Patent Application
20150322100
The present invention relates to polysubstituted arenes, more specifically, to polysubstituted benzenes and naphtalenes as well as to a method for their synthesis.
Fully substituted benzenes and naphtalenes are of great interest since they have significant bioactivity, for example, anti-inflammatory and anti-hyperglycemic properties (Ram, V. J.; Agarwal, N. Tetrahedron Lett. 2001, 42, pp. 7127-29). Such compounds have also often been used to synthesize bioactive heterocyclic compounds (Wang, X.-S.; Zhang, M.-M.; Li, Q.; Yao, C.-S.; Tu, S.-J. Tetrahedron Lett. 2007, 63, pp. 5265-73). Among these compounds, the so-called acceptor-donor-acceptor (A-D-A) systems (Xue, D.; Li, J.; Zhang, Z.-T.; Deng, J.-G., J. Org. Chem. 2007, 72, pp. 5443-45), e.g., 2,4-dicyanoaniline, on the aryl ring have shown great potential for synthetic photosynthesis systems (Heilman, W. P.; Battershell, R. D.; Pyne, W. J.; Goble, P. H.; Magee, T. A.; Matthews, R. J., J. Med. Chem. 1978, 21, pp. 906-13) and also non-linear optical properties (Singh, F. V.; Parihar, A.; Chaurasia, S.; Singh, A. B.; Singh, S. P.; Tamrakar, A. K.; Srivastava, A. K.; Goel, A., Bioorg. Med. Chem. Lett. 2009, 19, pp. 2158-61).
As opposed to naturally-occurring phosphate analogs, the phosphonate group does not easily hydrolyze in a biological environment and is therefore more useful for a plurality of applications (Yakaiah, T.; Lingaiah, B. P. V.; Narsaiah, B.; Shireesha, B.; Ashok Kumar, B.; Gururaj, S.; Parthasarathy, T.; Sridhar, B., Bioorg. Med. Chem. Lett. 2007, 17, pp. 3445-53). In contrast, fluorinated groups improve chemical and physical stability and also pass the blood-brain barrier more easily than comparable non fluorinated compounds (Dumur, F.; Gautier, N.; Gallego-Planas, N.; Sahin, Y.; Levillain, E.; Mercier, N.; Hudhomme, P.; Masino, M.; Girlando, A.; Lloveras, V.; Vidal-Gancedo, J.; Veciana, J.; Rovira, C., J. Org. Chem. 2004, 69, pp. 2164-77). It must be pointed out in this context that 20-25% of the drugs in the drug pipeline have at least one fluorine atom.
Polysubstituted benzenes and naphthalenes were until now mainly produced by a sequential introduction of specific substituents, e.g., electrophilic (Xiao, Y.; Qian, X., Tetrahedron Lett. 2003, 44, pp. 2087-91), nucleophilic aromatic substitution (Kuneck, H.; Huber, M., Angew. Chem. Int. Ed. 1995, 34, pp. 849-66) at the center of the arene, and by coupling reactions (Long, N. J., Angew. Chem. Int. Ed. 1995, 34, pp. 21-38). A transition metal catalyzed cyclization of the corresponding unsaturated substrates for producing aromatic compounds has also previously been described (Engel, R., Chem. Rev. 1977, 77, pp. 349-67). A reaction of 2-aminoprop-1-ene-1,3,3-tricarbonitrile (IIb) with nitro-alkene derivatives 1 has recently been successfully used to produce polysubstituted benzene 2 under microwave irradiation (O'Hagan, D., Chem. Soc. Rev. 2008, 37, pp. 308-19).
Singh et al. additionally described that 2H-pyrane-2-one 3 can be transformed into arylated benzene derivatives 4 by way of a nucleophilic induced ring transformation reaction with malonitrile in the presence of a strong base.
A good yield of naphthalene derivatives (Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, Y., Chem. Soc. Rev. 2008, 37, pp. 320-30) 6 was successfully obtained by reacting 2-(cyanomethyl)benzonitrile IIb with 3-Bromo-2-(ethylthio)but-2-enenitriles 5 (Pearson, D. E.; Buehler, C. A., Synthesis 1972, 1972, 533, pp. 42).
The difficulty of introducing functional groups, for example, amine, cyano or ester groups into an aromatic ring has previously been described (Buncel, E.; Dust, J. M.; Terrier, F., Chem. Rev. 1995, 95, pp. 2261-80). There is, however, a need for polysubstituted arenes, for example, for use as pharmacophores (Saito, S.; Yamamoto, Y., Chem. Rev. 2000, 100, pp. 2901-16) and for a method for their production.
