KR20030066797A - Excitatory amino acid receptor antagonists - Google Patents

Abstract

The present invention provides methods using novel pharmaceutically acceptable salts of the compounds of formula (I) and formula (Ia), as well as pharmaceutically acceptable salts, and also provides formulas (I) and (Ia) Provided are methods for preparing compounds of, or pharmaceutically acceptable salts thereof. Compounds of formula (I) and formula (Ia) are useful for the treatment of neurological disorders, especially migraine headaches.

Description

Excitatory amino acid receptor antagonist {EXCITATORY AMINO ACID RECEPTOR ANTAGONISTS}

In the mammalian central nervous system (CNS), the transmission of nerve excitability is regulated by the interaction between the neurotransmitter released by the sending neuron and the surface receptors on the recipient neuron, causing excitability of the recipient neuron. L-glutamate, the most abundant neurotransmitter in the CNS, mediates major excitatory pathways in mammals and is called excitatory amino acid (EAA). Receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors). Watkins & Evans, Ann. Rev. Pharmacol. Toxicol., 21,165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol., 29,365 (1989); Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharn. Sci., 11, 25 (1990). Excitatory amino acids are of physiological importance and play an important role in various physiological processes such as organ strengthening (learning and memory), development of junctional plasticity, motor control, respiration, cardiovascular control, and sensory perception.

Excitatory amino acid receptors are classified into two general types. Receptors that are directly linked to the opening of cation channels in the cell membranes of neurons are called "ionotropic". Receptors of this type are selective agonists N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and chinic acid (KA) Has been subdivided into three or more subtypes defined by the polarization action. Molecular biological studies have established that AMPA receptors are composed of subunits (GluR ₁ -GluR ₄ ) that can aggregate to form functional ion channels. _Five kainate receptors identified as either high affinity (KA1 and KA2) or low affinity (consisting of GluR ₅ , GluR ₆ , and / or GluR ₇ subunits) have been identified (Bleakman et al. , Molecular Phatmacology, 49, No. 4,581, (1996).

The second common type of receptor is a "metabotropic" excitatory amino acid receptor linked to a G-protein or linked to a secondary messenger. This second type is associated with multiple secondary messengers, which intensify phosphoinositide hydrolysis, activate phospholipase D, increase or decrease cAMP formation, and change ion channel function (Schoepp and Conn, Trends in Pharmaacol. Sci., 14, 13 (1993)]. Both types of excitatory amino acid receptors not only mediate normal junctional delivery along the excitatory pathway, but also appear to be involved in the modification of synaptic connections during development and throughout life (Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol). Sci., 11,508 (1990); McDonald and Johnson, Brain Research Reviews, 15,41 (1990)).

Excessive or inappropriate stimulation of the excitatory amino acid receptors can lead to damage or loss of neuronal cells through a mechanism known as excitatory toxicity. This process has been proposed to mediate neuron degeneration in various neurological disorders and conditions. Because of the degenerative medical significance of these neurons, the degeneration of these neuronal processes is an important therapeutic target. For example, excitatory toxicity of excitatory amino acid receptors can be attributed to numerous neurological disorders including cardiac bypass and post-transplant cerebral deficiency, stroke, cerebral ischemia, trauma or inflammation caused by spinal cord lesions, perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage. Has been associated with pathophysiology. In addition, excitatory toxicity is associated with chronic neurodegenerative conditions, including Alzheimer's disease, Huntington's chorea, congenital ataxia, AIDS-induced dementia, amyotrophic lateral sclerosis, idiopathic and drug-induced Parkinson's disease, as well as eye damage and retinopathy. Has been. Other nervous system disorders associated with excitatory toxicity and / or glutamate dysfunction include disorders associated with anxiety such as muscle stiffness including tremors, drug resistance and withdrawal, cerebral edema, convulsive disorders including epilepsy, depression, anxiety and post-traumatic stress syndrome , Dyskinesia, and depression, schizophrenia, bipolar disorder, fever, and psychosis related to drug addiction or drug addiction (see generally US Pat. Nos. 5,446,051 and 5,670,516). It may also be useful as an excitatory amino acid receptor antagonist analgesic and may be useful for treating or preventing various forms of headache, including cluster headaches, tension headaches, and chronic daily headaches. In addition, European patent application W098 / 45720 reports that it is involved in the pathogenesis of acute and chronic pain states including acute excitatory amino acid receptor excitatory toxic pain, intractable pain, neuropathic pain, post-traumatic pain.

It is also known that trigeminal ganglia and its associated nerve pathways are associated with headache, especially pain in the head and face, such as migraine. Moskowitz (Cephalalgia, 12,5-7, (1992)) suggests that vascular active neuropeptides from axons, where unknown triggers stimulate trigeminal ganglia by stimulating the pulse system in the head tissue, which in turn stimulates the pulse system It is proposed to cause the release of. These neuropeptides initiate a series of events leading to neurological inflammation of the meninges, which results in pain. This neurological inflammation is blocked by a sumatriptan at a dose similar to that required for treating acute migraine headaches in humans. However, this dosage of sumatriptan is associated with contraindications as a result of vasoconstrictive properties following sumatriptan (MacIntyre, PD et al., British Journal of Clinical Pharmacology, 34, 541-546 (1992); Chester, AH et al., Cardiovascular Research, 24,932-937 (1990); Conner, HE et al., European Journal of Pharmacology, 161,91-94 (1990)). Recently, it has been reported that all five elements of the catenate subtype of the ionotropic glutamate receptor were expressed in rat trigeminal neurons, in particular high levels of GluR ₅ and KA2 were observed (Sahara et al., The Journal of Neuroscience, 17 (17), 6611 (1997)]. As such, migraine headaches represent another neurological disorder that may be associated with glutamate receptor excitatory toxicity.

