Pharmaceutical combinations for the treatment of stroke and traumatic brain injury

专利摘要:
The present invention provides a NR2B subtype selective N-methyl-D-aspartate (NMDA) receptor antagonist to patients in need of treatment for traumatic brain injury (TBI), ischemic attack or hypoxic attack, (a) sodium channel antagonist. (b) nitric oxide synthase (NOS) inhibitors, (c) glycine site antagonists, (d) potassium channel openers, (e) AMPA (2-amino-3- (methyl-3-hydroxyisoxazole-4) -Yl) propanoic acid) / kainate receptor antagonists, (f) calcium channel antagonists, (g) gammaaminobutyric acid (GABA) -A receptor modulators (e.g. GABA-A receptor agonists) or (h) The present invention relates to a method of treating the above diseases, including administration in combination with an anti-inflammatory agent. The present invention also relates to a method for treating hypoxic or ischemic attack, comprising administering an NMDA receptor antagonist in combination with a thrombolytic agent to a patient in need of treatment for a hypoxic or ischemic attack.
公开号:KR20020020223A
申请号:KR1020010054688
申请日:2001-09-06
公开日:2002-03-14
发明作者:케나드버트랜드리오；멘니티프랭크사무엘；살타렐리마리오데이비드
申请人:실버스타인 아써 에이.；화이자 프로덕츠 인코포레이티드；
IPC主号:

专利说明:

