WO2003101381A2 - 1,2 diamido cycloalkyl sodium channel blockers - Google Patents
1,2 diamido cycloalkyl sodium channel blockers Download PDFInfo
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- WO2003101381A2 WO2003101381A2 PCT/US2003/016335 US0316335W WO03101381A2 WO 2003101381 A2 WO2003101381 A2 WO 2003101381A2 US 0316335 W US0316335 W US 0316335W WO 03101381 A2 WO03101381 A2 WO 03101381A2
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- βalkyl
- phenyl
- 6alkyl
- pharmaceutically acceptable
- optionally substituted
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- 0 *c1ccccc1-c1ccc(CNC(C(CCC2)[C@]2C(NCc2ccc(-c3ccc[s]3)[s]2)=O)=O)cc1 Chemical compound *c1ccccc1-c1ccc(CNC(C(CCC2)[C@]2C(NCc2ccc(-c3ccc[s]3)[s]2)=O)=O)cc1 0.000 description 4
- HKOLBPPNFQAWNS-FICMROCWSA-N CC(C)COc1ccc(CNC([C@H](CCC2)C2C(N(C)Cc(cc2)ccc2-c2ccccc2S(N)(=O)=O)=O)=O)cc1 Chemical compound CC(C)COc1ccc(CNC([C@H](CCC2)C2C(N(C)Cc(cc2)ccc2-c2ccccc2S(N)(=O)=O)=O)=O)cc1 HKOLBPPNFQAWNS-FICMROCWSA-N 0.000 description 1
- XSMOLSDEBRCUPH-PLYLYKGUSA-N CC(C)COc1ccc(CNC([C@H](CCC2)C2C(NCc(cc2)ccc2-c2ccccc2S(N)(=O)=O)=O)=O)cc1 Chemical compound CC(C)COc1ccc(CNC([C@H](CCC2)C2C(NCc(cc2)ccc2-c2ccccc2S(N)(=O)=O)=O)=O)cc1 XSMOLSDEBRCUPH-PLYLYKGUSA-N 0.000 description 1
- YPYBMHXWZYEIDB-UHFFFAOYSA-N CC(c1ccc(-c2ccc[s]2)[s]1)NC(C(CCC1)C1C(N(C)Cc(cc1)ccc1-c(cccc1)c1S(N)(=O)=O)=O)=O Chemical compound CC(c1ccc(-c2ccc[s]2)[s]1)NC(C(CCC1)C1C(N(C)Cc(cc1)ccc1-c(cccc1)c1S(N)(=O)=O)=O)=O YPYBMHXWZYEIDB-UHFFFAOYSA-N 0.000 description 1
- PJOKEKZAEQSHJB-DCWQJPKNSA-N CN(Cc(cc1)ccc1-c1ccccc1S(N)(=O)=O)C(C(CCCC1)[C@@H]1C(NCc(cc1)ccc1OC(F)(F)F)=O)=O Chemical compound CN(Cc(cc1)ccc1-c1ccccc1S(N)(=O)=O)C(C(CCCC1)[C@@H]1C(NCc(cc1)ccc1OC(F)(F)F)=O)=O PJOKEKZAEQSHJB-DCWQJPKNSA-N 0.000 description 1
- DKEZKVDZRFDXIV-XMMISQBUSA-N CN(Cc(nc1)ccc1-c1ccccc1S(N)(=O)=O)C([C@H](CCC1)C1C(NCc(cc1)ccc1OC(F)(F)F)=O)=O Chemical compound CN(Cc(nc1)ccc1-c1ccccc1S(N)(=O)=O)C([C@H](CCC1)C1C(NCc(cc1)ccc1OC(F)(F)F)=O)=O DKEZKVDZRFDXIV-XMMISQBUSA-N 0.000 description 1
- UYLBKRPGSNNVKY-PAOARYPWSA-N COc1ccccc1-c1ccc(CNC(C(CCC2)C2[C@@H](NCc(cc2)ccc2-c2ccccc2S(N)(=O)=O)O)=O)cc1 Chemical compound COc1ccccc1-c1ccc(CNC(C(CCC2)C2[C@@H](NCc(cc2)ccc2-c2ccccc2S(N)(=O)=O)O)=O)cc1 UYLBKRPGSNNVKY-PAOARYPWSA-N 0.000 description 1
- KYGSXGYZLQXGKX-CLJLJLNGSA-N Cc1ccccc1-c1ccc(CNC([C@H](CCC2)[C@@H]2C(NCc2ccc(-c3ccc[s]3)[s]2)=O)=O)cc1 Chemical compound Cc1ccccc1-c1ccc(CNC([C@H](CCC2)[C@@H]2C(NCc2ccc(-c3ccc[s]3)[s]2)=O)=O)cc1 KYGSXGYZLQXGKX-CLJLJLNGSA-N 0.000 description 1
- RFJIGTDPKFJVSH-UHFFFAOYSA-N NS(c1ccccc1-c1ccc(CNC(C(CCC2)C2C(NCc(cc2)ccc2Oc2ccccc2)=O)=O)cc1)(=O)=O Chemical compound NS(c1ccccc1-c1ccc(CNC(C(CCC2)C2C(NCc(cc2)ccc2Oc2ccccc2)=O)=O)cc1)(=O)=O RFJIGTDPKFJVSH-UHFFFAOYSA-N 0.000 description 1
- PCWWIPQRHXXHCW-PLYLYKGUSA-N NS(c1ccccc1-c1ccc(CNC(C(CCC2)[C@@H]2C(N(CC2)CCC2c2ccccc2)=O)=O)cc1)(=O)=O Chemical compound NS(c1ccccc1-c1ccc(CNC(C(CCC2)[C@@H]2C(N(CC2)CCC2c2ccccc2)=O)=O)cc1)(=O)=O PCWWIPQRHXXHCW-PLYLYKGUSA-N 0.000 description 1
- FWRZPPXUVDCATF-UHFFFAOYSA-N O=C(C(CCC1)C1C(NCc(cc1)ccc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1)=O)NCc1ccc(-c2ccc[s]2)[s]1 Chemical compound O=C(C(CCC1)C1C(NCc(cc1)ccc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1)=O)NCc1ccc(-c2ccc[s]2)[s]1 FWRZPPXUVDCATF-UHFFFAOYSA-N 0.000 description 1
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
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- C07C233/00—Carboxylic acid amides
- C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C233/59—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
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- C07C233/60—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
- C07C311/46—Y being a hydrogen or a carbon atom
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- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
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- C07C2601/14—The ring being saturated
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- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
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Abstract
1,2 Diamido cycloalkyl compounds that are sodium channel blockers; pharmaceutical compositions that include an effective amount of the aryl-link-aryl thiazolidin-dione and aryl-link-aryl oxazolodine-dione compounds and a pharmaceutically acceptable carrier; and a method of treatment of acute pain, chronic pain, visceral pain, inflammatory pain, or neuropathic pain, as well as irritable bowel syndrome, Crohns disease, epilepsy, partial and generalized tonic seizures, multiple sclerosis, bipolar disease, and tachy-arrhythmias by the administration of an effective amount of aryl-link-aryl thiazolidine-dione and aryl-link-aryl oxazolodine-dione compounds, either alone, or in combination with one or more therapeutically active compounds, are described.
Description
TITLE OF THE INVENTION
1,2 DIA DO CYCLOALKYL SODIUM CHANNEL BLOCKERS
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
The present invention is directed to cycloalkyl compounds substituted at the 1 and 2 positions with amido moieties. In particular, this invention is directed to 1,2 diamido cycloalkyl compounds that are sodium channel blockers useful for the treatment of chronic and neuropathic pain. The compounds of the present invention are also useful for the treatment of other conditions, including, for example, central nervous system (CNS) disorder such as epilepsy, manic depression and bipolar disease.
RELATED BACKGROUND
Voltage-gated ion channels allow electrically excitable cells to generate and propagate action potentials and therefore are crucial for nerve and muscle function. Sodium channels play a special role by mediating the rapid depolarization, which constitutes the rising phase of the action potential and in turn activates voltage-gated calcium and potassium channels. Voltage-gated sodium channels represent a multigene family. Nine sodium channel subtypes have been cloned and functionally expressed to date [Clare, J. J., Tate, S. N., Nobbs, M. & Romanos, M. A. Voltage-gated sodium channels as therapeutic targets. Drug Discovery Today 5, 506-520 (2000)]. They are differentially expressed throughout muscle and nerve tissues and show distinct biophysical properties. All voltage-gated sodium channels are characterized by a high degree of selectivity for sodium over other ions and by their voltage-dependent gating [Catterall, W. A. Structure and function of voltage-gated sodium and calcium channels. Current Opinion in Neurobiology 1, 5-13 (1991)]. At negative or hyperpolarized membrane potentials, sodium channels are closed. Following membrane depolarization, sodium channels open rapidly and then inactivate. Channels only conduct currents in the open state and, once inactivated, have to return to the resting state, favored by membrane hyperpolarization, before they can reopen. Different sodium channel subtypes vary in the voltage range over which they activate and inactivate as well as in their activation and inactivation kinetics.
Sodium channels are the target of a diverse array of pharmacological agents, including neurotoxins, antiarrhythmics, anticonvulsants and local anesthetics [Clare, J. J., Tate, S. N., Nobbs, M. & Romanos, M. A. Voltage-gated sodium channels as therapeutic targets. Drug Discovery Today 5, 506-520 (2000)]. Several regions in the sodium channel secondary structure are involved in interactions with these blockers and most are highly conserved. Indeed, most sodium channel blockers known to date interact with similar potency with all channel subtypes. Nevertheless, it has been possible to produce sodium channel blockers with therapeutic selectivity and a sufficient therapeutic window for the treatment of epilepsy (e.g. lamotrigine, phenytoin and carbamazepine) and certain cardiac arrhythmias (e.g. lignocaine, tocainide and mexiletine).
It is well known that the voltage-gated Na+ channels in nerves play a critical role in neuropathic pain. Injuries of the peripheral nervous system often result in neuropathic pain persisting long after the initial injury resolves. Examples of neuropathic pain include, but are not limited to postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, and pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias. It has been shown in human patients as well as in animal models of neuropathic pain, that damage to primary afferent sensory neurons can lead to neuroma formation and spontaneous activity, as well as evoked activity in response to normally innocuous stimuli [Carter, G.T. and B.S. Galer, Advances in the management of neuropathic pain. Physical Medicine and Rehabilitation Clinics of North America., 2001. 12(2): p. 447-459.]. The ectopic activity of normally silent sensory neurons is thought to contribute to the generation and maintenance of neuropathic pain. It is generally assumed to be associated with an increase in sodium channel activity in the injured nerve [Baker, M.D. and J.N. Wood, Involvement ofNa channels in pain pathways. TRENDS in Pharmacological Sciences, 2001. 22(1): p. 27-31.]. Indeed, in rat models of peripheral nerve injury, ectopic activity in the injured nerve corresponds to the behavioral signs of pain. In these models, intravenous application of the sodium channel blocker and local anesthetic lidocaine can suppress the ectopic activity and reverse the tactile allodynia at concentrations that do not affect general behavior and motor function [ Mao, J. and L.L. Chen, Systemic lidocaine for neuropathic pain relief. Pain, 2000. 87: p. 7-17.]. Effective concentrations were similar to concentrations shown to be clinically efficacious in humans [ Tanelian, D.L. and W.G. Brose, Neuropathic pain can be relieved by drugs
that are use-dependent sodium channel blockers: lidocaine, carbamazepine and mexϊletine. Anesthesiology, 1991. 74(5): p. 949-951.]. In a placebo-controlled study, continuous infusion of lidocaine reduced pain scores in patients with peripheral nerve injury , and in a separate study, intravenous lidocaine reduced pain intensity associated with postherpetic neuralgia (PHN) [ Mao, J. and L.L. Chen, Systemic lidocaine for neuropathic pain relief. Pain, 2000. 87: p. 7-17. Anger, T., et al., Medicinal chemistry of neuronal voltage-gated sodium channel blockers. Journal of Medicinal Chemistry, 2001. 44(2): p. 115-137.]. Indeed, LidodermR, lidocaine applied in the form of a dermal patch, is currently the only FDA approved treatment for PHN [Devers, A. and B.S. Galer, Topical lidocaine patch relieves a variety of neuropathic pain conditions: an open-label study. Clinical Journal of Pain, 2000. 16(3): p. 205- 208.].
In addition to neuropathic pain, sodium channel blockers have clinical uses in the treatment of epilepsy and cardiac arrhythmias. Recent evidence from animal models suggest that sodium channel blockers may also be useful for neuroprotection under ischaemic conditions caused by stroke or neural trauma and in patients with MS [Clare, J. J. et. al. And Anger, T. et. al.].
International Patent Publicaiton No. WO 02/28394 describes the use of a frequency dependent voltage activated sodium channel blocker for the prevention of noise induced hearing loss.
U.S. Patent Nos. 5,714,489 and 5,852,017 describe 2,3(lH,4H)quinoxalinedione compounds suitable for treatment of neurodegenerative disorders. International Patent Publications WO92/13838 and WO95/04732 describe oligopeptide antirepreviral agents. International Patent Publication WO94/11339 describes substituted cyclopentane chelating agents. International Patent Publication WO94/11339 describes cyclic amino acid derivatives that are inhibitors of matrix metalloproteases and TNF-alpha. U.S. Patent No. 5,278,311 describes nonionic radiographic contrast agents. L.J. Goldsworthy et al., J.Chem. Soc, 105:2639-2643(1914) describes the resolution of trans-cyclopentane-l:2-dicarboxylic acid. CG. Overberger et al., Am. Chem. Soc, Divn. Polymer Chem. Preprints. 5:210-215(1964) describes cyclopolymers derived from alicyclic 1,2-dialdehydes. Y. Chen et al., J. Polymer Sci., PartA: Polym. Chem., 30(13}:2699-2707(1992) describes optically active polyurethanes containing a coumarin dimer component. K.E. Rao et al., Actual.
Chim. Ther., 18(Recontres Int. Chim. Ther.. 26th 1990 :21-42(1991) describes linked bis-netropsin antiviral and antitumor agents. K.E. Rao, J.Org. Chem., 56:786- 797(1991) describes linked bis-N-methylpyrrole dipeptides. W. Wang et al., J. Med. Chem., 35:2890-2897(1992) describes linked lexitropsin anti-HTV-I agents. R.J. Perry et al, J.Org. Chem., 56(23 :6573-6579(1991) describes the preparation of N- substituted phthalimides. Y.Chen et al., Bull. Chem. Soc. Japan, 65:3423-3429(1992) describes a chiral stationary phase derived from a head-to-head coumarin dimer.
However, there remains a need for novel compounds and compositions that therapeutically block neuronal sodium channels with minimal side effects.
SUMMARY OF THE INVENTION
The present invention is directed to 1,2 diamido cycloalkyl compounds which are sodium channel blockers useful for the treatment of chronic and neuropathic pain and disorders of the CNS including, but not limited to treatment of the symptoms of epilepsy, manic depression and bipolar disease. This invention also provides a pharmaceutical composition that includes an effective amount of the novel
1,2 diamido cycloalkyl compounds, and a pharmaceutically acceptable carrier.
This invention further provides a method of treatment of acute pain, chronic pain, visceral pain, inflammatory pain, or neuropathic pain and disorders of the CNS including, but not limited to treatment of the symptoms of epilepsy, manic depression and bipolar disease by the administration of an effective amount of the novel 1,2 diamido cycloalkyl compounds.
DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention are represented by Formula
(I):
(I)
or a pharmaceutically acceptable salt thereof, wherein
X is phenyl, pyridyl, or thienyl, optionally substituted with 1-4 independent -Cι_6alkyl, halogen, -NO2, -N(Cθ-6alkyl)(C()-6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Cι_6alkyl, -OCι_6alkyl,
-SO2R6, -SO2NR7R8, -NR9SO2R10, or -NRllCONRl2Rl3; E is -Ci_6alkyl-; Rl is hydrogen or-Cι _(5alkyl; R2 is -Co-6alkyl-phenyl, -Cι_6alkyl-thienyl, -Cι_6alkyl-thiazolyl,
-Ci -6alkyl-pyridyl, -Cι _6alkyl-furanyl, -Cι_6alkyl-naphthyl, -Cι_6alkyl-indolyl, -C i _6alkyl-indanyl, -C i -6alkyl-methylenedioxyphenyl, -C i-6alkyl- tetrahydroquinolinyl, -C 1 _6alkyl-benzimidazolyl, -C 1 _6alkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl, benzimidazolyl, or benzothiophenyl is optionally substituted with 1-4 independent halogen, -NO2, -Cι_6alkyl, -C(O)-O-Cι_ 6alkyl, -O-Ci -6alkyl, -SR14, -SO2Rl5, -SO2NR16R17, -N(Cι_6alkyl)-SO2(Ci_ βalkyl), phenyl, or thienyl substituent, wherein the phenyl or thienyl substituent is optionally substituted with halogen, -Ci-6alkyl, -OCi_6alkyl, -SO2Rl8, - SO2NR19R20, _NRl 1SO2R22, -SO2NR23R24; or -NR25CONR26R27; or Rl and R2 form a five or six-member non-aromatic heterocyclic ring with the N to which Rl and R2 are connected, optionally containing a second N heteroatom, said ring optionally substituted with -Cθ-4alkyl-phenyl, -Cθ-4alkyl- pyridyl, said phenyl or pyridyl optionally substituted with -Ci_6alkyl; or Rl and R2 form a tetrahydroquinolinyl group with the N to which
Rl and R are connected, optionally substituted with 1-3 independent -Ci-βalkyl or halogen substituents;
R3 is -Co-6alkyl;
A is -CnH2n-; B is -CmH2m-; n and m each is 0, 1, 2, or 3; wherein the sum of n and m is 1, 2, or 3; R4 and R5 are each independently -Cθ-6alkyl, -OH, halogen, -O-Ci- 6alkyl, -O-Cθ-6alkyl-phenyl, or together form =O, -CH2CH2-, or =CH2; R6 to R27 are each independently -Cθ-6alkyl; and
any alkyl is optionally substituted with 1-6 independent halogen or
-Cι_4alkyl.
In one aspect, the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
X is phenyl, pyridyl, or thienyl, optionally substituted with 1-4 independent -Ci -6alkyl, halogen, -NO2, -N(Cθ-6alkyl)(Cθ-6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci_6alkyl, -OCi-6alkyl, -SO2R6, -SO2NR7R8, -NR9SO2R10, or -NRllCONRl2Rl3; E is -Cι _6alkyl-; Rl is hydrogen or -Cι_6alkyl; R2 is -Cθ-6alkyl-phenyl, -Ci_6alkyl-thienyl, -Ci -6alkyl-thiazolyl, -Ci-6alkyl-pyridyl, -Ci _6alkyl-furanyl, -Ci_6alkyl-napthyl, -Cι _6alkyl-indolyl, -Cι_6alkyl-indanyl, -Cι _6alkyl-methylenedioxyphenyl, -Ci-βalkyl- tetrahydroquinolinyl, -Ci-.6alkyl-benzimidazolyl, -Ci-βalkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl, benzimidazolyl, or benzothiophenyl is optionally substituted with 1-4 independent halogen, -NO2, -Cι_6alkyl, -C(O)-O-Cι_ 6alkyl, -O-Cι_6alkyl, -SR14, -SO2Rl5, -SO2NR16R17, -N(Ci-6alkyl)-SO2(Ci - 6alkyl), phenyl, or thienyl substituent, wherein the phenyl or thienyl substituent is optionally substituted with halogen, -Cι _6alkyl, -OCι -βalkyl, -SO2Rl8, - SO2NR19R20, -NR11S02R22, -SO2NR23R24; OΓ -NR25CONR26R27; or Rl and R2 form a five or six-member non-aromatic heterocyclic ring with the N to which Rl and R2 are connected, said ring optionally containing a second N heteroatom, said ring optionally substituted with -Cθ-4alkyl-phenyl, -Cø- 4alkyl-pyridyl, said phenyl or pyridyl optionally substituted with -Ci -6alkyl; or Rl and R2 form a tetrahydroquinolinyl group with the N to which Rl and R are connected, optionally substituted with 1-3 independent -Ci _6alkyl or halogen substituents;
R3 is -Co-6alkyl;
A is -CnH2n-;
B is -CmH2m-; n and m each is 0, 1 , or 2; wherein the sum of n and m is 2;
R4 and R5 are each independently -Cθ-6alkyl, -OH, halogen, -O-Cι_ βalkyl, -O-Cθ-6alkyl-phenyl, or together form =O, -CH CH2-, or =CH2; R6 to R27 are each independently -Cθ-6a-kyl; and any alkyl is optionally substituted with 1-6 independent halogen or -Ci-4alkyl.