It is believed that the use of neuroprotective agents, such as excitatory amino acid receptor antagonists, is useful for treating or preventing (or preventing) all these disorders and for reducing the extent of neurological damage associated with these disorders. For example, studies have shown that AMPA receptor antagonists are neuroprotective in local and global cerebral ischemia models. The competitive AMPA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo [f] quinoxaline) has been reported to be useful for preventing pre and local ischemic damage (Sheardown et al., Science, 247,571 (1900); Buchan et al., Neuroreport, 2,473 (1991); Le Peillet et al., Brain Research, 571, 115 (1992). The uncompetitive AMPA receptor antagonist GKYI 52466 has been shown to be an effective neuroprotective agent in the rat ischemic model (see LaPeillet et al., Brain Research, 571, 115 (1992)). European Patent Application Publication Nos. 590789A1 and US Pat. Nos. 5,446,051 and 5,670,516 disclose that certain decahydroisoquinoline derivative compounds are AMPA receptor antagonists and are themselves useful in the treatment of various disorder conditions such as pain and migraine headaches. . W098 / 45270 discloses that certain decahydroisoquinoline derivative compounds are selective antagonists of the iGluR ₅ receptor and are useful for the treatment of various forms of pain, including severe pain, chronic pain, intractable pain and neuropathic pain.

In accordance with the present invention, we have found novel compounds that are selective antagonists of the iGluR ₅ receptor subtype and thus may be useful for the treatment of various neurological disorders or neurodegenerative diseases discussed above. These selective antagonists have been able to address the long-awaited need for safe and effective treatment of neurological disorders that do not have side effects. Treatment of neurological disorders and neurodegenerative diseases is added herein.

Summary of the Invention

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof or prodrug thereof.

In a preferred embodiment, the present invention provides a compound of formula la or a pharmaceutically acceptable salt thereof.

Wherein R ¹ and R ² are each independently hydrogen, (C ₁ -C ₂₀ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkylaryl, (C ₁ -C ₆ ) Alkyl (C ₃ -C ₁₀ ) cycloalkyl, (C ₁ -C ₆ ) alkyl-N, NC ₁ -C ₆ dialkylamine, (C ₁ -C ₆ ) alkyl-pyrrolidine, (C ₁ -C ₆ ) Alkyl-piperidine or (C ₁ -C ₆ ) alkyl-morpholine, provided that at least one of R ¹ and R ² is other than hydrogen)

In a particularly preferred embodiment, the invention provides D-(-)-mandelate of formula (I) or formula (la), wherein formula (I) and formula (Ia) are as defined above.

In another embodiment, the invention provides a method of treating or preventing a neurological disorder, or neurodegenerative condition, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or Formula (Ia) or a pharmaceutically acceptable salt thereof. To provide. Examples of such neurological disorders, or neurodegenerative conditions, include cerebral deficiency after cardiac bypass and transplantation; stroke; Cerebral ischemia; Spinal cord lesions following trauma or inflammation; Perinatal hypoxia; Cardiac arrest; Hypoglycemic neuron damage; Alzheimer's disease; Huntington chorea; Congenital ataxia; AIDS-induced dementia; Amyotrophic lateral sclerosis; Idiopathic and drug-induced Parkinson's disease; Eye damage and retinopathy; Muscle stiffness, including tremors; Drug resistance and withdrawal; Brain edema; Convulsive disorders including epilepsy; depression; Anxiety related disorders such as anxiety and post-traumatic stress syndrome; Delayed dyskinesia; Depression, schizophrenia, bipolar disorder, fever, and psychosis associated with drug addiction or drug addiction; Headaches, including cluster headaches, tension headaches, and chronic daily headaches; migraine; And acute and chronic pain conditions including severe pain, intractable pain, neuropathic pain and post-traumatic pain.

In particular, the present invention provides a method for treating or preventing migraine headaches comprising administering to a patient in need thereof an effective amount of a compound of Formula I or Formula Ia or a pharmaceutically acceptable salt thereof.

More specifically, the present invention provides a method for treating or preventing migraine headaches comprising administering to a patient in need thereof an effective amount of D-(-)-mandelate of a compound of Formula (I) or Formula (Ia).

In addition, the present invention combines a compound of formula (2) and a suitable base together in a suitable solvent, and then adds a compound of formula (3), and then oxidizes to a compound of formula (5), followed by halogenation and a nitrogen protecting group. Provided is a process for the preparation of a compound of formula (Ia) comprising removing.

Where R ² is as previously defined herein, Pg is a suitable nitrogen protecting group and LgO is a suitable leaving group

Where R ¹ is as previously defined herein

The present invention also provides pharmaceutically acceptable salts and hydrates useful in the treatment of neurological disorders or neurodegenerative conditions, comprising as an active ingredient a compound of Formula (I) or Formula (Ia) together with a pharmaceutically acceptable carrier, diluent or excipient. Provided are pharmaceutical compositions of the compounds of Formula I and Formula Ia. The present invention also encompasses novel intermediates and methods for the synthesis of compounds of formula (I) and formula (Ia).

More specifically, the present invention is useful for treating or preventing migraine, comprising as active ingredient D-(-)-mandelate of Formula (I) or Formula (Ia) together with one or more pharmaceutically acceptable carriers, diluents or excipients. It provides a pharmaceutical composition.

The present invention also provides the use of a medicament for the treatment or prevention of a neurological disorder or neurodegenerative condition of a compound of formula (I) or formula (Ia).

More specifically, the present invention provides a use for the preparation of a medicament for treating or preventing migraine of a compound of Formula (I) or Formula (Ia).

Detailed description of the invention

The present invention provides compounds which function as selective iGluR ₅ receptor antagonists, as well as pharmaceutically acceptable salts thereof, prodrugs thereof and compositions thereof.

The present invention also provides a method of treating a neurological disorder or neurodegenerative condition. In particular, the present invention provides a method for treating migraines, which may be indicated by the inhibition of neuroeural dura protein extravasation, which is a specific mechanism of action. By treating migraine patients with compounds or compositions that are selective antagonists of iGluR ₅ receptors to other excitatory amino acid receptors, the neuropathy that mediates migraines without the side effects of drugs to optimize the vasoconstrictive activity of 5-HT ₁ -mediated sumatriptan Extravascular outflow can be suppressed.

It should be understood by those skilled in the art that all compounds useful in the methods of the invention are available for prodrug formulations. As used herein, the term “prodrug” refers to a parent compound (eg, a carboxylic acid) in which the prodrug is represented in formula I by, for example, a hydrolysis segment, an oxidation segment, a reduction segment, or an enzyme segment. (Drug) or, optionally, a parent dicarboxylic acid). Such prodrugs may be, for example, metabolically labile ester or diester derivatives of the parent compound with carboxylic acid groups. It is to be understood that such prodrugs, such as metabolically labile ester or diester derivatives of the compounds of formula I, are included in the present invention. In all cases, the use of the compounds described herein as prodrugs is contemplated, often preferred, and therefore, the prodrugs of all the compounds used are included in the name of the compounds herein. Diester derivatives of the compounds of I. Conventional procedures for the selection and preparation of appropriate prodrugs are known to those skilled in the art.