PHARMACEUTICAL COMBINATIONS FOR THE TREATMENT OF STROKE AND TRAUMATIC BRAIN INJURY
[1] The present invention provides a NR2B subtype selective N-methyl-D-aspartate (NMDA) receptor antagonist to patients in need of treatment for traumatic brain injury (TBI), ischemic attack or hypoxic seizures. A method of treating these diseases, comprising administering in combination with one or more other compounds that protect, inhibit the inflammatory response after brain injury, or promote cerebral reperfusion.
[2] More specifically, the present invention provides NR2B subtype selective N-methyl-D-aspartate (NMDA) receptor antagonist to patients in need of treatment of traumatic brain injury (TBI), ischemic attack or hypoxic attack, (a) sodium channel Antagonists, (b) nitric oxide synthase (NOS) inhibitors, (c) glycine site antagonists, (d) potassium channel openers, (e) AMPA (2-amino-3- (methyl-3-hydroxyisoxazole- 4-yl) propanoic acid) / kainate receptor antagonist, (f) calcium channel antagonist, (g) gammaaminobutyric acid (GABA) -A receptor modulator (e.g. GABA-A receptor agonist), (h ) An anti-inflammatory agent or (i) in combination with a matrix metalloproteinase (MMP) inhibitor.
[3] The present invention also relates to a method of treating the above diseases comprising administering an NR2B subtype selective NMDA receptor antagonist with thrombolytic agents to a patient in need of treatment for a hypoxic or ischemic attack.
[4] Brain and spinal cord injury from seizures, trauma or hypoxia often results in lifelong disability or early death. The cause of such disability or death is that the function of nerve cells and other cells in the central nervous system (CNS) is destroyed and eventually dies. Thus, therapies that reduce or prevent neuronal dysfunction and cell death after ischemic, hypoxic or traumatic CNS injury will certainly be beneficial.
[5] One of the causes of neuronal dysfunction and cell death after CNS injury is that glutamate and other excitatory amino acid (EAA) levels remain high over time and the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors This is because overactivity causes toxicity. Glutamate and other EAAs play a dual role not only as essential amino acids in the central nervous system but also as major excitatory neurotransmitters. There are four or more classes of EAA receptors, specifically NMDA receptors, AMPA (2-amino-3- (methyl-3-hydroxyisoxazol-4-yl) propanoic acid) receptors, kinate receptors, and metabotropic (metabotropic) receptor. These EAA receptors mediate a wide range of signaling events that affect all physiological functions of the brain. EAA is a neurotransmitter that is released from postsynaptic nerve endings and then rapidly recaptured by various intracellular reuptake mechanisms. As a result, the physiological level of EAA in the brain parenchyma remains low. However, after CNS injury, the level of EAA in the brain parenchyma increases sharply and can be maintained at high levels for hours to days. This eventually leads to pathological overactivity of the EAA receptor, resulting in neuronal dysfunction and cell death.
[6] From a series of evidence, it has been suggested that the NMDA subtype of glutamate receptors is a major mediator of the EAA-induced toxicity described above. Since early neuronal cultures are very sensitive to the toxic effects of NMDA receptor activation, antagonists of NMDA receptors protect cultured neurons from both NMDA toxicity and glutamate toxicity (Choi et al., J. Neurosci ., 8, 185-196, 1988; Rosenberg and reference [Neurosci. Lett., 103, 162, 1989], such as (Rosenberg)). NMDA receptor antagonists include focal ischemia (see McCulloch, J. Neural. Trans ., 71-79, 1994) and head trauma (Bullock et al., Acta Neurochir., 55 , 49). NMDA receptors are also believed to be mediators of neurotoxicity in vivo, as it can reduce neuronal loss in animal models. Neuroprotective effects of inhibiting NMDA receptors are achieved by several different classes of compounds targeting several sites on the NMDA receptor-channel complex. These include (R, E) -4- (3-phosphonoprop-2-enyl) piperazine-2-carboxylic acid (d-CPPene) (Lowe et al. , Neurochem. Int. , 25 , 583, 1994) and cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS-19,755) (see Murphy et al . , Br. J. Pharmacol. , 95 , 932, 1988). Competitive antagonists at the glutamate binding site, and 5,7-dichloro-4S- (3-phenyl-ureido) -1,2,3,4-tetrahydroquinoline-2R-carboxylic acid (L-689,560) and 5- See nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (ACEA-1021) (Leeson et al ., J. Med. Chem ., 37 , 4053, 1994). Glycine coagents (see Johnson et al. , Nature , 327 , 529-531, 1987) and Kemp et al . , Trends Pharmacol. Sci. , 14 , 20-25, 1993. Competitive antagonists at the binding site. In addition, phencyclidine (PCP), (+)-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptan-5,10-imine (MK-801) (Kemp et al. See Trends in Neurosci. , 10 , 294, 1987) and C- (1-naphthyl-N '-(3-ethyl-phenyl) -N'-methyl guanidine hydrochloride (CNS-1102) (Ready Compounds that block NMDA receptor-gate ion channels, including Reddy et al . (See J. Med. Chem ., 37 , 260, 1994), have been found.
[7] As the neuroprotective effects of NMDA receptor antagonists have been observed in experimental systems, considerable interest has been raised about the therapeutic efficacy of these types of compounds. Some prototype antagonists have progressed to clinical trials, particularly for seizures and head trauma (see Moore et al., Stroke , 26 , 503-513, 1995). However, side effects that appear at therapeutic drug levels have been a serious problem that prevented them from being developed as further drugs (see Moore et al., Supra). In particular, both glutamate competitive antagonists and channel blockers cause cardiovascular effects and psychosis in humans. Although the physiological basis for these side effects is not yet known, these types of compounds also exhibit locomotor activity that is evident by fearing neurons in cingulate cortice and retrosplenial cortice in rodents. It causes overexcitability of excess and retrograde neurons (see Olney et al., Science , 254 , 1515-1518, 1991). Antagonists against glycine co-agonist sites, when used in neuroprotective doses, cause low levels of motor activation in rodents and do not cause cavitation of neurons, so this class of antagonists may be better tolerated in humans. (See Kemp et al . , Trends Pharmacol. Sci. , 14 , 20-25, 1993). Unfortunately, the quinoxalinedione family of compounds has been difficult to use in clinical applications due to physiochemical problems (solubility, brain penetration, protein binding) associated with the quinoxalinedione nucleus.
[8] Compound (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidino) -1-propanol (hereinafter referred to as "Compound A") is an NMDA receptor The fourth mechanism family of antagonists. This class of compounds is unique in that it is specific for subtypes containing NR2B subunits expressed in the whole brain of NMDA receptors. With respect to other ligand gateway ion channels, functional NMDA receptors are composed of multiple protein subunits. To date, five subunits have been cloned, namely NR1 (there are eight splice variants) and NR2A to NR2D. Expression studies have shown that the composition comprises one or more NR1 subunits and one or more of the NR2 subunits (Monyer et al., Science , 256 , 1217-1221, 1992), Guswada ( Kutsuwada et al. , Nature , 358 , 36, 1992 and Chazot et al ., J. Biol. Chem ., 269 , 24403, 1994). In situ binding studies and immunohistochemical studies have shown that subunits are widely distributed throughout the brain (Monier et al., Neuron , 12 , 529-540, 1994), Kuswada et al. See Ishii et al ., J. Biol. Chem ., 268 , 2836, 1993 and Wenzel et al ., NeuroReport , 7 , 45, 1995).
[9] It has been found that Compound A and other structurally related compounds thereof are functionally selective for NMDA receptors, including the NR2B subunit. The fact that the NMDA receptor antagonists of this class are neuroprotective agents in various in vitro and in vivo experimental models (Dioke et al., Stroke , 28 , 2244-2251, 1997), Okiyama et al. Brain Res. , 792 , 291-298, 1998], Okiyama et al. , J. Neurotrauma , 14 , 211-222, 1997, and Tsuchida et al. , Neurotrama , 14 , 409-417, 1997 ] Implies that the NR2B subunit containing NMDA receptors are primarily involved in EAA-induced toxic cascades. It has also been found that antagonists selective to NR2B subunit containing NMDA receptors cause fewer toxic side effects in animals including humans than other classes of NMDA receptor antagonists and may be selected due to their superior pharmaceutical properties. Thus, the use of NR2B subtype selective NMDA receptor antagonists in therapeutically effective dosages significantly reduces the specific adverse cardiovascular and behavioral side effects seen by administering therapeutically effective dosages of subunit non-selective NMDA receptor antagonists. You can remove me or completely. NMDA antagonists used in the methods and pharmaceutical compositions of the present invention preferably exhibit selectivity for NR2B subunit containing NMDA receptors.
[10] The selectivity of the compounds for the NR2B subunit containing NMDA receptors is described by Chenard and Menenni, in Antagonists Selective for NMDA receptors containing the NR2B Subunit, Current Pharmaceutical Design , 5, 381-404, 1999. As disclosed, the racemate [ ³ H] (+)-(1S, 2S) -1- (4-hydroxy-phenyl) -2- (4-hydroxy-4-phenyl in the rat whole brain Affinity for piperidino) -1-propanol binding site. This affinity is assessed by radioligand binding assay as described later herein. An optional compound is a compound that replaces the specific binding of racemate [ ³ H] CP-101,606 from the forebrain membrane of the rat with a concentration of IC ₅₀ ≦ ₅ μM.
[11] Many compounds having selectivity for the NR2B subtype of the NMDA receptor also interact with and inhibit many other receptors and ion channels. For example, ifenprodil inhibits the α ₁ adrenergic receptor with an affinity similar to that of which the compound inhibits the NR2B subtype of the NMDA receptor. The inhibitory action of α ₁ adrenergic receptors is associated with specific structural features of ifenprodil and related molecules (see Kenard et al ., Med. Chem ., 34, 3085-3090, 1991). Compounds that block α ₁ adrenergic receptors (eg prazosin) are associated with hypotensive activity, which is contraindicated in drugs used to treat seizures, TBI and related symptoms. Thus, the NMDA antagonists used in the methods and pharmaceutical compositions of the present invention are preferably compounds that show selectivity for NR2B subunit containing NMDA receptors rather than for α ₁ adrenergic receptors, specifically for NR2B receptors. And a ratio of selectivity to a ₁ adrenergic receptor to at least about 3: 1. More preferably, the ratio is at least 5: 1.
[12] The present invention relates to further therapeutic advantages that can be obtained by treating traumatic brain injury, seizures, or hypoxic brain injury with NR2B subtype selective NMDA receptor antagonists in combination with other types of compounds. Other compounds include compounds that protect nerves from toxic injuries, inhibit inflammatory responses after brain injury, and / or promote cerebral reperfusion. NMDA receptor-mediated toxicity is a major cause of neuronal dysfunction and cell death following CNS injury, but additional mechanisms are also involved. By reducing the pathological consequences of these additional mechanisms, the overall benefit of the therapeutic intervention method may be increased. In addition, inhibiting multiple pathological processes can provide unexpectedly improved synergistic benefits over those achievable by using NMDA receptor antagonists alone.
[13] Numerous toxic products are formed during the ischemic, hypoxic or traumatic injury process to the CNS, which results in cells that are more injured by the primary pathological process or are not damaged from the primary injury. It can also be damaged. Such toxins include nitric oxide (NO); Other reactive oxygen and nitrogen intermediates such as superoxide and peroxynitrite; Lipid peroxides; Tumor necrosis factor (TNF) α, interleukin (IL) -1 and other interleukins, cytokines or chemokines; Cyclooxygenase derivatives, lipoxygenase derivatives and other fatty acid mediators (eg, leukotriene, glutamate and prostaglandins); And hydrogen ions, but are not limited thereto. By inhibiting the formation and action of the toxins or promoting their removal, the CNS cells can be protected from damage during ischemic, hypoxic or traumatic injury. In addition, other beneficial effects in inhibiting the formation and action of the toxins or promoting their removal may be additive or synergistic with the benefits obtained by inhibiting NR2B subunit containing NMDA receptors with NR2B subunit selective NMDA receptor antagonists. Can be.
[14] Examples of compounds that inhibit the formation or action of the toxins or promote their removal include antioxidants, sodium channel antagonists, NOS inhibitors, potassium channel openers, glycine site antagonists, AMPA / Cate receptor antagonists, calcium channel antagonists, GABA -A receptor modulators (eg, GABA-A receptor agonists) and anti-inflammatory agents are included, but are not limited to these.
[15] The formation and release of a number of the toxins disclosed above is induced by physiological signaling mechanisms that are pathologically activated by ischemic, hypoxic or traumatic CNS injury. When this signaling mechanism is activated, intracellular depolarization may also occur. When depolarization occurs, intracellular ion homeostasis is disrupted, and as cells work to maintain homeostasis, energy utilization can be promoted and / or the rate of formation and release of toxins can be further accelerated. Thus, by inhibiting these signaling mechanisms during ischemic, hypoxic or traumatic CNS injury, it is possible to reduce the levels of dysfunction and cell death. In addition, the beneficial effect of inhibiting the signaling mechanisms can be additive or synergistic with the benefits obtained by inhibiting NR2B subunit containing NMDA receptors with NR2B subunit selective NMDA receptor antagonists. Such signaling mechanisms include NMDA receptors other than NR2B subunit containing NMDA receptors; Other EAA receptors, such as AMPA receptors or kainic acid receptors, or metabotropic receptors; Other ligand gate ion channels that promote depolarization and / or release of toxins; Several types of potential acting calcium channels, including L-type, P-type, Q / R-type, N-type, or T-type; And potential working sodium channels. Examples of compounds that inhibit signaling pathways include, but are not limited to, AMPA / Cinate receptor antagonists, sodium channel antagonists and calcium channel antagonists.
[16] Another approach to inhibit intracellular depolarization and the deleterious effects resulting from ischemic, hypoxic or traumatic CNS damage is to activate signaling pathways that block the signaling pathways leading to depolarization. In addition, the beneficial effects of activating these signaling mechanisms can be additive or synergistic with the benefits obtained by inhibiting the NR2B subunit containing NMDA receptors with NR2B subunit selective NMDA receptor antagonists. These signaling mechanisms include GABA-A receptor activation; Potential action or ligand gateway potassium channel activation; And potential action or ligand gateway chloride channel activation. Examples of compounds that activate the signaling pathway include, but are not limited to, potassium channel openers and GABA-A receptor agonists.
[17] Excessive intracellular depolarization and loss of ion homeostasis can lead to the cell losing its ability to maintain physical strength, and cell death occurs sequentially by a process often referred to as necrotic cell death. However, ischemic, hypoxic or traumatic CNS damage can induce the activation of another mechanism that causes cell death in many cells, also called apoptosis. The relationship between necrotic cell death and necrotic cell death is not fully understood, and both necrotic and necrotic mechanisms that ultimately induce cell death in pathological conditions such as ischemic, hypoxic or traumatic CNS injury can work. Regardless of elucidating this correlation, it has been suggested that inhibiting the apoptosis mechanism of cell death may have therapeutic advantages in ischemic, hypoxic or traumatic CNS injury symptoms. The beneficial effect of inhibiting apoptosis during ischemic, hypoxic or traumatic CNS injury can be additive or synergistic with the benefits obtained by inhibiting NR2B subunit containing NMDA receptors with NR2B subunit selective NMDA receptor agonists. Apoptotic mechanisms include activation of FAS / TNFα / p75 receptors; Activation of caspases, including caspases 1-9; Activation of _NFκB ; Activation of JNK and / or p38 kinase signaling cascade; Inhibition of mitochondrial destruction and activation of mitochondrial permeable transition pores; And activation of intracellular proteases such as calpine. Examples of compounds which inhibit the apoptosis mechanism include, but are not limited to, caspase inhibitors and inhibitors of the other enzymes described above as mediators of the apoptosis mechanisms.
[18] Cells located in the CNS are heavily dependent on cell-to-cell interactions and interactions with extracellular matrices for survival and proper function. However, these interactions are often disrupted during ischemic, hypoxic or traumatic CNS injury, which can directly induce or contribute to cell dysfunction and cell death. Thus, therapies that maintain the interaction of cell-to-cell and cell-to-extracellular matrix during ischemic, hypoxic or traumatic CNS injury are expected to reduce cell dysfunction and cell death. In addition, therapies that maintain cell-to-cell and cell-to-extracellular matrix interactions during ischemic, hypoxic or traumatic CNS injury are obtained by inhibiting NR2B subunit containing NMDA receptors with NR2B subunit selective NMDA receptor antagonists. With this benefit it can be additive or synergistic. Mechanisms that contribute to disruption of cell-to-cell and cell-to-extracellular matrix interactions during ischemic, hypoxic or traumatic CNS injury include, but are not limited to, activation of proteases that degrade the extracellular matrix. These include, but are not limited to, matrix metalloproteinases such as MMP1 to MMP13. Examples of compounds that inhibit these enzymes include, but are not limited to, those disclosed in the following patents and patent applications: US Pat. No. 5,861,510, issued January 19, 1999; European Patent Application EP 606,046, published July 13, 1994; European Patent Application EP 935,963, published August 18, 1999; PCT Patent Publication No. WO 98/34918, published August 13, 1998; Both PCT Patent Publication No. WO 98/08825 and PCT Patent Publication No. WO 98/08815, published May 5, 1998; PCT Patent Publication No. WO 98/03516, published January 29, 1998; And PCT Patent Publication No. WO 98/33768, published August 6, 1998. All of these patents and patent applications are incorporated herein by reference in their entirety.
[19] Ischemia, hypoxia or trauma of the CNS induces an inflammatory response mediated by various components of the innate and adaptive immune systems. Due to the nature of the CNS and its inherent relationship with the immune system, immune system activation caused by ischemia, hypoxia or trauma of the CNS can exacerbate cell dysfunction and cell death. The mechanism by which immune activation exacerbates CNS damage consists of a number of processes. Immune cells present in the CNS, such as astrocytes and microglia, activate subsequent CNS damage. In addition, peripheral immune cells are also collected and introduced into the CNS and are activated. These cells include monocytes / macrophages, neutrophils and T lymphocytes. The phenomenon in which these peripheral immune cells gather and activate in the CNS after CNS injury includes many of the same mechanisms in which these cells gather into damaged tissue outside the CNS and are activated by the tissue. The cells in the damaged tissue area and the pulses around the damaged area begin to make proteins that signal to immune cells circulating in the bloodstream. These cells then attach to the vascular endothelium and enter the damaged tissue and the area around the tissue. Such activated immune cells then promote a number of deleterious events disclosed above, including the release of various toxins and disruption of cell-to-cell and cell-to-extracellular matrix interactions.
[20] Thus, in response to ischemia, hypoxia or trauma of the CNS, it inhibits the aggregation of immune cells, adhesion to the vascular system, activation, and the formation and release of toxins and proteases, thereby impairing the function and cell death of cells caused by the CNS injury. It is assumed to be reduced. The beneficial effects of inhibiting the aggregation, activation of immune cells, and the formation and release of toxins and proteases during ischemic, hypoxic or traumatic CNS injury are obtained by inhibiting NR2B subunit containing NMDA receptors with NR2B subunit selective NMDA receptor antagonists. With this benefit it can be additive or synergistic. Compounds that inhibit the aggregation of immune cells include, but are not limited to, antagonists for various cytokine and chemokine receptors. Compounds that inhibit the adhesion of immune cells to the vascular system include, but are not limited to, antibodies to various cell adhesion molecules. Compounds that inhibit the activation of immune cells include antagonists against various cytokine and chemokine receptors; Antibodies to several cell adhesion molecules; Antagonists of intracellular enzymes involved in converting an activity signal into an intracellular response, such as, but not limited to, antagonists of COX and COX-2, various proteins ser / thr and tyr kinases, and intracellular proteases. The phenomenon of aggregation, adhesion and activation of immune and peripheral immune cells present in the CNS can also be inhibited by activating cellular signaling pathways that interfere with this activation. Compounds that activate the signaling pathway include, but are not limited to, PPAR _γ activators.
[21] In the case of thrombotic or embolic seizures, it has been observed that administering agents that degrade thrombus and embolism can have a beneficial effect on the survival, recovery and / or activity of the patient. The mechanism of action of the agents is to promote reperfusion of the ischemic tissue. The beneficial effect of drugs that promote reperfusion after thrombotic or embolic seizures may be additive or synergistic along with the benefits obtained by inhibiting the NR2B subunit containing NMDA receptor with NR2B subunit selective NMDA receptor antagonist in these symptoms. Can be. Compounds that promote reperfusion after thrombotic or embolic seizures include, but are not limited to, tissue plasminogen activator (TPA), urokinase, and streptokinase.
[22] It is an object of the present invention to provide an NR2B subtype selective N-methyl-D-aspartate (NMDA) receptor antagonist with one or more other compounds that protect neurons from toxic injury, inhibit inflammatory responses after brain injury or promote cerebral reperfusion. When used in combination with the present invention, the present invention relates to a method and a pharmaceutical composition capable of synergistically treating traumatic brain injury (TBI), ischemic attack or hypoxic attack.
[23] The present invention,
[24] (a) thrombolytics or pharmaceutically acceptable salts thereof; And
[25] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof
[26] The present invention relates to a method for treating hypoxic or ischemic attack in a mammal, the method comprising administering to a mammal, including humans, in an amount such that each combination thereof is effective to treat hypoxic or ischemic attack.