An aspect of the present invention is to provide such polysubstituted arenes. Another aspect of the present invention is to provide a relatively simple, atom-efficient, and regioselective method for producing the polysubstituted arenes.
In an embodiment, the present invention provides a compound having general formula (I)
wherein, R1 and R2 are, independently of each other, CN or NH2, or together form a substituted aromatic ring system or an unsubstituted aromatic ring system. R3 and R4 are, independently of each other, C1-C12-alkyl. R5 is H, a halogen, or CnF2+1, wherein n=1-10
The present invention provides a compound with the general formula (I),
wherein
R1 and R2 are, independently of each other, CN or NH2, or together form a substituted or unsubstituted aromatic ring system,
R3 and R4 are, independently of each other, a C1-C12-alkyl, and
R5 is H, halogen or CnF2n+1, with n=1-10.
For the first time, the present invention thus provides polysubstituted arenes that are substituted with a group containing fluorine and a phosphonate group. The compound with the formula (I) according to the present invention contains, in addition to a cyano group and an amino group, a (hydrophilic) phosphonate group in the vicinity of a (lipophilic) group containing fluorine.
The term “substituted” means that one or several substituents are present which replace a hydrogen atom on one or several carbon atoms of a hydrocarbon structure, for example, on one or several of the ring carbon atoms of a cyclic aromatic hydrocarbon compound. Examples of such substituents are alkyl, oalkyl, cycloalkyl, aryl, heteroaryl, halogen, hydroxyl, phosphate, cyano and amino groups.
“Polysubstituted” means multi-substituted and here more specifically means that several, for example, all H atoms on the C atoms of the benzene ring in formula (I) are substituted by substituents. The substituents can be e.g., cyano groups, amino groups and the like. “Polysubstituted benzene” can mean, for example, that respectively one cyano group is bonded in place of H atoms with two C atoms of a benzene ring, respectively, one amino group is bonded with two other C atoms, a phosphonate group is bonded with one C atom, and a group containing fluorine is bonded with the remaining C atom. “Polysubstituted naphthalene” can mean that the four not common C atoms on one of the benzene rings are substituted with e.g., a cyano, an amino, a phosphonate group and a group containing fluorine.
“Polyfunctionally substituted” means polysubstituted with as many different functional groups as possible, at least, however, with two such functional groups, as substituents, e.g., substitution of the benzene ring with an amino, a cyano, a phosphonate group and a group containing fluorine. If not explicitly stated otherwise, the terms “polysubstituted” and “polyfunctionally substituted” are used here as synonyms.
“Completely substituted” means that the benzene ring of a compound with the formula I according to the present invention has a substitution at each of its ring C atoms, i.e., none of the ring C atoms carries H atoms.
The term “halogen” refers to elements of the group 17 of the periodic table of elements, e.g., fluorine, chlorine, bromine and iodine.
The feature according to which R1 and R2 together form an aromatic substituted or unsubstituted ring system means that the rests R1 and R2 are bonded covalently with each other so that, when including those C atoms of the benzene ring of the compound with the formula (I) with which the rests R1 and R1 are bonded, for example, an anellated, aromatic ring system is formed. The ring system can be a one-membered, two-membered or multi-membered ring system, i.e., it can consist of one, two, or several rings, wherein the rings can be five-membered or six-membered rings, i.e., rings consisting of five or six ring atoms. The rings can, for example, be six-membered, i.e., consist of six ring atoms. The ring atoms can, for example, be C atoms, but can also be heteroatoms, e.g., nitrogen, oxygen, phosphate or sulfur atoms. The ring system does not, for example, contain heteroatoms. Polycyclic aromatic ring systems can thereby be formed, which, when including the benzene ring of the compound with the formula (I), have a naphthalene, anthracene, phenantrene, tetracene, phenalene or fluorene structure.
The term “arenes” refers to cyclic, planar hydrocarbons with an aromatic system.
The term “alkyl” contains saturated and unsaturated aliphatic (non-aromatic) groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl) and branched alkyl groups (e.g., isopropyl, tert-Butyl, isobutyl).
R5 is H, halogen or CnF2n+1, wherein n=1-10, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. R5 can, for example, be CF3 (n=1), C2F5 (n=2), C3F7 (n=3) or C4F9 (n=4). R5 can, for example, be H, halogen or CF3.