More specifically, examples of prodrugs of formula I which are understood to be included within the scope of the present invention are represented by the following formula la or pharmaceutically acceptable salts thereof

<Formula Ia>

Wherein R ¹ and R ² are each independently hydrogen, (C ₁ -C ₂₀ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkylaryl, (C ₁ -C ₆ ) Alkyl (C ₃ -C ₁₀ ) cycloalkyl, (C ₁ -C ₆ ) alkyl-N, NC ₁ -C ₆ dialkylamine, (C ₁ -C ₆ ) alkyl-pyrrolidine, (C ₁ -C ₆ ) Alkyl-piperidine or (C ₁ -C ₆ ) alkyl-morpholine, provided that at least one of R ¹ and R ² is other than hydrogen)

Selective iGluR ₅ receptor antagonists of the present invention may exist as pharmaceutically acceptable salts, and therefore the salts themselves are understood to be within the scope of the present invention. As used herein, the term “pharmaceutically acceptable salts” refers to salts of the compounds provided or used in the present invention that are not substantially toxic to the living body. Typical pharmaceutically acceptable salts refer to compounds of the present invention and pharmaceuticals And salts thereof which are prepared by reacting an academically acceptable inorganic or organic acid or organic base or inorganic base. Such salts are known as acid addition salts and base addition salts.

It is understood by those skilled in the art that most or all of the compounds used in the present invention may form salts, and salt forms of pharmaceuticals are commonly used because often the salt forms of the pharmaceutical are crystallized and purified more readily than the free base. Will be. In all cases, the use of pharmaceutical substances described herein as salts is contemplated in the description herein and is often preferred, and pharmaceutically acceptable salts of all compounds are included in their names.

Acids commonly used to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and p-toluenesulfonic acid, mandelic acid, 1,5-naphthalenedisulfonic acid, methanesulfonic acid, oxalic acid, p Organic acids such as bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. Examples of such pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, bromides, iodine, Acetates, propionates, decanoates, caprylates, acrylates, formates, hydrochlorides, dihydrochlorides, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, Suverate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyn-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate , Phthalate, xylene sulfonate, phenyl acetate, phenyl propionate, phenyl butyrate, citrate, lactate , α-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, napadisylate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with inorganic acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as D-(-)-mandelic acid, 1,5-naphthalenedisulfonic acid, maleic acid, and methanesulfonic acid. have.

Base addition salts include those derived from inorganic bases such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates and the like. Accordingly, such bases useful for preparing the salts of the present invention include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium tricarbonate and the like. Particular preference is given to potassium and sodium salt forms. Particular counterions that form part of the salts of the present invention are generally recognized to be non-essential as long as the salts as a whole are pharmacologically acceptable and unless the counterions provide undesirable qualities to the salts as a whole. Should be. It should be further understood that such salts may be present as hydrates.

As used herein, the term “stereoisomer” refers to a compound composed of the same atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. A three-dimensional structure is called a configuration. As used herein, the term “enantiomer” refers to two stereoisomers whose molecules are mirror images of one another. The term "chiral center" denotes a carbon atom to which four groups which are different from each other are attached. The term "diastereomer" as used herein refers to stereoisomers that are not enantiomers. Also, two diastereomers having different arrangements from each other in only one chiral center are referred to herein as "epimers." The term "racemate", "racemic mixture" or "racemic modification" refers to a mixture of equivalent amounts of enantiomers.

The term "enantiomeric enrichment" as used herein refers to an increase in the amount of one enantiomer relative to the other enantiomer. A convenient way to express the concentration of enantiomers achieved is the concept of "ee" (enantiomeric excess) which can be found using the following equation.

Wherein E ¹ is the amount of the first enantiomer and E ² is the amount of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as when present in the racemic mixture, and sufficient enrichment of the enantiomers to achieve a final ratio of 50:30 is achieved, the ee of the first enantiomer Is 25%. However, when the final ratio is 90:10, the ee of the first enantiomer is 80%. More than 90% of the ee is preferred, more than 95% of the ee is most preferred, and more than 99% of the ee is most particularly preferred. Enrichment of enantiomers can be readily determined by one skilled in the art using standard techniques and procedures such as gas or high performance liquid chromatography with chiral columns. The choice of suitable chiral columns, eluents and conditions necessary to separate the enantiomer pairs will be apparent to those skilled in the art. In addition, enantiomers of compounds of formula (I) or formula (I ') are described in J. Chem. Jacques et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and can be partitioned by those skilled in the art using standard techniques known in the art.

Compounds of the present invention may have one or more chiral centers and exist in various stereoisomeric configurations. As a result of these chiral centers, the compounds of the present invention exist as racemates, as a mixture of enantiomers and as individual enantiomers, as well as as mixtures of diastereomers and diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention.

The terms "R" and "S" are used herein as is commonly used to refer to a particular arrangement of chiral centers in organic chemistry. The term "R" (rectus) refers to an arrangement of chiral centers where the priority of the groups (from the highest to the second lowest) has a clockwise relationship when viewed toward the lowest priority group along the bond. The term "S" (sinister) refers to an arrangement of chiral centers where the priority of the groups (from the highest to the second lowest) has a counterclockwise relationship when viewed along the bond and towards the lowest priority group. . The priority of groups is based on their atomic number (in order of decreasing atomic number). A partial list of priorities and discussion of stereochemistry is included in "Nomenclature of Organic Compounds: Principles and Practice", (J. H. Fletcher et al., 1974) at pages 103-120.

Specific stereoisomers and enantiomers of the compounds of Formula I and Formula Ia are described in Eliel and Wilen, "Stereochemistry of Organic Compound", John Wiley & Sons, Inc., 1994, Chapter 7, Separation of Stereoisomers. Resolution. Racemization, and by Collet and Wilen, "Enantiomers, Racemates, and Resolutions", John Wiley & Sons, Inc., 1981, can be prepared by those skilled in the art using known techniques and methods. For example, special stereoisomers and enantiomers can be prepared by stereospecific synthesis using enantiomeric and geometrically pure, enantiomeric or geometrically concentrated starting materials. Special stereoisomers and enantiomers can also be cleaved and recovered by chromatography using chiral stationary phases, enzymatic cleavage or fractional recrystallization of addition salts formed by reagents used for this purpose.