[27] The present invention also provides
[28] (a) thrombolytics or pharmaceutically acceptable salts thereof;
[29] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof; And
[30] (c) a pharmaceutically acceptable carrier
[31] Wherein said agents (a) and (b) are included in an amount such that the combination thereof is effective to treat hypoxic or ischemic seizures, for treating hypoxic or ischemic attacks in mammals, including humans. It relates to a pharmaceutical composition.
[32] As used herein, the term “treating” refers to delaying or reversing the progress of, or retarding, or reversing the progression of a disorder or condition to which the term applies, or one or more symptoms of such disorder or condition, or Refers to alleviating or preventing one or more symptoms of a disorder or symptom. As used herein, the term "treatment" refers to the act of treating a disorder or condition, as in the term "treating" as defined above.
[33] Preferred methods and pharmaceutical compositions of the present invention include the aforementioned methods and pharmaceutical compositions wherein the NMDA receptor antagonist is an NR2B subtype selective NMDA receptor antagonist of Formula 1 or a pharmaceutically acceptable acid addition salt thereof:
[34]
[35] Where
[36] (a) R ² and R ⁵ are present separately and R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, (C ₁ -C ₆ ) alkyl, halo, CF ₃ , OH or OR ⁷ , R ⁵ is methyl or ethyl, or
[37] (b) R ² and R ⁵ together To form a chroman-4-ol ring,
[38] R ¹ , R ³ and R ⁴ are each independently hydrogen, (C ₁ -C ₆ ) alkyl, halo, CF ₃ , OH or OR ⁷ ;
[39] R ⁶ is , or ego;
[40] R ⁷ is methyl, ethyl, isopropyl or n-propyl;
[41] R ⁸ is phenyl unsubstituted or substituted with up to 3 substituents independently selected from (C ₁ -C ₆ ) alkyl, halo and CF ₃ ;
[42] X is O, S or (CH ₂ ) _n ;
[43] n is 0, 1, 2 or 3.
[44] Compounds of Formula 1 are disclosed in US Pat. No. 5,185,343, issued Feb. 9, 1993, US Pat. No. 5,272,160, issued Dec. 21, 1993, US Pat. No. 5,338,754, issued Aug. 16, 1994, US Patent No. 5,356,905, issued October 18, 1994, US Patent No. 6,046,213, issued April 4, 2000, US Patent Application No. 08 / 292,651, filed August 18, 1994, 1994 US Patent Application No. 08 / 189,479, filed Jan. 31, US Patent Application No. 09 / 011,426, filed Jun. 20, 1996, PCT International Patent Application, filed May 26, 1995, and designates the US PCT / IB95 / 00398 (corresponding to International Patent Publication No. WO 96/37222), and PCT International Patent Application No. PCT / IB95 / 00380, filed May 18, 1995 and designated the United States (International Patent Corresponding to WO 96/06081. The patent, US patent application, and PCT international patent application are all incorporated herein by reference in their entirety.
[45] Preferred compounds for use in the methods and pharmaceutical compositions of the invention are those wherein R ² and R ⁵ are present individually, R ² and R ³ are each hydrogen, and R ⁶ is And R ⁸ is phenyl, 4-halophenyl or 4-trifluoromethylphenyl. In this compound crowd, more preferred specific compounds are those wherein R ⁵ in Formula 1 is methyl having a 1S ^* , 2S ^* relative stereochemical structure as in Formula 2:
[46]
[47] Other compounds preferred for use in the methods and pharmaceutical compositions of the present invention are those wherein R ² and R ⁵ together Compounds of formula (1) which form to form a chromoman-4-ol ring. In this compound crowd, preferred compounds also include compounds in which the C-3 and C-4 positions of the chroman-4-ol ring in Formula 1 have 3R ^* , 4S ^* relative stereochemical structures, as in Formula 3 below: :
[48]
[49] In the above compound the crowd, the preferred compounds are also the R ⁶ of the formula (I) And R ⁸ is phenyl or 4-halophenyl.
[50] Compounds of formula (I) comprise chiral centers and can therefore exist in a variety of different enantiomeric and diastereomeric forms. The present invention relates to the above methods of treatment using all optical isomers and all stereoisomers of the compound of formula 1 and mixtures thereof and to pharmaceutical compositions comprising them.
[51] As used herein, the term “alkyl” includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties, or combinations thereof unless otherwise indicated.
[52] As used herein, the term "one or more substituents" refers to the number of substituents corresponding to 1 to the maximum possible number of substituents, based on the number of available binding sites.
[53] As used herein, the terms "halo" and "halogen" include chloro, fluoro, bromo and iodo unless otherwise indicated.
[54] Compounds of Formula 1 include the same compounds as those indicated above except for the fact that one or more hydrogen, carbon or other atoms are replaced by their isotopes. Such compounds may be useful as research and diagnostic tools in metabolic pharmacokinetic studies and binding assays.
[55] Particularly preferred NMDA receptor antagonists of Formula 1 for use in the methods and pharmaceutical compositions of the present invention are: (+)-(1S, 2S) -1- (4-hydroxy-phenyl) -2- (4- Hydroxy-4-phenylpiperidino) -1-propanol; (1S, 2S) -1- (4-hydroxy-3-methoxyphenyl) -2- (4-hydroxy-4-phenylpiperidino) -1-propanol; (1S, 2S) -1- (4-hydroxy-3-methylphenyl) -2-hydroxy-4-phenyl- (piperidino) -1-propanol and (3R, 4S) -3- (4- ( 4-fluorophenyl) -4-hydroxypiperidin-1-yl) -chroman-4,7-diol.
[56] As mentioned above, examples of suitable thrombolytic agents that can be used in the methods and pharmaceutical compositions of the present invention are prourokinase, streptokinase and tissue plasminogen activator (TPA), which can be used in the methods and pharmaceutical compositions of the present invention. Other examples of suitable thrombolytics are the following proteins that can be obtained by changing TPA as described in US Pat. No. 5,976,530, issued Nov. 2, 1999: (a) lysine 277 is substituted with another amino acid TPA with 3-25 more amino acids at the C-terminus; And (b) 277 lysine is substituted with another amino acid, 3-25 more amino acids at the C-terminus, at least one of 117 asparagine, 184 asparagine and 448 asparagine is another amino acid Further substituted by TPA.
[57] Tissue plasminogen activator (TPA), a protein (serine protease) that can dissolve blood clots, is described in detail in US Pat. No. 5,112,609, issued May 12, 1992. This patent document is incorporated herein by reference in its entirety. TPA is a normal or neoplastic cell line of the type described in Biochimica et Biophysica Acta ., 580 , 140-153, 1979 and European Patent Application Publications EP-A-41766 and EP-A-113319. Can be obtained from. The TPA is also described, for example, in EP-A-93619, EP-A-117059 and EP-A-117060, and US Patent No. 5,976,530, issued November 2, 1999. As described, it can be obtained from transformed or transfected cultured cell lines derived using recombinant DNA techniques. Recombinant enzyme altepase is a tissue plasminogen activator produced by recombinant DNA techniques.
[58] The present invention also provides
[59] (a) an antagonist compound for the glycine site (eg gavestinyl) or a pharmaceutically acceptable salt thereof; And
[60] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof
[61] A method for treating traumatic brain injury, hypoxic seizures or ischemic seizures in a mammal comprising administering to a mammal, including humans, in an amount such that each combination is effective to treat hypoxic or ischemic seizures. will be.
[62] The present invention also provides
[63] (a) an antagonist compound for the glycine site (eg gavestinyl) or a pharmaceutically acceptable salt thereof; And
[64] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof
[65] To a pharmaceutical composition for treating such disorders in a mammal, including humans, wherein the combination thereof is effective to treat a traumatic brain injury, hypoxic attack or ischemic attack.
[66] Examples of glycine site antagonists suitable for use in the pharmaceutical compositions and methods of the present invention are those disclosed in the following documents: US Patent No. 5,942,540, issued August 24, 1999, issued July 15, 1999 International Patent Publication WO 99/34790, International Patent Publication WO 98/17878, published October 29, 1998, International Patent Publication WO 98/42673, published October 1, 1998 , European Patent Application Publication No. EP 966,475A1, published December 29, 1991, International Patent Publication No. WO 98/39327 published September 11, 1998, published February 5, 1998. International Patent Publication WO 98/104556, International Patent Publication WO 97/37652 published October 16, 1997, US Patent No. 5,837,705 issued October 9, 1996, June 1997 International Patent Publication No. WO 97/20553, published 12, US, issued March 23, 1999 Patent No. 5,886,018, US Patent No. 5,801,183, issued September 1, 1998, International Patent Publication No. WO 95/07887, published March 23, 1995, United States issued November 11, 1997. Patent No. 5,686,461, US Patent No. 5,614,509, issued March 25, 1997, US Patent No. 5,510,367, issued April 23, 1996, European Patent Application Publication No. 9,1992 517,347A1, and US Pat. No. 5,260,324, issued November 9, 1993. The above patents and patent applications are incorporated herein by reference in their entirety.
[67] Another example of a glycine site antagonist that may be used in the pharmaceutical compositions and methods of the present invention is N- (6,7-dichloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl ) -N- (2-hydroxy-ethyl) -methanesulfonamide and 6,7-dichloro-5- [3-methoxymethyl-5- (1-oxypyridin-3-yl)-[1,2, 4] -triazol-4-yl] -1,4-dihydro-quinoxaline-2,3-dione.
[68] The present invention also provides
[69] (a) a sodium channel blocker compound or a pharmaceutically acceptable salt thereof; And
[70] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof
[71] A method for treating traumatic brain injury, hypoxic seizures or ischemic seizures in a mammal comprising administering to a mammal, including humans, in an amount such that each combination is effective to treat hypoxic or ischemic seizures. will be.
[72] The present invention also provides
[73] (a) a sodium channel blocker compound or a pharmaceutically acceptable salt thereof;
[74] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof; And
[75] (c) a pharmaceutically acceptable carrier
[76] Wherein said agents (a) and (b) are included in an amount such that the combination thereof is effective to treat traumatic brain injury, hypoxic seizures or ischemic seizures. It relates to a pharmaceutical composition for the following.
[77] As mentioned above, examples of suitable sodium channel blocker compounds (ie sodium channel antagonists) that can be used in the methods and pharmaceutical compositions of the present invention are azimalin, procainamide, plecanide and lillusol.
[78] The present invention also provides
[79] (a) a calcium channel blocker compound or a pharmaceutically acceptable acid thereof; And
[80] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof
[81] A method for treating traumatic brain injury, hypoxic seizures or ischemic seizures in a mammal comprising administering to a mammal, including humans, in an amount such that each combination is effective to treat hypoxic or ischemic seizures. will be.
[82] The present invention also provides
[83] (a) a calcium channel blocker compound or a pharmaceutically acceptable salt thereof;
[84] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof; And
[85] (c) a pharmaceutically acceptable carrier
[86] Wherein said agents (a) and (b) are included in an amount such that the combination thereof is effective to treat traumatic brain injury, hypoxic seizures or ischemic seizures. It relates to a pharmaceutical composition for the following.
[87] As mentioned above, examples of suitable calcium channel blocker compounds (ie calcium channel antagonists) that can be used in the methods and pharmaceutical compositions of the present invention include diltiazem, omega-conotoxin GVIA, methoxyverafamyl, ammodipine, Felodipine, laccidipine and mibepradil.
[88] The present invention also provides
[89] (a) a potassium channel open compound or a pharmaceutically acceptable salt thereof; And
[90] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof
[91] A method for treating traumatic brain injury, hypoxic seizures or ischemic seizures in a mammal comprising administering to a mammal, including humans, in an amount such that each combination is effective to treat hypoxic or ischemic seizures. will be.
[92] The present invention also provides
[93] (a) a potassium channel open compound or a pharmaceutically acceptable salt thereof;
[94] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof; And
[95] (c) a pharmaceutically acceptable carrier
[96] Wherein said agents (a) and (b) are included in an amount such that the combination thereof is effective to treat traumatic brain injury, hypoxic seizures or ischemic seizures. It relates to a pharmaceutical composition for the following.
[97] As mentioned above, examples of suitable potassium channel openers that may be used in the methods and pharmaceutical compositions of the present invention include diazoxide, flupyrithin, pinacyl, levchromalim, lylmallim, chromalim, PCO-400 (See J. Vasc. Res ., 36 (6), 516-523, November-December 1999) and SKP-450 (2- [2 "-(1", 3 "-dioxolone) -2-methyl] -4- (2'-oxo-1'-pyrrolidinyl) -6-nitro-2H-1-benzopyran).
[98] The present invention also provides
[99] (a) an anti-inflammatory compound or a pharmaceutically acceptable salt thereof; And
[100] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof
[101] A method for treating traumatic brain injury, hypoxic seizures or ischemic seizures in a mammal comprising administering to a mammal, including humans, in an amount such that each combination is effective to treat hypoxic or ischemic seizures. will be.
[102] The present invention also provides
[103] (a) an anti-inflammatory compound or a pharmaceutically acceptable salt thereof;
[104] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof; And
[105] (c) a pharmaceutically acceptable carrier
[106] Wherein said agents (a) and (b) are included in an amount such that the combination thereof is effective to treat traumatic brain injury, hypoxic seizures or ischemic seizures. It relates to a pharmaceutical composition for the following.
[107] As mentioned above, examples of suitable anti-inflammatory compounds that can be used in the methods and pharmaceutical compositions of the present invention include non-steroidal anti-inflammatory agents (NSAIDs), COX-2 inhibitors, acetominophene and steroid-based anti-inflammatory agents (eg, methyl preds). Nirolone and cortisone). Examples of NSAIDs are diclofenac sodium, nabumetone, naproxen, naproxen sodium, ketorolac, ibuprofen and indomethacin.
[108] Examples of suitable COX-2 inhibitors that can be used in the methods and pharmaceutical compositions of the present invention are those disclosed in the following documents: US Provisional Application No. 60 / 134,311, filed May 14, 1999, filed May 14, 1999 US Provisional Application No. 60 / 134,312, filed with US Provisional Application No. 60 / 134,309, filed May 14,1999. Said patent applications are incorporated herein by reference in their entirety.
[109] Other examples of suitable COX-2 inhibitors that can be used in the methods and pharmaceutical compositions of the present invention are those disclosed in the following documents: US Pat. No. 5,817,700, issued October 6, 1998; International Patent Publication No. WO 97/28121, published August 7, 1997; US Patent No. 5,767,291, issued June 16, 1998; US Patent No. 5,436,265, issued July 25, 1995; US Patent No. 5,474,995, issued December 12, 1995; US Patent No. 5,536,752, issued July 16, 1996; US Patent No. 5,550,142, issued August 27, 1996; US Patent No. 5,604,260, issued February 18, 1997; US Patent No. 5,698,584, issued December 16, 1997; US Patent No. 5,710,140, issued January 20, 1998; US Patent No. 5,840,746, issued November 24, 1998; British Patent Application No. 986430, filed March 25, 1998; International Patent Publication No. WO 97/28120, published August 7, 1997; British Patent Application No. 9800689, filed Jan. 14, 1998; British Patent Application No. 9800688, filed January 14, 1998; International Patent Publication No. WO 94/14977, published July 7, 1994; International Patent Publication No. WO 98/43966, published October 8, 1998; International Patent Publication No. WO 98/03484, published January 29, 1998; International Patent Publication No. WO 98/41516, published September 24, 1998; International Patent Publication No. WO 98/41511, published September 24, 1998; British Patent 2,319,032, issued May 13, 1998; International Patent Publication No. WO 96/37467, published November 28, 1996; International Patent Publication No. WO 96/37469, published November 28, 1996; International Patent Publication No. WO 96/36623, published November 21, 1996; International Patent Publication No. WO 98/00416, published January 8, 1998; International Patent Publication No. WO 97/44027, published November 27, 1997; International Patent Publication No. WO 97/44028, published November 27, 1997; International Patent Publication No. WO 96/23786, published August 8, 1996; International Patent Publication No. WO 97/40012, published October 30, 1997; International Patent Publication No. WO 96/19469, published June 27, 1996; International Patent Publication No. WO 97/36863, published October 9, 1997; International Patent Publication No. WO 97/14691, published April 24, 1997; International Patent Publication No. WO 97/11701, published April 3, 1997; International Patent Publication No. WO 96/13483, published May 9, 1996; International Patent Publication No. WO 96/37468, published November 28, 1996; International Patent Publication No. WO 96/06840, published March 7, 1996; International Patent Publication No. WO 94/26731, published November 24, 1994; International Patent Publication No. WO 94/20480, published September 15, 1994; US Patent No. 5,006,549, issued April 9, 1991; US Patent No. 4,800,211, issued January 24, 1989; US Patent No. 4,782,080, issued November 1, 1988; US Patent No. 4,720,503, issued January 19, 1988; US Patent No. 4,760,086, issued July 26, 1988; US Patent No. 5,068,248, issued November 26, 1991; US Patent No. 5,859,257, issued January 12, 1999; International Patent Publication No. WO 98/47509, published October 29, 1998; International Patent Publication No. WO 98/47890, published October 29, 1998; International Patent Publication No. WO 98/43648, published October 8, 1998; International Patent Publication No. WO 98/25896, published June 18, 1998; International Patent Publication No. WO 98/22101, published May 28, 1998; International Patent Publication No. WO 98/16227, published April 23, 1998; International Patent Publication No. WO 98/06708, published February 19, 1998; International Patent Publication No. WO 97/38986, published October 23, 1997; US Patent No. 5,663,180, issued September 2, 1997; International Patent Publication No. WO 97/29776, published August 21, 1997; International Patent Publication No. WO 97/29775, published August 21, 1997; International Patent Publication No. WO 97/29774, published August 21, 1997; International Patent Publication No. WO 97/27181, published July 31, 1997; International Patent Publication No. WO 95/11883, published May 4, 1995; International Patent Publication No. WO 97/14679, published April 24, 1997; International Patent Publication No. WO 97/11704, published April 3, 1997; International Patent Publication No. WO 96/41645, published November 27, 1996; International Patent Publication No. WO 96/41626, published December 27, 1996; International Patent Publication No. WO 96/41625, published December 27, 1996; International Patent Publication No. WO 96/38442, published December 5, 1996; International Patent Publication No. WO 96/38418, published December 5, 1996; International Patent Publication No. WO 96/36617, published November 21, 1996; International Patent Publication No. WO 96/24585, published August 15, 1996; International Patent Publication No. WO96 / 24584, published August 15, 1996; International Patent Publication No. WO 96/16934, published June 6, 1996; International Patent Publication No. WO 96/03385, published February 8, 1996; International Patent Publication No. WO 96/12703, issued May 2, 1996; International Patent Publication No. WO 96/09304, published March 28, 1996; International Patent Publication No. WO 96/09293, published March 28, 1996; International Patent Publication No. WO 96/03392, published February 8, 1996; International Patent Publication No. WO 96/03388, published February 8, 1996; International Patent Publication No. WO 96/03387, published February 8, 1996; International Patent Publication No. WO 96/02515, published February 1, 1996; International Patent Publication No. WO 96/02486, published February 1, 1996; US Patent No. 5,476,944, published December 19, 1995; International Patent Publication No. WO 95/30652, published November 16, 1995; US Patent No. 5,451,604, issued September 19, 1995; International Patent Publication No. WO 95/21817, published August 17, 1995; International Patent Publication No. WO 95/21197, published August 10, 1995; International Patent Publication No. WO 95/15315, published June 8, 1995; US Patent No. 5,504,215, issued April 2, 1996; US Patent No. 5,508,426, issued April 16, 1996; US Patent No. 5,516,907, issued May 14, 1996; US Patent No. 5,521,207, issued May 28, 1998; US Patent No. 5,753,688, issued May 19, 1998; US Patent No. 5,760,068, issued June 2, 1998; US Patent No. 5,420,343, issued May 30, 1995; International Patent Publication No. WO 95/30656, published November 16, 1995; US Patent No. 5,393,790, issued February 28, 1995; And International Patent Publication No. WO 94/27980, published February 8, 1994. The above patents and patent applications are incorporated herein by reference in their entirety.
[110] The present invention also provides
[111] (a) a GABA-A receptor modulator (eg, GABA-A receptor agonist) or a pharmaceutically acceptable salt thereof; And
[112] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof
[113] A method for treating traumatic brain injury, hypoxic seizures or ischemic seizures in a mammal comprising administering to a mammal, including humans, in an amount such that each combination is effective to treat hypoxic or ischemic seizures. will be.
[114] The present invention also provides
[115] (a) a GABA-A receptor modulator (eg, GABA-A receptor agonist) or a pharmaceutically acceptable salt thereof;
[116] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof; And
[117] (c) a pharmaceutically acceptable carrier
[118] Wherein said agents (a) and (b) are included in an amount such that the combination thereof is effective to treat traumatic brain injury, hypoxic seizures or ischemic seizures. It relates to a pharmaceutical composition for the following.
[119] As noted above, examples of suitable GABA-A receptor modulators that may be used in the methods and pharmaceutical compositions of the present invention are clomethiazole, and other examples of GABA-A modulators that may be used in the pharmaceutical compositions and methods of the present invention include: The publications are: International Patent Publication No. WO 99/25353 published May 27, 1999, International Publication No. WO 96/25948 published August 29, 1996, 7 1999 International Patent Publication No. WO 99/37303, published on March 29, US Patent No. 5,925,770 issued July 20, 1999, US Patent No. 5,216,159 issued June 1, 1993, 7 1992 US Patent No. 5,130,430, issued May 14, US Patent No. 5,925,770, issued July 20, 1999, and International Patent Publication No. WO 99/10347, published March 4, 1999.
[120] The present invention also provides
