (ESI+): [M+H].sup.+=232; R.sub.t=1.03 min (Method E).
Step 2: methyl (2,4-difluoro-5-nitrophenyl)acetate
[0364] A solution of (2,4-difluoro-5-nitrophenyl)acetic acid (10 g, 46 mmol) from step 1 in methanol (85 mL) was cooled in an ice-bath and dropwise treated with concentrated sulfuric acid (3.50 eq., 8.6 mL, 161 mmol). Upon addition the mixture was warmed to rt and stirred at this temperature for 24 h. The reaction mixture was concentrated to the half volume in vacuo, diluted with ethyl acetate and the organic layer washed with water, saturated sodium hydrogencarbonate solution and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the title compound (10.5 g, 98%).
[0365] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=3.66 (s, 2H), 3.91 (s, 3H), 7.69-7.80 (m, 1H), 8.36 (t, 1H).
Step 3: methyl (2-fluoro-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-5-nitrophenyl)acetate
[0366] The title compound was prepared from methyl (2,4-difluoro-5-nitrophenyl)acetate (step 2) and (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexan-1-amine (CAS 2216-54-8) in analogy to intermediate 1-1 (step 1).
[0367] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=0.72 (d, 3H), 0.85-0.92 (m, 6H), 1.07-1.20 (m, 1H), 1.38-1.47 (m, 1H), 1.55-1.74 (m, 3H), 1.90-2.02 (m, 2H), 3.64 (s, 3H), 3.69 (s, 2H), 7.10 (d, 1H), 8.04 (d, 1H), 8.16 (d, 1H).
[0368] UPLC-MS (ESI+): [M+H].sup.+=367; R.sub.t=1.65 min (Method F).
Step 4: methyl (4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-2-methoxy-5-nitrophenyl)acetate
[0369] Methyl (2-fluoro-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-5-nitrophenyl)-acetate (1.7 g, 4.6 mmol, product from step 3) was suspended in methanol (40 mL) and treated with sodium methylate in methanol (8.7 mL, 46 mmol, 30% solution) overnight at rt. Then the mixture was partitioned between water and ethyl acetate, the layers separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried with sodium sulfate and concentrated in vacuo to give the title compound (1.7 g, 96%).
[0370] UPLC-MS (ESI+): [M+H].sup.+=379; R.sub.t=1.60 min (Method F).
Step 5: methyl (5-amino-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-2-methoxyphenyl)acetate
[0371] The title compound was synthesized from methyl (4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-2-methoxy-5-nitrophenyl)acetate (step 4) in analogy to intermediate 1-1 (step 2).
[0372] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=0.71 (d, 3H), 0.82-0.92 (m, 6H), 1.02-1.15 (m, 1H), 1.20-1.30 (m, 1H), 1.40-1.53 (m, 1H), 1.62-1.77 (m, 2H), 1.97-2.05 (m, 1H), 2.19-2.30 (m, 1H), 3.34 (s, 2H), 3.56 (s, 3H), 3.60 (s, 3H), 3.96-4.14 (m, 2H), 6.13 (s, 1H), 6.34 (s, 1H).
[0373] UPLC-MS (ESI+): [M+H].sup.+=349; R.sub.t=1.48 min (Method F).
Intermediate 1-7
methyl 3-(3-amino-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}phenyl)propanoate
[0374] ##STR00031##
Step 1: methyl 3-(4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-3-nitro-phenyl)propanoate
[0375] A solution of methyl 3-(4-fluoro-3-nitrophenyl)propanoate (870 mg, 3.8 mmol, commercially available) in 1,4-dioxane (40 mL) was treated with 600 mg (3.86 mmol) (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexan-1-amine (CAS 2216-54-8), potassium carbonate (Ig, 7.7 mmol) and cesium carbonate (1.25 g, 3.8 mmol), warmed to 90 C. and stirred at this temperature for 96 h. Upon cooling to rt the precipitate was filtered off and washed with ethyl acetate. The combined filtrates were concentrated in vacuo and the obtained residue partitioned between water and ethyl acetate. The phases were separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with water (twice) and brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound (1.25 g, 89%) which was not further purified.
[0376] UPLC-MS (ESI+): [M+H].sup.+=363; R.sub.t=1.67 min (Method D).
Step 2: methyl 3-(3-amino-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-phenyl)propanoate
[0377] The title compound was synthesized from methyl 3-(4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-3-nitrophenyl)propanoate (from step 1) in analogy to intermediate 1-1 (step 2).