The term "Pg" as used herein refers to a suitable nitrogen protecting group. Examples of suitable nitrogen protecting groups as used herein refer to those groups intended to protect or block nitrogen groups against undesirable reactions during the synthesis process. The choice of the appropriate nitrogen protecting group to be used will depend on the conditions that can be used in subsequent reaction steps that require protection, which will be apparent to those skilled in the art. Commonly used nitrogen protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981)). Suitable nitrogen protecting groups are formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl , acyl groups such as α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl and the like, sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl, benzyloxycarbonyl, p- Chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl , 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4 , 5-trimethoxybenzyloxycarbonyl, l- (p-biphenylyl) -1-methylethoxycarbonyl, α, α-dimethyl-3,5-dimethoxybenzyl Cycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2 , 2, -trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohex Carbamate generators such as siloxycarbonyl, phenylthiocarbonyl and the like, alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like, and silyl groups such as trimethylsilyl and the like. Preferred suitable nitrogen protecting groups are formyl, acetyl, methoxycarbonyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz) .

The term “(C ₁ -C ₄ ) alkyl” as used herein refers to a straight or branched chain monovalent saturated aliphatic chain of 1 to 4 carbon atoms, methyl, ethyl, n-propyl, isopropyl, n- Butyl, isobutyl, and the like.

The term “(C ₁ -C ₆ ) alkyl” as used herein refers to a straight or branched chain monovalent saturated aliphatic chain of 1 to 6 carbon atoms, methyl, ethyl, n-propyl, isopropyl, n- Butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.

The term "(C ₁ -C ₁₀ ) alkyl" as used herein refers to a straight or branched chain monovalent saturated aliphatic chain of 1 to 10 carbon atoms, methyl, ethyl, propyl, isopropyl, n-butyl, Isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl, octyl, 4-methyl- 3-heptyl and the like.

The term “(C ₁ -C ₂₀ ) alkyl” as used herein refers to a straight or branched chain monovalent saturated aliphatic chain of 1 to 20 carbon atoms, methyl, ethyl, propyl, isopropyl, butyl, isobutyl , t-butyl, pentyl, isopentyl, hexyl, 3-methylpentyl, 2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n- Tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-nonadecyl, n-eicosyl, and the like. The terms "(C ₁ -C ₄ ) alkyl", "(C ₁ -C ₆ ) alkyl", and "(C ₁ -C ₁₀ ) alkyl" are included within the definition of "(C ₁ -C ₂₀ ) alkyl" It is understood that.

The terms "Me", "Et", "Pr", "iPr", "Bu" and "t-Bu" as used herein refer to methyl, ethyl, propyl, isopropyl, butyl and tert-butyl, respectively.

As used herein, the term “(C ₁ -C ₄ ) alkoxy” refers to an oxygen atom having a straight or branched chain monovalent saturated aliphatic chain of 1 to 4 carbon atoms, methoxy, ethoxy, n-pro Foxy, isopropoxy, n-butoxy, and the like, are not limited thereto.

As used herein, the term "(C ₁ -C ₆ ) alkoxy" refers to an oxygen atom having a straight or branched chain monovalent saturated aliphatic chain of 1 to 6 carbon atoms, methoxy, ethoxy, n-pro Foxy, isopropoxy, n-butoxy, n-pentoxy, n-hexoxy and the like.

As used herein, the term “(C ₁ -C ₆ ) alkyl (C ₁ -C ₆ ) alkoxy” refers to a straight chain of 1 to 6 carbon atoms having a (C ₁ -C ₆ ) alkoxy group attached to an aliphatic chain or Branched chain monovalent represents a saturated aliphatic chain.

As used herein, the terms "halo", "halide" or "Hal" refer to chlorine, bromine, iodine or fluorine atoms unless otherwise defined herein.

As used herein, the term “(C ₂ -C ₆ ) alkenyl” refers to a straight or branched monovalent, unsaturated aliphatic chain having 2 to 6 carbon atoms. Typical C ₂ -C ₆ alkenyl groups are ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-1 -propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2 -Propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl and the like.

As used herein, the term "aryl" refers to a monovalent carbocyclic group comprising one or more fused or unfused phenyl rings, for example phenyl, 1- or 2-naphthyl, 1,2-di Hydronaphthyl, 1,2,3,4-tetrahydronaphthyl and the like.

The term "substituted aryl" refers to halogen, hydroxy, cyano, nitro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) alkyl (C ₃ -C ₁₀ ) Selected from the group consisting of cycloalkyl, (C ₁ -C ₆ ) alkylaryl, (C ₁ -C ₆ ) alkoxycarbonyl, protected carboxy, carboxymethyl, hydroxymethyl, amino, aminomethyl, or trifluoromethyl An aryl group substituted with one or two residues is shown.

The term “(C ₁ -C ₆ ) alkylaryl” as used herein refers to a straight or branched chain monovalent saturated aliphatic chain of 1 to 6 carbon atoms having an aryl group attached to an aliphatic chain. The following are included within the term "C ₁ -C ₆ alkylaryl"

Etc.

The term "aryl (C ₁ -C ₆ ) alkyl" as used herein denotes an aryl group having a straight or branched chain monovalent saturated aliphatic chain of 1 to 6 carbon atoms attached to an aryl group. The following are included within the term "aryl (C ₁ -C ₆ ) alkyl"

Etc.

As used herein, the term "(C ₃ -C ₁₀ ) cycloalkyl" refers to a saturated hydrocarbon ring structure consisting of one or more fused or unfused rings comprising 3 to 10 carbon atoms. Typical C ₃ -C ₁₀ cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantanyl, and the like.

The term "(C ₁ -C ₆ ) alkyl (C ₃ -C ₁₀ ) cycloalkyl" as used herein refers to one to six carbon atoms having (C ₃ -C ₁₀ ) cycloalkyl attached to an aliphatic chain. Linear or branched monovalent saturated aliphatic chains. The following are included within the term "(C ₁ -C ₆ ) alkyl (C ₃ -C ₁₀ ) cycloalkyl"

Etc.