In one embodiment of this one aspect, the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein X is phenyl, optionally substituted with 1-4 independent -Ci-βalkyl, halogen, -NO2, -N(Cθ-6alkyl)(Cθ-6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Cι _6alkyl, -OCι _6alkyl, -SO2R6, - SO2NR7R8, -NR9SO2R10, or - RllCOMRl2Rl3; E is -Cι_6alkyl-;
Rl is hydrogen or -Ci-6alkyl;
R2 is -Cθ-6alkyl-phenyl, -Ci-βalkyl-thienyl, -Ci .βalkyl-thiazolyl, -Ci-6alkyl-pyridyl, -Ci-6alkyl-furanyl, -Ci_6alkyl-napthyl, -Ci _6alkyl-indolyl, -C ι_6alkyl-indanyl, -C i -βalkyl-methylenedioxyphenyl, -C 1 _6alkyl- tetrahydroquinolinyl, -Cι_6alkyl-benzimidazolyl, -Ci -6alkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl, benzimidazolyl, or benzothiophenyl is optionally substituted with 1-4 independent halogen, -NO2, -Ci-6alkyl, -C(O)-O-Cι_ 6alkyl, -O-Ci -6alkyl, -SR14, -SO2Rl5, -SO2NR16R17, -N(Ci-6alkyl)-SO2(Ci- 6alkyl), phenyl, or thienyl substituent, wherein the phenyl or thienyl substituent is optionally substituted with halogen, -Ci_6alkyl, -OCι_6alkyl, -SO2Rl8, - SO2NRl9R20, _NRl lSO2R22, -SO2NR23R24; 0r -NR25CONR26R27; or Rl and R2 form a five or six-member non-aromatic heterocyclic ring with the N to which Rl and R2 are connected, said ring optionally containing a second N heteroatom, said ring optionally substituted with -Cθ-4alkyl-phenyl, -Cθ- 4alkyl-pyridyl, said phenyl or pyridyl optionally substituted with -Ci-6alkyl; or Rl and R2 form a tetrahydroquinolinyl group with the N to which Rl and R are connected, optionally substituted with 1-3 independent -Ci -βalkyl or halogen substituents;
R3 is -Co-6alkyl; A is -CnH2n-; B is -CmH2m-; n and m each is 0, 1, or 2; wherein the sum of n and m is 2; R4 and R5 are each independently -Cθ-6alkyl, -OH, halogen, -O-Cι_ 6alkyl, -O-Cθ-6alkyl-phenyl, or together form =O, -CH2CH2- or =CH2; R6 to R27 are each independently -Cθ-6alkyl; and any alkyl is optionally substituted with 1-6 independent halogen or -Ci-4alkyl.
In a second embodiment of this one aspect, the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
X is phenyl optionally substituted with 1-4 independent -Cι_6alkyl, halogen, -NO2, or -N(Cθ-6alkyl)(Cθ-6alkyl) substituents;
E is -Cι_6alkyl-;
Rl is hydrogen or-Ci -βalkyl;
R2 is -Cθ-6alkyl-phenyl, -Ci-6alkyl-thienyl, -Cι_6alkyl-thiazolyl, -Ci-6alkyl-pyridyl, -Cι _6alkyl-furanyl, -Ci _6alkyl-napthyl, -Cι _6alkyl-indolyl, -Cι_6alkyl-indanyl, -Cι_6alkyl-methylenedioxyphenyl, -Ci -βalkyl- tetrahydroquinolinyl, -Ci-6alkyl-benzimidazolyl, -Cι_6alkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl, benzimidazolyl, or benzothiophenyl is optionally substituted with 1-4 independent halogen, -NO2, -Ci _6alkyl, -C(O)-O-Cχ_ 6alkyl, -O-Cι.6alkyl, -SR14, -SO2Rl5, -SO2NR16R17, 0r -N(Cι_6alkyl)-SO2(Ci - 6alkyl) substituent; or Rl and R2 form a five or six-member non-aromatic heterocyclic ring with the N to which Rl and R are connected, said ring optionally containing a second N heteroatom, said ring optionally substituted with -Cθ-4alkyl-phenyl, -Cθ- 4alkyl-pyridyl, said phenyl or pyridyl optionally substituted with -Ci _6alkyl; or Rl and R2 form a tetrahydroquinolinyl group with the N to which Rl and R are connected, optionally substituted with 1-3 independent -Ci_6alkyl or halogen substituents;
R3 is -Co-6alkyl;
A is -CnH2n-; B is -CmH2m-; n and m each is 0, 1, or 2; wherein the sum of n and m is 2; R4 and R5 are each independently -C()-6alkyl, -OH, halogen, -O-Cι_ 6alkyl, -O-Cθ-6alkyl-phenyl, or together form =O, -CH2CH2-, or =CH2; R6 to R27 re each independently -Cø-6alkyl; and any alkyl is optionally substituted with 1-6 independent halogen or -Cι_4alkyl.
In a third embodiment of this one aspect, the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
X is phenyl substituted with a phenyl substituent, and further optionally substituted with 1-4 independent -Cι_6alkyl, halogen, -NO2, -N(Cθ- 6alkyl)(C()-6alkyl) substituents, wherein the phenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci -galkyl, -OCι -βalkyl, -SO2R6, -SO2NR7R8, -NR9SO2R10, or -NRllCONRl2Rl3; E is -Ci_6alkyl-; Rl is hydrogen or-Cι_6alkyl; R2 is -Cθ-6alkyl-phenyl, -Cι _6alkyl-thienyl, -Ci-6alkyl-thiazolyl,
-Ci -6alkyl-pyridyl, -Cι_6alkyl-furanyl, -Ci-6alkyl-napthyl, -Cι_6alkyl-indolyl, -C i _6alkyl-indanyl , -C i _6alkyl-methylenedioxyphenyl , -C i _6alkyl- tetrahydroquinolinyl, -Ci-βalkyl-benzimidazolyl, -Ci-βalkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl, benzimidazolyl, or benzothiophenyl is optionally substituted with 1-4 independent halogen, -NO2, -Ci-6alkyl, -C(O)-O-Ci- 6alkyl, -O-Cι.6alkyl, -SR14, -SO2Rl5, -SO2NR16R17, -N(Ci-6alkyl)-SO2(Ci_ 6alkyl), phenyl, or thienyl substituent, wherein the phenyl or thienyl substituent is optionally substituted with halogen, -Ci-6alkyl, -OCι _6alkyl, -SO Rl8, - SO2NR19R20, _NR11SO2R 2, -SO2NR23R24; or -NR25CONR26R27; or Rl and R2 form a five or six-member non-aromatic heterocyclic ring with the N to which Rl and R2 are connected, said ring optionally containing a second N heteroatom, said ring optionally substituted with -Cθ-4alkyl-phenyl, -Cθ- 4alkyl-pyridyl, said phenyl or pyridyl optionally substituted with -Cι _6alkyl;
or Rl and R form a tetrahydroquinolinyl group with the N to which Rl and R are connected, optionally substituted with 1-3 independent -Cι_6alkyl or halogen substituents;
R3 is -Co-6alkyl; A is -CnH2n-;
B is -CmH2m-; n and m each is 0, 1, or 2; wherein the sum of n and m is 2; R4 and R5 are each independently -Cfj-6alkyl, -OH, halogen, -O-Ci_ βalkyl, -O-Cθ-6alkyl-phenyl, or together form =O, -CH2CH2- or =CH2; R6 to R27 are each independently -Cθ-6alkyl; and any alkyl is optionally substituted with 1-6 independent halogen or -Ci_4alkyl.
In a fourth embodiment of this one aspect, the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
X is phenyl substituted with a pyridyl, pyrimidyl, or benzothiophenyl substituent, and further optionally substituted with 1-4 independent -Ci_6alkyl, halogen, -NO2, or -N(C()-6alkyl)(Cθ-6alkyl) substituents, wherein the pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci-6alkyl, -OCi -6alkyl, -SO2R6, -SO2NR7R8;
-NR9SO2R10, or -NRllCONRl2Rl3; E is -Cι_6alkyl-; Rl is hydrogen or-Ci_6alkyl; R2 is -Co-6alkyl-phenyl, -Ci-βalkyl-thienyl, -Cι _6alkyl-thiazolyl,
-Ci-6alkyl-pyridyl, -Ci_6alkyl-furanyl, -Ci-βalkyl-napthyl, -Ci-6alkyl-indolyl, -C i _6alkyl-indanyl, -C i _6alkyl-methylenedioxyphenyl, -C 1 _6alkyl- tetrahydroquinolinyl, -Ci-βalkyl-benzimidazolyl, -Cι_6alkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl, benzimidazolyl, or benzothiophenyl is optionally substituted with 1-4 independent halogen, -NO2, -Ci -βalkyl, -C(O)-O-Cι_ 6alkyl, -O-Ci -6alkyl, -SR14, -SO2Rl5, -SO2NRl6Rl7, -N(Ci -6alkyl)-SO2(Ci- 6alkyl), phenyl, or thienyl substituent, wherein the phenyl or thienyl substituent is
optionally substituted with halogen, -Cι_6alkyl, -OCi -βalkyl, -SO2Rl8, - SO2NR19R20, -NR11S02R22, -SO2NR23R24; 0r-NR25cONR26R27; or Rl and R form a five or six-member non-aromatic heterocyclic ring with the N to which Rl and R are connected, said ring optionally containing a second N heteroatom, said ring optionally substituted with -Cθ-4alkyl-phenyl, -Cθ- 4alkyl-pyridyl, said phenyl or pyridyl optionally substituted with -Cι_6alkyl; or Rl and R2 form a tetrahydroquinolinyl group with the N to which Rl and R are connected, optionally substituted with 1-3 independent -Ci -6alkyl or halogen substituents; R3 is -Co-6alkyl;
A is -CnH2n-; B is -CmH2m-; n and m each is 0, 1, or 2; wherein the sum of n and m is 2; R4 and R5 are each independently -Cfj-6alkyl, -OH, halogen, -O-Cι_ 6alkyl, -O-Cθ-6alkyl-phenyl, or together form =O, -CH2CH2- or =CH2; R6 to R27 are each independently -C()-6alkyl; and any alkyl is optionally substituted with 1-6 independent halogen or -Cl-4alkyl.
In a fifth embodiment of this one aspect, the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
X is thienyl, optionally substituted with 1-4 independent -Ci_6alkyl, halogen, -NO2, -N(Cθ-6alkyl)(Cθ-6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Cι _6alkyl, -OCι _6alkyl, -SO2R6, -
SO2NR7R8, _NR9SO2R10, or -NRHCONRl2Rl3;
E is -Cι_6alkyl-; Rl is hydrogen or -Ci -βalkyl;
R2 is -Ci_6alkyl-thienyl, -Cι_6alkyl-thiazolyl, -Cι _6alkyl-pyridyl, -Ci-6alkyl-furanyl, -Ci _6alkyl-naρthyl, -Cι _6alkyl-indolyl, -Cι_6alkyl-indanyl, -C l -6alkyl-methylenedioxyphenyl, -C i _6alkyl-tetrahydroquinolinyl, -C i -6alkyl- benzimidazolyl, -Ci -6alkyl-benzothiophenyl, wherein the thienyl, thiazolyl, pyridyl,
furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl, benzimidazolyl, or benzothiophenyl is optionally substituted with 1-4 independent halogen, -NO2, -Cι _6alkyl, -C(O)-O-Ci-6alkyl, -O-Ci-6alkyl, -SR14, -SO2Rl5, - SO2NRl6Rl7, -N(Cι_6alkyl)-SO2(Ci_6alkyl), phenyl, or thienyl substituent, wherein the phenyl or thienyl substituent is optionally substituted with halogen, -Cι_6alkyl, - OCi -6alkyl, -SO2Rl8, -SO2NR19R20, -NRHSO2R22, -SO2NR23R24; or-
NR25CONR26R27; or Rl and R2 form a five or six-member non-aromatic heterocyclic ring with the N to which R and R2 are connected, said ring optionally containing a second N heteroatom, said ring optionally substituted with -Cθ-4alkyl-phenyl, -Cθ- 4alkyl-pyridyl, said phenyl or pyridyl optionally substituted with -Cι _6alkyl; or Rl and R2 form a tetrahydroquinolinyl group with the N to which Rl and R are connected, optionally substituted with 1-3 independent -Ci -βalkyl or halogen substituents; R3 is -Co-6alkyl;
A is -CnH2n-; B is -CmH2m-; n and m each is 0, 1, or 2; wherein the sum of n and m is 2; R4 and R5 are each independently -Cø-6alkyl, -OH, halogen, -O-Cι _ 6alkyl, -O-Cθ-6alkyl-phenyl, or together form =O, -CH2CH2- or =CH2; R6 to R27 are each independently -C()-6alkyl; and any alkyl is optionally substituted with 1-6 independent halogen or -Cι_4alkyl.
In a sixth embodiment of this one aspect, the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
X is pyridyl optionally substituted with 1-4 independent -Cι _6alkyl, halogen, -NO2, -N(Cθ-6alkyl)(C()-6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Cι_6alkyl, -OCι _6alkyl, -SO2R6,
-SO2NR7R8, -NR9SO2R10, or -NRllCONRl2Rl3; E is -Ci_6alkyl-; Rl is hydrogen or -Cι_6alkyl;
R2 is -Cθ-6alkyl-phenyl, -Cι_6alkyl-thienyl, -Ci_6alkyl-thiazolyl, -Ci_6alkyl-pyridyl, -Ci_6alkyl-furanyl, -Ci-6alkyl-napthyl, -Cι_6alkyl-indolyl, -C i -βalkyl-indanyl, -C i -βalkyl-methylenedioxyphenyl, -C \ _6alkyl- tetrahydroquinolinyl, -C i -βalkyl-benzimidazolyl, -C 1.βalkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl, benzimidazolyl, or benzothiophenyl is optionally substituted with 1-4 independent halogen, -NO2, -Ci_6alkyl, -C(O)-O-Cι_ 6alkyl, -O-Cι _6alkyl, -SR14, -SO2Rl5, -SO2NR16R17, -N(Ci-6alkyl)-SO2(Cι_ 6alkyl), phenyl, or thienyl substituent, wherein the phenyl or thienyl substituent is optionally substituted with halogen, -Ci_6alkyl, -OCι _6alkyl, -SO2Rl8, - SO2NR19R20, -NR11S02R22, -SO2NR23R24; or -NR25CONR26R27; or Rl and R2 form a five or six-member non-aromatic heterocyclic ring with the N to which Rl and R2 are connected, said ring optionally containing a second N heteroatom, said ring optionally substituted with -Cθ-4alkyl-phenyl, -Cθ- 4alkyl-pyridyl, said phenyl or pyridyl optionally substituted with -Ci-6alkyl; or Rl and R2 form a tetrahydroquinolinyl group with the N to which Rl and R are connected, optionally substituted with 1-3 independent -Ci_6alkyl or halogen substituents;
R3 is -Co-6alkyl; A is -CnH2n-;
B is -CmH2m-; n and m each is 0, 1, or 2; wherein the sum of n and m is 2; R and R5 are each independently -Cθ-6alkyl, -OH, halogen, -O-Cι _ 6alkyl, -O-Cθ-6alkyl-phenyl, or together form =O, -CH2CH2- or =CH2; R6 to R27 are each independently -Cθ-6alkyl; and any alkyl is optionally substituted with 1-6 independent halogen or -Ci_4alkyl.
In a seventh embodiment of this one aspect, the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
X is phenyl, pyridyl, or thienyl, optionally substituted with 1-4 independent -Cι_6alkyl, halogen, -NO2, -N(Cθ-6alkyl)(Cθ-6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl,
thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci-βalkyl, -OCι_6alkyl, -SO2R6, -SO2NR7R8, -NR9SO2R1 , or -NRl 1CONR12R13; E is -Cι_6alkyl-; Rl is hydrogen or -Ci-6alkyl;
R2 is -Cθ-6alkyl-phenyl, -Ci-6alkyl-thienyl, -Cι_6alkyl-thiazolyl, -Cι_6alkyl-pyridyl, -Cι_6alkyl-furanyl, -Ci-6alkyl-napthyl, -Ci-6alkyl-indolyl, -Ci_6alkyl-indanyl, -Ci-βalkyl-methylenedioxyphenyl, -Ci_6alkyl- tetrahydroquinolinyl, -Cι_6alkyl-benzimidazolyl, -Cι_6alkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl, benzimidazolyl, or benzothiophenyl is optionally substituted with 1-4 independent halogen, -NO2, -Ci -βalkyl, -C(O)-O-Ci_ 6alkyl, -O-Cι_6alkyl, -SR14, -SO2Rl5, -SO2NR16R17, -N(Ci-6alkyl)-SO2(Cι _ βalkyl), phenyl, or thienyl substituent, wherein the phenyl or thienyl substituent is optionally substituted with halogen, -Ci.βalkyl, -OCi-βalkyl, -SO2Rl8, - SO2NRl9R20, _NRllSO2R22, -SO2NR23R24; OΓ -NR25CONR26R27; or Rl and R2 form a five or six-member non-aromatic heterocyclic ring with the N to which Rl and R2 are connected, said ring optionally containing a second N heteroatom, said ring optionally substituted with -Cθ-4alkyl-phenyl, -Cø- 4alkyl-pyridyl, said phenyl or pyridyl optionally substituted with -Ci -.βalkyl; or Rl and R2 form a tetrahydroquinolinyl group with the N to which Rl and R2 are connected, optionally substituted with 1-3 independent -Ci .βalkyl or halogen substituents;
R3 is -Co-6alkyl; A is -CnH2n-;
B is -CmH2m-; n and m each is 0, 1, or 2; wherein the sum of n and m is 2; R4 and R5 together form =CH2; R6 to R27 are each independently -Cθ-6alkyl; and any alkyl is optionally substituted with 1-6 independent halogen or
-Ci-4alkyl.
In an eighth embodiment of this one aspect, the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
X is phenyl, pyridyl, or thienyl, optionally substituted with 1-4 independent -Ci-βalkyl, halogen, -NO2, -N(Cθ-6alkyl)(Cθ-6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Cι_6alkyl, -OCi-βalkyl, -SO2R6, -SO2NR7R8, -NR9SO2R10, or-NRllCONRl2Rl3; E is -Cl-6alkyl-; Rl is hydrogen or -Ci .βalkyl; R2 is -Cθ-6alkyl-phenyl, -Cl-βalkyl-thienyl, -Ci-βalkyl-thiazolyl, -Ci_6alkyl-pyridyl, -Ci -6alkyl-furanyl, -Ci-βalkyl-napthyl, -Ci-βalkyl-indolyl, -C ι_6alkyl-indanyl, -C 1.βalkyl-methylenedi oxyphenyl, -C \ -βalkyl- tetrahydroquinolinyl, -C i -βalkyl-benzimidazolyl, -C i -βalkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl, benzimidazolyl, or benzothiophenyl is optionally substituted with 1-4 independent halogen, -NO2, -Ci-βalkyl, -C(O)-O-Cι. βalkyl, -O-Cj. -βalkyl, -SR14, -SO2Rl5, -SO2NR16R17, -N(Cι_6alkyl)-SO2(Cι_ βalkyl), phenyl, or thienyl substituent, wherein the phenyl or thienyl substituent is optionally substituted with halogen, -Ci.βalkyl, -OCi-βalkyl, -SO Rl8, - SO2NR19R20, -NR11S02R22, -SO2NR23R24; or -NR25CONR26R27; or Rl and R form a five or six-member non-aromatic heterocyclic ring with the N to which Rl and R are connected, said ring optionally containing a second N heteroatom, said ring optionally substituted with -Cθ-4alkyl-phenyl, -Cø- 4alkyl-pyridyl, said phenyl or pyridyl optionally substituted with -Ci-βalkyl; or Rl and R form a tetrahydroquinolinyl group with the N to which Rl and R are connected, optionally substituted with 1-3 independent -C]_ .βalkyl or halogen substituents;
R3 is -Co-6alkyl;
A is -CnH2n-; B is -CmH2m-; n and m each is 0, 1 , or 2; wherein the sum of n and m is 2;
R4 and R5 together form -CH2CH2-; R6 to R27 are each independently -Cθ-6alkyl; and any alkyl is optionally substituted with 1-6 independent halogen or -Ci-4alkyl.