In an embodiment of the present invention, R1 and R2 form, together with those C atoms of the benzene ring of the compound with the formula (I) with which the rests R1 and R2 are bonded, a six-membered substituted or unsubstituted aromatic ring, for example, a benzene ring. The present invention thus provides, for example, polysubstituted naphthalene and/or naphthalene derivatives. The rests R1 and R2 can, however, also be bonded with other aromatic ring systems.
In an embodiment of the present invention, the compound has the general formula (Ia)
or the general formula (Ib)
R3 and R4 are C1-C12-alkyl groups, i.e., alkyl groups with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 C-atoms. Examples thereof are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-Butyl, isobutyl and isopentyl groups. R3 and R4 can, for example, both be methyl or ethyl (Et).
In a second aspect, the present invention also relates to a compound according to the first aspect of the present invention for use as a drug. Compounds according to the general formula (I) have a promising potential as drugs, e.g., as anti-inflammatory and anti-hyperglycemic drugs.
In a third aspect, the present invention provides a method for producing a compound with the general formula (I),
wherein
R1 and R2 are, independently of each other, CN or NH2 or together form a substituted or unsubstituted aromatic ring system,
R3 and R4 are, independently of each other, C1-C12-alkyl, and
R5 is H, halogen or CnF2n+1, with n=1-10, wherein a compound with the general formula (II)
is reacted with a compound with the general formula (III)
The method according to the present invention is relatively atom-efficient, easily implementable, and regioselective, and for the first time allows synthesizing polysubstituted arenes with a phosphonate group and a (vicinal) group containing fluorine as substituents.
In an embodiment of the method according to the present invention, a compound with the formula (II) is used, wherein R1 and R2, including those C atoms to which R1 and R2 are bonded, form a six-membered substituted or unsubstituted aromatic ring, for example, a benzene ring. The method can also be advantageously implemented, however, with compounds with the formula (II), wherein R1 and R2 form more complex aromatic ring systems, as described above, with regard to the first aspect of the present invention.
The method according to the present invention can, for example, lead to the formation of a compound with the general formula (Ia)
wherein a compound with the general formula (IIa)
is reacted with a compound with the general formula (III)
The method according to the present invention can, for example, also lead to the production of a compound with the general formula (Ib)
wherein a compound with the general formula (IIb)
is reacted with a compound with the general formula (III)
In an embodiment of the method according to the present invention, an aprotic nonpolar solvent, e.g., benzole or toluol, is added at room temperature to a mixture of a compound with the general formula (II), (IIa) or (IIb) and a base, which can be K2CO3 or a tertiary amine such as, for example, iPr2NEt, NEt3 (Et=ethyl, Pr=propyl) or DABCO (1,4-Diazabicyclo[2.2.2]octane), and the resulting mixture is refluxed, i.e., cooked under reflux. The solvent used can, for example, be anhydrous, e.g., anhydrous toluol.
The present invention is described in more detail below based on exemplary embodiments for illustrative purposes only.
Exemplary compounds according to the present invention were produced according to the following schema:
Anhydrous toluol (20 ml) was added at room temperature to a mixture of IIa or IIb and K2CO3 (5 mmol). The acetylenic compounds IIA1-5 (IIIA1: R5═F; IIIA2: R5═Cl; IIIA3: R5═Br; IIIA4: R5═H; IIIA5: R5═CF3) (5 mmol) were then slowly added. The solution was cooked for another 11-13 hours under reflux. The K2CO3 was filtered out and the remaining solution was concentrated at a reduced pressure. The residue was cleaned by flash column chromatography on silica gel using DCM:EtOAc (ratio 5:1; DCM=dichloromethane, EtOAc=ethyl acetate) as an eluent.
Colorless crystals (98%); Smp. 145-149° C.; 1H NMR (CDCl3, 400 MHz): δ 1.27 (t, J=6.9 Hz, 6H), 4.11 (m, 4H), 5.84 (s, 2H); 13C NMR (100 MHz): δ 16.0 (d, J=6.7 Hz), 63.3 (d, J=5.7 Hz), 83.1 (d, 3JC-P=15.4 Hz), 85.0 (dq, 3JC-P=14.4 Hz, 3JC-F=2.9 Hz), 97.7 (d, 1JC-P=191.7 Hz), 114.2, 121.8 (qd, 1JC-F=278.9 Hz), 3JC-P=6.7 Hz), 142.6 (qd, 2JC-F=32.6 Hz, 2JC-P=5.6 Hz), 155.1, 158.2 (d, 2JC-P=10.5 Hz); 15NMR (41 MHz): δ 275.2 (—CN), 266.6 (—CN), 83.1 (—NH2), 72.7 (—NH2); 19F NMR (376 MHz): δ —55.3; 31P NMR (161 MHz): δ 16.3.