The term "(C ₁ -C ₆ ) alkoxycarbonyl" as used herein refers to a carbonyl group having a (C ₁ -C ₆ ) alkyl group attached to a carbonyl carbon via an oxygen atom. Examples of such groups include t-butoxycarbonyl, methoxycarbonyl and the like.

As used herein, the term “heterocycle” refers to a 5- or 6-membered ring comprising 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen. To those skilled in the art, the remaining atoms of the ring are recognized as carbon. The ring may be saturated or unsaturated. Examples of heterocyclyl groups include thiophenyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, thiazolidinyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thidiazolyl, oxdiazolyl, Tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, imidazolyl, dihydropyrimidyl, tetrahydropyrimidyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, pyri Midinyl, imidazolidinyl, morpholinyl, pyranyl, thiomorpholinyl, and the like. The term "substituted heterocycle" refers to halogen, hydroxy, cyano, nitro, oxo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) alkoxy, C ₁ -C ₆ alkyl (C ₃ -C ₁₀ ) Cycloalkyl, (C ₁ -C ₆ ) alkylaryl, (C ₁ -C ₆ ) alkoxycarbonyl, protected carboxy, carboxymethyl, hydroxymethyl, amino, aminomethyl, or trifluoromethyl Heterocycle group substituted with 1 or 2 residues selected.

The term "N, NC ₁ -C ₆ -dialkylamine" as used herein refers to a nitrogen atom substituted two times with a straight or branched chain monovalent saturated aliphatic chain of 1 to 6 carbon atoms. -N (CH ₃ ) ₂ , -N- (CH ₂ CH ₃ ) ₂ , -N (CH ₂ CH ₂ CH ₃ ) ₂ , -N (CH ₂ CH ₂ CH ₂ CH ₃ ) _2, and the like. NC ₁ -C ₆ dialkylamine.

The term "C ₁ -C ₆ alkyl-N, NC ₁ -C ₆ dialkylamine" as used herein refers to 1 to 6 carbon atoms with N, NC ₁ -C ₆ dialkylamine attached to an aliphatic chain. Straight or branched chain monovalent is a saturated aliphatic chain. The following are included within the term "C ₁ -C ₆ alkyl-N, NC ₁ -C ₆ dialkylamine":

Etc.

The term “(C ₁ -C ₆ ) alkyl-pyrrolidine” as used herein refers to a straight or branched chain monovalent saturated aliphatic chain of 1 to 6 carbon atoms with pyrrolidine attached to an aliphatic chain. . The following are included within the scope of the term “(C ₁ -C ₆ ) alkyl-pyrrolidine”:

Etc.

The term “(C ₁ -C ₆ ) alkyl-piperidine” as used herein refers to a straight or branched chain monovalent saturated aliphatic chain of 1 to 6 carbon atoms with piperidine attached to an aliphatic chain. . The following are included within the scope of the term “(C ₁ -C ₆ ) alkylpiperidine”:

Etc.

The term “(C ₁ -C ₆ ) alkyl-morpholine” as used herein refers to a straight or branched chain monovalent saturated aliphatic chain of 1 to 6 carbon atoms with morpholine attached to an aliphatic chain. The following are included within the scope of the term “C ₁ -C ₆ alkyl-morpholine”:

Etc.

Designation " Indicates a bond protruding forward of the page face.

Designation " Indicates a bond that protrudes to the rear of the page face.

The term “iGluR ₅ ” as used herein refers to the upper class of kinate ionogenic glutamate receptor, subtype 5, of the excitatory amino acid receptor.

As used herein, the term “migraine” refers to the nervous system, which is characterized by neurological symptoms such as regular seizures of head pain (which are not due to structural brain abnormalities such as those resulting from tumors or strokes), gastrointestinal disorders and, in all cases, visual distortions. It may indicate a disorder. Migraine-specific headaches usually last for one day and usually involve vomiting, hemophilia and glare.

Migraine headaches can appear in "chronic" states or "acute" seizures (career, episodes, episodes). As used herein, the term “chronic” means a slow running and long lasting state. This chronic condition is treated when diagnosed, and treatment continues over the entire duration of the disease. In contrast, the term “acute” means a short term worsening event or seizure followed by a period of remission. Thus, the treatment of migraine headaches takes into account both acute events and chronic conditions. In the acute case, the compound is administered when symptoms appear and is discontinued when the symptoms disappear. As mentioned above, chronic conditions are treated over the entire duration of the disease.

The term "patient" as used herein refers to a mammal such as a mouse, gerbils rat, guinea pig, rat, dog or human. However, it is understood that the preferred patient is a human.

The term "selective iGluR ₅ receptor antagonist" as used herein is understood to include excitatory amino acid receptor antagonists that selectively bind to the iGluR ₅ kinate receptor subtype rather than the iGluR ₂ AMPA receptor subtype. Preferably the selective iGluR ₅ antagonist used according to the method of the invention has at least 10 times greater binding affinity for iGluR ₅ than iGluR ₂ and more preferably at least 100 times greater binding affinity. Selective iGluR ₅ receptor antagonists are readily available to those skilled in the art or are readily prepared by those skilled in the art by procedures known below. For example, WO 98/45270 provides examples of selective iGluR ₅ receptor antagonists and discloses synthetic methods.

The terms “treating”, “treatment”, or “treat” as used herein, respectively, alleviate the symptoms, temporarily or permanently eliminate the cause of the symptoms that occur, and prevent or prevent the symptoms of the listed disorders. By slowing the appearance, or reversing its progress or depth. As such, the methods of the present invention include both therapeutic and prophylactic administration.

As used herein, the term “effective amount” refers to the amount or dosage of a compound at one or multiple doses to a patient that provides the desired effect to the patient being diagnosed or treated. Effective amounts can be readily determined by the attending physician in the art by the use of known techniques and by observing the results obtained under similar circumstances. In determining the effective amount or effective dose of a compound to be administered, the attending physician is responsible for determining the mammalian species, its size, age, and general health, the degree of involvement or depth of the associated migraine, the response of the individual patient, the specific compound administered. Many factors are considered, including, but not limited to, the method of administration, the bioavailability characteristics of the formulation to be administered, the selected dosage regimen, the use of concomitant agents, and other related circumstances.

Typical daily dosages include from about 0.01 mg / kg to about 100 mg / kg of each compound used in the present method of treatment. Preferably, the daily dose is about 0.05 mg / kg to about 50 mg / kg, more preferably about 0.1 mg / kg to about 25 mg / kg.