In a ninth embodiment of this one aspect, the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
X is phenyl, pyridyl, or thienyl, optionally substituted with 1-4 independent -Cι_βalkyl, halogen, -NO2, -N(Cθ-6alkyl)(Cθ-6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Cι_βalkyl, -OCi-βalkyl,
-SO2R6, -SO2NR7R8, -NR9SO2R10, or -NRHCONRl2Rl3; E is -Ci_6alkyl-;
Rl is hydrogen or -Ci .βalkyl;
R2 is -Cθ-6alkyl-phenyl, -Cι _βalkyl-thienyl, -Ci -βalkyl-thiazolyl, -Ci-βalkyl-pyridyl, -Ci-βalkyl-furanyl, -Cι_βalkyl-napthyl, -Ci-βalkyl-indolyl, -C i -βalkyl-indanyl, -C i .βalkyl-methylenedioxyphenyl, -C 1 -βalkyl- tetrahydroquinolinyl, -Ci -βalkyl-benzimidazolyl, -Ci-βalkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl, benzimidazolyl, or benzothiophenyl is optionally substituted with 1-4 independent halogen, -NO2, -Ci_6alkyl, -C(O)-O-Cι _ βalkyl, -O-Ci.βalkyl, -SR14, -SO2Rl5, -SO2NR16R17, -N(Ci-βalkyl)-SO2(Ci- βalkyl), phenyl, or thienyl substituent, wherein the phenyl or thienyl substituent is optionally substituted with halogen, -Ci -βalkyl, -OCi-βalkyl, -SO2Rl8, - SO2NR19R20, -NRllSO2R22, -SO2NR23R24; or -NR25cONR26R27; or Rl and R2 form a five or six-member non-aromatic heterocyclic ring with the N to which Rl and R2 are connected, said ring optionally containing a second N heteroatom, said ring optionally substituted with -Cθ-4alkyl-phenyl, -Cθ- 4alkyl-pyridyl, said phenyl or pyridyl optionally substituted with -Ci -βalkyl; or Rl and R2 form a tetrahydroquinolinyl group with the N to which Rl and R2 are connected, optionally substituted with 1-3 independent -Cι_βalkyl or halogen substituents; R3 is -Co-6alkyl;
A is -CnH2n-; B is -CmH2m-; n and m each is 0, 1, or 2; wherein the sum of n and m is 2; R4 and R5 together form =O; R6 to R 7 are each independently -Cθ-6alkyl; and
any alkyl is optionally substituted with 1-6 independent halogen or -Ci-4alkyl.
In a second aspect, the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridyl, or thienyl, optionally substituted with 1-4 independent -Ci-βalkyl, halogen, -NO2, -N(Cθ-6alkyl)(Cθ-6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci -βalkyl, -OCι -βalkyl, -SO2R6, -SO2NR7R8, -NR9SO2R1°, or -NRHCONR12R13; E is -Ci -βalkyl-; Rl is hydrogen or -Ci -βalkyl;
R2 is -Cθ-βalkyl-phenyl, -Cj. -βalkyl-thienyl, -Ci -βalkyl-thiazolyl, -Ci-βalkyl-pyridyl, -Ci-βalkyl-furanyl, -Ci-βalkyl-napthyl, -Ci_βalkyl-indolyl, -Ci -βalkyl-indanyl, -Ci-βalkyl-methylenedioxyphenyl, -Ci-βalkyl- tetrahydroquinolinyl, -Ci -βalkyl-benzimidazolyl, -Cι _βalkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl, benzimidazolyl, or benzothiophenyl is optionally substituted with 1-4 independent halogen, -NO2, -Ci -βalkyl, -C(O)-O-Cι . βalkyl, -O-Cι -βalkyl, -SR1 -SO2Rl5, -SO2NR16R17, -N(Ci-βalkyl)-SO2(Cι_ βalkyl), phenyl, or thienyl substituent, wherein the phenyl or thienyl substituent is optionally substituted with halogen, -Ci -βalkyl, -OCι_βalkyl, -SO Rl8, - SO2NR19R20, -NRllSO2R22, -SO2NR23R24; or -NR25CONR26R27; or Rl and R2 form a five or six-member non-aromatic heterocyclic ring with the N to which Rl and R2 are connected, said ring optionally containing a second N heteroatom, said ring optionally substituted with -Cθ-4alkyl-phenyl, -Cθ- 4alkyl-pyridyl, said phenyl or pyridyl optionally substituted with -Ci -βalkyl; or Rl and R2 form a tetrahydroquinolinyl group with the N to which Rl and R2 are connected, optionally substituted with 1-3 independent -Ci -βalkyl or halogen substituents;
R3 is -Co-6alkyl;
A is -CnH2n-;
B is -CmH2m-; n and m each is 0, 1, 2, or 3; wherein the sum of n and m is 3;
R4 and R5 are each independently -Cθ-βalkyl, -OH, halogen, -O-C1 _ βalkyl, -O-C0-βalkyl-phenyl, or together form =0, -CH2CH2- or =CH2; R6 to R27 are each independently -Cθ-6alkyl; and any alkyl is optionally substituted with 1-6 independent halogen or -Ci-4alkyl.
In one embodiment of this second aspect, the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein X is phenyl, optionally substituted with 1-4 independent -Ci-βalkyl, halogen, -N02, -N(Cθ-βalkyl)(Cθ-βalkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci-βalkyl, -OCi-βalkyl, -SO2R6, -SO2NR7R8, -NR9SO2R10, or -NRHCONRl2Rl3; E is -Ci -βalkyl-; Rl is hydrogen or -Ci -βalkyl;
R2 is -Cθ-βalkyl-phenyl, -Ci -βalkyl-thienyl, -Ci -βalkyl-thiazolyl, -Ci -βalkyl-pyridyl, -Ci -βalkyl-furanyl, -Ci -βalkyl-napthyl, -Cι_βalkyl-indolyl, -Ci -βalkyl-indanyl, -Ci -βalkyl-methylenedioxyphenyl, -Ci -βalkyl- tetrahydroquinolinyl, -C -βalkyl-benzimidazolyl, -Ci-βalkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl, benzimidazolyl, or benzothiophenyl is optionally substituted with 1-4 independent halogen, -NO2, -Ci-βalkyl, -C(O)-O-Cι _ βalkyl, -O-Cj. -βalkyl, -SR14, -SO2Rl5, -SO2NR16R17, -N(Cι -βalkyl)-SO2(Cι _ βalkyl), phenyl, or thienyl substituent, wherein the phenyl or thienyl substituent is optionally substituted with halogen, -Ci -βalkyl, -OCι -βalkyl, -SO2Rl8, - SO2NR19R20, _NR11SO2R22, -SO2NR23R24; or -NR25CONR26R27; or Rl and R2 form a five or six-member non-aromatic heterocyclic ring with the N to which Rl and R are connected, said ring optionally containing a second N heteroatom, said ring optionally substituted with -Cθ-4alkyl-phenyl, -Cθ- 4alkyl-pyridyl, said phenyl or pyridyl optionally substituted with -Ci -βalkyl;
or Rl and R2 form a tetrahydroquinolinyl group with the N to which Rl and R are connected, optionally substituted with 1-3 independent -Ci_βalkyl or halogen substituents;
R3 is -Co-6alkyl; A is -CnH2n-;
B is -CmH2m-; n and m each is 0, 1, 2, or 3; wherein the sum of n and m is 3; R4 and R5 are each independently -Cθ-βalkyl, -OH, halogen, -O-Ci- βalkyl, -O-Co-βalkyl-phenyl, or together form =0, -CH2CH2- or =CH2; R6 to R27 are each independently -Cθ-6alkyl; and any alkyl is optionally substituted with 1-6 independent halogen or -Ci-4alkyl.
In a second embodiment of this second aspect, the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
X is phenyl substituted with a phenyl substituent, further optionally substituted with 1-4 independent -Ci -βalkyl, halogen, -N02, or -N(Cθ-βalkyl)(Cθ- βalkyl) substituent, wherein the phenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci -βalkyl, -OCi-βalkyl, -SO2R6, -S02NR7R8, -NR9S02R10, or -NRllCONRl2Rl3; E is -Ci -βalkyl-; Rl is hydrogen or -Ci -βalkyl;
R2 is -Cθ-βalkyl-phenyl, -Ci -βalkyl-thienyl, -Cι_βalkyl-thiazolyl, -Ci-βalkyl-pyridyl, -Cι _βalkyl-furanyl, -Ci-βalkyl-napthyl, -Ci -βalkyl-indolyl, -Ci -βalkyl-indanyl, -Ci -βalkyl-methylenedi oxyphenyl, -Cj. -βalkyl- tetrahydroquinolinyl, -C i -βalkyl-benzimidazolyl, -C 1 -βalkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl, benzimidazolyl, or benzothiophenyl is optionally substituted with 1-4 independent halogen, -N02, -Ci -βalkyl, -C(O)-O-Cι . βalkyl, -O-Cι -βalkyl, -SR14, -SO2Rl5, -SO2NRl6Rl7, -N(Cι_βalkyl)-SO2(Cι _ βalkyl), phenyl, or thienyl substituent, wherein the phenyl or thienyl substituent is optionally substituted with halogen, -Ci -βalkyl, -OCi -βalkyl, -SO2Rl8, - SO2NR19R20, -NR11S02R22, -SO2NR23R24; or -NR25CONR26R27;
or Rl and R2 form a five or six-member non-aromatic heterocyclic ring with the N to which Rl and R2 are connected, said ring optionally containing a second N heteroatom, said ring optionally substituted with -Cθ-4alkyl-phenyl, -Cθ- 4alkyl-pyridyl, said phenyl or pyridyl optionally substituted with -Ci-βalkyl; or Rl and R2 form a tetrahydroquinolinyl group with the N to which
Rl and R2 are connected, optionally substituted with 1-3 independent -Ci-βalkyl or halogen substituents;
R3 is -Co-βalkyl;
A is -CnH2n-; B is -CmH2m-; n and m each is 0, 1, 2, or 3; wherein the sum of n and m is 3; R4 and R5 are each independently -Cθ-βalkyl, -OH, halogen, -O-Cι _ βalkyl, -O-Cθ-βalkyl-phenyl, or together form =O, -CH2CH2- or =CH2; R6 to R27 are each independently -Cθ-6alkyl; and any alkyl is optionally substituted with 1-6 independent halogen or
-Ci-4alkyl.
In a third aspect, the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridyl, or thienyl, optionally substituted with 1-4 independent -Ci -βalkyl, halogen, -NO2, -N(Cθ-βalkyl)(Cθ-βalkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci -βalkyl, -OCι _βalkyl, -SO2R6, -SO2NR7R8, -NR9SO2R10, or-NRHCONRl2Rl3;
E is -Cι_βalkyl-;
Rl is hydrogen or -Ci -βalkyl;
R2 is -Cθ-βalkyl-phenyl, -Ci-βalkyl-thienyl, -Ci -βalkyl-thiazolyl, -Ci-βalkyl-pyridyl, -Ci-βalkyl-furanyl, -Ci-βalkyl-napthyl, -Ci .βalkyl-indolyl, -Ci -βalkyl-indanyl, -Ci -βalkyl-methylenedioxyphenyl, -Ci-βalkyl- tetrahydroquinolinyl, -Ci_βalkyl-benzimidazolyl, -Ci-βalkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl, benzimidazolyl, or benzothiophenyl is optionally substituted with 1-4 independent halogen, -NO2, -Ci -βalkyl, -C(O)-O-Cι .
βalkyl, -O-Cι _βalkyl, -SR14, -SO2Rl5, -SO2NR16R17, -N(Ci-βalkyl)-SO2(Cι _ βalkyl), phenyl, or thienyl substituent, wherein the phenyl or thienyl substituent is optionally substituted with halogen, -Ci.βalkyl, -OCι_βalkyl, -SO2Rl8, - SO2NR19R20, -NR11S02R22, -SO2NR23R24; or -NR25cONR26R27; or Rl and R2 form a five or six-member non-aromatic heterocyclic ring with the N to which Rl and R2 are connected, said ring optionally containing a second N heteroatom, said ring optionally substituted with -Cθ-4alkyl-phenyl, -Cθ- 4alkyl-pyridyl, said phenyl or pyridyl optionally substituted with -Ci -βalkyl; or Rl and R2 form a tetrahydroquinolinyl group with the N to which Rl and R2 are connected, optionally substituted with 1-3 independent -Ci -βalkyl or halogen substituents;
R3 is -Co-βalkyl;
A is -CnH2n-; B is -CmH2m-; n and m each is 0, or 1 ; wherein the sum of n and m is 1 ;
R4 and R5 are each independently -Cθ-βalkyl, -OH, halogen, -O-Cι _ βalkyl, -O-Cθ-βalkyl-phenyl, or together form =O, -CH2CH2-, or =CH2; R6 to R27 are each independently -Cθ-6alkyl; and any alkyl is optionally substituted with 1-6 independent halogen or -Ci-4alkyl.
In an embodiment of this third aspect, the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
X is phenyl, optionally substituted with 1-4 independent -Cι _βalkyl, halogen, -NO2, -N(Cθ-βalkyl)(Cθ-6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Cι_βalkyl, -OCι -βalkyl, -SO R6, -SO2NR7R8, -NR9SO2R10, or -NRHCONR12R13; E is -Cι_βalkyl-;
Rl is hydrogen or -Ci -βalkyl;
R2 is -Cθ-βalkyl-phenyl, -Ci -βalkyl-thienyl, -Ci -βalkyl-thiazolyl, -Ci-βalkyl-pyridyl, -Cι _βalkyl-furanyl, -Ci.βalkyl-napthyl, -Cι_βalkyl-indolyl, -Ci-βalkyl-indanyl, -Ci-βalkyl-methylenedioxyphenyl, -Ci.βalkyl-
tetrahydroquinolinyl, -C 1 -βalkyl-benzimidazolyl, -C i_βalkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl, benzimidazolyl, or benzothiophenyl is optionally substituted with 1-4 independent halogen, -N02, -Cι_βalkyl, -C(O)-O-Cι _ βalkyl, -O-Ci -βalkyl, -SR14, -SO2Rl5, -SO2NR16R17, -N(Ci-βalkyl)-SO2(Cι _ βalkyl), phenyl, or thienyl substituent, wherein the phenyl or thienyl substituent is optionally substituted with halogen, -Ci-βalkyl, -OCi.βalkyl, -SO2Rl8, - SO2NRl9R20, -NR11S02R22, -SO2NR23R24; or-NR25cONR26R27; or Rl and R2 form a five or six-member non-aromatic heterocyclic ring with the N to which Rl and R2 are connected, said ring optionally containing a second N heteroatom, said ring optionally substituted with -Cθ-4alkyl-phenyl, -Cθ- 4alkyl-pyridyl, said phenyl or pyridyl optionally substituted with -Ci -βalkyl; or Rl and R2 form a tetrahydroquinolinyl group with the N to which Rl and R2 are connected, optionally substituted with 1-3 independent -Ci -βalkyl or halogen substituents;
R3 is -Co-βalkyl;
A is -CnH2n-; B is -CmH2m-; n and m each is 0, or 1 ; wherein the sum of n and m is 1 ; R and R5 are each independently -Cθ-βalkyl, -OH, halogen, -O-Cι _ βalkyl, -O-Cθ-βalkyl-phenyl, or together form =O, -CH2CH2- or =CH2; R6 to R27 are each independently -Cθ-6alkyl; and any alkyl is optionally substituted with 1-6 independent halogen or -Cι_4alkyl.
In a second embodiment of this third aspect, the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
X is phenyl substituted with a phenyl substituent, further optionally substituted with 1-4 independent -Ci -βalkyl, halogen, -NO2, or -N(Cθ-βalkyl)(Cθ- βalkyl) substituent, wherein the phenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Cι_βalkyl, -OCi-βalkyl, -SO2R6, -SO2NR7R8, -NR9SO2R10, or -NRHCONRl2Rl3;
E is -Cι_βalkyl-;
Rl is hydrogen or -Cι_βalkyl;
R2 is -Cθ-βalkyl-phenyl, -Ci -βalkyl-thienyl, -Cι_βalkyl-thiazolyl, -Ci-βalkyl-pyridyl, -Ci-βalkyl-furanyl, -Ci-βalkyl-napthyl, -Ci_βalkyl-indolyl, -Ci -βalkyl-indanyl, -Ci_βalkyl-methylenedioxyphenyl, -Ci.βalkyl- tetrahydroquinolinyl, -Ci-βalkyl-benzimidazolyl, -Ci-βalkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl, benzimidazolyl, or benzothiophenyl is optionally substituted with 1-4 independent halogen, -N02, -Ci-βalkyl, -C(0)-0-Cι . βalkyl, -O-Cι -βalkyl, -SR14, -SO2Rl5, -SO2NR16R17, -N(Cι.βalkyl)-SO2(Cι _ βalkyl), phenyl, or thienyl substituent, wherein the phenyl or thienyl substituent is optionally substituted with halogen, -Cι_βalkyl, -OCi-βalkyl, -SO2Rl8, - SO2NR19R20, -NRllSO2R22, -SO2NR23R24; OΓ -NR25CONR26R27; or Rl and R2 form a five or six-member non-aromatic heterocyclic ring with the N to which Rl and R2 are connected, said ring optionally containing a second N heteroatom, said ring optionally substituted with -Cθ-4alkyl-phenyl, -Cθ- 4alkyl-pyridyl, said phenyl or pyridyl optionally substituted with -Ci-βalkyl; or Rl and R2 form a tetrahydroquinolinyl group with the N to which Rl and R2 are connected, optionally substituted with 1-3 independent -Ci -βalkyl or halogen substituents; R3 is -Co-βalkyl;
A is -CnH2n-; B is -CmH2m-; n and m each is 0, or 1; wherein the sum of n and m is 1; R4 and R5 are each independently -Cθ-βalkyl, -OH, halogen, -O-Cι_ βalkyl, -O-Cθ-βalkyl-phenyl, or together form =O, -CH2CH2- or =CH2; R6 to R27 are each independently -Cθ-6alkyl; and any alkyl is optionally substituted with 1-6 independent halogen or -Cι_4alkyl.
As used herein, "alkyl" as well as other groups having the prefix "alk" such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl,
hexyl, heptyl and the like. "Alkenyl", "alkynyl" and other like terms include carbon chains containing at least one unsaturated C-C bond.
The term "cycloalkyl" means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzofused carbocycles. Cycloalkyl includes such fused ring systems as spirofused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4- tetrahydronaphalene and the like. Similarly, "cycloalkenyl" means carbocycles containing no heteroatoms and at least one non-aromatic C-C double bond, and include mono-, bi- and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like. The term "aryl" means an aromatic substituent which is a single ring or multiple rings fused together. When formed of multiple rings, at least one of the constituent rings is aromatic. The preferred aryl substituents are phenyl and naphthyl groups.
The term "cycloalkyloxy" unless specifically stated otherwise includes a cycloalkyl group connected by a short Ci _2alkyl length to the oxy connecting atom. The term "Cθ-βalkyl" includes alkyls containing 6, 5, 4, 3, 2, 1, or no carbon atoms. An alkyl with no carbon atoms is a hydrogen atom substituent when the alkyl is a terminal group and is a direct bond when the alkyl is a bridging group.
The term "hetero" unless specifically stated otherwise includes one or more O, S, or N atoms. For example, heterocycloalkyl and heteroaryl include ring systems that contain one or more O, S, or N atoms in the ring, including mixtures of such atoms. The hetero atoms replace ring carbon atoms. Thus, for example, a heterocycloCsalkyl is a five-member ring containing from 4 to no carbon atoms.
Examples of heteroaryls include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl. Examples of heterocycloalkyls include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.
The term "heteroCθ-4alkyl" means a heteroalkyl containing 3, 2, 1, or no carbon atoms. However, at least one heteroatom must be present. Thus, as an example, a heteroCθ-4alkyl having no carbon atoms but one N atom would be a -NH- if a bridging group and a -NH-2 if a terminal group. Analogous bridging or terminal groups are clear for an O or S heteroatom.
The term "amine" unless specifically stated otherwise includes primary, secondary and tertiary amines substituted with Cθ-6alkyl.
The term "carbonyl" unless specifically stated otherwise includes a Cθ- βalkyl substituent group when the carbonyl is terminal. The term "halogen" includes fluorine, chlorine, bromine and iodine atoms.
The term "optionally substituted" is intended to include both substituted and unsubstituted. Thus, for example, optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring. Further, optionally substituted multiple moieties such as, for example, alkylaryl are intended to mean that the aryl and the aryl groups are optionally substituted. If only one of the multiple moieties is optionally substituted then it will be specifically recited such as "an alkylaryl, the aryl optionally substituted with halogen or hydroxyl."
Compounds described herein contain one or more double bonds and may thus give rise to cis/trans isomers as well as other conformational isomers. The present invention includes all such possible isomers as well as mixtures of such isomers unless specifically stated otherwise.