[0378] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=0.67 (d, 3H), 0.82-0.91 (m, 6H), 1.00-1.13 (m, 1H), 1.22-1.30 (m, 1H), 1.34-1.47 (m, 1H), 1.60-1.74 (m, 2H), 1.96-2.05 (m, 1H), 2.23-2.33 (m, 1H), 2.57-2.63 (m, 2H), 2.99-3.11 (m, 1H), 3.57 (s, 3H), 3.82 (d, 1H), 4.35-4.49 (m, 2H), 6.26-6.38 (m, 3H).
[0379] UPLC-MS (ESI+): [M+H].sup.+=333; R.sub.t=1.60 min (Method B).
Intermediate 1-8
methyl 3-(5-amino-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-2-methoxyphenyl)propanoate
[0380] ##STR00032##
Step 1: 3-(2,4-difluoro-5-nitrophenyl)propanoic acid
[0381] A mixture of 3-(2,4-difluorophenyl)propanoic acid (CAS No. [134672-70-1]; 15.1 g, 81.2 mmol) in concentrated sulfuric acid (118 mL) was cooled to 5 C. and treated dropwise with a freshly prepared mixture of fuming nitric acid (1.05 eq., 3.6 mL, 85 mmol) and concentrated sulfuric acid (1.85 eq., 8.0 mL, 150 mmol). The reaction mixture was stirred at 0 C. for 15 minutes and poured in small portions on ice water (750 mL). The mixture was stirred for 30 minutes upon which the formed precipitate was filtered off and washed with cold water (250 mL). The solid was taken up with dichloromethane (250 mL), the solution dried with sodium sulfate and concentrated in vacuo. The obtained material was dried in vauo to give the title compound (17.9 g, 94%) which was not further purified.
[0382] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=2.59 (t, 2H), 2.89 (t, 2H), 7.68 (dd, 1H), 8.23 (t, 1H).
Step 2: methyl 3-(2,4-difluoro-5-nitrophenyl)propanoate
[0383] A solution of 3-(2,4-difluoro-5-nitrophenyl)propanoic acid (17.9 g, 77.5 mmol) from step 1 in methanol (140 mL) was cooled in an ice-bath and dropwise treated with concentrated sulfuric acid (3.50 eq., 14.5 mL, 271 mmol). Upon addition the mixture was warmed to rt and stirred at this temperature for one hour. The reaction mixture was concentrated to half of its volume in vacuo, diluted with ethyl acetate (150 mL) and the organic layer washed with water (2150 mL). The aqueous layer was re-extracted with ethyl acetate (100 mL) and the combined organic layers were washed with saturated sodium hydrogencarbonate solution and brine (75 mL each). The organic layer was dried over sodium sulfate and concentrated in vacuo to give the title compound (19 g, 98%) which was not further purified.
[0384] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=2.68 (t, 2H), 2.93 (t, 2H), 3.59 (s, 3H), 7.68 (dd, 1H), 8.24 (t, 1H).
[0385] UPLC-MS (ESI+): [M+H].sup.+=246; R.sub.t=1.09 min (Method E).
Step 3: methyl 3-(2-fluoro-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-5-nitrophenyl)propanoate
[0386] A solution of methyl 3-(2,4-difluoro-5-nitrophenyl)propanoate (1.00 g, 4.08 mmol) from step 2 in acetonitrile (40 mL) was treated with (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexan-1-amine (CAS No. [2216-54-8], 1.00 eq, 759 L, 4.08 mmol) and triethylamine (1.10 eq., 625 L, 4.49 mmol) and stirred at 60 C. for 54 h and at rt for 42 h. The reaction mixture was concentrated in vacuo at 40 C. and the residue taken up with ethyl acetate (60 mL). The organic layer was washed with water (250 mL) and brine (50 mL), dried over sodium sulfate and concentrated in vacuo to give the title compound (1.6 g, 97%) which was not further purified.
[0387] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=0.70 (d, 3H), 0.86-0.90 (m, 7H), 1.07-1.16 (m, 2H), 1.38-1.44 (m, 1H), 1.55-1.71 (m, 3H), 1.90-1.96 (m, 2H), 2.60 (t, 2H), 2.77 (t, 2H), 3.52-3.58 (m, 4H), 7.06 (d, 1H), 7.97-7.99 (m, 1H), 8.04 (d, 1H).
[0388] UPLC-MS (ESI+): [M+H].sup.+=381; R.sub.t=1.70 min (Method E).