Whether administered alone or in combination with compounds that can act as selective iGluR ₅ receptor antagonists, oral administration is the preferred route of administering the compounds used in the present invention. However, oral administration is not the only route, and not even the only preferred route. Other preferred routes of administration include the intradermal, dermal, intravenous, intramuscular, intranasal, buccal, or rectal routes. When a selective iGluR ₅ receptor antagonist is administered as a combination of compounds, one of the compounds may be administered by one route, such as the oral route, and the other is intradermal, dermal, intravenous, depending on the particular situation required. It can be administered by intramuscular, intranasal, pulmonary, buccal, or rectal routes. The route of administration may vary in any way and is limited by the physical properties of the compound and the convenience of the patient and caregiver.

The compounds used in the present invention can be administered as pharmaceutical compositions, and therefore pharmaceutical compositions incorporating a compound of formula (I) or formula (Ia) are an important embodiment of the present invention. Such compositions may take any pharmaceutically acceptable physical form, but pharmaceutical compositions administered orally are particularly preferred. Such pharmaceutical compositions comprise an effective amount of a compound of Formula (I) or Formula (Ia), including pharmaceutically acceptable salts, prodrugs, and hydrates as active ingredients, the effective amount being related to the daily dose of the compound being administered. Each dosage unit may comprise a daily dosage of a given compound or may comprise a portion of the daily dosage, such as ½ or ⅓ of the daily dosage. The amount of each compound included in each dosage unit depends on other factors such as the identity of the particular compound selected for treatment and the indication for which it is provided. The pharmaceutical compositions of the present invention may be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by using known procedures.

Preferably the composition comprises each dose in an amount of about 1 to about 500 mg, more preferably about 5 to about 300 mg (eg, 25 mg), alone or in a single unit dosage form. Formulated in unit dosage form. The term “unit dosage form” refers to a physically discrete unit suitable as a single administration to a patient, comprising a predetermined amount of active substance, together with a suitable pharmaceutical carrier, diluent, or excipient, calculated so that each unit produces the desired therapeutic effect. Indicates.

Inactive ingredients and methods for the formulation of pharmaceutical compositions are conventional. Most formulation methods used in pharmaceuticals can be used herein. All forms of conventional compositions can be used, including tablets, chewable tablets, capsules, solutions, parenteral solutions, intranasal sprays or powders, oral tablets, suppositories, intradermal patches and suspensions. Generally, depending on the desired dosage and the type of composition used, the composition comprises from about 0.5% to about 50% total of the compound. However, the amount of a compound is best defined as an "effective amount" which is the amount of each compound that provides the desired dosage to a patient in need of such treatment.

Since the activity of the compounds used in the present invention does not depend on the nature of the composition, the composition is therefore selected and formulated only in consideration of convenience and economy.

Capsules are prepared by mixing the compound with an appropriate diluent and filling the appropriate amount of the mixture into the capsule. Common diluents include inert powder materials such as starch, powdered cellulose, in particular sugars such as crystalline and microcrystalline cellulose, fructose, mannitol and sucrose, grain flour and similar edible powders.

Tablets are prepared by direct compression, wet granulation or dry granulation. Their formulations usually incorporate compounds as well as diluents, binders, lubricants and disintegrants. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, various forms of calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugars. Also useful are powdered cellulose derivatives. Typical tablet binders are substances such as starch, gelatin, and sugars such as lactose, fructose, glucose and the like. Also suitable are natural and synthetic gums including acacia, alginate, methylcellulose, polyvinylpyrrolidine and the like. In addition, polyethylene glycol, ethylcellulose and waxes can be used as the binder.

Tablets are often coated with sugars, which are flavor and sealants. In addition, compounds are currently well established in practice and can be formulated as chewable tablets by using large amounts of good taste substances such as mannitol in the formulation. In addition, preparations such as tablets that dissolve immediately are now frequently used to confirm that a patient has run out of dosage forms and to avoid the difficulty of swallowing solids that have plagued some patients.

Lubricants are often needed in tablet formulations to prevent tablets and punches from sticking in the mold. Lubricants are selected from these slippery solids such as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.

Tablet disintegrants are substances that, when wet, swell and destroy tablets to release compounds. These include starch, clay, cellulose, algins and gums. More specifically, for example, corn and potato starch, methylcellulose, radish, bentonite, wood cellulose, powdered natural sponges, cation exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, as well as sodium Lauryl sulfate may be used.

Enteric preparations are often used to protect the active ingredient from the amount of strong acids in the stomach. Such formulations may be produced by coating the solid dosage form with a film of polymer that is insoluble in the acid environment and soluble in the base environment. Exemplary films include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.

If it is desired to administer the compound as a suppository, conventional bases can be used. Cocoa butter is a traditional suppository base that can be modified by adding wax to slightly raise its melting point. In addition, in particular, various suppository bases are used which are miscible with water, including polyethylene glycols of various molecular weights.

In recent years, transdermal patches are popular. Typically, transdermal patches include resinous compositions in which the drug is dissolved or partially dissolved, which is fixed in contact with the skin by a film protecting the composition. Recently, many patents have appeared in this field. In addition, more complex patch compositions are also used, in particular patch compositions having a myriad of perforated membranes in which the drug is pumped by osmotic action.

The table below provides an exemplary list of agents suitable for use with the compounds used in the present invention. The following is merely to illustrate the invention and is not intended to limit the invention.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

The ingredients are mixed and filled into hard gelatin capsules in an amount of 460 mg.

Formulation 2

Tablets using the following ingredients are prepared:

The ingredients are blended and compressed to yield tablets weighing 665 mg each.

Formulation 3

An aerosol solution is prepared comprising the following components:

The active compound is mixed with ethanol, the mixture is added to a portion of propalant 22, cooled to -30 ° C and transferred to the filling device. The required amount is then supplied to a stainless steel container and diluted with the remainder of the sanding agent. Then, the valve unit is installed in the container.