Compounds described herein can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The above chemical Formulas are shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of the chemical Formulas and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
The pharmaceutical compositions of the present invention comprise a compound represented by Formula I (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. Such additional therapeutic ingredients include, for example, i) opiate agonists or antagonists, ii) calcium channel antagonists, iii) 5HT receptor agonists or antagonists iv) sodium channel antagonists, v) NMDA receptor agonists or antagonists, vi) COX-2 selective inhibitors, vii) NK1 antagonists, viii) non-steroidal anti-inflammatory drugs ("NSAID"), ix) selective serotonin
reuptake inhibitors ("SSRI") and/or selective serotonin and norepinephrine reuptake inhibitors ("SSNRI"), x) tricyclic antidepressant drugs, xi) norepinephrine modulators, xii) lithium, xiii) valproate, and xiv) neurontin (gabapentin). The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. The compositions are useful in the treatment of chronic, visceral, inflammatory and neuropathic pain syndromes. They are useful for the treatment of pain resulting from traumatic nerve injury, nerve compression or entrapment, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, and pain resulting from cancer and chemotherapy, HIV and HIV treatment-induced neuropathy, chronic pelvic pain, neuroma pain, complex regional pain syndrome, chronic arthritic pain and related neuralgias. Compounds of this invention may also be utilized as local anesthetics. Compounds of this invention are useful in the treatment of irritable bowel syndrome and related disorders, as well as Crohns disease. Pharmaceutical compositions of the present invention have clinical uses in the treatment of epilepsy and partial and generalized tonic seizures. They are also useful for neuroprotection under ischaemic conditions caused by stroke or neural trauma and in patients with multiple sclerosis.
Pharmaceutical compositions of the present invention have clinical uses in the treatment of bipolar disease.
Pharmaceutical compositions of the present invention have clinical uses in the treatment of tachy-arrhythmias.
Further, it is understood that compounds of this invention can be administered at prophylactically effective dosage levels to prevent the above-recited conditions.
The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be
conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
Creams, ointments, jellies, solutions, or suspensions containing the compound of Formula I can be employed for topical use. Mouth washes and gargles are included within the scope of topical use for the purposes of this invention. Dosage levels from about O.Olmg/kg to about 140mg/kg of body weight per day are useful in the treatment of inflammatory and neuropathic pain, or alternatively about 0.5mg to about 7g per patient per day. For example, inflammatory pain may be effectively treated by the administration of from about O.Olmg to 75mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day. Neuropathic pain may be effectively treated by the administration of from about O.Olmg to 125mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 5.5g per patient per day. Further, it is understood that the compounds of this invention can be administered at prophylactically effective dosage levels to prevent the above-recited conditions.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration to humans may conveniently contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about lmg to about lOOOmg of the active ingredient, typically 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or lOOOmg. It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. In practice, the compounds represented by Formula I, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration
such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I, or pharmaceutically acceptable salts thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of Formula I. The compounds of Formula I, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.
In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques
A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or
adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about O.lmg to about 500mg of the active ingredient and each cachet or capsule preferably containing from about O.lmg to about 500mg of the active ingredient. Thus, a tablet, cachet, or capsule conveniently contains O.lmg, lmg, 5mg, 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, or 500mg of the active ingredient taken one or two tablets, cachets, or capsules, once, twice, or three times daily.
Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5
wt% to about 10 wt of the compound, to produce a cream or ointment having a desired consistency.
Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
The compounds and pharmaceutical compositions of this invention have been found to block sodium channels. Accordingly, another aspect of the invention is the treatment in mammals of, for example, acute pain, chronic pain, visceral pain, inflammatory pain, or neuropathic pain, as well as tinnitus and noise induced hearing loss - maladies that are amenable to amelioration through blockage of neuronal sodium channels - by the administration of an effective amount of the compounds of this invention. The term "mammals" includes humans, as well as other animals such as, for example, dogs, cats, horses, pigs, and cattle. Accordingly, it is understood that the treatment of mammals other than humans is the treatment of clinical correlating afflictions to those above recited examples that are human afflictions.
Further, as described above, the compound of this invention can be utilized in combination with other therapeutic compounds. In particular, the sodium channel blocking compound of this invention can be advantageously used in combination with i) opiate agonists or antagonists, ii) calcium channel antagonists, iii) 5HT receptor agonists or antagonists iv) sodium channel antagonists, v) NMDA receptor agonists or antagonists, vi) COX-2 selective inhibitors, vii) NK1 antagonists, viii) non-steroidal anti-inflammatory drugs ("NSAID"), ix) selective serotonin reuptake inhibitors ("SSRI") and/or selective serotonin and norepinephrine reuptake
inhibitors ("SSNRI"), x) tricyclic antidepressant drugs, xi) norepinephrine modulators, xii) lithium, xiii) valproate, and xiv) neurontin (gabapentin).
The abbreviations used herein have the following tabulated meanings. Abbreviations not tabulated below have their meanings as commonly used unless specifically stated otherwise.
ALKYL GROUP ABBREVIATIONS
The following in vitro and in vivo assays were used in assessing the biological activity of the compounds described in this invention.
Compound Evaluation (in Vitro assay):
The identification of inhibitors of the sodium channel can be accomplished using Aurora Biosciences technology, and is based on the ability of sodium channels to cause cell depolarization when sodium ions permeate through agonist-modified channels. In the absence of inhibitors, exposure of agonist-modified channel to sodium ions will cause cell depolarization. Sodium channel inhibitors will prevent cell depolarization caused by sodium ion movement through agonist-modified sodium channel. Changes in membrane potential can be determined with voltage- sensitive fluorescence resonance energy transfer (FRET) dye pairs that use two components, a donor coumarin (CC2DMPE) and an acceptor oxanol (DiSBAC2(3)). Oxanol is a lipophilic anion and distributes across the membrane according to membrane potential. In the presence of sodium channel agonist, but in the absence of sodium, the inside of the cell is negative with respect to the outside, oxanol is accumulated at the outer leaflet of the membrane and excitation of coumarin will cause FRET to occur. Addition of sodium will cause membrane depolarization leading to redistribution of oxanol to the inside of the cell, and, as a consequence, to a decrease in FRET. Thus, the ratio change (donor/acceptor) increases after membrane depolarization. In the presence of a sodium channel inhibitor cell depolarization will not occur, and therefore the distribution of oxanol and FRET will remain unchanged. Cells stably transfected with the PN1 sodium channel (HEK-PN1) were grown in polylysine-coated 96-well plates at a density of ca. 140,000 cells/well. Media was aspirated, cells washed with PBS buffer, and incubated with lOOμL of lOμM CC2-DMPE in 0.02% pluronic acid. After incubation at 25°C for 45min, media
was removed and cells were washed 2x with buffer. Cells were incubated with lOOμL of DiSBAC2(3) in TMA buffer containing 20μM veratridine, 20nM brevetoxin-3, and test sample. After incubation at 25°C for 45min in the dark, plates were placed in the VTPR instrument, and the fluorescence emission of both CC2-DMPE and DiSBAC2(3) recorded for 10s. At this point, lOOμL of saline buffer was added to the wells to determine the extent of sodium-dependent cell depolarization, and the fluorescence emission of both dyes recorded for an additional 20s. The ratio CC2- DMPE DiSBAC2(3), before addition of saline buffer equals 1. In the absence of inhibitors, the ratio after addition of saline buffer is > 1.5. When the sodium channel has been completely inhibited by either a known standard or test compound, this ratio remains at 1. It is possible, therefore, to titrate the activity of a sodium channel inhibitor by monitoring the concentration-dependent change in fluorescence ratio.
Electrophysiological Assays (In Vitro assays): Cell preparation: A HEK-293 cell line stably expressing the PN1 sodium channel subtype was established in-house. The cells were cultured in MEM growth media (Gibco) with 0.5mg/mL G418, 50 units/mL Pen/Strep and lmL heat- inactivated fetal bovine serum at 37°C and 10% CO2. For electrophysiological recordings, cells were plated on 35mm dishes coated with poly-D-lysine. Whole-cell recordings: HEK-293 cells stably expressing the PN1 sodium channel subtype were examined by whole cell voltage clamp (Hamill et. al. Pfluegers Archives 391:85-100 (1981)) using an EPC-9 amplifier and Pulse software (HEKA Electronics, Lamprecht, Germany). Experiments were performed at room temperature. Electrodes were fire-polished to resistances of 2-4 MΩ. Voltage errors were minimized by series resistance compensation, and the capacitance artefact was canceled using the EPC-9' s built-in circuitry. Data were acquired at 50 kHz and filtered at 7-10 kHz. The bath solution consisted of 40 mM NaCl, 120 mM NMDG CI, 1 mM KC1, 2.7 mM CaCl2, 0.5 mM MgCl2, 10 mM NMDG HEPES, pH 7.4, and the internal (pipet) solution contained 110 mM Cs-methanesulfόnate, 5 mM NaCl, 20mM CsCl, lOmM CsF, 10 mM BAPTA (tetra Cs salt), 10 mM Cs HEPES, pH 7.4. The following protocol was used to estimate the steady-state affinity of compounds for the resting and inactivated state of the channel (Kr and K,, respectively):
1) 8ms testpulses to depolarizing voltages from -60mV to +50mV from a holding potential of -90mV were used to construct current- voltage relationships (TV-curves). A voltage near the peak of the IV-curve (typically -10 or 0 mV) was used as the testpulse voltage throughout the remainder of the experiment. 2) Steady-state inactivation (availability) curves were constructed by measuring the current activated during an 8ms testpulse following 10s conditioning pulses to potentials ranging from -120mV to -lOmV.
3) Compounds were applied at a holding potential at which 20-50% of the channels were inactivated and block was monitored during 8ms test pulses at 2s intervals.
4) After the compounds equilibrated, the voltage-dependence of steady-state inactivation in the presence of compound was determined (same protocol as 2) ). Compounds that block the resting state of the channel decrease the current elicited during testpulses from all holding potentials, whereas compounds that primarily block the inactivated state shift the mid-point of the steady-state inactivation curve. The maximum curcent at negative holding potentials (Imaχ) and the difference in the mid-points of the steady-state inactivation curves (ΔV) in control and in the presence of a compound were used to calculate Kr and K; using the following equations:
_ [Drug]* IMax Drug
Kr —
I Max,Control - I Max,Drug
In cases were the compound did not affect the resting state, K; was calculated using the following equation:
R _ [Drug]
-ΔV k
Formalin test
Compounds were assessed for their ability to inhibit the behavioral response evoked by a 50μL injection of formalin (5%) using a modified procedure described in D. Dubuisson and S. G. Dennis, Pain 4, 161-74 (1977). A metal band was affixed to the left hind paw of male Sprague-Dawley rats (Charles River, 200- 250g) and each rat was conditioned to the band for 60min within a plastic cylinder (15cm diam.). Rats were dosed with either vehicle or a test compound either before (local) or after (systemic) formalin challenge. For local administration, compounds were prepared in a 1:4:5 vehicle of ethanol, PEG400 and saline (EPEGS) and injected subcutaneously into the dorsal surface of the left hind paw 5min prior to formalin. For systemic administration, compounds were prepared in either a EPEGS vehicle or a Tween80 (10%)/sterile water (90%) vehicle and were injected i.v. (via the lateral tail vein 15min after formalin) or p.o. (60min before formalin). The number of flinches was counted continuously for 60min using an automated nociception analyzer (UCSD Anesthesiology ReseaiOh, San Diego, CA). Statistical significance was determined by comparing the total flinches detected in the early (0-10min) and late (ll-60min) phase with an unpaired t-test.
CFA Unilateral inflammation was induced with a.2mL injection of complete
Freund's adjuvant (CFA: Mycobacterium tuberculosis, Sigma; suspended in an oil/saline (1:1) emulsion; 0.5mg Mycobacterium/ml) in the plantar surface of the left hindpaw. This dose of CFA produced significant hind paw swelling but the animals exhibited normal grooming behavior and weight gain over the course of the experiment. Mechanical hyperalgesia was assessed 3 days after tissue injury using a Randall-Selitto test (S. G. Khasar, F. J. Miao, J. D. Levine, Neuroscience 69, 685-90. (1995). Repeated Measures ANOVA, followed by Dunnett's Post Hoc test.
SNL: Mechanical Allodynia Tactile allodynia was assessed with calibrated von Frey filaments using an up-down paradigm (S. R. Chaplan, F. W. Bach, J. W. Pogrel, J. M. Chung, T. L. Yaksh, J Neurosci Methods 53, 55-63 (1994) before and two weeks following nerve injury (S. H. Kim, J. M. Chung, Pain 50, 355-63. (1992). Briefly, animals were placed in plastic cages with a wire mesh floor and allowed to acclimate for 15min before each test session. To determine the 50% response threshold, the von Frey
filaments (over a range of intensities from 0.4 to 28.8g) were applied to the mid- plantar surface for 8s or until a withdrawal response occurred. Following a positive response, an incrementally weaker stimulus was tested. If there was no response to a stimulus, then an incrementally stronger stimulus was presented. After the initial threshold crossing, this procedure was repeated for four stimulus presentations per animal per test session. Mechanical sensitivity was assessed 1 and 2 hour post oral administration of the test compound.
The compounds described in this invention displayed sodium channel blocking activity of <50μM in the in vitro assays. It is preferred that the compounds display sodium channel blocking activity of <5μM in the in vitro assays. It is more advantageous that the compounds display sodium channel blocking activity of <lμM in the in vitro assays. It is even more advantageous that the compounds display sodium channel blocking activity of <0.5μM in the in vitro assays. It is still more preferred that the compounds display sodium channel blocking activity of <0.1μM in the in vitro assays.
Thus, because the instant compounds display sodium channel blocking activity of <5μM in the in vitro assays, the compositions of this invention are useful in the treatment of chronic, visceral, inflammatory and neuropathic pain syndromes. They are also useful for the treatment of pain resulting from traumatic nerve injury, nerve compression or entrapment, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, and pain resulting from cancer and chemotherapy, HIV and HIV treatment-induced neuropathy, chronic pelvic pain, neuroma pain, complex regional pain syndrome, chronic arthritic pain and related neuralgias. Further, they are useful as local anesthetics. Compounds of this invention are useful in the treatment of irritable bowel syndrome and related disorders, as well as Crohns disease, tinnitus and noise induced hearing loss.
Pharmaceutical compositions of the present invention have clinical uses in the treatment of epilepsy and partial and generalized tonic seizures.
They are also useful for neuroprotection under ischaemic conditions caused by stroke or neural trauma and in patients with multiple sclerosis.
Pharmaceutical compositions of the present invention have clinical uses in the treatment of bipolar disease.
Pharmaceutical compositions of the present invention have clinical uses in the treatment of tachy-arrhythmias.
Further, it is understood that compounds of this invention can be administered at prophylactically effective dosage levels to prevent the above-recited conditions.
The examples that follow are intended as an illustration of certain preferred embodiments of the invention and no limitation of the invention is implied. Unless specifically stated otherwise, the experimental procedures were performed under the following conditions. All operations were carried out at room or ambient temperature - that is, at a temperature in the range of 18-25°C. Evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600- 4000pascals: 4.5-30mm. Hg) with a bath temperature of up to 60°C. The course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only. Melting points are uncorrected and 'd' indicates decomposition. The melting points given are those obtained for the materials prepared as described. Polymorphism may result in isolation of materials with different melting points in some preparations. The structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data. When given, yields are for illustration only. When given, NMR data is in the form of delta (δ) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300MHz, 400MHz or 500MHz using the indicated solvent. Conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc. In addition, "Ar" signifies an aromatic signal. Chemical symbols have their usual meanings; the following abbreviations are used: v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (liter(s)), mL (milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq (equivalent(s)).
Methods of Synthesis
Compounds of the present invention can be prepared according to the following methods. The substituents are the same as in Formula I except where defined otherwise or otherwise apparent in context to one in the art. Several methods for preparing the compounds of this invention are illustrated in the following SCHEMES and Examples. Starting materials are made from known procedures, as illustrated in the SCHEMES or for specific Examples.
SCHEME 1
EDC, HOBt HNR1Ra
THF
In one protocol, the compounds of the present invention are prepared by sequential amide formation. A cyclic dicarboxylic acid 1 (in this case, cyclopentane-l,2-dicarboxylic acid) is activated by reaction with CDI (carbonyldiimidazole) in an aprotic solvent such as THF (tetrahydrofuran) or CH2C1 (dichloromethane) or a combination of the two. To the activated acid is then added an amine to give compound 2. Appropriate equivalents of activating reagents and amine will give primarily the mono-amide. Subsequent activation of compound 2 with CDI or by use of HOBt (hydroxybenzotriazole) in the presence of a suitable carbodiimide such as EDC [l-(3-dimethylaminopropyl)-3-ethylcarbodiimide) in THF followed by reaction with R^NH gives compound 3. There are numerous other suitable methods to activate carboxylic acids for amide formation (see March J. "Advanced Organic Chemistry", 5th ed., John Wiley & Sons, New York, pp. 506-512 (2001). One example is via an acid chloride intermediate using SOCl2 (thionyl chloride). An effective method is by reacting compounds 1 or 2 with pyr-BOP (benzotriazol-1- yloxytripyrrolidinophosphonium hexafluorophosphate) or the BOP-Reagent (benzotriazol-l-yloxytris(dimethylamino) phosphonium hexafluorophosphate) in a solvent such as DMF (dimethylformamide) followed by the appropriate amine in the presence of a base such as diisopropylethylamine.
SCHEME 2
CDI, THF
1. TFA, THF
2. EDC, HOBt HNR1R2 THF
In an alternative embodiment of SCHEME 1, dicarboxylic acid compound 4 wherein one of the acids is protected as a t-butyl ester, for instance, is converted to amide 5 as described in SCHEME 1. Compound 5 is then converted to its free acid by reaction with TFA (trifluoroacetic acid) or HCl in solvents such as THF. The free acid is then converted to compound 3 as described in SCHEME 1.
SCHEME 3
Suzuki ArB(OH)2
Na2C03, H20, toluene, ETOH (Ph3P)4Pd
Compounds in the present invention that contain arylphenyl substitution can be prepared as described in SCHEME 3. Bromobenzyl amide derivative 6 is prepared as described in SCHEME 1. There are a variety of methods to couple aromatic groups. One of the more useful is the Suzuki reaction where
aryltriflates or aryl bromides such as compound 6 are coupled with arylboronic acids (ArB(OH)2 in the presence of palladium catalysts to give derivatives 7 (see March J. "Advanced Organic Chemistry", 5th ed., John Wiley & Sons, New York, pp. 868 (2001).
SCHEME 4
Suzuki ArX
Na2C03, H20, toluene, ETOH (Ph3P)4Pcl
In an alternative to SCHEME 3, boronic acid 8 is reacted under Suzuki-type conditions with aryltriflates or aryl bromides in the presence of palladium catalysts to give derivatives 7.
SCHEME 5
luene
SCHEME 6
N-substituted aryl and biarylmethylamine intermediates 16 can be prepared by an approach exemplified in SCHEME 6. Reaction of compound 12 with the appropriate substituted amine R3NH2 in a solvent such as THF gives 16.
SCHEME 7
Pd(OAc)2, [iPrO)3P CH302C ,,C02CH3
16 *- l-I Q toluene, 100°C
C02CH3 17
Cyclopentane diacid intermediates containing an exo-methylene group at position 4 can be prepared by a 3+2 cycloaddition reaction of a trimethylenemethane - Pd[0] complex with olefins as described in SCHEME 7. Reaction of dimethyl fumarate 17 with (2-(acetoxymethyl)-3-allyl)trimethylsilane (Aldrich) 17 and a Pd [0] reagent such as [Ph3P]4Pd in THF gives almost exclusively trans diester 18. (see Trost, B. M. J. Am. Chem. Soc, 105, 2315-2325 (1983). If dimethyl maleate is used in this reaction, the cis diester is produced as a 1:1 mix with the trans diester. Compound 18 can be converted to the corresponding diacid by standard hydrolysis methodology and elaborated as described in previous reaction schemes.
SCHEME 8
21 22
Compound 19 prepared as described in SCHEME 7 can be converted to methyl derivative 20 by hydrogenation in a solvent such as EtOH and a catalyst such as 10% Pd/C typically at a pressure of hydrogen of 40 psi. Compound 19 is also converted to cyclopropane derivative 21 by variations of the Simmons - Smith reaction (see March J. "Advanced Organic Chemistry", 5th ed., John Wiley & Sons, New York, pp. 1088 (2001). To a solution of compound 19 in a solvent such as CH2C12 is added diethyl zinc and trifluoroacetic acid followed by di-iodomethane resulting in compound 21. Compound 21 can be converted to compound 22 by hydrogenaolysis in a solvent such as acetic acid and a catalyst such as platinum oxide.
23
1. Et2Zn, TFA 2. CH -2. CH2CI2
CH302C. 0C02CH
24 25
In SCHEME 9, similar transformations with compound 18 can be accomplished as were described in SCHEME 8. The diester intermediates can be further elaborated as described in earlier schemes.