Step 4: methyl 3-(4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-2-methoxy-5-nitrophenyl)propanoate
[0389] An ice-cooled solution of methyl 3-(2-fluoro-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-5-nitrophenyl)propanoate (1.55 g, 4.08 mmol) from step 3 in methanol (4 mL) was slowly treated with a solution of sodium methanolate in methanol (CAS No. [124-41-4]; 10 eq., 9.3 mL of a 30 wt % solution) and stirred at 0 C. for 2 hours. An additional amount of methanol (11 mL) was added and stirring at rt continued for 45 minutes. The suspension was taken up with crushed ice (75 mL) and ethyl acetate and the layers separated. The aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic layers were washed with saturated sodium hydrogencarbonate solution and brine, dried with sodium sulfate and concentrated in vacuo to give the title compound (1.54 g, 81%) which was not further purified.
[0390] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=0.74 (d, 3H), 0.88-0.96 (m, 8H), 1.11-1.23 (m, 1H), 1.33-1.39 (m, 1H), 1.56-1.73 (m, 3H), 1.90-1.98 (m, 1H), 2.02-2.05 (m, 1H), 2.53 (t, 2H), 2.69 (t, 2H), 3.58 (s, 3H), 3.63-3.71 (m, 1H), 3.91 (s, 3H), 6.39 (s, 1H), 7.83 (s, 1H), 8.34 (d, 1H).
[0391] UPLC-MS (ESI+): [M+H].sup.+=393; R.sub.t=1.65 min (Method E).
Step 5: methyl 3-(5-amino-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-2-methoxyphenyl)propanoate
[0392] A solution of methyl 3-(4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-2-methoxy-5-nitrophenyl)propanoate (604 mg, 1.54 mmol) from step 4 in a mixture of methanol/tetrahydrofurane (1:1, 12 mL) was treated with Pd/C (10 wt %; 0.100 eq., 164 mg, 0.154 mmol) and shaken under a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtrated over a PTFE filter (pore size 0.45 M), washed with ethyl acetate (50 mL) and the filtrate concentrated in vacuo to give the title compound (542 mg, 86%) which was not further purified.
[0393] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=0.65-0.74 (m, 4H), 0.84-0.89 (m, 7H), 1.03-1.13 (m, 1H), 1.21-1.27 (m, 1H), 1.41-1.50 (m, 1H), 1.63-1.72 (m, 2H), 1.98-2.01 (m, 1H), 2.21-2.29 (m, 1H), 2.42 (t, 2H), 2.58 (t, 2H), 3.09-3.11 (m, 1H), 3.57 (s, 3H), 3.63 (s, 3H), 3.89-3.91 (m, 1H), 4.30 (br. s., 2H), 6.11 (s, 1H), 6.32 (s, 1H).
[0394] UPLC-MS (ESI): [MH].sup.=361; R.sub.t=1.55 min (Method B).
EXAMPLES
Example 2-1
methyl 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-{[4-(trifluoromethoxy)-phenyl]amino}-1H-benzimidazole-5-carboxylate
[0395] ##STR00033##
[0396] 400 mg (1.3 mmol) Methyl 3-amino-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}benzoate (intermediate 1-1) were dissolved in 20 mL tetrahydrofurane. 287 mg (1.3 mmol) 4-Trifluormethoxyphenylisothiocyanate and 406 L (2.6 mmol) N,N-diisopropylcarbodiimide were added and the reaction mixture was stirred at 60 C. for 24 hours. The solvent was removed and the residue was purified by HPLC yielding 420 mg (65%) of the desired product.
[0397] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=0.61 (d, 3H), 0.67 (d, 3H), 1.00 (d, 3H), 1.11-1.28 (m, 2H), 1.67-2.01 (m, 5H), 2.19-2.29 (m, 1H), 3.84 (s, 3H), 4.40-4.51 (m, 1H), 7.35 (d, 2H), 7.68 (s, 2H), 7.88 (d, 2H), 7.95 (s, 1H), 9.26 (s, 1H).
[0398] UPLC-MS (ESI+): [M+H].sup.+=490; R.sub.t=1.68 min (Method B).
[0399] The examples in Table 2 were prepared in an analogous manner to example 2-1, starting from the intermediates 1-1-1-7 and the corresponding commercially available thioisocyanates.