Colorless crystals (94%); Smp. 150-153° C.; 1H NMR (CDCl3, 400 MHz): δ 1.33 (t, J=7.1 Hz, 6H), 4.13 (m, 4H), 5.71 (s, 2H); 13C NMR (100 MHz): δ 16.2 (d, J=6.7 Hz), 63.4 (d, J=6.7 Hz), 82.7 (d, 3JC-P=15.3 Hz), 85.0 (dt, 3JC-P=14.3 Hz, 3JC-F=3.8 Hz), 96.6 (d, 1JC-P=192.6 Hz), 114.2, 114.4, 123.2 (td, 1JC-F=295.2 Hz), 3JC-P=4.8 Hz), 148.6 (td, 2JC-F=26.8 Hz, 2JC-P=5.7 Hz), 154.9, 158.0 (d, 2JC-P=10.5 Hz); 19F NMR (376 MHz): δ −43.5; 31P NMR (161 MHz): δ 16.8.
Yellowish crystals (97%); Smp. 162-165° C.; 1H NMR (CDCl3, 400 MHz): δ 1.33 (t, J=7.1 Hz, 6H), 4.11 (m, 2H), 4.19 (m, 2H), 7.63 (t, J=7.6 Hz, 1H), 7.74 (t, J=7.8 Hz, 1H), 7.97 (br. s, 2H), 7.97 (d, J=8.5 Hz, 1H), 8.25 (d, J=8.3 Hz, 1H); 13C NMR (100 MHz): δ 16.1 (d, J=7.3 Hz), 63.0 (d, J=6.0 Hz), 96.9 (dq, 1JC-P=186.6 Hz, 3JC-F=1.2 Hz) 98.2 (dq, 3JC-P=13.8 Hz, 3JC-F=3.9 Hz), 116.9, 122.0 122.8 (qd, 1JC-F=278.3 Hz, 3JC-P=5.3 Hz), 123.1 (d, 3JC-P=14.3 Hz), 127.0, 128.9, 131.5, 133.4, 136.4 (qd, 2JC-F=31.8 Hz, 2JC-P=6.4 Hz), 155.7 (d, 2JC-P=8.7 Hz); 19F NMR (376 MHz): δ −53.1; 31P NMR (161 MHz): δ 19.3.
Yellowish crystals (92%); Smp. 179-182° C.; 1H NMR (CDCl3, 400 MHz): δ 1.35 (t, J=7.1 Hz, 6H), 4.10 (m, 2H), 4.16 (m, 2H), 7.62 (t, J=8.3 Hz, 1H), 7.73 (t, J=8.1 Hz, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.94 (br. s, 2H), 8.25 (d, J=8.4 Hz, 1H); 13C NMR (100 MHz): δ 16.3 (d, J=7.0 Hz), 63.1 (d, J=6.7 Hz), 96.9 (d, 1JC-P=188.3 Hz), 98.2 (dt, 3JC-P=13.0 Hz, 3JC-F=4.5 Hz), 116.2, 121.5 122.8 (d, 3JC-P=13.2 Hz), 124.3 (td, 1JC-F=294.5 Hz, 3JC-P=3.5 Hz), 126.9, 128.8, 131.5, 133.5, 142.8 (td, 2JC-F=26.2 Hz, 2JC-P=6.6 Hz), 155.4 (d, 2JC-P=9.1 Hz); 19F NMR (376 MHz): δ −40.0; 31P NMR (161 MHz): δ 19.8 (t, 4JP-F=1.6 Hz).
The present invention is not limited to embodiments described herein; reference should be had to the appended claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10 2012 104 007.9 | May 2012 | DE | national |
This application is a U.S. National Phase application under 35 U.S.C. §371 of International Application No. PCT/DE2013/100150, filed on Apr. 23, 2013 and which claims benefit to German Patent Application No. 10 2012 104 007.9, filed on May 7, 2012. The International Application was published in German on Nov. 14, 2013 as WO 2013/167117 A1 under PCT Article 21(2).
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/DE2013/100150 | 4/23/2013 | WO | 00 |