SCHEME 10
Compound 19 prepared as described in SCHEME 7 can be converted to ketone 26 by a variety of oxidative conditions including ozonolysis. A mild sequence involves reaction of compound 19 with catalytic amounts of osmium tetroxide (OsO4) and sodium metaperiodate (NaI0 ) typically in a solvent mixture of t-butanol, H2O and EtOAc. (see March J. "Advanced Organic Chemistry", 5th ed.,
John Wiley & Sons, New York, pp. 1526 (2001). Ketone 26 is reduced to alcohol 27 with sodium borohydride in CH2C1 and methanol. Various chiral reducing agents can be used to achieve chiral reductions of ketone 26. Alcohol 26 can then be converted to a variety of compounds (ethers, carbamates, esters etc. using commonly practiced procedures.
SCHEME 11
CH302C C02CH3 CH302C .,C02CH3
In SCHEME 11, similar transformations with compound 18 can be accomplished as were described in SCHEME 10. The diester intermediates can be further elaborated as described in earlier schemes.
EXAMPLE 1
Trans-l-(RS)-[(4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)- benzylaminocarbonyl cvclopentane
Step A: 4-(2-aminosulfonylphenyl)benzylamine: Step A-l: 4-methylphenylboronic acid
To a stirred solution of 84g (0.49mol) of 4-bromotoluene in 800mL of diethyl ether at -60°C, was carefully added a solution of 462mL of a 1.7M solution of t-butyl lithium in pentane (0.78mol) and the reaction mixture was stirred at -60°C for lh. To this reaction mixture at -60°C was added a solution of 97g (0.52mol) of tri- isopropyl borate in lOOmL of diethyl ether and the mixture was stirred at -60°C for lh. To the reaction mixture was carefully added 400mL of 2N HCl solution. The layers were separated and the aqueous layer was extracted twice with ether. The combined organic fractions were washed twice with 2N NaOH solution. The combined aqueous fractions, cooled by ice, were carefully acidified with 2N HCl to give a white precipitate which was filtered. The solid was washed with hexanes and dried to the title compound which was used without further purification. Step A-2: T-butyl-2-bromophenylsulfonamide
To a stirred solution of 25.4g of 2-bromophenylsulfonyl chloride (O.lmol) in 200mL of dichloromethane at rt was slowly added 31.5mL of t- butylamine (0.3mol). After stirring for 2h at rt, the reaction mixture was filtered and the filtrate was concentrated to give the title compound. 1H NMR (500 MHz, CDC13) 6 8.18 (dd, IH, J=\ and 8 Hz), 7.73 (dd, IH, 7=1 and 8 Hz), 7.46 (dt, 1 H, 7=1.5 and 8 Hz), 7.38 (dt, IH, 7 = 1.5 8 Hz). Step A-3: 4-(2-T-butylaminosulfonylphenyl)toluene. A mixture of 19. lg (O.065mol) of t-butyl-2-bromophenylsulfonamide,
11.7g (0.085mol) of 4-methylphenylboronic acid, 15.3g (0.14mol) of K2C03 in 400mL of toluene, 200mL of ethanol and 80mL of H20 was heated at 80°C for 30min to degas the reaction mixture. To the reaction mixture was added 1.51g (0.0013mol) of [Ph3P]4Pd. After stiπing at 80°C for 3h, the reaction mixture was cooled and the layers were separated. The organic fraction was washed three times with H2O, once with sat'd NaCl solution (brine), dried over MgS0 and filtered. The filtrate was concentrated to -lOOmL whereupon crystals began to form. To the mixture was added 400mL of hexanes and the mixture was allowed to sit 12h at 4°C. The crystals were isolated by filtration, washed with hexanes and dried to give the title compound. Step A-4: 4-(2-T-butylaminosulfonylphenyl)benzyl bromide
A mixture of lOg (0.033mol) of 4-(2-t-butylaminosulfonyl phenyl)toluene, 5.9g (0.03mol) of N-bromosuccinimide, 0.081g (0.0005mol) of AIBN (2,2'-azobisisobutyronitrile) in 8mL of acetic acid and lOOmL of dichloromethane was heated at reflux for 24h. The reaction mixture was washed twice with H2O, dried over MgSO4 , filtered and the filtrate was concentrated. The residue was purified by
chromatography (silica, 5:95, EtOAc: hexanes) to give the title compound. 1H NMR (500 MHz, CD3OD) δ 8.11 (dd, IH, 7=1 and 8 Hz), 7.61 (dt, IH, 7= 1.5 and 8 Hz), 7.53 (dt, IH, 7=1.5 and 8 Hz), 7.46 (AA'BB', 4H, 7=8 and 21 Hz), 7.33 (dd, IH, 7= 1 and 8 Hz), 4.63 (s, 2H), 1.02 (s, 9H). Step A-5: 4-(2-T-butylaminosulfonylphenyl)benzylazide
A mixture of 5.55g (0.0145mol) of 4-(2-t-butylaminosulfonylphenyl) benzyl bromide and 1.89g (0.029mol) of sodium azide in 80mL of DMSO was stirred for 18h at rt. To the reaction mixture was carefully added IL of H2O. The mixture was extracted twice with ether and the combined organic fractions were dried (MgSO4) filtered and the filtrate was concentrated to give the title compound which was used without further purification. Step A-6: 4-(2-T-butylaminosulfonylphenyl)benzylamine
A solution of 4.8g (0.014mol) of 4-(2-t-butylaminosulfonylphenyl) benzyl azide, 7.35g (0.028mol) of triphenylphosphine in 50mL of THF and 5mL of H2O was stirred for 18h at rt. The reaction mixture as concentrated and the residue was purified by chromatography (silica, first with 5: 95 CH3OH: CH2C12, then 5: 95: 0.1 CH3OH: CH2C12: NH4OH) to give the title compound. 1H NMR (500 MHz, CD3OD) δ 8.11 (dd, IH, 7=1 and 8 Hz), 7.60 (dt, IH, 7=1.5 and 8Hz), 7.51 (dt, IH, 7=1.5 and 8 Hz), 7.42 (AA'BB', 4H, 7=8.5 and 15.5 Hz), 7.31 (dd, IH, 7=1 and 8 Hz), 3.87 (s, 2H), 1.02 (s, 9H).
Step A-7: 4-(2-aminosulfonylphenyl)benzylamine
A solution of 4.2g (0.0132mol) of 4-(2-t-butylaminosulfonylphenyl) benzylamine in 20mL of trifluoroacetic acid (TFA) was heated at reflux for 2h whereupon it was concentrated to give 4.8g of an off-white solid. The residue was stirred for 2h in lOOmL of a sat'd K CO3 solution. The reaction mixture was extracted with a 2:8 mixture of methanol and dichloromethane. The combined organic fractions were dried (Na2SO4) filtered and the filtrate was concentrated to give the title compound. 1H NMR (500 MHz, CD3OD) δ 8.10 (dd, IH, 7=1 and 8 Hz), 7.56 (dt, IH, 7=1.5 and 7.5 Hz), 7.50 (dt, IH, 7=1.5 and 7.5 Hz), 7.40 (AA'BB', 4H, 7=8 and 14 Hz), 7.28 (dd, IH, 7=1 and 8 Hz), 3.83 (s, 2H).
Step B: trans-l-(RS)-[4-(2-Aminosulfonylphenyl)1-benzylaminocarbonyl-2-
(SR)-carboxycyclopentane
To a solution of 0.94g (5.94mmol) of trans-DL-cyclopentane dicarboxylic acid (Aldrich Chemical Co.) in lOmL of THF at 0°C was added 0.96g (5.94mmol) of carbonyldiimidazole and the reaction mixture was warmed to rt, then
heated at reflux for lh. The reaction mixture was cooled to 50°C and to it was added 1.42g (5.4mmol) of 4-(2-aminosulfonylphenyl)benzylamine and the reaction mixture was heated at reflux for lh. The reaction mixture was cooled to rt, diluted with H2O and the pH was reduced to pH=12 with 10% NaOH solution. The mixture was washed twice with CH2C12. The aqueous fraction was made acidic with 3N HCl and was extracted three times with EtOAc. The organic fractions were dried (MgSO ), filtered and the filtrate was concentrated to give the title compound. 1H NMR (CD3OD) δ 8.43 (m, IH), 8.10 (dd, IH, 7=1 and 8 Hz), 7.60 (dt, IH, 7=1.5 and 8 Hz), 7.50 (dt, IH, 7=1.5 and 8 Hz), 7.12-7.39 (m, 5H), 4.41 (AA'BB', 2H, 7=14 and 34 Hz), 2.97-3.12 (m, 2H), 2.12 (m, 2H), 1.69-1.94 (m, 4H).
Step C: trans- 1 -(RS)-[4-(2-Aminosulfonylphenyl)l -benzylaminocarbonyl-2-
(SR)-benzylaminocarbonylcyclopentane To a solution of 0.05g (0.12mmol) of l-(RS)-(4-(2- aminosulfonylphenyl)-benzylamino carbonyl-2-(SR)-carboxycyclopentane, 0.034g (0.24mmol) of N-hydroxybenzotriazole (HOBt) and 0.046mL (0.24mmol) of diisopropylethylamine in 2mL of dichloromethane was added 0.1 lg (0.24mmol) of benzotriazol-l-yloxytris(dimethylamino) phosphonium hexafluorophosphate (BOP reagent) and 0.027g (0.24mmol) of benzylamine and the reaction was stirred for 30min at rt. The reaction mixture was then diluted with dichloromethane and was washed twice with H2O once with brine solution and was dried (MgSO4) filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 3: 2, ethyl acetate: hexanes) to give the title compound. 1H NMR (CD3OD) δ 8.38 (m, IH), 8.12 (dd, IH, 7=1 and 8 Hz), 7.59 (dt, IH, 7=1.5 and 8 Hz), 7.49 (dt, IH, 7=1.5 and 8 Hz), 7.39-7.22 (m, 8H), 7.21 (dd, IH, 7=1 and 8 Hz), 4.19 (m, 4H), 3.0 (m, 2H), 2.05 (m, 2H), 1.81 (m, 4H). Mass Spectrum (ESI) m/e 492 M+l .
EXAMPLE 2
trans-l-(RS)-[4-(2-an--dnosulfonylphenyl)1-benzylaminocarbonyl-2-(SR)-[4-(thien-2- yl -thien-2-vHmethylaminocarbonyl cyclopentane
Step A: [4-(Thien-2-yl -thien-2-yllmethylamine:
Step A-l: r4-(Thien-2-yl)-thien-2-vnmethanol
To a stirred solution of 21g (0.13mol) of 2,2'-bithiophene (Aldrich) in 250mL of THF at -78°C, was added 79mL of n-butyl lithium (1.6M solution on hexanes, 0.13mol) over a period of 30min. After stirring for 3h at -78°C, 4.55g (0.15mol) of paraformaldehyde was added and the reaction mixture was allowed to slowly warm to rt. After stirring at rt for 18h, the reaction mixture was partitioned between H2O and ethyl acetate. The aqueous layer was extracted twice with EtOAc and the combined organic fractions were concentrated. The residue was purified by chromotography (silica, 3:7 EtOAc: hexanes) to give the title compound. Step A-2: r4-(Thien-2-yl -thien-2-yllmethylazide
A solution of 0.5g (0.00255mol) of [4-(thien-2-yl)-thien-2- yl]methanol, 0.824mL (0.31mol) of diphenylphosphorylazide (DPP A), 0.48mL (0.0031mol) of diethylazodicarboxylate (DEAD) and 0.8g (0.0031mol) of triphenylphosphine in lOmL of THF was stirred at rt for 18h. The reaction mixture was diluted with dichloromethane, washed three times with H2O, once with brine solution, dried (MgSO4) filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 5: 95, EtOAc: hexanes to give the title compound. Step A-3: [4-(Thien-2-yl)-thien-2-vnmethylamine
A mixture of 2.78g (0.0126mol) of [4-(thien-2-yl)-thien-2- yl]methylazide and 4.95g (0.019mol) of triphenylphosphine in 20mL of THF and 2mL of H2O was stirred at rt for 18h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, 5: 95: 0.1, EtOAc: hexanes: NHjOH to give the title compound. 1H NMR (500MHz, CD3OD) δ 7.28 (dd, IH, 7=1 and 5 Hz), 7.15 (dd, IH, 7= 1 and 4 Hz), 7.03 (m, 2H), 6.88 (d, IH, 4 Hz). Step B: Trans-l-(SR)-[4-(thien-2-yl -thien-2-vnmethylamino- carbonylcyclopentane-2-(RS)-carboxylic acid To a stirred solution of O.lg (0.63mmol) of trans-l,2-cyclopentane carboxylic acid in 2mL of THF at rt was added a solution of 0.107g (0.63mmol) of carbonyldiimidazole (CDI) in 2mL of THF and 2mL of CH2C12. After stirring at rt for 30min., a solution of O.lg (0.5mmol) of [4-(thien-2-yl)-thien-2-yl]methylamine dissolved in lmL of CH2C12 was added and the reaction mixture was stirred for 20h. The reaction mixture was diluted with CH2C12 and lOmL of a 10% aqueous NaHSO solution. The aqueous layer was extracted with CH2C1 and the combined organic
fractions were concentrated and purified by chromatography (silica, 1: 10 CH3OH: CH2C12) to give the title compound which was used without further purification. Step C: Trans-l-(RS)-r(4-(2-aminosulfonylphenyl)1-benzylaminocarbonyl-2-
(SR)-[4-(thien-2-yl)-thien-2-yllmethylaroinocarbonyl cyclopentane A solution of 0.1 lg (0.33mmol) of trans-l-(SR)-[4-(thien-2-yl)-thien-
2-yl]methylaminocarbonylcyclopentane-2-(RS)-carboxylic acid, 0.129g (0.49mmol) of [4-(2-aminosulfonylphenyl)]benzylamine (Example 1), 0.34g (0.66mmol) of benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (pyr-BOP) and 0.57mL of diisopropylethylamine in lOmL of THF and lmL of DMF was stirred at rt for 2.5h. The reaction mixture was concentrated and redissolved in 15mL of CH2C12 and lOmL of a 10% aqueous NaHSO4 solution. The aqueous layer was extracted with CH2C12 and the combined organic fractions were dried (Na2SO ), filtered and the filtrate was concentrated. The residue was purified by chromatography (HPLC YMC- Pack Pro-C18; 90: 10: 0.1 H2O: CH3CN: TFA to 100: 0.1 CH3CN: TFA) to give the title compound as a light pink solid. 1H NMR (500MHz, CD3OD) δ 8.08 (dd, IH, 7=1 and 8 Hz), 7.56 (dt, IH, 7=1.5 and 8Hz), 7.49 (dt, IH, J=1.5 and 8 Hz), 7.32 (m, 2H), 7.24 (m, 3H), 7.10 (m, IH), 6.97 (m, 3H), 6.86 (m, IH), 4.49 (AA'BB', 2H, 7= 6 and 44 Hz), 4.41 (AA'BB', 2H, J=16 and 26Hz), 2.97 (m, 2H), 2.05 (m, 2H), 1.82 (m, 4H). Mass Spectrum (ESI) m/e 580.3 M+l.
The following Examples were prepared according to procedures that are described in Examples 1 or 2. Synthetic procedures will be provided for intermediates that were not commercially available.
EXAMPLE 3
trans-l-(RS)-[4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(RS)-(4-(2- aminosulfonylphenyD-benzylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 647.3 M+l.
EXAMPLE 4
trans-l-(RS)-[4-(thien-2-yl)-thien-2-yllmethylaminocarbonyl -2-(SR)-r4-(thien-2-yl)- thien-2-yllmethylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 513.04 M+l.
EXAMPLE 5
trans-l-(RS)-[4-(2-Methylsulfonylaminophenyl)l-benzylaminocarbonyl-2-(SR)-[4- (thien-2-yl)-thien-2-ynmethylaminocarbonyl cyclopentane
Step A: 4-(2-aminophenyl)benzylamine: The title compound was prepared as described in Example 1, Step A with the exception that 2-nitrobromobenzene is used in Step A-3 of Example 1. The nitro group is subsequently hydrogenated to give the title compound. Step B. l-(RS)-r4-(2-aminophenyl)l-benzylaminocarbonyl-2-(SR)-[4-(thien-2- yl)-thien-2-yllmethylaminocarbonyl cyclopentane The title compound is prepared from l-(SR)-[4-(thien-2-yl)-thien-2- yl]methylaminocarbonylcyclopentane-2-(RS)-carboxylic acid and 4-(2- aminophenyl)benzylamine as described in Example 2, Step C. Step C. trans-l-(RS)-[4-(2-Methylsulfonylaminophenyl)1- benzylaminocarbonyl-2-(SR)-[4-(thien-2-yl)-thien-2- yllmethylaminocarbonyl cyclopentane
To a solution of 0.012g (0.0233mmol) of l-(RS)-[4-(2-aminophenyl)]- benzyla-minocarbonyl-2-(SR)-[4-(thien-2-yl)-thien-2-yl]methylaminocarbonyl cyclopentane in 2mL of CH2C12 and 0.005.5g (0.046mmol) of pyridine at rt was added 0.0053g (0.046mmol) of methanesulfonyl chloride and the reaction mixture
was stirred at rt for lh. The reaction mixture was purified directly by chromatography to give the title compound. Mass Spectrum (ESI) m/e 594.3 M+l.
EXAMPLE 6
trans-l-(RS)-(3-Phenylprop-l-yl)aminocarbonyl-2-(SR)-(4- benzylpiperidinyDcarbonyl cyclopentane
EXAMPLE 7
trans-l-(RS -r4-(phenethyl)-piperizin-l-yllcarbonyl -2-fSR)-[4-(thien-2-yl)-thien-2- yllmethylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 508.3 M+l.
EXAMPLE 8
trans-l-(RS)-[4-(2-trifluoromethylphenyl)-piperizin-l-yncarbonyl -2-(SR)-[4-(thien- 2-yl)-thien-2-vnmethylaminocarbonyl cyclopentane
EXAMPLE 9
trans-l-(RS -( 5-Fluoro-7-trifuloromethyltetrahydroquinolinyl')carbonyl -2-(SR)-[4- (thien-2-yl)-thien-2-ynmethylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 537.3 M+l.
EXAMPLE 10
trans-l-(RS)-[4-(2-aminosulfonylphenyl)l-(2-fluoro)benzylaminocarbonyl-2-(SR)-[4- (thien-2-yl)-thien-2-ynmethylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 598.3 M+l.
Preparation of 4-(2-aminosulfonylphenyl)-2-fluorobenzylamine Step A-l: 4-(2-aminosulfonylphenyl)benzylamine
The title compound was prepared as described in Example 1, Step A with the exception that 4-methyl-2-fluorophenylboronic acid was used.
EXAMPLE 11
trans-l-(RS)-[4-(2-Methylsulfonylphenyl)l-benzylaminocarbonyl-2-(SR)-r4-(thien-2- yl)-thien-2-yllmethylaminocarbonyl cyclopentane
Mass Spectrum (ESI) m/e 579.3 M+l.
Preparation of 4-(2-methylsulfonylphenyl)benzylamine
Step A-l: 4-(2-methylmercaptophenyl)toluene The title compound was prepared according to procedures described in
Example 1, Step A-3 with the exception that 2-methylmercaptophenybromide was used.
Step A-2: 4-(2-methylsulfonylphenyl toluene
A mixture of 1.52g (7.1mmol) of 4-(2-methylmercaptophenyl)toluene and 4.9g (28.4mmol) of 3-chloroperoxybenzoic acid in lOmL of CH2C12 was stirred for 18h at rt. The solid 3-chlorobenzoic acid was removed by filtration. The filtrate was diluted with CH2C12 and the mixture was washed with sat'd NaHCO3 solution.
The organic fraction was dried (MgSO4), filtered and the filtrate was concentrated to give the title compound used without further purification. Step A-3: 4-(2-methylsulfonylphenyl)benzylamine
4-(2-Methylsulfonylphenyl)toluene was converted to the title compound as described in example 1, Steps A-4 to A-6.
EXAMPLE 12
trans-l-(RS)-[(4-benzyl)piperidin-l-vncarbonyl-2-(SR)-[4-(thien-2-yl -thien-2- yllmethylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 493.2 M+l.
EXAMPLE 13
trans-l-(RS)-[4-(pyrid-4-ylmethyl)piperidin-l-yl1carbonyl-2-(SR)-[4-(thien-2-yl)- thien-2-yllmethylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 495.3 M+l.
EXAMPLE 14
trans-l-(RS)-(4-phenylbut-l-yl aminocarbonyl-2-(SR -r4-(thien-2-yl)-thien-2- yllmethylaminocarbonyl cyclopentane Mass Spectrum (ESI) m e 467.4 M+l.