TABLE-US-00002 TABLE 2 Example No Structure/Name Analytical data 2-2
Example 2-22
1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-{[4-(trifluoromethoxy)phenyl]-amino}-1H-benzimidazole-5-carboxylic acid
[0400] ##STR00054##
[0401] A solution of methyl 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-{[4-(trifluoro-methoxy)phenyl]amino}-1H-benzimidazole-5-carboxylate (example 2-1; 100 mg, 0.2 mmol) in a mixture of tetrahydrofurane/water (1:1, 6 mL) was treated with lithium hydroxide (24 mg, 1 mmol) and stirred at 60 C. for 72 h. After cooling to rt the reaction mixture was acidified with 2 M aqueous hydrochloric acid (pH 4-5) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried with sodium sulfate and concentrated in vacuo. The obtained crude product (75 mg, 77%) was not further purified.
[0402] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=0.61 (d, 3H), 0.68 (d, 3H), 1.00 (d, 3H), 1.10-1.28 (m, 2H), 1.68-2.00 (m, 5H), 2.20-2.30 (m, 1H), 4.40-4.51 (m, 1H), 7.35 (d, 2H), 7.61-7.72 (m, 2H), 7.88 (d, 2H), 7.93 (m, 1H), 9.22 (s, 1H), 12.54 (s, 1H).
[0403] UPLC-MS (ESI+): [M+H].sup.+=476; R.sub.t=0.9 min (Method F).
[0404] The examples in table 3 were prepared in an analogous manner to example 2-22, starting from the examples 2-2-2-21.
TABLE-US-00003 TABLE 3 Example No Structure/Name Analytical data 2-23
Example 2-43
methyl 3-(1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-2-{[4-(tri-fluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoate
[0405] ##STR00075##
[0406] A solution of methyl 3-(5-amino-4-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}-2-methoxyphenyl)propanoate (intermediate 1-8; 177 mg, 0.488 mmol) in THF (5 mL) was treated with 1-isothiocyanato-4-(trifluoromethoxy)benzene (CAS No. [64285-95-6]; 1.00 eq., 107 mg, 0.488 mmol) and stirred at rt for 2 hours. EDC (2.00 eq., 187 mg, 0.977 mmol) was added, the reaction mixture heated to 70 C. and stirring at this temperature continued for 20 hours. The mixture was cooled to rt and poured into an aqueous sodium hydrogen carbonate solution (10%, 50 mL). The aqueous layer was extracted with ethyl acetate (320 mL), the combined organic layers washed with saturated ammonium chloride solution (30 mL) and brine, dried over sodium sulfate and concentrated in vacuo. The obtained material was purified by preparative HPLC to give the title compound (136 mg, 47%).
[0407] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=0.58 (d, 3H), 0.70 (d, 3H), 0.95-1.00 (m, 4H), 1.10-1.24 (m, 2H), 1.75-1.82 (m, 3H), 1.85-1.92 (m, 2H), 2.19-2.25 (m, 1H), 2.54-2.65 (m, 2H), 2.78-2.91 (m, 2H), 3.58 (s, 3H), 3.83 (s, 3H), 4.30-4.37 (m, 1H), 6.97 (s, 1H), 7.16 (s, 1H), 7.27-7.29 (m, 2H), 7.74-7.78 (m, 2H), 8.91 (s, 1H).
[0408] UPLC-MS (ESI+): [M+H].sup.+=548; R.sub.t=1.66 min (Method F).
[0409] The examples in Table 4 were prepared in an analogous manner to example 2-43, starting from intermediate 1-8 and the corresponding commercially available thioisocyanates.
TABLE-US-00004 TABLE 4 Example No Structure/Name Analytical data 2-44
Example 2-46
3-(1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoic acid
[0410] ##STR00078##
[0411] A solution of methyl 3-(1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoate (example 2-43; 127 mg, 0.233 mmol) in a mixture of THF/water (1:1, 5 mL) was treated with lithium hydroxide (5.0 eq., 28 mg, 1.2 mmol) and stirred at 70 C. overnight. The reaction mixture was acidified with 2 M aqueous hydrochloric acid (pH 4-5) and diluted with ethyl acetate. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried with sodium sulfate and concentrated in vacuo. The obtained crude product (131 mg, quant.) was not further purified.
[0412] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=0.58 (d, 3H), 0.71 (d, 3H), 0.95-1.00 (m, 4H), 1.14-1.21 (m, 2H), 1.75-1.82 (m, 3H), 1.85-1.89 (m, 2H), 2.19-2.25 (m, 1H), 2.75-2.88 (m, 2H), 3.83 (s, 3H), 4.30-4.37 (m, 1H), 6.97 (s, 1H), 7.16 (s, 1H), 7.27-7.30 (m, 2H), 7.75-7.77 (m, 2H), 8.92 (br. s., 1H), 12.07 (br. s., 1H).