[121] (a) an antioxidant compound (eg, alpha-tocopherol) or a pharmaceutically acceptable salt thereof; And
[122] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof
[123] A method for treating traumatic brain injury, hypoxic seizures or ischemic seizures in a mammal comprising administering to a mammal, including humans, in an amount such that each combination is effective to treat hypoxic or ischemic seizures. will be.
[124] The present invention also provides
[125] (a) an antioxidant compound (eg, alpha-tocopherol) or a pharmaceutically acceptable salt thereof;
[126] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof; And
[127] (c) a pharmaceutically acceptable carrier
[128] Wherein said agents (a) and (b) are included in an amount such that the combination thereof is effective to treat traumatic brain injury, hypoxic seizures or ischemic seizures. It relates to a pharmaceutical composition for the following.
[129] As mentioned above, examples of suitable antioxidant compounds that can be used in the methods and pharmaceutical compositions of the present invention include vitamin E, vitamin A, calcium dobesylate, stovadine, alpha-tocopherol, ascorbic acid, alpha-lipoic acid, corcumin , Catalase, prevastatin, N-acetylcysteine, nordihydroguaiaretic acid, pyrrolidine dithiocarbamate, LY371122 and methexyl (4-methoxy-2,2,6,6-tetramethyl Piperidine-1-oxyl).
[130] The present invention also provides
[131] (a) an antagonist compound for AMPA / Cateate receptor or a pharmaceutically acceptable salt thereof; And
[132] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof
[133] A method for treating traumatic brain injury, hypoxic seizures or ischemic seizures in a mammal comprising administering to a mammal, including humans, in an amount such that each combination is effective to treat hypoxic or ischemic seizures. will be.
[134] The present invention also provides
[135] (a) an antagonist compound for AMPA / Cateate receptor or a pharmaceutically acceptable salt thereof;
[136] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof; And
[137] (c) a pharmaceutically acceptable carrier
[138] Wherein said agents (a) and (b) are included in an amount such that the combination thereof is effective to treat traumatic brain injury, hypoxic seizures or ischemic seizures. It relates to a pharmaceutical composition for the following.
[139] As mentioned above, examples of antagonist compounds for the appropriate AMPA / Cyanate receptors that can be used in the methods and pharmaceutical compositions of the present invention are 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 6 -Nitro-7-sulfamoylbenzo [f] quinoxaline-2,3-dione (NBQX), 6,7-dinitroquinoxaline-2,3-dione (DNQX), 1- (4-aminophenyl)- 4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo [f] quinoxaline.
[140] The present invention also provides
[141] (a) a NOS inhibitory compound or a pharmaceutically acceptable salt thereof; And
[142] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof
[143] The present invention relates to a method for treating hypoxic or ischemic attack in a mammal, the method comprising administering to a mammal, including humans, in an amount such that each combination thereof is effective to treat hypoxic or ischemic attack.
[144] The present invention also provides
[145] (a) a NOS inhibitory compound or a pharmaceutically acceptable salt thereof;
[146] (b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof; And
[147] (c) a pharmaceutically acceptable carrier
[148] To a pharmaceutical composition for treating the disorder in a mammal, including humans, comprising the agent (a) and (b) in an amount such that a combination thereof is effective to treat hypoxic or ischemic attacks. It is about.
[149] Three isoforms are known for NOS, and these isoforms are inducible forms (I-NOS) and 2, called neuronal NOS (N-NOS) and endothelial NOS (E-NOS), respectively. Eggplant is a permanent form. Each of these enzymes produces one molecule of nitric oxide (NO) during the conversion of arginine to citrulline in response to various stimuli. Excess nitric oxide (NO) produced by NOS is believed to play an important role in the pathology of many disorders and symptoms in mammals. For example, NO produced by I-NOS is believed to play an important role in diseases including systemic hypotension, such as toxic shock, and in diseases seen in therapies using certain cytokines. Cancer patients treated with cytokines such as interleukin-1 (IL-1), interleukin-2 (IL-2), or tumor necrosis factor (TNF), have cytokine-induced shock and macrophages (ie, induced NOS (I). -NOS)) has been shown to suffer from hypotension by NO produced by (see Chemical & Engineering News , 33 , December 20, 1993). I-NOS inhibitors can reverse this phenomenon. I-NOS is also thought to play an important role in the pathology of diseases of the central nervous system such as ischemia. For example, inhibition of I-NOS has been shown to reduce ischemic cerebral damage in rats (see Am. J. Physiol. , 268, R286, 1995). By selectively inhibiting I-NOS, it is possible to inhibit adjuvant induced arthritis, see Eur. J. Pharmacol. , 273 , 15-24, 1995.
[150] NO produced by N-NOS is believed to play an important role in diseases such as cerebral ischemia, pain and anesthetic resistance. For example, inhibition of N-NOS reduces infarct volume following proximal middle cerebral artery occlusion in rats (see J. Cerebr. Blood Flow Meta. , 14, 924-929, 1994). Induction of N-NOS has also been shown to be effective in preventing invasion, as evidenced by the activity shown later in formalin-induced hind limb symptom assay and acetic acid-induced abdominal contraction assay ( Br. J. Pharmacol). see., 110, 219-224, 1993). In addition, subcutaneous injection of Freund's adjuvant to rats leads to an increase in NOS-positive neurons in the spinal cord, as is evident with increased sensitivity to pain, which is treated with NOS inhibitors. (See Japanese Journal of Pharmacology , 75 , 327-335, 1997). Finally, opioid withdrawal in rodents is reported to be reduced by the inhibition of N-NOS (see Neuropsychopharmacol. , 12 , 269-293, 1995).
[151] Examples of NOS inhibitory compounds that can be used in the methods and pharmaceutical compositions of the present invention are those disclosed in the following documents: 2-Aminopyridine containing 2-fused ring substituents, filed Aug. 27, 1997. US Provisional Application No. 60 / 057,094, entitled "Aminopyridines Containing Fused Ring Substituents"; PCT Patent Application, filed May 5, 1998, having the same name as above, designating the United States and claiming priority from US Provisional Application No. 60 / 057,094; PCT Patent Publication No. WO 97/36871, published October 9, 1997, designating the United States; John A. Lowe III, filed August 28, 1997, entitled “6-Phenylpyridin-2-yl-amine Derivatives” Provisional application 60 / 057,739; "4-Amino-6- (2-substituted-4-phenoxy) -substituted-pyridine, filed Jan. 29, 1998 and assigned the United States phenoxy) -substituted-pyridines) "PCT Patent Application No. PCT / IB98 / 00112; PCT Patent Application No. PCT / IB97 / 01446, filed November 17, 1997, entitled “6-Phenylpyridyl-2-amine Derivatives”; And US Provisional Application, filed June 3, 1998, entitled "2-Aminopyridine with Fusion Ring Substituents". Said patent applications are incorporated herein by reference in their entirety.
[152] The NR2B subtype selective NMDA antagonist of Formula 1 is readily prepared. Formula 1 wherein R ² and R ⁵ together form a chroman-4-ol ring, and R ¹ , R ³ and R ⁴ are each hydrogen is selected from the synthetic methods described in US Pat. No. 5,356,905 disclosed above. It may be prepared by one or more. Compounds of formula (I) wherein R ² and R ⁵ are present separately and R ¹ , R ² , R ³ and R ⁴ are each hydrogen are synthetic methods disclosed in the above-described US Pat. Nos. 5,185,343, 5,272,160 and 5,338,754 It may be prepared by one or more of these. Compounds of Formula 1 may also be described in US Patent Application Nos. 08 / 292,651, 08 / 189,479 and 09 / 011,426; PCT International Patent Application No. PCT / IB95 / 00398, filed May 26, 1995, designating the United States (corresponding to International Patent Publication No. WO 96/37222); And one or more of the synthetic methods described in PCT International Patent Application No. PCT / IB95 / 00380, filed May 18, 1995, corresponding to US Patent Publication No. WO 96/06081. It can be prepared by.
[153] Preferred Compound (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol ((1S, 2S) free base) And tartrate salts thereof can be prepared as described in US Pat. No. 5,272,160, disclosed above. The racemate 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol is cleaved to give (1S, 2S) free base and the corresponding ( The method for preparing the 1R, 2R) enantiomers can be done as described in US Patent Application Serial No. 09 / 011,426 disclosed above and as illustrated in Example 1 below.
[154] Anhydrous mesylate of (1S, 2S) free base can be prepared as described in US Pat. No. 5,272,160, disclosed above. Anhydrous mesylate of (1S, 2S) free base will be converted to the mesylate salt trihydrate of the (1S, 2S) enantiomer when equilibrated in an 81% relative humidity environment.
[155] Mesylate salt trihydrate of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol is described above in "( 1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol methanesulfonate trihydrate ((1S, 2S)- 1- (4-Hydroxyphenyl) -2- (4-Hydroxy-4-Phenylpiperidine-1-yl) -1-Propanol Methansulfonate Trihydrate), prepared from a (1S, 2S) free base as described in the US provisional application entitled " Can be. In this method, the (1S, 2S) free base is dissolved in water at 30 ° C. To this solution is added at least one equivalent of methanesulfonic acid and the resulting mixture is warmed to 60-65 ° C. The warmed solution can be filtered to make it free of particulates. This solution was concentrated to about 40% of the initial volume, cooled to below 10 ° C., then isolated by filtration and dried to a moisture content of about 11.3% (measured by Karl Fischer titration). The resulting crystalline mesylate salt trihydrate can be further purified by recrystallization.
[156] Another preferred compound (3R, 4S) -3- [4- (4-fluorophenyl) -4-hydroxy-piperidin-1-yl] -chroman-4,7-diol ((3R, 4S ) -Chromanol) are described in US Patent Nos. 5,356,905, US Patent Application Nos. 08 / 189,479, and "cis-racemic 7-benzyloxy-3- [4- (4-fluorophenyl) -4 Process For The Resolution of Cis-Racemic 7-Benzyloxy-3- [4- (4- Fluorophenyl) -4-Hydroxy-Piperidin-1-yl] -Chroman-4-ol Dibenzoyl-D-Tartrate) "as described in US Provisional Application. Starting materials and reagents necessary for synthesizing (3R, 4S) -chromanol can be readily obtained commercially or according to the synthetic methods disclosed in the literature or the synthetic methods illustrated below.
[157] (3R, 4S) -Cromanol is a racemate cis-7-benzyloxy-3- [4- (4-fluorophenyl) -4, as described in U.S. Patent Application Serial No. 08 / 189,479 disclosed above. It can be prepared by fractional crystallization of L-proline ester of -hydroxy-piperidin-1-yl] -chroman-4-ol. A preferred method is the above-mentioned "cis-racemic 7-benzyloxy-3- [4- (4-fluorophenyl) -4-hydroxy-piperidin-1-yl] -chroman-4-ol di Method of cleavage of benzoyl-D-tartrate ", as described in US Provisional Application and illustrated in Example 3 below. In this method, the mochromanol is the racemate cis-7-benzyloxy-3- [4- (4-fluorophenyl) -4-hydroxy-piperidin-1-yl] -chroman-4 -Ol is prepared by dissolving in equimolar amounts of dibenzoyl-D-tartaric acid in boiling ethanol. Racemic cis-7-benzyloxy-3- [4- (4-fluorophenyl) -4-hydroxy-piperidin-1-yl] -chroman-4-ol is described in US Patent Application No. Prepared as described in 08 / 189,479. The concentration of aqueous ethanol is not critical and may vary between 75 and 95% ethanol (EtOH). A concentration of 9: 1 EtOH: H ₂ O has been found to be effective and is preferred. Sufficient amount of aqueous ethanol solvent is required to dissolve the racemate compound. This amount was found to be about 17 ml per gram of racemic compound.
[158] When stirred while heating under reflux, the racemate compound dissolves to form a turbid solution which, when left to cool under stirring, (+) isomer, (3R, 4S) -7-benzyloxy-3- [4- (4-fluorophenyl) -4-hydroxy-piperidin-1-yl] -chroman-4-ol dibenzoyl-D-tartrate precipitates, which is collected by filtration and washed with aqueous ethanol can do. This is the tartrate salt of (3R, 4S) cromanol. The lactate and mandelate salts of (3R, 4S) cromanol are prepared in a similar manner. This initial product has an optical purity of about 90%. If high purity is desired, the product can be heated again with aqueous ethanol to cool, then the product can be collected and washed. This two treatments revealed that the positive isomer of 99.4% optical purity was obtained in a total yield of 74%. This procedure is preferred over the procedure described in US patent application Ser. No. 08 / 189,479 disclosed above, in that it is more desirable for bulky operations since the step of reducing with lithium aluminum hydride is not necessary. This procedure also produces the desired product in significantly greater yield.
[159] The (+) isomers described above are (3R, 4S) -3- [4- (4-fluorophenyl) -4-hydroxy-piperidin-1-yl] -chroman-4,7 according to standard procedures. Can be converted to diols. For example, the piperidinyl base can be removed by treatment with dilute base, followed by hydrogenation to remove the 7-benzyl group (3R, 4S) cromanol.
[160] In general, pharmaceutically acceptable acid addition salts of compounds of Formula 1 can be readily prepared by reacting the base form with an appropriate acid. The salt may be a salt with a monobasic acid (eg hydrochloride, hydrobromide, p-toluenesulfonate, acetate), a salt in the hydrogen form of a dibasic acid (eg hydrogen sulfate, succinate) or tribasic acid In the case of salts in the dihydrogen form of (eg dihydrogen phosphate, citrate), at least 1 molar equivalent and usually molar excess of acid are used. However, when sulfate, hemisuccinate, hydrogen phosphate or phosphate is preferred as the salt, an appropriate and accurate chemical equivalent acid will generally be used. The free base and acid can generally be combined in a cosolvent in which the desired salt is precipitated, or alternatively isolated by concentrating and / or adding a nonsolvent.
[161] As noted above, the selectivity of a compound for an NR2B subunit containing NMDA receptor is described by Kennard and Menity in Antagonists Selective for NMDA receptors containing the NR2B Subunit, Current Pharmaceutical Design , 5, 381-404, 1999. Likewise, racemate [ ³ H] (+)-(1S, 2S) -1- (4-hydroxy-phenyl) -2- (4-hydroxy-4-phenylpiperidino)-in the whole brain of the rat. Defined as affinity for the 1-propanol binding site. This affinity is assessed by radioligand binding assay as described later herein. An optional compound is a compound that replaces the specific binding of racemate [ ³ H] CP-101,606 from the forebrain membrane of the rat with a concentration of IC ₅₀ ≦ ₅ μM.
[162] Of rats of racemate [ ³ H] (+)-(1S, 2S) -1- (4-hydroxy-phenyl) -2- (4-hydroxy-4-phenylpiperidino) -1-propanol Binding to the anterior membrane is measured as described in Menity et al. (CP-101,606, a potent neuroprotectant selective for forebrain neurons, European Journal of Pharmacology , 331 , 117-126, 1997). The whole brain of adult male CD rats is homogenized in 0.32M sucrose at 4 ° C. Crude nuclear pellets are removed by centrifugation at 1,000 x g for 10 minutes, and the supernatant is centrifuged at 17,000 x g for 25 minutes. The resulting pellet is resuspended in 5 mM Tris acetate (pH 7.4) at 4 ° C. for 10 minutes to dissolve the cell particles, followed by centrifugation again at 17,000 × g. The resulting pellet is washed twice with Tris acetate, resuspended to a concentration of 10 mg protein / ml and stored at −20 ° C. until use.
[163] For binding assays, membranes are thawed, homogenized and diluted to a concentration of 0.5 mg protein / ml in 50 mM Tris HCl, pH 7.4. After addition of the compounds to be studied at various concentrations, the racemate [ ³ H] (+)-(1S, 2S) -1- (4-hydroxy-phenyl) -2- (4-hydroxy-4-phenyl Piperidino) -1-propanol (inert 42.8 Ci / mmol, 5 nM final concentration) is added. After incubation at 30 ° C. for 20 minutes in a shaking water bath, the samples were taken MB-48R Cell Harvester (Brandel Research and Development Laboratories, Gaitsburg, Md.) Laboratories) are filtered on Whatman GFB glass fiber filters. The filters are washed with ice cold Tris HCl buffer for 10 seconds and the radioactivity collected on the filter is quantified by liquid scintillation spectroscopy. Nonspecific binding comprises 100 μM of racemate (+)-(1S, 2S) -1- (4-hydroxy-phenyl) -2- (4-hydroxy-4-phenylpiperidino) -1-propanol Determine by incubating the test tubes correspondingly. Specific binding is defined as the total binding excluding nonspecific binding.
[164] Compounds of Formula 1 have selectivity for NR2B subunit containing NMDA receptors rather than α ₁ -adrenergic receptors. The affinity for the NR2B subunit containing NMDA receptor is as described above from racemic [ ³ H] (+)-(1S, 2S) -1- (4-hydroxy-phenyl) -2- ( It is measured as an IC ₅₀ value for replacing 4-hydroxy-4-phenylpiperidino) -1-propanol. Affinity for α ₁ -adrenergic receptors is described by Greengrass and Bremner in Binding Characteristics of [ ³ H] prazosin to Rat Brain α-Adrenergic Receptors, European Journal of Pharmacology, 55 , 323-326, 1979 is defined as an IC ₅₀ value for replacing the specific binding of racemate [ ³ H] prazosin from the rat brain membrane. [ ³ H] prazosin greater than ³ : [ ³ H] (+)-(1S, 2S) -1- (4-hydroxy-phenyl) -2- (4-hydroxy-4-phenylpiperidino) Compounds having an affinity ratio of -1-propanol are considered selective.
[165] Whole brains of mature male Sprague Dawley rats are homogenized in 20 volumes of ice cold 50 mM Tris / HCl buffer (pH 7.7). The homogenate is centrifuged at 50,000 x g for 10 minutes at 4 ° C. The pellet is resuspended under the same conditions and centrifuged and the final pellet is resuspended at 4 ° C. in 80 volumes of 50 mM Tris / HCl, pH 8.0.
[166] For binding assays, the compound to be studied was added to 500 μg of membrane protein in 1 ml of 50 mM Tris / HCl buffer at various concentrations, followed by [ ³ H] prazosin (Amersham, inactive 33 Ci / mmol, 0.2 nM final concentration) is added. After 30 minutes incubation at 25 ° C. in a shaking water bath, samples were prepared using MB-48R cell harvesters (Brandel Research and Development Laboratories, Gaitsburg, Maryland, USA). Filter on filter. The filters are washed three times with ice cold Tris HCl buffer for 10 seconds and the radioactivity captured on the filters is quantified by liquid scintillation spectroscopy. Nonspecific binding is determined by corresponding incubation of in vitro containing 100 μM of prazosin. Specific binding is defined as the total binding excluding nonspecific binding.
[167] NR2B selective NMDA receptor antagonists useful in the practice of the present invention may also be used in the form of pharmaceutically acceptable salts. The expression “pharmaceutically acceptable acid addition salts” includes hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, Salts such as methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, including but not limited to. Acid addition salts of the compounds of the present invention can be readily prepared by reacting the base form with an appropriate acid. The salt may be a salt with a monobasic acid (eg hydrochloride, hydrobromide, p-toluenesulfonate, acetate), a salt in the hydrogen form of a dibasic acid (eg hydrogen sulfate, succinate) or tribasic acid In the case of salts in the dihydrogen form of (eg dihydrogen phosphate, citrate), at least 1 molar equivalent and usually molar excess of acid are used. However, when sulfate, hemisuccinate, hydrogen phosphate or phosphate is preferred as the salt, an appropriate and accurate chemical equivalent acid will generally be used. The free base and acid can generally be combined in a cosolvent in which the desired salt is precipitated, or alternatively isolated by concentrating and / or adding a nonsolvent.
[168] NMDA receptor antagonists, and in particular NR2B selective NMDA receptor antagonists, may also be administered in combination with selective serotonin reuptake inhibitors (SSRIs). Examples of selective serotonin reuptake inhibitors that can be administered as part of the same pharmaceutical composition or as separate pharmaceutical compositions with NR2B selective NMDA receptor antagonists include fluoxetine, fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptable thereof Possible salts are included.
[169] The present invention provides a method of treatment in which the NMDA antagonist and other active ingredients in the claimed combinations are administered together as part of the same pharmaceutical composition, as well as separately as part of a suitable dosage regimen designed to obtain the benefits of a combination regimen. The method of treatment is administered. Appropriate dosing regimens, each dosage, and interval of administration of the active agent will depend on the particular NMDA antagonist and other active ingredients used in the formulation, the type of pharmaceutical combination used, the characteristics of the patient to be treated and the severity of the disorder to be treated. .
[170] Generally, when carrying out the methods of the present invention, the COX-2 inhibitor will be administered to the general adult in the range of about 5 to about 300 mg per day, depending on the COX-2 inhibitor, the severity of the headache and the route of administration. . When performing the methods of the present invention, NSAIDs will generally be administered to the general adult in the range of about 7 to about 2,000 mg per day. When carrying out the methods of the invention, NMDA receptor antagonists comprising glycine site antagonists will generally be administered to the general adult in the range of about 25 to about 1500 mg per day.
[171] When performing the methods of the present invention, thrombolytics will generally be administered to the general adult in the range of about 7,000 to about 36,000 IU / kg of normal adult body weight per day.
[172] When carrying out the methods of the invention, calcium channel antagonists, potassium channel openers, sodium channel antagonists and antioxidants are generally administered to the general adult in an amount within the range used when each of the agents is administered as a single active pharmaceutical agent. Will be. Such dosages can be found in scientific and medical literature, and for materials approved for human use by the US Food and Drug Administration, Medical Economics, Montvale, NJ The latest edition of the Physician's Desk Reference, now 53, is published by the Company.
[173] In some cases, dosages below the lower limit of this range may be more appropriate, while in other cases, more dosages may still be used than the lower limit in order not to cause any detrimental side effects. It is divided into small doses and administered for 1 day.
[174] Pharmaceutically active agents used in the methods and pharmaceutical compositions of the present invention may be administered alone or parenterally, parenterally or topically, with a pharmaceutically acceptable carrier or diluent, and may be administered in single or multiple doses. May be administered in an amount. More specifically, the therapeutic agents of the present invention can be administered in a wide variety of dosage forms. That is, the therapeutic agent may be combined with various pharmaceutically acceptable inert carriers to give tablets, capsules, medicinal drops, troches, hard candy, powders, sprays, creams, plasters, suppositories, jelly, gels, pastes, It may be administered in the form of lotions, ointments, aqueous suspensions, injections, elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media, various non-toxic organic solvents, and the like. In addition, pharmaceutical compositions for oral administration may suitably be sweetened and / or flavored. Generally the therapeutically effective compounds of the invention are present in such dosage forms at a concentration of about 5.0% to about 70% by weight.