EXAMPLE 15
trans- 1 -(RS)- r2-(4-methoxyphenyl)eth- 1 -yll aminocarbonyl-2-(SRVr4-f thien-2-ylV thien-2-yllmethylaminocarbonyl cyclopentane Mass Spectrum (ESI) m e 469.3 M+l .
EXAMPLE 16
trans-l-(RS)-[4-(2-a----ninosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)-(4-fluoro)- benzylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 510.4 M+l.
EXAMPLE 17
trans-l-(RS)-[4-(2-aminosulfonylphenyl)1-benzylaminocarbonyl-2-(SR)-(4-chluoro)- benzylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 526.3 M+l.
EXAMPLE 18
trans-l-(RS)-r4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)-(4-methoxy)- benzylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 522.2 M+l .
EXAMPLE 19
trans-l-(RS)-[4-(2-aminosulfonylphenyl 1-benzylaminocarbonyl-2-(SR)-(2- trifluoromethvD-benzylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 560.4 M+l.
EXAMPLE 20
trans-l-(RS)-[4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)-(4-methyl)- benzylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 506.4 M+l.
EXAMPLE 21
trans-l-(RS)-[4-(2-an-unosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)-(4-bromo)- benzylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 572.3 M+l .
EXAMPLE 22
trans-l-(RS -[4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)- pyrrolidinocarbonyl cyclopentane Mass Spectrum (ESI) m/e 456.4 M+l.
EXAMPLE 23
trans-l-(RS)-[4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)- piperdinylcarbonylcyclopentane
Mass Spectrum (ESI) m/e 470.4 M+l.
EXAMPLE 24
trans-l-(RS)-r4-(2-aniinosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)-(furan-2- vDmethylaminocarbonylcvclopentane
EXAMPLE 25
trans-l-(RS -[4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)-(pyrid-3- yDmethylaminocarbonylcyclopentane
EXAMPLE 26
trans-l-(RS)-[4-(2-a-minosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)-(3- thrifluoromethvD-benzylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 560.3 M+l.
EXAMPLE 27
trans-l-(RS)-[4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)-(2,3- dichloro)-benzylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 560.2 M+l.
EXAMPLE 28
trans-l-(RS)-[4-(2-aminosulfonylphenyl l-benzylaminocarbonyl-2-(SR)-(naphth-l- vDmethylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 542.3 M+l.
EXAMPLE 29
trans-l-(RS)-[4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)[2-(indol-3- yl)eth- 1 -ylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 545.3 M+l.
EXAMPLE 30
trans-l-(RS)-[4-(2-aminosulfonylphenyl)1benzylaminocarbonyl-2-(SR)-(4-phenyl)- benzylaminocarbonyl cyclopentane
EXAMPLE 31
trans-l-(RS -[4-(2-aminosulfonylphenyl l-benzylaminocarbonyl-2-(SR)-(pyrid-4-yl)- methylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 493.4 M+l.
EXAMPLE 32
trans-l-(RS)-r4-(2-aminosulfonylphenyl)1-benzylaminocarbonyl-2-(SR)-(3,5- dichloro)-benzylaminocarbonyl cyclopentane
EXAMPLE 33
trans-l-(RS)-[4-(2-aminosulfonylphenyl)1-benzylaminocarbonyl-2-(SR)-(4-nitro)- benzylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 537.2 M+l.
EXAMPLE 34
trans-l-(RS -[4-(2-aminosulfonylphenyl l-benzylaminocarbonyl-2-(SR)-(4- dimethylamino')-benzylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 535.3 M+l.
EXAMPLE 35
trans-l-(RS)-[4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)-(4-amino)- benzylaminocarbonylcyclopentane
EXAMPLE 36
trans-l-(RS)-[4-(2-aminosulfonylphenyl)1-benzylaminocarbonyl-2-(SR)-(indan-l- yDmethylaminocarbonylcyclopentane
EXAMPLE 37
trans-l-(RS)-[4-(2-aminosulfonylphenyl)1-benzylaminocarbonyl-2-(SR)-(2,4- difluoro -benzylaminocarbonylcyclopentane
EXAMPLE 38
trans-l-(RS)-r4-(2-aminosulfonylphenyl)1-benzylaminocarbonyl-2-(SR)-r2-(4- fluoro)phen1eth-l-ylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 524.4 M+l.
EXAMPLE 39
trans-l-(RS')-[4-(2-aminosulfonylphenyl)1-benzylaminocarbonyl-2-(SR)-(2,6- difluoro)-benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 528.3 M+l.
EXAMPLE 40
trans-l-(RS)-[4-(2-aminosulfonylphenyl)1-benzylaminocarbonyl-2-(SR)-(3,5- methylenedioxy)-benzylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 536.4 M+l.
EXAMPLE 41
trans-l-(RS)-[4-(2-aminosulfonylphenyl)1-benzylaminocarbonyl-2-(SR)-(4- benzyDpiperidinylcarbonyl cyclopentane Mass Spectrum (ESI) m/e 560.5 M+l.
EXAMPLE 42
trans-l-(RS)-r4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(SR -(4- methoxycarbonyD-benzylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 550.3 M+l.
EXAMPLE 43
trans-l-(RS)-[4-(2-aminosulfonylphenyl 1-benzylaminocarbonyl-2-(SR)-(4-carboxy)- benzylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 536.3 M+l.
EXAMPLE 44
trans-l-(RS)-[4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)-(3,5- dimethoxy)-benzylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e 552.4 M+l.
EXAMPLE 45
trans-l-(RS)-[4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)-(4-methoxy)- benzylaminocarbonyl cyclopentane
EXAMPLE 46
trans-l-(RS)-(4-(2-aminosulfonylphenyl))-benzylaminocarbonyl-2-(SR)-(4-trifluoro methoxy)-benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 576.3 M+l.
EXAMPLE 47
trans-l-(RS)-r4-(2-aminosulfonylphenyl l-benzylaminocarbonyl-2-(SR)-(2-chloro)- benzylaminocarbonylcyclopentane
Mass Spectrum (ESI) m/e 560.3 M+l.
EXAMPLE 48
trans-l-(RS)-[4-(2-aminosulfonylphenyl)1-benzylaminocarbonyl-2-(SR)-(4-bromo - benzylaminocarbonylcyclopentane
Mass Spectrum (ESI) m/e 558.3 M+l.
EXAMPLE 49
trans-l-(RS)-[4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)-(3-bromo - benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 570.5 M+l.
EXAMPLE 50
trans-l-(RS)-r4-(2-aminosulfonylphenyl)1-benzylaminocarbonyl-2-(SR)- tetrahydroquniolinylcarbonylcyclopentane
Mass Spectrum (ESI) m/e 518.3 M+l.
EXAMPLE 51
trans-l-(RS)-r4-(2-aminosulfonylphenyl)]-benzylaminocarbonyl-2-(SR)-[2-(4- phenox ylphenl eth- 1 -ylaminocarbonyl cyclopentane Mass Spectrum (ESI) m/e598.3 M+l.
EXAMPLE 52
trans-l-(RS)-r4-(2-aminosulfonylphenyl)1-benzylaminocarbonyl-2-(SR)-[2-(4- bromo)phen1eth- 1 -ylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 586.3 M+l.
EXAMPLE 53
EXAMPLE 54
trans-l-(RS)-[4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)-(4- phenylthiazol-2-yl)methylaminocarbonylcyclopentane
Mass Spectrum (ESI) m e 575.3 M+l.
EXAMPLE 55
trans-l-(RS)-[4-(2-aminosulfonylphenyl)1-benzylaminocarbonyl-2-(SR)- (benzimidazol-2-yl)methylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 532.4 M+l.
EXAMPLE 56
trans-l-(RS)-r4-(2-aminosulfonylphenyl)1-benzylaminocarbonyl-2-(SR)-(thiazol-4- vDmethylaminocarbonylcyclopentane
Mass Spectrum (ESI) m/e 499.3 M+l.
EXAMPLE 57
trans-l-(RS)-[4-(2-aminosulfonylphenyl)1-benzylaminocarbonyl-2-(SR)-ri-(furan-2- yDeth- 1 -ylaminocarbonylcyclopentane
EXAMPLE 58
trans-l-(RS)-[4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)-(3,5- difluoro)-benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 528.3 M+l.
EXAMPLE 59
trans-l-(RS)-[4-(2-aminosulfonylphenyl)l-benzylarninocarbonyl-2-(SR)-(furan-3-yl) methylaminocarbonylcyclopentane
Mass Spectrum (ESI) m/e 482.3 M+l.
EXAMPLE 60
trans-l-(RS -r4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)-(2,5- difluoro)-benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 528.3 M+l .
EXAMPLE 61
trans-l-(RS)-[4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)- (benzthiaphen-3-yl)methylaminocarbonylcyclopentane
EXAMPLE 62
trans-N-methyl- 1 -(RS)- F4-(2-aminosulfonylphenyl)1 -benzylaminocarbonyl-2-(SR)- (thiazol-2-yl)methylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 513.3 M+l.
EXAMPLE 63
trans-l-(RS)-[4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)-4-(4- trifluoromethylphenvDpiperidin- 1 -ylcarbonylcyclopentane Mass Spectrum (ESI) m/e 614.3 M+l.
Preparation of 4-(4-trifluoromethylphenyl)piperidine Step A-l: 4-Trifluoromethylphenylboronic acid
To a solution of lmL (7.1mmol) of 4-trifluoromethylphenyl bromide (JRD Fluoro Chemical LTD) in 20mL of THF at -78°C in a nitrogen atmosphere was added 7.1mL (8.5mmol) of nBuLi (1.6M in THF). After stirring for30 min, 2.5mL (10.65mmol) of triisopropyl borate (Aldrich) was slowly added and the reaction mixture was slowly warmed to rt. After lh at rt, the reaction mixture was concentrated and dissolved in lOmL of a mixture of acetic acid and H2O (2: 1). After stirring for 3h, the reaction mixture was concentrated and dissolved in lOOmL of ethyl acetate. The solution was washed with sat'd NaCl solution, and the organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated to give the title compound.
Step A-2: 1 -t-Butoxycarbonyl-4-trifluoromethylsulfonyloxy- 1,2,3,6- tetrahydropyridine
To a solution of 14mL of LDA (2M in THF) at -78°C in a nitrogen atmosphere was slowly added 5g (25mmol) of 4-t-butoxycarbonyl piperidone. The reaction mixture was warmed to 0°C and stirred for 3h. The reaction mixture was then cooled to -78°C and to it was slowly added a solution of 9.82g (27.5mmol) of (CF3SO2)2 Ph (Aldrich) in 50mL of THF. The reaction mixture was slowly warmed to 0°C and stirred for 12h. The reaction mixture was concentrated, redissolved in CH2O2 and filtered though a plug of alumina and the filtrate was concentrated to give the title compound.
Step A-3: 1 -t-Butoxycarbonyl-4-(4-trifluoromethylphenyl)- 1 ,2,3 ,6- tetrahydropyridine
To a solution of 0.66g (2mmol) of l-t-butoxycarbonyl-4- trifluoromethylsulfonyloxy-l,2,3,6-tetrahydropyridine and 0.57g (6mmol) of 4- trifluoromethylphenylboronic acid in 6 mL of DME (dimethoxyethane) was added 2.5mL (5mmol) of a 2M solution of Na2CO3, 0.24g (6mmol) of LiCl and 0.115g (O.lmmol) of Pd(PPh3)4 and the reaction mixture was heated at reflux for 4h. The reaction mixture was concentrated and dissolved in lOmL of CH2CI2. The solution was washed with sat'd NaHCO3 solution, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes: ethyl acetate, 10:1) to give the title compound. Step A-4: 4-(4-Trifluoromethylphenyl)- 1 ,2,3 ,6-tetrahydropyridine
A solution of 0.4g (0.112mmol) of l-t-butoxycarbonyl-4-(4- trifluoromethyl phenyl)- 1, 2,3, 6-tetrahydropyridine in lmL of TFA and 3mL of CH2CI2 was stirred at rt for lh. The reaction mixture was then concentrated. A
mixture of the residue and O.lg of 10% Pd/C in 20mL of MeOH was hydrogenated at 45psi for 4h. The reaction mixture was filtered though a plug of celite and concentrated to the title compound. Step A-5. 4-(4-Trifluoromethylphenyl)piperidine
A mixture of 0.54g (1.22mmol) of 4-(4-trifluoromethylphenyl)-l,2,3,6- tetrahydropyridine and O.lg of 10% Pd/C in 20mL of MeOH was stirred under a hydrogen atmosphere at 45psi for 4h. The reaction mixture was filtered through a thin pad of celite eluting with CH C12. The filtrate was concentrated to give the title compound.
EXAMPLE 64
trans-l-(RS)-r4-(2-aminosulfonylphenyl)1-benzylaminocarbonyl-2-(SR)-(4- phenyDpiperidin-l-ylcarbonylcyclopentane Mass Spectrum (ESI) m/e 546.4 M+l.
Preparation of 4-phenylpiperidine:
A mixture of 20.5g (104.9mmol) of 4-phenyltetrahydropyridine hydrochloride (Aldrich) and 0.5g of 10% Pd/C in 40mL of H2O and 160mL of EtOH was stirred under hydrogen at 45psi for 2h. The reaction mixture was then filtered though a thin pad of celite eluting with EtOH and H2O. The filtrate was concentrated and the residue was stirred in 75mL of ether. To it at 0°C was added 5g of solid NaOH. The layers were separated and the aqueous layer was extracted with ether. The combined organic fractions were washed with sat'd NaCl solution, dried over
Na2SO4, filtered and the filtrate was concentrated. The residue was crystalized from cold heptane to give the title compound.
EXAMPLE 65
trans-l-(RS)-[4-(2-aminosulfonylphenyl)l-benzylaminocarbonyl-2-(SR)-4-(4-fluoro- phenyDpiperidin- 1 -ylcarbonylcyclopentane Mass Spectrum (ESI) m/e 564.3 M+l.
4-(4-fluorophenyl)piperidine was prepared according to procedures described in Example 63)
EXAMPLE 66
trans-l-(RS)-[4-(2-aminosulfonylphenyl)1-benzylaminocarbonyl-2-(SR)-4-(4-chloro- phenyDpiperidin- 1 -ylcarbonylcyclopentane
4-(4-chlorophenyl)piperidine was prepared according to procedures described in Example 63)
EXAMPLE 67
trans- 1 -(RS)- [4-(2-aminosulfonylphenyD1-benzylaminocarbonyl-2-(SR)-(3 ,4- difluoro)-benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 528.3 M+l.
EXAMPLE 68
trans-l-(RS)-[4-(2-aminosulfonylphenyDl-benzylaminocarbonyl-2-(SR)-(2-chloro)- benzylaminocarbonylcyclopentane
Mass Spectrum (ESI) m/e 526.2 M+l.
EXAMPLE 69
trans-l-(RS)-r4-(2-aminosulfonylphenvD1-benzylaminocarbonyl-2-(SR)-(3,5-bis- trifluoromethvD-benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 628.2 M+l .
EXAMPLE 70
trans-l-(RS -[4-(2-aminosulfonylphenyD1-benzylaminocarbonyl-2-(SR)-(3-fluoro)- benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 510.2 M+l.
EXAMPLE 71
trans-l-(RS)-[4-(2-aminosulfonylphenvDl-benzylaminocarbonyl-2-(SR)-(3-nitro)- benzylaminocarbonylcvclopentane
Mass Spectrum (ESI) m/e 537.2 M+l.
EXAMPLE 72
trans-l-(RS)-r4-(2-a-minosulfonylphenvDl-benzylaminocarbonyl-2-(SR)-(3-methoxy)- benzylaminocarbonylcyclopentane
EXAMPLE 73
trans-l-(RS)-[4-(2-aminosulfonylphenvDl-benzylaminocarbonyl-2-(SR)-(3-chloro)- benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 526.2 M+l .
EXAMPLE 74
trans-l-(RS)-[4-(2-aminosulfonylphenyDl-benzylaminocarbonyl-2-(SR)-(4-phenoxy - benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 584.3 M+l.
EXAMPLE 75
trans-l-(RS)-[4-(2-aminosulfonylphenvDl-benzylaminocarbonyl-2-(SR)-(3- trifluoromethoxy)-benzylaminocarbonylcyclopentane
EXAMPLE 76
EXAMPLE 77
EXAMPLE 78
trans-l-(RS)-N-methyl-r4-(2-aminosulfonylphenyD1benzylaminocarbonyl-2-(SR)-[4- (thien-2-yl)-thien-2-yllmethylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 594.3 M+l.
Preparation of N-methyl-4-(2-aminosulfonylphenyl)benzylamine: Step A-l: N-methyl-4-(2-T-butylaminosulfonylphenyDbenzylamine A solution of lg (2.6mmol) of 4-(2-t-butylaminosulfonylphenyl)benzyl bromide [Example 1] in 25mL of THF was saturated with methylamine gas and the reaction mixture was stirred at rt for 3h. The reaction mixture was partitioned between EtOAc and Na C03 solution. The aqueous fraction was extracted twice with EtOAc and the combined organic fractions were dried (K2C03), filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 2: 3, EtOAc: hexanes, then 1: 10, CH2OH: CH C12) to give the title compound. Step A-2: N-methyl-4-(2-aminosulfonylphenyDbenzylamine:
The title compound was prepared from N-methyl-4-(2-t- butylaminosulfonylphenyl)benzylamine as described in Example 1, Step A-7.
EXAMPLE 80
trans-l-(RS)-[4-(2-aminosulfonylphenyDl-benzylaminocarbonyl-2-(SR)-N-methyl-r4- (thien-2-yl)-thien-2-yl1methylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 594.3 M+l.
Preparation of N-methyl-[4-(thien-2-yl)-thien-2-yl]methylamine: Step A-l: 2-trimethylstannylthiophene To a stirred solution of 200mL (0.2 mol) of a IM solution of 2- thienyllithium in THF (Aldrich) in 400mL of THF at -40°C was added 40g (0.2mol) of trimethyltin chloride over lOmin. The reaction was mixture was allowed to warm to rt and was stirred for 2h. The reaction was quenched with a sat'd solution of NH-4CI and the reaction mixture was concentrated. The residue was partitioned between H20 and ether. The organic fraction was washed twice with brine, dried (Na2S04), filtered and the filtrate was concentrated to give the title compound which was used as is. Step A-2: 4-[(thien-2-yl)-thien-2-yl1carboxaldehvde
A mixture of 21.5mL (O.lδmol) of 4-bromo-2- thiophenecarboxaldehyde (Aldrich), 44.4g (0.18mol) of 2-trimethylstannylthiophene and 2.1g (0.0018mol) of tefralάs(triphenylphosphine)palladium (0) in 600mL of dry toluene was heated at reflux for 18h. The reaction mixture was cooled and diluted with 2N HCl. The mixture was neutralized with sat'd NaHC03 solution. The organic fraction was washed with brine, dried (MgS04), filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 1:9, ethyl acetate: hexanes) to give the title compound. Step A-3: N-methyl-[4-(thien-2-vD-thien-2-yllmethylamine
A solution of 0.28g (1.44mmol) of 4-[(thien-2-yl)-thien-2- yl]carboxaldehyde in lOmL of CH C1 at 0°C was saturated with methylamine gas. To the mixture was added 1.5g (7.1mmol) of NaB(OAc)3H and 30mg (0.5mmol) of acetic acid and the reaction mixture was stirred 12h at rt. To the mixture was added
20mL of sat'd Na2C03 solution and the mixture was extracted. The aqueous layer was extracted with EtOAc, and the combined organic fractions were dried (K2C03), filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 4:6, hexanes: EtOAc) to give the title compound.
EXAMPLE 81
trans-l-(RS)-N-methyl-[4-(2-aminosulfonylphenvDl-benzylaminocarbonyl-2-(SR)-N- methyl-r4-(thien-2-vD-thien-2-yllmethylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 608.3 M+l.
EXAMPLE 82
trans-l-(RS)-[l-(4-(2-aminosulfonylphenvDphenyDleth-l-ylaminocarbonyl-2-(SR)-
[4-(thien-2-yl)-thien-2-yllmethylaminocarbonylcyclopentane
Mass Spectrum (ESI) m/e 594.2 M+l.