[0413] UPLC-MS (ESI+): [M+H].sup.+=534; R.sub.t=1.03 min (Method F).
[0414] The examples in table 5 were prepared in an analogous manner to example 2-46, starting from the examples 2-44 and 2-45. Example 2-47 was purified by preparative HPLC.
TABLE-US-00005 TABLE 5 Example Ester No Structure/Name Analytical data precursor 2-47
[0415] Further, the compounds of formula (I) of the present invention can be converted to any salt as described herein, by any method which is known to the person skilled in the art. Similarly, any salt of a compound of formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
Pharmaceutical Compositions of the Compounds of the Invention
[0416] This invention also relates to pharmaceutical compositions containing one or more compounds of the present invention. These compositions can be utilised to achieve the desired pharmacological effect by administration to a patient in need thereof. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention. A pharmaceutically acceptable carrier is preferably a carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A pharmaceutically effective amount of compound is preferably that amount which produces a result or exerts an influence on the particular condition being treated. The compounds of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like. For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatine type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
[0417] In another embodiment, the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatine, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, colouring agents, and flavouring agents such as peppermint, oil of wintergreen, or cherry flavouring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both. Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavouring and colouring agents described above, may also be present.
[0418] The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
[0419] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more colouring agents; one or more flavouring agents; and one or more sweetening agents such as sucrose or saccharin.
[0420] Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavouring and colouring agents.
[0421] The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in preferably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants.
[0422] Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
[0423] The parenteral compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimise or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
[0424] Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
[0425] The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.
[0426] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.
[0427] A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycol.
[0428] Another formulation employed in the methods of the present invention employs transdermal delivery devices (patches). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
[0429] Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art.
[0430] It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in U.S. Pat. No. 5,011,472, issued Apr. 30, 1991.
[0431] The compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M. F. et al., Compendium of Excipients for Parenteral Formulations PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311; Strickley, R. G Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)Part-1 PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. et al., Excipients and Their Use in Injectable Products PDA Journal of Pharmaceutical Science & Technology 1997, 51(4), 166-171.
[0432] Commonly used pharmaceutical ingredients that can be used as appropriate to formulate the composition for its intended route of administration include:
acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);
alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine);
adsorbents (examples include but are not limited to powdered cellulose and activated charcoal);
aerosol propellants (examples include but are not limited to carbon dioxide, CCl.sub.2F.sub.2, F.sub.2ClCCClF.sub.2 and CClF.sub.3)
air displacement agents (examples include but are not limited to nitrogen and argon);
antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate);
antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal);
antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite);
binding materials (examples include but are not limited to block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene-butadiene copolymers);
buffering agents (examples include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate)
carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection)
chelating agents (examples include but are not limited to edetate disodium and edetic acid)
colourants (examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red);
clarifying agents (examples include but are not limited to bentonite);
emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate);
encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate)
flavourants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin);
humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol);
levigating agents (examples include but are not limited to mineral oil and glycerin); oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil);
ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment);
penetration enhancers (transdermal delivery) (examples include but are not limited to monohydroxy or polyhydroxy alcohols, mono- or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas)
plasticizers (examples include but are not limited to diethyl phthalate and glycerol);
solvents (examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation);
stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax);
suppository bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures));
surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono-palmitate);
suspending agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum);
sweetening agents (examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose);
tablet anti-adherents (examples include but are not limited to magnesium stearate and talc);
tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch);
tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch);
tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac);
tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate);
tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, crosslinked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch);
tablet glidants (examples include but are not limited to colloidal silica, corn starch and talc);
tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate);
tablet/capsule opaquants (examples include but are not limited to titanium dioxide);
tablet polishing agents (examples include but are not limited to carnuba wax and white wax);
thickening agents (examples include but are not limited to beeswax, cetyl alcohol and paraffin);
tonicity agents (examples include but are not limited to dextrose and sodium chloride);
viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth); and
wetting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).
[0433] Pharmaceutical compositions according to the present invention can be illustrated as follows:
Sterile IV Solution: A 5 mg/mL solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1-2 mg/mL with sterile 5% dextrose and is administered as an IV infusion over about 60 min.