[175] For oral administration, tablets containing various excipients, such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, may be dispensed with starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates. It can be used with various disintegrants and granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for purification purposes. Solid compositions of a similar type can also be used as fillers in gelatin capsules. Preferred materials for this include lactose or milk sugar, and high molecular weight polyethylene glycols. If aqueous suspensions and / or elixirs are preferred for oral administration, the active ingredients thereof may be combined with various sweetening or flavoring agents, colorants or dyes, and optionally emulsifiers and / or suspending agents, together with water, ethanol, propylene glycol, glycerin and It can be combined with a diluent such as a combination thereof.
[176] For parenteral administration, solutions of the pharmaceutically active agents of the invention in sesame oil or peanut oil, or aqueous propylene glycol can be used. The aqueous solution should be properly buffered as desired (preferably at a pH greater than 8) and the liquid diluent should first be isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. All of these solutions are readily prepared by standard pharmaceutical techniques well known to those skilled in the art under sterile conditions.
[177] In addition, the active agents used according to the invention can be administered topically, which can be carried out in the form of creams, jellies, gels, pastes, patches, ointments and the like in accordance with standard pharmaceutical practice.
[178] Certain NMDA antagonists of Formula 1 are illustrated by the following examples.
[179] All non-aqueous reactions were carried out under nitrogen for convenience and generally to maximize yield. All solvents / diluents were purchased dried or pre-dried in accordance with published standard procedures. All reactions were stirred with a magnetic rod or mechanically stirred. Nuclear magnetic resonance (NMR) spectra were recorded in ppm at 300 MHz. NMR solvent was CDCl ₃ unless otherwise indicated. Infrared (IR) spectra were recorded in cm ⁻¹ , generally specifying only strong signals.
[180] Example
[181] Example 1
[182] (1S, 2S)-and (1R, 2R) -1- (4-hydroxy-phenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol enantiomer
[183] (+)-Tartaric acid (300 mg, 2 mmol) was dissolved in 30 ml of warm methanol. Racemate 1 S ^* , 2 S ^* -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol (655 mg, 2 mmol) Add at once. Warm up slowly with stirring, a colorless homogeneous solution was obtained. Upon standing at ambient temperature for 24 hours, 319 mg (66%) of downy white precipitate was obtained. This product was recrystallized from methanol to give 263 mg of the (+)-tartrate salt of the lefty title product as a white solid. Melting point 206.5 to 207.5 ° C; [a] _D = -36.2 °. The salt (115 mg) was added to 50 ml of saturated NaHCO ₃ . Ethyl acetate (5 mL) was added and the mixture was vigorously stirred for 30 minutes. The aqueous phase was extracted repeatedly with ethyl acetate. The organic layer was collected, washed with brine, dried over calcium sulfate and concentrated. The tan residue was recrystallized from ethyl acetate-hexane to give 32 mg (39%) of the white leprosy title product. Melting point 203 to 204 ° C; [α] _D = -58.4 °. Anal for C ₂₀ H ₂₅ NO ₃ : Calcd: C, 73.37; H, 7. 70; N, 4.28. Found: C, 72.61; H, 7. 45; N, 4.21.
[184] The filtrate from the (+)-tartrate salt prepared above was treated with 100 mL of saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The collected organic extracts were washed with brine, dried over calcium sulfate and concentrated to give 380 mg of regenerated starting material (partially divided). This material was treated with (-)-tartaric acid (174 mg) in 30 ml methanol as described above. After standing for 24 hours, filtration gave 320 mg (66%) of product which was further recrystallized from methanol to give 239 mg of the (-)-tartrate salt of the preferential title compound. Melting point 206.5 to 207.5 ° C; [a] _D = + 33.9 °. The latter compound was converted to the preferential title product in 49% yield in the manner disclosed above. Melting point 204 to 205 ° C; [a] _D = + 56.9 °. Anal for C ₂₀ H ₂₅ NO ₃ : Found: C, 72.94; H, 7. 64; N, 4.24.
[185] Example 2
[186] (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol methanesulfonate trihydrate
[187] Step 1
[188]
[189] 50 gallons were charged with 17.1 gallons of acetone, 8.65 kg (57.7 mol) of 4'-hydroxypropiophenone, 9.95 kg (72.0 mol) of potassium carbonate and 6.8 L (57.7 mol) of benzylbromide. The mixture was heated to reflux (56 ° C.) for 20 hours. Thin layer chromatography (TLC) analysis showed that the reaction was essentially complete. This suspension was concentrated under atmospheric pressure to a volume of 10 gallons and 17.1 gallons of water was charged. This suspension was granulated at 25 ° C. for 1 hour. The product was filtered over a 30 inch Lapp, washed with 4.6 gallons of water and then with a mixture of 6.9 gallons of hexane and 2.3 gallons of isopropanol. After vacuum drying at 45 ° C., 13.35 kg (96.4%) of the title product were obtained.
[190] The second procedure was performed with 9.8 kg (65.25 mol) of 4'-hydroxypropiophenone using this procedure. After drying, 15.1 kg (96.3%) of the title product were obtained.
[191] Step 2
[192]
[193] Under a nitrogen atmosphere, 75 gallons of methylene chloride and 28.2 kg (117.5 mol) of the product of step 1 above were charged to a 100 gallon glass tube reactor. After stirring this solution for 5 minutes, 18.8 kg of bromine was added. The reaction was stirred at 22 ° C. for 0.5 h. TLC analysis showed that the reaction was essentially complete. 37 gallons of water were added to this solution, and the mixture was stirred for 15 minutes. Methylene chloride was separated and washed with 18.5 gallons of saturated aqueous sodium bicarbonate. Methylene chloride was separated, concentrated to 40 gallons under atmospheric pressure, and 60 gallons of isopropanol were added. Concentration was continued to a pot temperature of 80 ° C., giving a final volume of 40 gallons. This suspension was cooled to 20 ° C. and granulated for 18 hours. The product was filtered over a 30 inch wrap and washed with 10 gallons of isopropanol. After drying in vacuo at 45 ° C., 29.1 kg (77.6%) of the title product were obtained.
[194] Step 3
[195]
[196] Under a nitrogen atmosphere, a 20 gallon glass tube reactor was placed with 4.90 kg (15.3 mol), 7.0 gallon of ethyl acetate, 2.70 kg (15.3 mol) of 4-hydroxy-4-phenylpiperidine and 1.54 kg of the product of step 2 above. Triethylamine (15.3 mol) was added. This solution was heated to reflux (77 ° C.) for 18 hours. The resulting suspension was cooled to 20 ° C. TLC analysis showed that the reaction was essentially complete. The byproduct (triethylamine hydrobromide salt) was filtered over a 30 inch lap and washed with 4 gallons of ethyl acetate. The filtrate was concentrated in vacuo to 17 L of volume. The concentrate was taken up in 48 L of hexane and the resulting suspension was granulated at 20 ° C. for 2 hours. The product was dried on a 30 inch lap and washed with 4 gallons of hexane. After drying in vacuo at 50 ° C., 4.9 kg (77%) of the title product were obtained.
[197] The second procedure was carried out with 3.6 kg (11.3 mol) of the product obtained from step 2 using the above procedure. After drying, 4.1 kg (87%) of the title product were obtained.
[198] Step 4
[199]
[200] Under a nitrogen atmosphere, 87.0 gallons of 2B ethanol and 1.7 kg (45.2 mol) of sodium borohydride were charged into a 100 gallon glass tube reactor. The resulting solution was stirred at 25 ° C. and 9.4 kg (22.6 mol) of the product obtained from step 3 above were added. This suspension was stirred at 25-30 ° C. for 18 hours. TLC analysis showed that the reaction was essentially complete with the desired threo isomer. 7.8 liters of water was added to the suspension. This suspension was concentrated in vacuo to a volume of 40 gallons. After granulation for 1 hour, the product was filtered over a 30 inch lap and washed with 2 gallons of 2B ethanol. The wet product, 9.4 gallons of 2B ethanol and 8.7 gallons of water were charged to a 100 gallon glass tube reactor. This suspension was heated to reflux (78 ° C.) for 16 h. The suspension was cooled to 25 ° C. and filtered on a 30 inch lap, then washed with 7 gallons of water followed by 4 gallons of 2B ethanol. After air drying at 50 ° C., 8.2 kg (86.5%) of the title product were obtained. This material was recrystallized in the following manner.
[201] Into a 100 gallon glass tube reactor was charged 7.9 kg (18.9 mol) of product obtained from step 3, 20 gallons of 2B ethanol and 4 gallons of acetone. This suspension was heated to 70 ° C. to produce a solution. This solution was concentrated to 15 gallons under atmospheric pressure. This suspension was cooled to 25 ° C. and granulated for 1 hour. This product was filtered over a 30 inch lap. The wet product and 11.7 gallons of 2B ethanol were charged to a 100 gallon glass tube reactor. This suspension was heated to reflux (78 ° C.) for 18 hours. The suspension was cooled to 25 ° C., filtered over a 30 inch wrap and washed with 2 gallons of 2B ethanol. After air drying at 50 ° C., 5.6 kg (70.6%) of the title product were obtained.
[202] Step 5
[203]
[204] Under a nitrogen atmosphere, 825 g of 10% palladium on carbon (50% wetted with water) in a 50 gallon glass tube reactor, 5.5 kg (13.2 mol) of product obtained from step 4 and 15.5 gallons of tetrahydrofuran (THF) were charged It was. This mixture was hydrogenated at 40-50 ° C. for 2 hours. At this time, analysis by TLC showed that the reduction reaction was essentially completed. The reaction was filtered through a 14 inch sparkler precoated with Celite (trade name) and washed with 8 gallons of THF. The filtrate was transferred to a clean 100 gallon glass tube reactor and concentrated in vacuo to 7 gallons followed by 21 gallons of ethyl acetate. This suspension was concentrated to a volume of 10 gallons at a pot temperature of 72 ° C. under atmospheric pressure. The suspension was cooled to 10 ° C., filtered over a 30 inch wrap and washed with 2 gallons of ethyl acetate. After air drying at 55 ° C., 3.9 kg (90%) of the title product (ie free base) were obtained.
[205] Step 6
[206]
[207] Into a 100 gallon glass tube reactor was charged 20 gallons of methanol and 3.7 kg (11.4 mol) of the product obtained from step 5 (ie free base). This suspension was heated to 60 ° C. and 1.7 kg (11.4 mol) of D-tartaric acid was added. The resulting solution was heated to reflux (65 ° C.) for 3 hours and then a suspension formed. The suspension was cooled to 35 ° C., filtered over a 30 inch wrap and washed with 1 gallon of methanol. The wet solid was charged to a 100 gallon glass tube reactor containing 10 gallons of methanol. This suspension was stirred at 25 ° C. for 18 hours. This suspension was filtered over a 30 inch lap and washed with 2 gallons of methanol. After air drying at 50 ° C., 2.7 kg (101%) of the companion product (ie, the tartaric acid salt of the free base (R-(+)-enantiomer)) were obtained. This material was purified in the following manner:
[208] Into a 100 gallon glass tube reactor was charged 10.6 gallons of methanol and 2.67 kg (5.6 mol) of the tartaric acid salt. This suspension was heated to reflux (80 ° C.) for 18 hours. The suspension was cooled to 30 ° C., filtered over a 30 inch wrap and washed with 4 gallons of methanol. After air drying at 50 ° C., 2.05 kg (76.7%) of the title product (ie, tartaric acid salt of free base) were obtained.
[209] Step 7
[210]
[211] A 55 L nalgene tub was charged with 30 L of water and 1056 g (12.6 mol) of sodium bicarbonate at 20 ° C. To the resulting solution was charged 2.0 kg (4.2 mol) of the product obtained from step 6 (ie, tartaric acid salt of free base). This suspension was stirred for 4 hours, during which the foaming reaction occurred largely. After stopping the foaming reaction, the suspension was filtered on a 32 cm funnel and then washed with 1 gallon of water. After air drying at 50 ° C., 1.28 kg (93.5%) of the title product (ie free base) were obtained.
[212] Step 8
[213]
[214] Into a 22 L flask was charged 1277 g (3.9 mol) and 14 L of the product obtained from step 7. This suspension was warmed to 30 ° C. and 375 g (3.9 mol) of methanesulfonic acid were charged. The resulting solution was warmed to 60 ° C., clarified by filtration through diatomaceous earth (celite) and washed with 2 L of water. The filtrate without suspended particles was concentrated to a volume of 6 liters under vacuum. This suspension was cooled to 0-5 ° C. and granulated for 1 hour. The product was filtered on an 18 inch filter funnel and washed with 635 mL of water free of suspended particles. After air drying at 25 ° C. for 18 hours, 1646 g (88%) of the title product (ie mesylate salt trihydrate) Was obtained.
[215] Example 3
[216] (1R ^*, 2R ^*) -1- (4-hydroxy-3-methylphenyl) -2- (4- (4-fluorophenyl) -4-hydroxypiperidin-1-yl) -propan-1-ol-mesylate
[217] 3-Methyl-4-triisopropylsilyloxy-α-bromopropiophenone (9.17 g, 22.97 mmol), 4- (4-fluorophenyl) -4-hydroxypiperidine in ethanol (180 mL) (6.73 g, 34.45 mmol) and triethylamine (8.0 mL, 57.43 mmol) were refluxed for 6 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The phases were separated and the organic layer was washed with brine, then dried over calcium sulfate and concentrated. The residue was flash chromatographed on silica gel (3 * 3.5 inches packed in hexane), eluting as follows: 10% ethyl acetate / hexane (1000 mL), none; 20% ethyl acetate / hexanes (700 mL), none; 20% ethyl acetate / hexane (1300 mL) and 25% ethyl acetate / hexane (700 mL), 7.66 g (65%) of 1- (3-methyl-4-triisopropylsilyl, suitable for use without further purification Oxyphenyl) -2- (4- (4-fluorophenyl) -4-hydroxypiperidin-1-yl) -propane-1-one is obtained as a yellow foam. The sample was recrystallized from ethyl acetate / hexanes to give white crystals having a melting point of 78 to 82 ° C.
[218] A mixture of sodium borohydride (0.564 g, 14.92 mmol) and ethanol (60 mL) was stirred for 10 minutes and then 1- (3-methyl-4-triisopropylsilyloxyphenyl) -2- (4- (4 -Fluorophenyl) -4-hydroxypiperidin-1-yl) -propan-1-one (7.66 g, 14.92 mmol in 10 mL ethanol) was added and washed twice with 30 mL ethanol. . The reaction mixture was stirred at ambient temperature overnight. The precipitated white solid was collected by filtration and dried to 5.72 g (74%) of (1R ^* , 2R ^* )-1- (3-methyl-4-triisopropylsilyloxyphenyl) -2- (4- ( 4-Fluorophenyl) -4-hydroxypiperidin-1-yl) -propan-1-ol was obtained, which was suitable for use without further purification and had a melting point of 188-189 ° C.
[219] The product of the reaction (5.72 g, 11.1 mmol) was dissolved in tetrahydrofuran (150 mL) and tetrabutylammonium fluoride (12.21 mL, 12.21 mmol, 1M tetrahydrofuran solution) was added. The reaction was stirred at ambient temperature for 1 hour and then concentrated. The residue was partitioned between ethyl acetate and water and the two phases separated. The organic layer was slurried with methylene chloride. The precipitated white solid was collected by filtration and dried to 3.41 g (85%) of (1R ^* , 2R ^* )-1- (4-hydroxy-3-methylphenyl) -2- (4- (4-fluoro Phenyl) -4-hydroxypiperidin-1-yl) -propan-1-ol was obtained. Samples (0.16 g, 0.447 mmol) were converted to the corresponding mesylate salts. The salt was slurried in methanol (8 mL) and methanesulfonic acid (0.029 mL, 0.45 mmol) was added. This mixture was filtered and concentrated. The mixture was then recrystallized from ethanol to yield 0.152 g (58%) mesylate salt having a melting point of 215-216 ° C. Anal for C ₂₁ H ₂₅ FNO ₃ CH ₄ SO ₃ : Calcd: C, 58.01; H, 6. 64; N, 3.07. Found: C, 57.99; H, 6. 72; N, 3.17.
[220] Example 4
[221] (1R, 2R) -1- (4-hydroxy-3-methoxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -propan-1-ol and (1S, 2S) -1- (4-hydroxy-3-methoxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -propan-1-ol
[222] 2-bromo-1- (2,2-diphenyl-benzo (1,3) -dioxol-5-yl) -propan-1-one (2.00 g, 4.89 mmol), 4-hydroxy in ethanol A mixture of -4-phenylpiperidine (0.9 g, 5.08 mmol) and triethylamine (1.40 mL, 10.04 mmol) was refluxed overnight. The solvent was removed under reduced pressure and the residue was partitioned between ether and water. The phases were separated and the organic layer was washed with brine, then dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (2 × 5 inches filled with hexane), eluting as follows: 20% ethyl acetate / hexane (500 mL), unweighed precursor; 50% ethyl acetate / hexane (500 mL), 1.76 g (71%) of 1-((2,2) -diphenyl-benzo (1,3) -dioxol-5- suitable for use without further purification Il) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -propan-1-one was obtained as a light tan foam.
[223]
[224] After stirring a mixture of sodium borohydride (0.15 g, 3.97 mmol) and ethanol (5 mL) for 10 minutes, 1- (2,2-diphenyl-benzo (1,3) dioxol-5-yl)- 2- (4-hydroxy-4-phenylpiperidin-1-yl) -propan-1-one (1.70 g, 3.36 mmol in 20 mL ethanol) was added. The reaction was stirred for one week at ambient temperature. The white precipitate was collected, washed with ethanol and ether and then air dried to yield 1.35 g of crude product. The product was recrystallized from ethanol / ethyl acetate / methylene chloride to yield 1.05 g (61%) of (1R ^* , 2R ^* )-1- (2,2-diphenyl-benzo (1,3) having a melting point of 224 to 224.5 ° C. ) -Dioxol-5-yl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -propan-1-ol was obtained. Anal for C ₃₃ H ₃₃ NO ₄ : Calcd: C, 78.08; H, 6.55; N, 2.76. Found: C, 78.16; H, 6. 46; N, 2.72.
[225] A mixture of the reaction product (1.00 g, 1.97 mmol) and 10% palladium on carbon (0.175 g) in methanol (50 mL) and acetic acid (1.0 mL) was hydrogenated at 50 psi (initial pressure) at ambient temperature for 5 hours. Additional catalyst (0.18 g) was added and hydrogenation continued overnight. The reaction was filtered through diatomaceous earth and the filter pad was washed with methanol. The filtrate was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous bicarbonate and then vigorously stirred for 1 hour. The phases were separated and the aqueous layer was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (1 × 4 inch), eluting as follows: 20% ethyl acetate / hexane (500 mL), none; 10% methanol / ethyl acetate (250 mL), 20% methanol / ethyl acetate (250 mL) and 50% methanol / ethyl acetate, 0.51 g (75%) of a bright yellow green solid were obtained. This solid was recrystallized from ethanol to give (1R ^* , 2R ^* )-1- (3,4-dihydroxyphenyl) -2- (4-hydroxy-4-phenyl having a melting point of 167 to 168 DEG C as a white solid. Piperidin-1-yl) -propan-1-ol was obtained. Anal for C ₂₀ H ₂₅ NO ₄ .0.5C ₂ H ₆ O: Calcd: C, 68.83; H, 7. 70; N, 3.82. Found: C, 68.78; H, 8.05; N, 3.70.
[226] The racemate product was dissolved in ethanol and separated into enantiomers by HPLC using the following chromatographic conditions: column, Chiralcel OD; Mobile phase, 25% ethanol / 75% hexane; Temperature, ambient temperature (about 22 ° C.); Detection, ultraviolet (UV) detector at 215 nM. Under these conditions, (1R, 2R) -1- (4-hydroxy-3-methoxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -propan-1-ol This was eluted with a residence time of about 9.12 minutes and was (1S, 2S) -1- (4-hydroxy-3-methoxyphenyl) -2- (4-hydroxy-4-phenyl-piperidine-1- Il) -propan-1-ol eluted with a residence time of about 16.26 minutes.
[227] Example 5
[228] (3R ^*, 4S ^*) -3- (4- (4-fluorophenyl) -4-hydroxypiperidin-1-yl) -chroman-4,7-diol
[229] 7-benzyloxy-3,3-dibromochromenone (54.7 g, 133 mmol), 4- (4-fluorophenyl) -4-hydroxypiperidine (52.0 g, 266 mmol in acetonitrile (2.5 L) ) And triethylamine (38 mL, 270 mmol) were stirred at ambient temperature for 16 hours. A yellow precipitate formed which was collected and washed well with water and ether and then air dried. The yield of 7-benzyloxy-3- {4- (4-fluorophenyl) -4-hydroxy-piperidin-1-yl} -chromanone was 55.4 g (93%) and used without further purification. Was appropriate for. Samples recrystallized from ethanol / tetrahydrofuran had a melting point of 220-221 ° C .:
[230]
[231] Anal for C ₂₇ H ₂₄ FNO ₄ : Calcd: C, 72.80; H, 5. 43; N, 3.13. Found: C, 72.83; H, 5. 82; N, 2.82.
[232] 7-benzyloxy-3- [4- (4-fluorophenyl) -4-hydroxy-piperidin-1-yl] -chromenone (8.24) in ethanol (400 mL) and tetrahydrofuran (600 mL) g, 18.5 mmol) was added sodium borohydride (7.0 g, 185 mmol). This mixture was stirred overnight. Additional sodium borohydride (7.0 g) was added and the reaction mixture was stirred for 3 days. Water was added and the solvent was removed at 45 ° C. under reduced pressure. The solid formed was collected and washed well with water and then ether. The solid is further dried under vacuum overnight to allow 5.01 g (60%) of (3R ^* , 4S ^* )-7-benzyloxy-3- [4- (4-fluorophenyl)-suitable for use without further purification. 4-hydroxy-piperidin-1-yl] -chroman-4-ol was obtained. Samples recrystallized from ethyl acetate / chloroform had a melting point of 194-195 ° C .:
[233]
[234] Anal for C ₂₇ H ₂₈ FNO ₄ : Calcd: C, 72.14; H, 6. 28; N, 3.12. Found: C, 72.15; H, 6. 21; N, 3.12.
[235] (3R ^* , 4S ^* )-7-benzyloxy-3- [4- (4-fluorophenyl) -4-hydroxy-piperidin-1-yl] -chroman-4-ol (0.80 g, 1.78 mmol), a mixture of 10% palladium on carbon (0.16 g), methanol (40 mL) and acetic acid (0.8 mL) was hydrogenated under a starting pressure of 48.5 psi for 8 hours. The reaction was filtered through celite to concentrate the filtrate. The residue was vigorously stirred for 1 h with ether and saturated sodium bicarbonate. The solid was washed with water and ether and dried in vacuo. 0.35 g (54%) of (3R ^* , 4S ^* )-3- [4- (4-fluorophenyl) -4-hydroxy-piperi as a white solid having a melting point of 159 to 160 ° C by recrystallization from ethanol Din-1-yl] -chroman-4,7-diol was obtained:
[236]
[237] Anal for C ₂₀ H ₂₂ FNO ₄ .0.25H ₂ O: Calcd: C, 66.01; H, 6. 23; N, 3.85. Found: C, 66.22; H, 6. 58; N, 3.46.
[238] Racemate [ ³ H] (+)-(1S, 2S) -1- (4-hydroxy-phenyl) -2- (4-hydroxy-4-phenylpiperidino)-for rat premalignment Affinity of Compound A and Other Compounds for Reactions That Replace Specific Binding of 1-propanol or [ ³ H] prazosin compoundRacemate [ ³ H] (+)-(1S, 2S) -1- (4-hydroxy-phenyl) -2- (4-hydroxy-4-phenylpiperidino) -1-propanol bond (nM )[ ³ H] prazosin bonds (nM)[ ³ H] prazosin / [ ³ H] (+)-(1S, 2S) -1- (4-hydroxy-phenyl) -2- (4-hydroxy-4-phenylpiperidino) -1- Rain of propanol (+)-(1S, 2S) -1- (4-hydroxy-phenyl) -2- (4-hydroxy-4-phenylpiperidino) -1-propanol13 ± 419,500 ± 5,0001,500 (1R ^* , 2R ^* )-1- (4-hydroxy-3-methylphenyl) -2- (4- (4-fluorophenyl) -4-hydroxypiperidin-1-yl) -propane-1 -All mesylate14 ± 2.110,000714 (1S, 2S) -1- (4-hydroxy-3-methoxyphenyl) -2- (4-hydroxy-4-phenylpiperidino) -1-propanol948,10086 (3R, 4S) -3- (4- (4-Fluorophenyl) -4-hydroxypiperidin-1-yl) -chroman-4,7-diol18 ± 3> 10,000≥555 Ifenprodil (comparative)70 ± 25114 ± 51.6 Eliprodil (comparative)450 ± 130980 ± 2202.2
[239] According to the present invention, at least one NR2B subtype selective N-methyl-D-aspartate (NMDA) receptor antagonist is another compound that protects neurons from toxic injuries, inhibits the inflammatory response after brain injury or promotes cerebral reperfusion. When used in combination with, it is possible to synergistically treat traumatic brain injury (TBI), ischemic attacks or hypoxic seizures.