Formulation 4

Tablets each containing 60 mg of active ingredient are prepared as follows:

Active ingredients, starch, and cellulose. 45 mesh U.S. Pass the sieve and mix thoroughly. The powder thus obtained was mixed with a solution of polyvinylpyrrolidone, and then No. 14 mens U.S. Pass the sieve. The granules thus produced are dried at 50 deg. 18 mens U.S. Pass the sieve. Sodium carboxymethyl starch, magnesium stearate, and talc in advance. 60 mesh U.S. After passing through a sieve, it is added to the granules and after mixing the granules are compressed with a tableting machine to obtain tablets each weighing 150 mg.

Formulation 5

Capsules containing 80 mg of each drug are prepared as follows:

Blending the active ingredient, cellulose, starch, and magnesium stearate, Pass through 45 sieves and fill into hard gelatine capsules in an amount of 200 mg.

Formulation 6

Suppositories each containing 225 mg of active ingredient can be prepared as follows:

Active ingredient No. 60 mesh U.S. The sieve is passed through and suspended in pre-melted saturated fatty acid glycerides using the minimum heating required. The mixture is then poured into suppository molds of nominal 2 g dose and cooled.

Formulation 7

Suspensions containing 50 mg of drug each 5 ml dose are prepared as follows:

No. 45 mesh U.S. Pass through a sieve and mix with sodium carboxymethyl cellulose and syrup to form a smooth dough. The benzoic acid solution, flavor and colorant are diluted with some water and added with stirring. Then sufficient water is added to obtain the required volume.

Formulation 8

Intravenous formulations may be prepared as follows:

It is understood by those skilled in the art that the procedure as mentioned above can be readily applied to methods of treating neurological disorders or neurodegenerative conditions, especially migraine headaches, comprising administering to a patient an effective amount of a compound of Formula I or Formula Ia. .

Compounds of formula (I) and formula (Ia) can be prepared, for example, by following the procedure shown in scheme I. These schemes are not intended to limit the scope of the invention in any way. Unless stated otherwise, all substituents are as defined above. Reagents and starting materials are readily available to those skilled in the art. For example, certain necessary starting materials are prepared by one of skill in the art according to the procedures disclosed in US Pat. Nos. 5,356,902 (registered October 18, 1994) and 5,446,051 (registered August 29, 1995). Can be.

In Scheme I, step A, compound (1) is 6- (hydroxymethyl) -2- (methoxycarbonyl) decahydroisoquinoline-3-carboxylate, wherein Pg is a suitable nitrogen as defined above Protecting group and methoxycarbonyl is preferred) by treating with a compound of formula Lg-Hal, wherein Lg is a suitable leaving group and Hal represents a chloro, bromo or iodo atom, under standard conditions Obtain the compound. For example, a solution of Compound (1) dissolved in a suitable organic solvent such as dichloromethane and cooled to 0 ° C. is treated with an excess of an appropriate organic base such as triethylamine, followed by Compound 1 of formula Lg-Hal. To 2 equivalents. Examples of Lg-Hal are m-nitrobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, p-bromobenzenesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, trifluor Romethanesulfonyl chloride, and the like (also skilled in the art will recognize that halo atoms such as chloro, bromo, or iodo may also be used as appropriate leaving groups instead of LgO). The reaction mixture is warmed to room temperature and stirred for about 5 to 20 hours. Compound (2) is then isolated using standard procedures. For example, the reaction mixture is washed with water, the organic layer is separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford crude compound (2). Then, appropriate chromatography is performed on silica gel using a suitable eluent such as 10-50% ethyl acetate / hexanes to give purified compound (2).

In Scheme I, step B, compound (2) is treated with pyrrolidine of formula (3) under standard conditions to give a compound of formula (4). For example, compound (2) is mixed with about 1-1.5 equivalents of 4-hydroxy-L-proline ethyl ester (R ³ is ethyl) and 1-1.5 equivalents of potassium carbonate, and a suitable solvent such as acetonitrile Heat at reflux for about 60-70 hours in the air. The reaction mixture is cooled to room temperature and the solvent is removed under vacuum. Compound (4) is then isolated using standard procedures such as extraction techniques. For example, the reaction mixture is partitioned between water and an organic solvent such as diethyl ether and the aqueous layer is extracted 2-6 times with diethyl ether. The organic layers are combined together, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford compound (4). Compound (4) can then be purified by chromatography using silica gel using a suitable eluent such as 10-50% ethyl acetate / hexane or methanol / chloroform.

Alternatively, in step B, the pyrrolidine of formula (3) can be combined together with a suitable resin filter cake and the mixture thus obtained can be treated with a compound of formula (2) to give a compound of formula (4). For example, Amberite IRA 67 resin is treated with water, then stirred, filtered and the filter cake is washed with a suitable solvent such as acetone until the water content of the wash is less than about 5% by weight. The filter cake is combined together with 4-hydroxy-L-proline ethyl ester hydrochloride and acetone and the mixture is stirred at room temperature for about 1-2 hours. The mixture is then filtered and the filter cake is washed again with acetone. The solution of this filtered hydroxyproline ethyl ester can then be used directly. The slurry of Amberlite IRA 67 resin in water is stirred and the mixture is filtered. The filter cake is washed with a suitable solvent such as acetone until the water content of the wash is less than about 5% by weight. This second filter cake is then combined together with the hydroxyproline ethyl ester solution and solution of compound (2), and the mixture is heated while refluxing. After about 24 hours, the reaction is cooled and filtered. The filter cake is washed with about 300 mL of dichloromethane and the combined filtrates are concentrated in vacuo. The residue can then be concentrated several times with dichloromethane to afford compound (4) as an oil, which can be used directly in the next step.

In Scheme I, step C, compound (4) is oxidized under standard conditions to give a compound of formula (5). For example, a solution of dichloromethane is treated with phosphorus pentoxide and the reaction is cooled to about -10 ° C. Dimethyl sulfoxide is added with stirring, and then the reaction mixture is treated with a solution of compound (4) dissolved in dichloromethane. The reaction is warmed to about 20-22 ° C. over about 4-5 hours, stirred for about 8-20 hours, cooled to about 0 ° C., and then at a rate to maintain the reaction at a temperature below about 5 ° C. Treat with triethylamine. The reaction is warmed to room temperature, stirred for about 1 hour and then added to a solution of 0.1 M HCl at a rate to maintain the reaction at a temperature below about 10 ° C. Compound (5) is then isolated using standard procedures. For example, additional dichloromethane is added to partition the reaction mixture. The aqueous layer is then extracted 2-6 times with dichloromethane, the organics combined together, washed with 1M NaHCO ₃ , dried over magnesium sulphate and concentrated in vacuo to give compound (5). The crude material can then be purified by chromatography on silica gel using a suitable eluent such as toluene or 10-50% ethyl acetate in methanol / dichloromethane.