Lyophilised powder for IV administration: A sterile preparation can be prepared with (i) 100-1000 mg of the desired compound of this invention as a lyophilised powder, (ii) 32-327 mg/mL sodium citrate, and (iii) 300-3000 mg Dextran 40. The formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2-0.4 mg/mL, and is administered either IV bolus or by IV infusion over 15-60 min.
Intramuscular suspension: The following solution or suspension can be prepared, for intramuscular injection:
50 mg/mL of the desired, water-insoluble compound of this invention
5 mg/mL sodium carboxymethylcellulose
4 mg/mL TWEEN 80
9 mg/mL sodium chloride
9 mg/mL benzyl alcohol
Hard Shell Capsules: A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
Soft Gelatin Capsules: A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
Immediate Release Tablets/Capsules: These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
Combination Therapies
[0434] The term combination in the present invention is used as known to persons skilled in the art and may be present as a fixed combination, a non-fixed combination or kit-of-parts.
[0435] A fixed combination in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity. One example of a fixed combination is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a fixed combination is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.
[0436] A non-fixed combination or kit-of-parts in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the said first active ingredient and the said second active ingredient are present separately. The components of the non-fixed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
[0437] The compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. The present invention relates also to such combinations. For example, the compounds of this invention can be combined with known chemotherapeutic agents or anti-cancer agents, e.g. anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof. Other indication agents include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, anti-metabolites, DNA-intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, toposisomerase inhibitors, biological response modifiers, or anti-hormones.
[0438] Examples of chemotherapeutic agents and anti-cancer agents include:
131I-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib, crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin+estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (123I), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, lanreotide, lapatinib, lasocholine, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone+pentazocine, naltrexone, nartograstim, nedaplatin, nelarabine, neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone+sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, romidepsin, romiplostim, romurtide, roniciclib, samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur+gimeracil+oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine+tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.
[0439] The compounds of the invention may also be administered in combination with protein therapeutics. Such protein therapeutics suitable for the treatment of cancer or other angiogenic disorders and for use with the compositions of the invention include, but are not limited to, an interferon (e.g., interferon .alpha., .beta., or .gamma.) supraagonistic monoclonal antibodies, Tuebingen, TRP-1 protein vaccine, Colostrinin, anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab, trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1, bevacizumab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab, rhMBL, MFE-CP1+ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-35, MT-103, rinfabate, AS-1402, B43-genistein, L-19 based radioimmunotherapeutics, AC-9301, NY-ESO-1 vaccine, IMC-1C11, CT-322, rhCC10, r(m)CRP, MORAb-009, aviscumine, MDX-1307, Her-2 vaccine, APC-8024, NGR-hTNF, rhH1.3, IGN-311, Endostatin, volociximab, PRO-1762, lexatumumab, SGN-40, pertuzumab, EMD-273063, L19-IL-2 fusion protein, PRX-321, CNTO-328, MDX-214, tigapotide, CAT-3888, labetuzumab, alpha-particle-emitting radioisotope-linked lintuzumab, EM-1421, HyperAcute vaccine, tucotuzumab celmoleukin, galiximab, HPV-16-E7, Javelinprostate cancer, Javelinmelanoma, NY-ESO-1 vaccine, EGF vaccine, CYT-004-MelQbG10, WT1 peptide, oregovomab, ofatumumab, zalutumumab, cintredekin besudotox, WX-G250, Albuferon, aflibercept, denosumab, vaccine, CTP-37, efungumab, or 131I-chTNT-1/B. Monoclonal antibodies useful as the protein therapeutic include, but are not limited to, muromonab-CD3, abciximab, edrecolomab, daclizumab, gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevicizumab, efalizumab, adalimumab, omalizumab, muromomab-CD3, rituximab, daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.
[0440] A compound of general formula (I) as defined herein can optionally be administered in combination with one or more of the following: ARRY-162, ARRY-300, ARRY-704, AS-703026, AZD-5363, AZD-8055, BEZ-235, BGT-226, BKM-120, BYL-719, CAL-101, CC-223, CH-5132799, deforolimus, E-6201, enzastaurin, GDC-0032, GDC-0068, GDC-0623, GDC-0941, GDC-0973, GDC-0980, GSK-2110183, GSK-2126458, GSK-2141795, MK-2206, novolimus, OSI-027, perifosine, PF-04691502, PF-05212384, PX-866, rapamycin, RG-7167, RO-4987655, RO-5126766, selumetinib, TAK-733, trametinib, triciribine, UCN-01, WX-554, XL-147, XL-765, zotarolimus, ZSTK-474.