权利要求:
Claims (11)
[1" claim-type="Currently amended] (a) thrombolytics or pharmaceutically acceptable salts thereof; And
(b) antagonistic compounds or pharmaceutically acceptable salts thereof for the NR2B subtype selective N-methyl-D-aspartate (NMDA) receptor
A method of treating hypoxic or ischemic seizures in a mammal comprising administering to the mammal in an amount such that each combination thereof is effective to treat hypoxic or ischemic attack.
[2" claim-type="Currently amended] (a) thrombolytics (eg, tissue plasminogen activator (TPA), urokinase, prourokinase or streptokinase) or pharmaceutically acceptable salts thereof;
(b) an antagonist compound for the NR2B subtype selective NMDA receptor or a pharmaceutically acceptable salt thereof; And
(c) a pharmaceutically acceptable carrier
A pharmaceutical composition for treating a hypoxic or ischemic attack in a mammal comprising a medicament comprising (a) and (b) in an amount such that the combination thereof is effective to treat hypoxic or ischemic attack.
[3" claim-type="Currently amended] The method of claim 1,
A method of administering a thrombolytic agent selected from tissue plasminogen activator (TPA), urokinase, prourokinase and streptokinase.
[4" claim-type="Currently amended] The method of claim 2,
A pharmaceutical composition comprising a thrombolytic agent selected from tissue plasminogen activator (TPA), urokinase, prourokinase and streptokinase.
[5" claim-type="Currently amended] The method of claim 1,
A method of administering an NMDA receptor antagonist, an NR2B subtype selective NMDA receptor antagonist of Formula 1 or a pharmaceutically acceptable acid addition salt thereof:
Formula 1