Preparation of l-[4-(2-aminosulfonylphenyl)phenyl]eth-l-ylamine: Step A-l: 4-(2-T-butylaminosulfonylphenyDacetophenone
The title compound was prepared from t- butylbromophenylsulfonamide and 4-acetophenoneboronic acid as described in Example 1, Step A-3. Step A-2: 4-(2-T-butylaminosulfonylphenvDacetophenone hydroxamate
A solution of 0.62g (1.78mmol) of 4-(2-t-butylaminosulfonylphenyl) acetophenone, 0.5g (7.1mmol) of hydroxylamine hydrochloride and 2.5g (17.8mmol)
of K2C03 in lOmL of EtOH and 5mL of THF was stirred at 80°C for 72h. To the reaction mixture was added 200mL of EtOAc and it was filtered. The filtrate was concentrated to give the title compound which was carried to the next step. Step A-3: l-[4-(2-T-butylaminosulfonylphenyDphenylleth-l-ylamine
A mixture of 0.6g of 4-(2-t-butylaminosulfonylphenyl)acetophenone hydroxamate and 0.06g of Pd(OH)2 (20% on carbon) in 50mL of CH3OH and lOmL. of EtOAc was hydrogenated at 60psi until the reaction was complete (~48h). The reaction mixture was filtered and the filtrate was concentrated to give the title compound which was carried to the next step. Step A-4: 1 - [4-(2-aminosulf onylphenvDphenyll eth- 1 -ylamine
The title compound was obtained from l-[4-(2-t-butylaminosulfonyl phenyl)phenyl] eth- 1 -ylamine according to procedures described in Example 1, Step A-7. The product was purified by chromatography (silica, 1: 20, (2M NH3 in CH3OH: CH2C12).
EXAMPLE 83
trans- 1 -(RS)- 1 - [4-(2-aminosulf onylphenyD1benzylaminocarbonyl-2-(SR)-[ 1 ~r4- (thien-2-yl)-thien-2-yllleth-l-ylaminocarbonylcyclopentane (isomers A and B)
The isomers were separated by HPLC [YMC-Pack Pro-C18 (Waters) 90: 10: 0.1 H20: CH3CN : TFA to 75: 25: 0.1 CH3CN: H2O: TFA to 100: 0.1 CH3CN: TFA] Isomer A: Mass Spectrum (ESI) m/e 594.4 M+l.
Isomer B: Mass Spectrum (ESI) m/e 594.4 M+l. Preparation of l-[4-(thien-2-yl)-thien-2-yl]eth-l-ylamine Step A-l: 1 -r4-(thien-2-vD-thien-2-vn eth- 1-yl alcohol
To a solution of 0.8g (4.8mmol) of bithiophene (Aldrich) in lOmL of THF at -78°C was added 3mL (4.8mmol) of a solution of 1.6M of n-butyl lithium in hexanes over a 3min period. After stirring at -78°C for 1.5h, 0.3mL (5.3mmol) of
acetaldehyde was added and the reaction mixture was allowed to warm to rt over 2h.
To the reaction mixture was added sat'd NH-4CI solution and EtOAc. The layers were separated and the aqueous fraction was extracted with EtOAc. The combined organic fractions were dried (K2C03), filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 1: 5, EtOAc: hexanes) to give the title compound.
Step A-2: l-[4-(thien-2-vD-thien-2-ylleth-l-ylamine
The title compound was prepared from l-[4-(thien-2-yl)-thien-2-yl]eth- 1-yl alcohol according to procedures described in Example 2, Steps A-2 and A-3.
EXAMPLE 84
trans- l-(RS)-N-methyl-l-(4-(2-aminosulfonylphenyl))benzylaminocarbonyl-2-(SR)- [l-[4-(thien-2-vD-thien-2-yllleth-l-ylaminocarbonylcyclopentane (isomers A and B)
Isomers were separated as described in Example 84.
Isomer A: Mass Spectrum (ESI) m/e 608.32 M+l. Isomer B: Mass Spectrum (ESI) m/e 608.32 M+l.
EXAMPLE 85
trans- 1 -(RS)-N-methyl- 1 -[4-(2-a-minosulfonylphenyl)]benzylaminocarbonyl-2-(SR - (3,5-dichloro)benzylaminocarbonylcyclopentane
EXAMPLE 86
trans-l-(RS)-N-methyl-l-[4-(2-aminosulfonylphenyDlbenzylaminocarbonyl -2-(SRV (4-trifluoromethyDbenzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 590.1 M+l .
EXAMPLE 87
trans-l-(RS)-N-methyl-l-[4-(2-anιinosulfonylphenyl)benzylaminocarbonyl -2-(SR)- (4-trifuoromethoxy)benzylan--ιinocarbonylcyclopentane (isomers A and B)
The individual enantiomers of Example 86 (dl mixture) were separated by HPLC (ChiralCel OJ column, eluent: 20% ethanol in heptane); enantiomer A (fast-moving isomer); enantiomer B (slow-moving isomer) Mass Spectrum (ESI) of each isomer m/e 590.1 M+l.
EXAMPLE 88
trans-l-(RS -N-methyl-l-[4-(2-aminosulfonylphenyDlbenzylaminocarbonyl-2-(SRV (4-methoxy benzylaminocarbonylcvclopentane
EXAMPLE 89
trans-l-(RS)-N-methyl-l-[4-(2-aminosulfonylphenyDlbenzylaminocarbonyl -2-(SR)- (3-trifluoromethoxy)benzylaminocarbonylcyclopentane
EXAMPLE 90
trans-l-(RS)- N-methyl-l-[4-(2-aminosulfonylphenyD1benzylaminocarbonyl-2-(SR)- (3,4-dichloro)benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 574.4 M+l.
EXAMPLE 91
EXAMPLE 93
trans-l-(RS)- N-methyl-l-[4-(2-aminosulfonylphenyD1benzylaminocarbonyl-2-(SR)- benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 506.4 M+l.
EXAMPLE 94
trans-l-(RS)- N-methyl-l-r4-(2-aminosulfonylphenvDlbenzylaminocarbonyl 2-(SR)-
(4-trifluoromethvDbenzylaminocarbonylcyclopentane
Mass Spectrum (ESI) m/e 574.1 M+l.
EXAMPLE 95
EXAMPLE 96
trans- 1 -(RS)-N-methyl- 1 -r4-(2-aminosulf onylphenyl)lbenzylaminocarbonyl-2-(SR)- (4-t-butoxy)benzylaminocarbonvIcvclopentane Mass Spectrum (ESI) m/e 578.2 M+l.
EXAMPLE 97
trans-l-(RS)-N-methyl-l-[4-(2-aminosulfonylphenyD1benzylaminocarbonyl-2-(SR')- (4-trifluoiOethoxy)benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 604.5 M+l.
EXAMPLE 98
EXAMPLE 99
trans-l-(RS)-N-methyl-l-[4-(2-aminosulfonylphenyDlbenzylaminocarbonyl-2-(SR)- (4-trifluoromethylmercapto)benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 604.4 M+l.
EXAMPLE 100
trans-l-(RS)- N-methyl-l-[4-(2-aminosulfonylphenyD1benzylaminocarbonyl-2-(SR)-
(4-trifluoromethylsulfonyl)benzylaminocarbonylcyclopentane
Mass Spectrum (ESI) m/e 638.4 M+l.
EXAMPLE 101
trans-l-(RS)- N-methyl-l-(4-[2-aminosulfonylphenyl)lbenzylaminocarbonyl-2-(SR)- (4-ethoxy)benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 572.4 M+l .
EXAMPLE 102
trans-l-(RS)-(4-bromo)-benzylaminocarbonyl-2-(SR)-[4-(thien-2-vD-thien-2- yllmethylaminocarbonyl cyclopentane
EXAMPLE 103
trans-l-(RS)-[4-(2-trifluoromethylphenyl)l-benzylaminocarbonyl-2-(SR)-[4-(thien-2- yP-thien-2-yHmethylaminocarbonyl cyclopentane
Step A-l: trans-l-(RS)-[4-(2-trifluoromethylpenyDl-benzylaminocarbonyl-2- (SR)-carboxycyclopentane
A mixture of 0.5g (1.5 mmol) of trans- l-(RS)-(4-bromo)- benzylaminocarbonyl-2-(SR)-carboxycyclopentane (prepared according to procedures described in Example 1), 0.44g (2.3mmol) of 2-trifluoromethylphenylboronic acid and 0.061g (0.075mmol) of [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium
(II) in 20mL of EtOH was heated at reflux for 5h. The reaction mixture was concentrated and partitioned between EtOAc and 1 N HCl solution. The aqueous fraction was extracted with EtOAc and the combined organic fractions were dried (MgS04) filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 10: 0.5: 0.1, CH2C12: CH3OH: HOAc) to give the title compound.
Step A-2: trans- 1 -(RS )- [4-(2-trifluoromethylphenvD1 -benzylaminocarbonyl-2- (SRV[4-(thien-2-yD-thien-2-yllmethylaminocarbonyl cyclopentane The title compound was prepared from 1 trans-l-(RS)-[4-(2- trifluoromethylpenyl)]-benzylaminocarbonyl-2-(SR)-carboxycyclopentane and [4-
(thien-2-yl)-thien-2-yl]methylamine according to procedures described in Example 2. Mass Spectrum (ESI) m/e 569.2 M+l.
The following Examples 104 - 120 were prepared according to procedures described in Example 103.
EXAMPLE 104
trans-l-(RS)-r4-(3-trifluoromethylphenyDlbenzylaminocarbonyl-2-(SR)-[4-(thien-2- yD-thien-2-yllmethylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 569.2 M+l.
EXAMPLE 105
trans-l-(RS -[4-(4-trifluoromethylphenyD1benzylaminocarbonyl-2-(SR)-[4-(thien-2- yD-thien-2-yl1methylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 569.2 M+l.
EXAMPLE 106
trans-l-(RS)-[4-(3,5-bis-trifluoromethylphenyD1benzylaminocarbonyl-2-(SR)-[4-
(thien-2-yD-thien-2-yllmethylaminocarbonylcyclopentane
Mass Spectrum (ESI) m/e 637.3 M+l.
EXAMPLE 107
trans-l-(RS)-[4-(2-methoxyphenyDlbenzylaminocarbonyl-2-(SR)-[4-(thien-2-yD- thien-2-vHmethylaminocarbonylcyclopentane
Mass Spectrum (ESI) m/e 531.2 M+l.
EXAMPLE 108
trans-l-(RS -[4-(2-methylphenyl)lbenzylaminocarbonyl-2-(SR)-[4-(thien-2-vD-thien- 2-yllmethylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 515.2 M+l.
EXAMPLE 109
trans-l-(RS)-N-methyl-[4-(2-trifluoiOmethylphenvDlbenzylaminocarbonyl-2-(SR)-[4- (thien-2-yD-thien-2-ynmethylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 583.2 M+l.
EXAMPLE 110
trans-l-(RS)-[4-(2-methoxyphenvDl-benzylaminocarbonyl-2-(SR)-(3,5- dichloro)benzylaminocarbonylcyclopentane
Mass Spectrum (ESI) m/e 511.2 M+l.
EXAMPLE 111
trans-l-(RS)-[4-(2-methylphenvDl-benzylaminocarbonyl-2-(SR -(3,5- dichloro)benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 495.2 M+l .
EXAMPLE 112
trans-l-(RS)-[4-(2-trifluoromethylphenyD1-benzylaminocarbonyl-2-(SR)-(3,5- dichloro)benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 549.2 M+l.
EXAMPLE 113
trans-l-(RS)-[4-(2-aminosulfonylphenvD1-benzylaminocarbonyl-2-(SR)-(4-(2- methoxyphenyDbenzylaminocarbonylcyclopentane
Mass Spectrum (ESI) m/e 598.3 M+l.
EXAMPLE 114
EXAMPLE 115
trans-l-(T S)-[4-(2-aminosulfonylphenyDl-benzylaminocarbonyl-2-(SR)-[4-(2- methylphenyDlbenzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 582.3 M+l.
EXAMPLE 116
trans-l-(RS)-N-methyl-[4-(2-trifluoromethylphenvDl-benzylaminocarbonyl-2-(SR)- (3 , 5 -dichloro)benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 563.2 M+l.
EXAMPLE 117
trans-l-(RS)-N-methyl-[4-(2-trifluoromethylphenvDlbenzylaminocarbonyl-2-(SR')- N- methyl-r4-(2-trifluoromethylphenyD1benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 653.4 M+l.
EXAMPLE 118
EXAMPLE 119
trans-l-(RS)-N-methyl-[4-(2-methylphenyDl-benzylaminocarbonyl-2-(SR -[4-(thien- 2-yD-thien-2-ynmethylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 529.4 M+l.
The following Examples 121-124 were prepared according to procedures that were previously described, with the exception that trans- 1,2- cyclohexane dicarboxylic acid (Aldrich) was used.
EXAMPLE 121
trans-l-(RS)[-4-(2-aminosulfonylphenvDlbenzylaminocarbonyl-2-(SR)-[4-(thien-2- yD-thien-2-vHmethylaminocarbonylcvclohexane Mass Spectrum (ESI) m/e 594.1 M+l.
EXAMPLE 122
teans-l-(RS)-N-methyl-[4-(2-aminosulfonylphenvDlbenzylaminocarbonyl-2-(SR)- (4- trifluoromethoxy)benzylaminocarbonylcyclohexane
Mass Spectrum (ESI) m/e 604.4 M+l.
EXAMPLE 123
trans-l-(RS)-[4-(2-aminosulfonylphenvD1benzylaminocarbonyl-2-(SR)-(4-(2- aminosulfonylphenyD)-benzylaminocarbonylcyclohexane
Mass Spectrum (ESI) m/e 661.25 M+l.
EXAMPLE 124
trans-l-(RS)- )-r4-(thien-2-vD-thien-2-vnmethylaminocarbonyl-2-(SR -[4-(thien-2- vD-thien-2-yllmethylaminocarbonylcyclohexane Mass Spectrum (ESI) m/e 527.04 M+l.
trans-l-(RS)-4-[2-aminosulfonylphenvD1-benzylaminocarbonyl-2-(SR)-(4- trifluoromethoxy)benzylaminocarbonylcyclobutane Mass Spectrum (ESI) m/e 576.5 M+l. trans- 1,2-cyclobutanedicarboxylic acid was obtained from Fluka
The following Examples 126 - 144 were prepared according to procedures that are described in Examples 1 or 2. Synthetic procedures will be provided for intermediates that were not commercially available.
EXAMPLE 126
trans-l-(RS)-(3,5-dichloro)benzylaminocarbonyl-2-(SR)-[4-(thien-2-vD-thien-2- yllmethylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 493.2 M+l.
EXAMPLE 127
trans-l-(RS)-(2-chloro-5-trifluoromethyl)-benzylaminocarbonyl-2-(SR)-(3,5- dichloro)benzylaminocarbonylcyclopentane
Mass Spectrum (ESI) m/e 507.1 M+l.
EXAMPLE 128
trans-l-(RS)-(3-difluoromethyDbenzylaminocarbonyl-2-(SR -(3,5- dichloro)benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 471.2 M+l.
EXAMPLE 129
trans-l-(RS)-(4-trifluoromethvDbenzylaminocarbonyl-2-(SR)-(3,5- dichloro)benzylaminocarbonylcvclopentane
Mass Spectrum (ESI) m/e 473.1 M+l.
EXAMPLE 130
trans-l-(RS)-(4-chloro)benzylaminocarbonyl-2-(SR)-(3,5- dichloro)benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 439.2 M+l .
EXAMPLE 131
trans-l-(RS)-(4-chloro-3-trifluoromethyDbenzylaminocarbonyl-2-(SR)-(3,5- dichloro)benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 507.1 M+l .
EXAMPLE 132
trans-l-(RS)-(3,5-dimethoxy)benzylaminocarbonyl-2-(SR)-(3,5- dichloro)benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 465.2 M+l.
EXAMPLE 133
EXAMPLE 135
EXAMPLE 136
trans-l-(RS)-(3-methyDbenzylaminocarbonyl-2-(SR)-(3,5- dichloro)benzylaminocarbonylcyclopentane
Mass Spectrum (ESI) m/e 419.2 M+l.
EXAMPLE 137
EXAMPLE 138
trans-l-(RS)-(pyrid-2-yDmethylaminocarbonyl-2-(SR)-(3,5-dichloro)benzyl aminocarbonylcyclopentane Mass Spectrum (ESI) m/e 406.1 M+l.
EXAMPLE 139
EXAMPLE 140
trans- 1 -(RS)-(pyrid-4-yl)methylaminocarbonyl-2-(SR)-(3 ,5-dichloro)benzyl aminocarbonylcyclopentane Mass Spectrum (ESI) m/e 406.1 M+l .
EXAMPLE 141
trans-l-(RS)-[2-(3-methoxyphenyD]eth-l-ylaminocarbonyl-2-(SR)-(3,5- dichloro)benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 449.2 M+l.
EXAMPLE 142
trans-l-(RS)-(4-phenyD-benzylaminocarbonyl-2-(SR)-[4-(thien-2-vD-thien-2- yllmethylaminocarbonyl cyclopentane
EXAMPLE 143
trans- 1 -(RS)-(4-phenvDbenzylaminocarbonyl-2-(SR)-(3 ,5-dichloro)benzyl aminocarbonylcyclopentane Mass Spectrum (ESI) m/e 481.1 M+l .
trans-l-(RS)-benzylaminocarbonyl-2-(SR)-(3,5-dichloro)benzyl aminocarbonylcyclopentane
Mass Spectrum (ESI) m/e 405.2 M+l.
EXAMPLE 145
trans- 1 -(RS)-N-ethyl- 1 - [4-(2-aminosulf onylphenyDlbenzylaminocarbonyl -2-(SR)-(4- trifluoromethoxy benzylaminocarbonylcyclopentane
The title compound was prepared according to procedures describe in Example 79. Mass Spectrum (ESI) m/e 604.1 M+l.
The following Examples 146 - 153 were prepared from trans-N- methyl- 1 -(RS)-(4-bromo)-benzylaminocarbonyl-2-(SR)-(4-
trifluoromethoxy)benzylaminocarbonyl cyclopentane according to procedures described in Example 104.
EXAMPLE 146
trans-l-(RS)-N-methyl-l-[4-(2-aminosulfonyl-4-fluorophenyl)lbenzylaminocarbonyl 2-(SR)-(4-trifluoromethoxy)benzylaminocarbonylcvclopentane Mass Spectrum (ESI) m/e 608.4 M+l.
EXAMPLE 147
EXAMPLE 148
trans-l-(RS)-N-methyl-l-[4-(2-aminosulfonyl-5-fluorophenyDlbenzylaminocarbonyl -2-(SR)-(4-trifluoromethoxy)benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 608.3 M+l.
EXAMPLE 149
trans-l-(RS)-N-methyl-l-r4-(2-methylsulfonyl-5-fluorophenyD1benzylaminocarbonyl -2-(SR)-(4-trifluoromethoxy)benzylaminocarbonylcvclopentane Mass Spectrum (ESI) m/e 589.3 M+l.
EXAMPLE 150
EXAMPLE 151
trans-l-(RS)-N-methyl-l-[4-(pyrid-4-vDlbenzylaminocarbonyl -2-(SR)-(4- trifluoromethoxy)benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 512.4 M+l.
EXAMPLE 152
EXAMPLE 153
trans-l-(RS)-N-methyl-l-[4-(benzothiophen-7-vDlbenzylaminocarbonyl -2-(SR)-(4- trifluoromethoxy)benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 567.4 M+l.
The following Examples 154 - 159 were prepared from trans-N- methyl-l-(RS)-(6-bromo)-pyrid-3-ylmethylaminocarbonyl-2-(SR)-(4- trifluoromethoxy) benzylaminocarbonylcyclopentane or trans-N-methyl-l-(RS)-(5- bromo)-pyrid-2-ylmethylaminocarbonyl-2-(SR)-(4- trifluoromethoxy)benzylaminocarbonylcyclopentane according to procedures described in Example 104.
EXAMPLE 154
trans-l-(RS)-N-methyl-l-[6-(2-aminosulfonylphenyDlpyrid-3-ylmethylaminocarbonyl -2-(SR)-(4-trifluoromethoxy)benzylaminocarbonylcyclopentane Mass Spectrum (ESD m/e 591.3 M+l.
EXAMPLE 155
trans-l-(RS)-N-methyl-l-[6-(2-methylsulfonylphenyl)1pyrid-3- ylmethylaminocarbonyl -2-(SR)-(4-trifluoromethoxy) benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 596.3 M+l.
EXAMPLE 156
trans-l-(RS)-N-methyl-l-[6-(2-chloro-4-fluorophenyl)1pyrid-3- ylmethyla inocarbonyl -2-(SR)-(4-trifluoromethoxy) benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 564.1 M+l.
EXAMPLE 157
trans-l-(RS)-N-methyl-l-[5-(2-aminosulfonylphenvDlpyrid-2-ylmethylaminocarbonyl -2-(SR)-(4-trifluoromethoxy)benzylaminocarbonylcvclopentane Mass Spectrum (ESI) m/e 591.2 M+l.
EXAMPLE 158
trans- l-(RS)-N-methyl- 1 - [5-(2-methylsulfonylphenyl)1pyrid-2- ylmethylaminocarbonyl -2-(SR)-(4-trifluoromethoxy) benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 596.5 M+l.