[0441] Generally, the use of cytotoxic and/or cytostatic agents in combination with a compound or composition of the present invention will serve to:
(1) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone,
(2) provide for the administration of lesser amounts of the administered chemotherapeutic agents,
(3) provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies,
(4) provide for treating a broader spectrum of different cancer types in mammals, especially humans,
(5) provide for a higher response rate among treated patients,
(6) provide for a longer survival time among treated patients compared to standard chemotherapy treatments,
(7) provide a longer time for tumor progression, and/or
(8) yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.
Methods of Sensitizing Cells to Radiation
[0442] In a distinct embodiment of the present invention, a compound of the present invention may be used to sensitize a cell to radiation. That is, treatment of a cell with a compound of the present invention prior to radiation treatment of the cell renders the cell more susceptible to DNA damage and cell death than the cell would be in the absence of any treatment with a compound of the invention. In one aspect, the cell is treated with at least one compound of the invention.
[0443] Thus, the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the invention in combination with conventional radiation therapy.
[0444] The present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of the invention prior to the treatment of the cell to cause or induce cell death. In one aspect, after the cell is treated with one or more compounds of the invention, the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.
[0445] In one embodiment, a cell is killed by treating the cell with at least one DNA damaging agent. That is, after treating a cell with one or more compounds of the invention to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell. DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g., cisplatinum), ionizing radiation (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents.
[0446] In another embodiment, a cell is killed by treating the cell with at least one method to cause or induce DNA damage. Such methods include, but are not limited to, activation of a cell signalling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signalling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage. By way of a non-limiting example, a DNA repair pathway in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an abnormal accumulation of DNA damage in a cell.
[0447] In one aspect of the invention, a compound of the invention is administered to a cell prior to the radiation or other induction of DNA damage in the cell. In another aspect of the invention, a compound of the invention is administered to a cell concomitantly with the radiation or other induction of DNA damage in the cell. In yet another aspect of the invention, a compound of the invention is administered to a cell immediately after radiation or other induction of DNA damage in the cell has begun.
[0448] In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo.
[0449] As mentioned supra, the compounds of the present invention have surprisingly been found to effectively inhibit mutated isocitratdehydrogenase 1 (mIDH1 R132H) and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses are affected by inhibition of mutated isocitratdehydrogenase 1 (mIDH1 R132H), such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
[0450] In accordance with another aspect therefore, the present invention covers a compound of general formula (I), or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described and defined herein, for use in the treatment or prophylaxis of a disease, as mentioned supra.
[0451] Another particular aspect of the present invention is therefore the use of a compound of general formula (I), described supra, or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of a disease.
[0452] Another particular aspect of the present invention is therefore the use of a compound of general formula (I) described supra for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease.
[0453] The diseases referred to in the two preceding paragraphs are diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
[0454] The term inappropriate within the context of the present invention, in particular in the context of inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, as used herein, is to be understood as meaning a response which is less than, or greater than normal, and which is associated with, responsible for, or results in, the pathology of said diseases.
[0455] Preferably, the use is in the treatment or prophylaxis of diseases, wherein the diseases are haemotological tumours, solid tumours and/or metastases thereof.
Method of Treating Hyper-Proliferative Disorders
[0456] The present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat mammalian hyper-proliferative disorders. Compounds can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc. which is effective to treat the disorder. Hyperproliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukaemias.
[0457] Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
[0458] Examples of cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
[0459] Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, anaplastic astrocytoma, diffuse astrocytoma, glioblastoma, oligodendroglioma, secondary glioblastoma multiforme as well as neuroectodermal and pineal tumour.
[0460] Tumours of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tumours of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
[0461] Tumours of the digestive tract include, but are not limited to anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
[0462] Tumours of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
[0463] Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma. Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
[0464] Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
[0465] Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell. Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
[0466] Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
[0467] Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
[0468] These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.
[0469] The term treating or treatment as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma.
Methods of Treating Angiogenic Disorders
[0470] The present invention also provides methods of treating disorders and diseases associated with excessive and/or abnormal angiogenesis.
[0471] Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism. A number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity [Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer et al. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD; see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855], neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc. In addition, the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumour enlargement and metastasis. Moreover, the growth of new blood and lymph vessels in a tumour provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer. Thus, compounds of the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis disorders, e.g., by inhibiting and/or reducing blood vessel formation; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.
Dose and Administration
[0472] Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative disorders and angiogenic disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
[0473] The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, drug holidays in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
[0474] Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
[0475] Preferably, the diseases of said method are haematological tumours, solid tumour and/or metastases thereof.