Where
(a) R ² and R ⁵ are present separately and R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, (C ₁ -C ₆ ) alkyl, halo, CF ₃ , OH or OR ⁷ , R ⁵ is methyl or ethyl, or
(b) R ² and R ⁵ together To form a chroman-4-ol ring,
R ¹ , R ³ and R ⁴ are each independently hydrogen, (C ₁ -C ₆ ) alkyl, halo, CF ₃ , OH or OR ⁷ ;
R ⁶ is , or ego;
R ⁷ is methyl, ethyl, isopropyl or n-propyl;
R ⁸ is phenyl unsubstituted or substituted with up to 3 substituents independently selected from (C ₁ -C ₆ ) alkyl, halo and CF ₃ ;
X is O, S or (CH ₂ ) _n ;
n is 0, 1, 2 or 3.
[6" claim-type="Currently amended] The method of claim 5,
As an NR2B subtype selective NMDA receptor antagonist, (+)-(1S, 2S) -1- (4-hydroxy-phenyl) -2- (4-hydroxy-4-phenylpiperidino) -1-propanol or A method of administering a pharmaceutically acceptable acid addition salt thereof.
[7" claim-type="Currently amended] The method of claim 5,
As an NR2B subtype selective NMDA receptor antagonist, (1S, 2S) -1- (4-hydroxy-3-methoxyphenyl) -2- (4-hydroxy-4-phenylpiperidino) -1-propanol or A method of administering a pharmaceutically acceptable acid addition salt thereof.
[8" claim-type="Currently amended] The method of claim 5,
As an NR2B subtype selective NMDA receptor antagonist, (3R, 4S) -3- (4- (4-fluorophenyl) -4-hydroxypiperidin-1-yl) chroman-4,7-diol or its A method of administering a pharmaceutically acceptable acid addition salt.
[9" claim-type="Currently amended] The method of claim 5,
NR2B subtype selective NMDA receptor antagonist, which is (1R ^* , 2R ^* )-1- (4-hydroxy-3-methylphenyl) -2- (4- (4-fluorophenyl) -4-hydroxypiperidine -1-yl) -propan-1-ol mesylate.
[10" claim-type="Currently amended] The method of claim 1,
A method of administering an NR2B subtype selective NMDA receptor antagonist having a ratio of activity for at least about 3: 1 NR2B receptors to activity for α ₁ -adrenergic receptors.
[11" claim-type="Currently amended] The method of claim 1,
A method of administering an NMDA receptor antagonist having a ratio of activity for at least about 5: 1 NR2B receptors to activity for α ₁ -adrenergic receptors.