EXAMPLE 159
trans-l-(RS)-N-methyl-l-[5-(2-chloro-4-fluorophenvD1pyrid-5-ylaminocarbonyl -2- (SR)-(4-trifluoromethoxy)benzylaminocarbonylcvclopentane Mass Spectrum (ESI) m/e 564.2 M+l.
EXAMPLE 160
trans-l-(RS)-N-methyl-l-[4-(2-tetrazol-5-ylphenyl)1benzylaminocarbonyl -2-(SR)-(4- trifluoromethoxy)benzylaminocarbonylcyclopentane Mass Spectrum (ESI) m/e 579.2 M+l.
The title compound was prepared from trans-N-methyl-l-(RS)-(4- bromo)-benzylaminocarbonyl-2-(SR)-(4-trifluoromethoxy)benzylaminocarbonyl cyclopentane according to procedures described in Example 104. Tetrazol-5- ylphenylboronic acid was prepared as described by Larsen, Robert D., J. Org. Chem. (1994), 59, 6391.
EXAMPLE 161
trans- 1 -(RS)-N-methyl- 1 -[4-(2-aminosulfonylphenvD1benzylaminocarbonyl -2-(SR)-
(4-trifluoromethyDbenzylaminocarbonyl-4-methylenylcyclopentane
Mass Spectrum (ESI) m/e 602.3 M+l.
The title compound was prepared according to procedures that were previously described, with the exception that 4-methylene-trans-l,2-cyclopentane dicarboxylic acid (Lancaster) was used.
Ill
EXAMPLE 162
trans- 1 -(RS)-N-methyl- 1 - r4-(2-aminosulfonylphenyDlbenzylaminocarbonyl -2-(SR)- (4-trifluoromethvDbenzylaminocarbonyl-4-methylcyclopentane Mass Spectrum (ESI) m/e 604.2 M+l .
The title compound was prepared from trans-l-(RS)-N-methyl-l-[4-(2- aminosulfonyl phenyl)]benzylaminocarbonyl-2-(SR)-(4- trifluoromethyl)benzylaminocarbonyl-4-methylenylcyclopentane (Example 161) by hydrogenation at 40psi in an ethanol solution using 10% Pd/C as a catalyst.
trans- 1 -(RS)-N-methyl- 1 - r4-(2-aminosulf onylphenyDlbenzylaminocarbonyl -2-(SR)- (4-trifluoromethvDbenzylaminocarbonyl-4-cyclopropylcyclopentane
To a solution of 0.66mL (0.66mmol) of diethylzinc (IM solution in toluene) in 2mL of CH2C12 at 0°C was added dropwise 0.05mL (0.66mmol) of TFA. After stirring for lOmin, 0.053mL (0.66mmol) of methylene di-iodide (CH2I2) was added and the reaction mixture was stirred forlOmin. To the reaction mixture was added a solution of O.lg (0.166mmol) of trans-l-(RS)-N-methyl-l-[4-(2- aminosulfonyl phenyl)] benzylaminocarbonyl-2-(SR)-(4-trifluoromethyl) benzylaminocarbonyl-4-methylenylcyclopentane (Example 161) in lmL of CH C12. After the reaction mixture was stirred at rt for lh, it was quenched with lOmL of IN HCl solution. The mixture was extracted with 2:1 EtOAc: hexanes and the combined
organic fractions were dried (Na2S04) filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 3:1 EtOAc: hexanes) to give the title compound. Mass Spectrum (ESI) m/e 615 M+l.
EXAMPLE 164
trans-l-(RS)-N-methyl-l-[4-(2-aminosulfonylphenvDlbenzylaminocarbonyl -2-(SR)- (4-trifluoromethyDbenzylaminocarbonyl-4,4-dimethylcyclopentane
Step A: trans-Diethyl-4-cyclopropyl-l ,2-cvclopentane dicarboxylate
The title compound was prepared from 4-methylene-trans-diethyl- 1,2- cyclopentane dicarboxylate according to procedures described in Example 163. Step B: trans-Diethyl-4,4-dimethyl- 1 ,2-cvclopentane dicarboxylate A reaction mixture of 0.2g (0.83mmol) of trans-diethyl-4-cyclopropyl-
1,2-cyclopentane dicarboxylate and O.lg of Pt02 in 8mL of EtOH and 2mL of HOAc was hydrogenated for 1 week at 50psi. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 15% EtOAc: hexanes) to give the title compound. Step C: trans- 1 -(RS)-N-methyl- 1 - r4-(2-aminosulfonylphenvDl benzylaminocarbonyl -2-(SR)-(4-trifluoromethvD benzylaminocarbonyl-4,4-dimethylcyclopentane The title compound was prepared from trans-diethyl-4,4-dimethyl- 1,2- cyclopentane dicarboxylate according to procedures previously described. Mass Spectrum (ESI) m/e 617 M+l .
EXAMPLE 165
trans- 1 -(RS)-N-methyl- 1 -[4-(2-aminosulfonylphenvDlbenzylaminocarbonyl -2-(SR - (4-trifluoromethyDbenzylaminocarbonyl-4-oxocyclopentane
To a solution of O.lg (0.166mmol) of trans-l-(RS)-N-methyl-l-[4-(2- aminosulfonyl phenyl)]benzylaminocarbonyl -2-(SR)-(4-trifluoromethyl) benzylaminocarbonyl-4-methylenylcyclopentane in 3mL of t-butanol and 3mL of H20 at rt was added 0.178g (O.83mmol) of NaI04 followed by O.lmL of a 1% solution of OsO4 in 1:1 t-butanol and H2O. After 15min, 4mL of EtOAc was added and the reaction mixture was stirred for 2h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic fractions were dried (MgS04) filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 3: 1 EtOAc: hexanes) to give the title compound. Mass Spectrum (ESI) m/e 604.3 M+l.
EXAMPLE 166
μans-l-(RS)-N-methyl-l-[4-(2-aminosulfonylphenvDlbenzylaminocarbonyl -2-(SR)- (4-trifluoromethyDbenzylaminocarbonyl-4-hvdroxycvclopentane
To a solution of 0.012g (0.02mmol) of trans-l-(RS)-N-methyl-l-[4-(2- aminosulfonyl phenyl)]benzylaminocarbonyl-2-(SR)-(4- trifluoromethyl)benzylaminocarbonyl-4-oxocyclopentane in 0.5mL of 9: 1 CH2C12: CH3OH at rt was added 0.0015g (0.04mmol) of NaBF-U and the reaction mixture was stirred for 15min. To the reaction mixture was added 6mL of sat'd NEUCl solution.
After 15min, the reaction mixture was extracted with 3:1 EtOAc: hexanes. The combined organic fractions were dried (MgS04) filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 10:1 CH2C12: CH3OH) to give the title compound. Mass Spectrum (ESI) m/e 606.3 M+l.
EXAMPLE 167
trans-l-(RS)-N-methyl-l-[4-(2-aminosulfonylphenyDlbenzylaminocarbonyl -2-(SR)- (4-trifluoromethyDbenzylaminocarbonyl-4,4-difluorocyclopentane
To a solution of 0.035g (0.058mmol) of trans-l-(RS)-N-methyl-l-[4- (2-aminosulfonyl phenyl)]benzylaminocarbonyl-2-(SR)-(4-trifluoromethyl) benzylaminocarbonyl-4-oxocyclopentane in lmL of CH2C12 at 0°C was added dropwise 0.062mL (0.464mmol) of DAST reagent (Et2NSF3). The reaction mixture was stirred for 30min at 0°C and 1.5h at rt at which time, it was diluted with H2O. The mixture was extracted with 3:1 EtOAc :hexanes and the combined organic fractions were dried (Na2SO4) filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 3:1 EtOAc: hexanes) to give the title compound. Mass Spectrum (ESI) m/e 626.1 M+l.
EXAMPLE 168
trans- 1 -(RS)-N-methyl- 1 - [4-(2-aminosulfonylphenvD1benzylaminocarbonyl -2-(SR)- (4-trifluoiOmethvDbenzylaminocarbonyl-4-benzyloxycvclopentane
Step A.: trans-Dimethyl-4-hydroxy-l ,2-cvclopentane dicarboxylate
The title compound was prepared from 4-methylene-trans-dimethyl- 1,2-cyclopentane dicarboxylate according to procedures described in Examples 165 and 166. Step B: frans-Dimethyl-4-benzyloxy- 1 ,2-cyclopentane dicarboxylate
To a solution of 0.21g (lmmol) of trans-dimethyl-4-hydroxy- 1,2- cyclopentane dicarboxylate and 0.39g (1.53mmol) of benzyl 2,2,2- trichloroacetimidate (Aldrich) in 20mL of CH2C12 at 0°C was added 0.06mg of trifloromethanesulfonic acid and the reaction mixture was stirred at rt for 24h. To the reaction mixture was added sat'd NaHC03 solution and the mixture was extracted with ether. The combined organic fractions were dried over Na2S0 , filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 1 : 3 EtOAc: hexanes) to give the title compound.
Step C: trans-l-(RS)-N-methyl-l-[4-(2-aminosulfonylphenvDl benzylaminocarbonyl -2-(SR)-(4-trifluoromethvD benzylaminocarbonyl-4-benzyloxycyclopentane The title compound was prepared from trans-dimethyl-4-benzyloxy- 1,2-cyclopentane dicarboxylate according to procedures previously described. Mass Spectrum (ESI) m/e 695 M+l.
EXAMPLE 169
trans-l-(RS)-N-methyl-l-[4-(2-aminosulfonylphenvDlbenzylaminocarbonyl -2-(SR)- (4-trifluoromethvDbenzylaminocarbonyl-4-(2,2,2-trifluoroethoxy)cyclopentane
Step A.: trans-Diethyl-4-(2,2,2-trifluoroethoxy)- 1 ,2-cvclopentane dicarboxylate
To a mixture of 0.63g (2.7mmol) of trans-diethyl-4-hydroxy- 1,2- cyclopentane dicarboxylate and 2.7g (10.8mmol) of l,l'-azodicarbonyl-dipiperidine (Aldrich) in 70mL of benzene at rt was added 2.2g (10.8mmol) of tri-n- butylphosphine and the reaction mixture was stirred at rt for lOmin. To the reaction
mixture was added 2.7g (27mmol) of 2,2,2-trifluoroethanol and the mixture was stirred at 65°C for 3h and at rt for 3h. The reaction mixture was diluted with hexanes and filtered. The combined organic fractions were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 10% to 25% EtOAc: hexanes) to give the title compound.
Step B: trans- 1 -(RS)-N-methyl- 1 -r4-(2-aminosulf onylphenv l benzylaminocarbonyl -2-(SR)-(4-trifluoromethyD benzylaminocarbonyl-4-(2,2,2-trifluoroethoxy)cyclopentane The title compound was prepared from trans-diethyl-4-(2,2,2- trifluoroethoxy)- 1,2-cyclopentane dicarboxylate according to procedures previously described. Mass Spectrum (ESI) m/e 687 M+l.
Other variations or modifications, which will be obvious to those skilled in the art, are within the scope and teachings of this invention. This invention is not to be limited except as set forth in the following claims.
Claims
1. A compound represented by Formula (I):
(i)
or a pharmaceutically acceptable salt thereof, wherein
X is phenyl, pyridyl, or thienyl, optionally substituted with 1-4 independent -Ci .-βalkyl, halogen, -NO2, -N(Cθ-6aιkyl)(Cθ-6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci.βalkyl, -OCi-βalkyl,
-SO2R6, -SO2NR7R8, -NR9SO2R10, or -NRllCONRl2Rl3; E is -Cι.6alkyl-; Rl is hydrogen or -Ci-βalkyl;
R2 is -Cθ-6alkyl-phenyl, -Cι_6alkyl-thienyl, -Ci -βalkyl-thiazolyl, -Cι_6alkyl-pyridyl, -Ci-βalkyl-furanyl, -Ci-βalkyl-napthyl, -Ci-βalkyl-indolyl, -C i -βalkyl-indanyl, -C i -βalkyl-methylenedioxyphenyl, -C i -βalkyl- tetrahydroquinolinyl, -C 1 -βalkyl-benzimidazolyl, -C i -βalkyl-benzothiophenyl, wherein the phenyl, thienyl, thiazolyl, pyridyl, furanyl, napthyl, indolyl, indanyl, methylenedioxyphenyl, tetrahydroquinolinyl, benzimidazolyl, or benzothiophenyl is optionally substituted with 1-4 independent halogen, -NO2, -Cχ-βalkyl, -C(O)-O-Cχ- βalkyl, -O-Ci -βalkyl, -SR14, -SO2Rl5, -SO2NR16R17, -N(Ci-6alkyl)-SO2(Ci- βalkyl), phenyl, or thienyl substituent, wherein the phenyl or thienyl substituent is optionally substituted with halogen, -Ci-βalkyl, -OCi_6alkyl, -SO2Rl8, - SO2NR19R20, -NRllSO2R22, -SO2NR23R24; OΓ -NR25CONR26R27; or Rl and R2 form a five or six-member non-aromatic heterocyclic ring with the N to which Rl and R2 are connected, said ring optionally containing a second N heteroatom, said ring optionally substituted with -Cθ-4alkyl-phenyl, -Cθ- 4alkyl-pyridyl, said phenyl or pyridyl optionally substituted with -Ci-βalkyl; or Rl and R2 form a tetrahydroquinolinyl group with the N to which Rl and R2 are connected, optionally substituted with 1-3 independent -Cι_βalkyl or halogen substituents;
R3 is -Cθ-βalkyl;
A is -CnH2n-; B is -CmH2m-; n and m each is 0, 1, 2, or 3; wherein the sum of n and m is 1, 2, or 3; R4 and R5 are each independently -Cθ-βalkyl, -OH, halogen, -O-Ci- βalkyl, -O-Cθ-6alkyl-phenyl, or together form =O, -CH2CH2-, or =CH2; R6 to R27 are each independently -Cθ-6alkyl; and any alkyl is optionally substituted with 1-6 independent halogen or -Cι_4alkyl.
2. The compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein n and m each is 0, 1, or 2; and the sum of n and m is
2.
3. The compound according to Claim 2, or a pharmaceutically acceptable salt thereof, wherein X is phenyl optionally substituted with 1-4 independent -Cι_βalkyl, halogen, -NO2, -N(Cθ-6alkyl)(Cθ-6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci-βalkyl, -OCi-βalkyl,
-SO2R6, -SO2NRVR8, -NR9SO2R10, or -NRllCONRl2Rl3.
4. The compound according to Claim 2, or a pharmaceutically acceptable salt thereof, wherein X is phenyl, substituted with a phenyl substituent, further optionally substituted with 1-4 independent -Cι_βalkyl, halogen, -NO2, or -N(Cθ-6alkyl)(Cθ-6alkyl) substituent, wherein the phenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Cι_βalkyl, -OCι_βalkyl, -SO2R6, -SO2NRVR8, -NR9SO2R10, or-NRllCONRl2Rl3.
5. The compound according to Claim 2, or a pharmaceutically acceptable salt thereof, wherein X is thienyl optionally substituted with 1-4 independent -Ci .βalkyl, halogen, -NO2, -N(Cθ-6alkyl)(Cθ-6alkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci _βalkyl, -OCι_βalkyl, -SO2R6, -SO2NR7R8, -NR9SO2R10, or -NRllCONRl2Rl3.
6. The compound according to Claim 2, or a pharmaceutically acceptable salt thereof, wherein X is pyridyl optionally substituted with 1-4 independent -Ci -βalkyl, halogen, -NO2, -N(Cθ-6alkyl)(Cθ-6 lkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Ci .βalkyl, -OCι_βalkyl, -SO2R6, -SO2NR7R8, -NR9SO2R10, or -NRHCONR12R13.
7. The compound according to Claim 2, or a pharmaceutically acceptable salt thereof, wherein R4 and R5 together form =O, -CH2CH - or =CH2.
8. The compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein n and m each is 0 or 1, wherein the sum of n and m is 1.
9. The compound according to Claim 8, or a pharmaceutically acceptable salt thereof, wherein X is phenyl optionally substituted with 1-4 independent -Ci -βalkyl, halogen, -NO2, -N(Cθ-βalkyl)(Cθ-βalkyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Cι_βalkyl, -OCi-βalkyl, -SO2R6, -SO2NR7R8, -NR9sO2RlO, or -NRHCONR12R13.
10. The compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein n and m each is 0, 1, or 3, wherein the sum of n and m is 3.
11. The compound according to Claim 10, or a pharmaceutically acceptable salt thereof, wherein X is phenyl optionally substituted with 1-4 independent -Ci -βalkyl, halogen, -NO2, -N(Cθ-βalkyl)(Cθ-βa-kyl), phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent, wherein the phenyl, thienyl, oxyphenyl, pyridyl, pyrimidyl, or benzothiophenyl substituent is optionally substituted with tetrazolyl, or 1-4 independent halogen, -Cι_βalkyl, -OCi_βalkyl,
-SO2R6, -SO2NR7R8, -NR9SO2R10, OΓ -NRHCONR12R13.
12. The compound according to Claim represented by
13. The compound according to Claim represented by
14. The compound according to Claim 1 represented by 
or a pharmaceutically acceptable salt thereof.
15. The compound according to Claim 1 represented by
16. The compound according to Claim represented by
17. The compound according to Claim 1 represented by
18. The compound according to Claim 1 represented by o o
.NΛA s
- < H <^_) H U~
or a pharmaceutically acceptable salt thereof.
19. The compound according to Claim 1 represented by
or a pharmaceutically acceptable salt thereof.
20. The compound according to Claim 1 represented by
or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising: a therapeutically effective amount of the compound according to claim
1, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
22. The pharmaceutical composition according to claim 21, further comprising i) opiate agonists, ii) opiate antagonists, iii) calcium channel antagonists, iv) 5HT receptor agonists, v) 5HT receptor antagonists vi) sodium channel antagonists, vii) NMDA receptor agonists, viii) NMDA receptor antagonists, ix) COX-2 selective inhibitors, x) NK1 antagonists, xi) non-steroidal anti-inflammatory drugs ("NSAID"), xii) selective serotonin reuptake inhibitors ("SSRI"), xiii) selective serotonin and norepinephrine reuptake inhibitors ("SSNRI"), xiv) tricyclic antidepressant drugs, xv) norepinephrine modulators, xvi) lithium, xvii) valproate, or xviii) neurontin.
23. A method of treatment or prevention of pain comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
24. A method of treatment of chronic, visceral, inflammatory and neuropathic pain syndromes comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
25. A method of treatment of pain resulting from traumatic nerve injury, nerve compression or entrapment, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, and pain resulting from cancer and chemotherapy comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
26. A method of treatment of HtV and HIV treatment-induced neuropathy, chronic pelvic pain, neuroma pain, complex regional pain syndrome, chronic arthritic pain and related neuralgias comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
27. A method of administering local anesthesia comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
28. A method of treatment of irritable bowel syndrome and Crohns disease comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
29. A method of treatment of epilepsy and partial and generalized tonic seizures comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
30. A method for neuroprotection under ischaemic conditions caused by stroke or neural trauma comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
31. A method of treatment of multiple sclerosis comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
32. A method of treatment of bipolar depression comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
33. A method of treatment of tachy-arrhythmias comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
34. A method of treatment of tinnitus or noise induced hearing loss comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
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| AU2003237224A AU2003237224A1 (en) | 2002-05-29 | 2003-05-23 | 1,2 diamido cycloalkyl sodium channel blockers |
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| IL293592A (en) * | 2019-12-06 | 2022-08-01 | Vertex Pharma | Substituted tetrahydrofurans as modulators of sodium channels |
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| US8492382B2 (en) | 2004-12-24 | 2013-07-23 | Spinifex Pharmaceuticals Pty Ltd | Method of treatment or prophylaxis |
| US8722675B2 (en) | 2004-12-24 | 2014-05-13 | Spinifex Pharmaceuticals Pty Ltd | Method of treatment or prophylaxis |
| US8609630B2 (en) | 2005-09-07 | 2013-12-17 | Bebaas, Inc. | Vitamin B12 compositions |
| US8551950B2 (en) | 2006-03-20 | 2013-10-08 | Spinifex Pharmaceuticals Pty Ltd | Method of treatment or prophylaxis of inflammatory pain |
| US9227968B2 (en) | 2006-03-20 | 2016-01-05 | Novartis Ag | Method of treatment or prophylaxis of inflammatory pain |
| WO2009156889A1 (en) * | 2008-06-25 | 2009-12-30 | Pfizer Inc. | Diaryl compounds and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2003237224A8 (en) | 2003-12-19 |
| WO2003101381A3 (en) | 2004-02-12 |
| AU2003237224A1 (en) | 2003-12-19 |
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