[0476] The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth.
[0477] Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art.
[0478] The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.
Biological Assays:
[0479] Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein [0480] the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and [0481] the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.
[0482] Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.
Mutant IDH1 R132H Biochemical Assay mIDH1 catalyzes the NADPH-dependent reduction of alpha-ketoglutarate (a-KG) to (2R)-2-hydroxyglutarate (2-HG). NADPH consumption was measured by luminescent readout.
[0483] The biochemical reactions were performed at 32 C. in 384-well plates using a reaction volume of 41 L and the following assay buffer conditions: 50 mM Tris pH 7.5, 100 mM NaCl, 20 mM MgCl.sub.2, 0.05% BSA, 0.01% Brij, 1 M NADPH, and 250 M -KG. The IDH1 R132H enzyme was used in a final concentration of 1.5 nM. Test compounds were used in a concentration range between 0.002 and 10 M. The final DMSO concentration was 2.4%.
[0484] The reaction was incubated for 30 minutes, then 40 L of detection mix (0.75 g/ml Luciferase, 0.02 U/ml Oxidoreductase, 4 g/mL FMN, 2 L/ml decanal/ethanol, 50 mM Tris pH 7.5, 0.5% Glycerin, 0.01% Tween-20, 0.05% BSA) was added. Luminescence was measured on a luminescent reader (10 seconds measuring time, 1 second integration period, 30% sensitivity). The decrease in luminescence is proportional to mIDH1 activity. IC.sub.50 values are determined by interpolation from plots of relative luminescence versus inhibitor concentration.
TABLE-US-00006 TABLE 6 IC.sub.50 values of selected examples in mutant IDH1 R132H biochemical assay Example Mutant IDH1 R132H IC.sub.50 [M] 2-1 1.2E7 2-2 6.5E8 2-3 2.0E7 2-4 3.8E8 2-5 4.0E8 2-6 2.2E7 2-7 1.0E7 2-8 1.3E7 2-9 2.8E7 2-10 1.2E7 2-11 8.0E8 2-12 3.0E7 2-13 4.5E8 2-14 3.5E8 2-15 8.0E8 2-16 7.0E8 2-17 6.8E8 2-18 1.2E7 2-19 9.5E8 2-20 1.3E7 2-21 3.8E7 2-22 4.0E9 2-23 6.3E9 2-24 1.3E8 2-25 8.0E9 2-26 7.5E9 2-27 1.5E8 2-28 1.6E8 2-29 1.3E8 2-30 1.5E8 2-31 1.4E8 2-32 1.1E8 2-33 4.5E8 2-34 6.3E9 2-35 8.3E9 2-36 3.0E8 2-37 2.3E8 2-38 1.2E8 2-39 7.0E8 2-40 1.5E8 2-41 1.2E8 2-42 1.2E8 2-43 1.9E7 2-44 6.2E7 2-45 1.8E7 2-46 1.5E8 2-47 2.8E6 2-48 1.1E8
Mutant IDH1 Cellular Assay
[0485] Levels of (2R)-2-hydroxyglutarate (2HG) were measured in medium of a cell line with overexpression of mutated isocitrate dehydrogenase (mIDH) protein. mIDH catalyzes the NADPH-dependent reduction of alpha-ketoglutarate to 2-HG. Cells (LN229 R132H, Mohrenz et al., Apoptosis (2013) 18:1416-1425) were grown in DMEM containing 10% FCS. They were harvested by trypsin and seeded into 96-well plates. Cells were incubated overnight at 37 C. in 5% CO.sub.2. The next day test compounds were added to each cell well. The final concentration of DMSO was 0.1% and DMSO controls were included. The plates were then placed in an incubator for 24 hours.
[0486] 2-HG was measured according to Balss et al. (Acta Neuropathol (2012) 124: 883-891). Briefly, HClO.sub.4 was added to each well and the plates were centrifuged. Aliquots are removed and incubated with hydroxyglutarate dehydrogenase (HGDH), diaphorase, NAD+, and resazurin. The conversion of resazurin to resorufin was detected by fluorescence spectroscopy at Ex 540 nm Em 600 nm. The increase in fluorescence is proportional to 2-HG production. IC.sub.50 values are determined by interpolation from plots of relative fluorescence vs inhibitor concentration.
TABLE-US-00007 TABLE 7 IC.sub.50 values of selected examples in mutant IDH1 cellular assay Example Mutant IDH1 IC.sub.50 [M] 2-28 3.8E8 2-29 4.0E8 2-30 8.4E8