类似技术:

---

公开号 | 公开日 | 专利标题

---

US9969711B2|2018-05-15|NK1 antagonists

---

EP2747754B1|2017-04-05|Morphinan-derivatives for treating diabetes and related disorders

---

KR101663436B1|2016-10-06|N-substituted benzamides and methods of use thereof

---

KR20170008320A|2017-01-23|Nicotinamide riboside analogs and pharmaceutical compositions and uses thereof

---

KR101991327B1|2019-06-20|Opioid Receptor Ligands and Methods of Using and Making Same

---

US8012997B2|2011-09-06|Isoindole-imide compounds, compositions, and uses thereof

---

ES2343744T3|2010-08-09|Phentilsulphones replaced for the treatment of inflammatory, infectious, immunological or malignal diseases.

---

KR101564153B1|2015-10-28|Isoindoline compounds and methods of making and using the same

---

KR100404717B1|2004-03-30|Novel amino acid derivatives with superior resistance activity

---

US6476052B1|2002-11-05|Isoindolines, method of use, and pharmaceutical compositions

---

US5668132A|1997-09-16|HIV Protease inhibitors useful for the treatment of AIDS

---

EP1363900B1|2007-01-24|Isoindole-imide compounds, compositions and uses thereof

---

AU2002337277B2|2008-06-05|Compositions for the treatment of Parkinson's disease containing CB1 receptor antagonist and a product that activates dopaminergic neurotransmission in the brain

---

US7879863B2|2011-02-01|Aniline derivatives

---

EP1787982B1|2010-05-12|11Beta-Hydroxysteroid dehydrogenase type 1 active compounds

---

US7723323B2|2010-05-25|Pharmaceutical use of fused 1,2,4-triazoles

---

KR100197454B1|1999-06-15|Diazabicyclic neurokinin antagonists

---

JP5852565B2|2016-02-03|Deuterated isoindoline-1,3-dione derivatives as PDE4 and TNF-α inhibitors

---

US7674820B2|2010-03-09|Ion channel modulating activity I

---

US7282510B2|2007-10-16|Small molecule inhibitors of rotamase enzyme activity

---

US5968957A|1999-10-19|Method of using neurotrophic sulfonamide compounds

---

JP3118090B2|2000-12-18|1-acyl piperidine compound

---

ES2306087T3|2008-11-01|Substituted morpholine and tiomorpholine derivatives.

---

US8138342B2|2012-03-20|11β-hydroxysteroid dehydrogenase type 1 active spiro compounds

---

US7700583B2|2010-04-20|11β-hydroxysteroid dehydrogenase type 1 active compounds

同族专利:

---

公开号 | 公开日

---

TWI255719B|2006-06-01|

---

NZ513984A|2001-09-28|

---

ZA200107315B|2003-03-04|

---

HU0103558A3|2003-03-28|

---

EP1186304A3|2003-02-05|

---

IL145209D0|2002-06-30|

---

CA2356545A1|2002-03-06|

---

AU6564301A|2002-03-07|

---

HU0103558A2|2002-07-29|

---

US20020123510A1|2002-09-05|

---

JP2002322096A|2002-11-08|

---

EP1186304A2|2002-03-13|

---

US6821985B2|2004-11-23|

---

HU0103558D0|2001-11-28|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

法律状态:
2000-09-06|Priority to US23094300P

---

2000-09-06|Priority to US60/230,943

---

2001-09-06|Application filed by 실버스타인 아써 에이., 화이자 프로덕츠 인코포레이티드

---

2002-03-14|Publication of KR20020020223A

优先权:

---

申请号 | 申请日 | 专利标题

---

US23094300P| true| 2000-09-06|2000-09-06|

---

US60/230,943|2000-09-06|