In Scheme I, step D, compound (5) is fluorinated to give the compound of formula (6). For example, a solution of compound (5) in ethanol is dissolved in a suitable organic solvent such as 1,2-dichloroethane and deoxofluor ([bis- (2-methoxyethyl) amino] sulfur trifluor Ride) and stir at room temperature for about 20-25 hours. The reaction mixture is then treated with concentrated NaHCO ₃ solution and stirred for about 15 minutes. The layers are separated and the aqueous layer is extracted 2-6 times with toluene. The layers are separated and the organics are combined together, filtered, dried over Na ₂ SO ₄ and concentrated in vacuo to afford the compound of formula (6). The crude material can then be purified by chromatography using silica gel using a suitable eluent such as (50:50) toluene / heptane and / or 10-50% ethyl acetate in toluene.

In Scheme I, step E, compounds of formula (6) are deprotected under standard conditions known in the art to afford compounds of formula (Ia). For example, when Pg is a methoxycarbonyl protecting group, compound (6) is dissolved in a suitable organic solvent such as dichloromethane under nitrogen atmosphere and treated with trimethylsilyl iodide. The reaction mixture is warmed to room temperature and stirred for 10-20 hours. The reaction is quenched by addition of saturated aqueous NaHCO ₃ solution. The aqueous layer is then extracted 2-6 times with dichloromethane. The organics are then combined together, washed with a solution of 1N sodium thiosulfate, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the compound of formula la. This material can then be purified by chromatography on silica gel with an appropriate eluent such as methanol / dichloromethane to afford the purified compound of formula la.

In Scheme I, step F, compounds of formula (Ia) can optionally be hydrolyzed under conditions known in the art to afford compounds of formula (I). For example, the compound of formula (Ia) is dissolved in a suitable organic solvent such as methanol and treated with an excess of appropriate base. Examples of suitable bases include aqueous lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, with lithium hydroxide being preferred. The reaction is stirred for about 10-20 hours. The reaction mixture is then neutralized to pH 6 with 1N HC1 and concentrated in vacuo to afford the crude compound of formula (I). This material can then be purified using techniques known in the art such as chromatography using appropriate eluents.

In Scheme I, step G, compound (6) can optionally be simultaneously deprotected and hydrolyzed to afford the compound of formula (I). For example, a solution of compound (6) dissolved in 6.0 N HCl is heated at reflux for about 15-20 hours. The reaction mixture is then cooled to room temperature and concentrated in vacuo to afford the compound of formula (I). The compound of formula I can then be purified by techniques known in the art, such as cation exchange chromatography using methanol / water followed by 2 N ammonia in methanol or ethanol as eluent to obtain purified compound of formula I. have.

One skilled in the art will also recognize that compounds of formula I can be esterified under standard conditions to afford compounds of formula la. For example, the compound of formula I can be dissolved in a suitable organic solvent such as ethanol and treated with an excess of appropriate acid. Examples of suitable acids include gaseous hydrochloric acid, aqueous sulfuric acid solution, p-toluene sulfonic acid and the like, with gaseous hydrochloric acid being the preferred acid. The reaction mixture is heated to reflux for an appropriate time. The reaction mixture can then be concentrated, for example under vacuum, to afford the crude compound of formula (la). This material can then be purified by techniques known in the art, such as cation exchange chromatography using methanol / water followed by 2 N ammonia in ethanol as eluent to obtain purified compounds of formula (Ia).

The compounds of formula (I) and formula (Ia) of the present invention can be chemically synthesized from the common intermediate 6-hydroxymethyl-2methoxycarbonyl-decahydroisoquinoline-3-carboxylate. Such intermediates can also be chemically synthesized from 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid intermediates, the synthesis of which is described in US Pat. Nos. 4,902,695, 5,446,051, and 5,356,902. The entire contents of which are hereby incorporated by reference.

Synthetic routes of 6- (hydroxymethyl) -2- (methoxycarbonyl) decahydroisoquinoline-3-carboxylate intermediates useful for the synthesis of the compounds of the present invention are shown in Schemes IIa and lb below.

In Scheme IIa, step A, 6-oxo-decahydroisoquinoline-3-carboxylic acid is treated with methyltriphenylphosphonium bromide to give 6-methylidenedecahydroisoquinoline-3-carboxyl of compound (ia). Get acid. For example, a slurry of about 1.4 equivalents of methyltriphenylphosphonium bromide and 1 equivalent of 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid in THF and DMF is subjected to a nitrogen atmosphere. Stir mechanically and cool to -10 ° C. A solution of 2.4 equivalents of potassium tert-butoxide in THF is added dropwise over 10 minutes. Warm up the slurry to room temperature, and for 2.5 hours

Stir (confirm by TLC that the reaction is complete at this point). The reaction is partitioned between water and EtOAc and the layers are separated. The organic phase is extracted twice with water, the aqueous portions are combined together and washed 2-6 times with dichloromethane. By adding 6 M HCl solution

The aqueous solution is made acidic and extracted 2-6 times with dichloromethane. The last three organic extracts are combined together, dried over sodium sulfate and concentrated under reduced pressure to give the compound of formula (i-a).

In Scheme IIa, step B, the intermediate 6-methylidene-decahydroisoquinoline-3-carboxylic acid (compound (ia)) is substituted for the formula R ² -Br, wherein R ² is as defined herein. Reaction with the compound to esterify gives 6-methylidene-decahydroisoquinoline-3-carboxylate intermediate, which is compound (ii). For example, 6-methylidene-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid is dissolved in acetonitrile and treated with triethylamine and bromoethane. The reaction is heated at 50 ° C. for about 3 hours, cooled and partitioned between 50:50 ethyl acetate / heptane and 1N HCL. The organic phase is isolated, washed three times with water, saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the compound of formula (ii). This crude material is dissolved in 10% ethyl acetate / heptane and applied to a plug of silica gel (10 g in 10% ethyl acetate / heptane). The plug is eluted with 10% ethyl acetate / heptane, 15% ethyl acetate / heptane and 25% ethyl acetate / heptane. The eluates are combined together and concentrated under vacuum to afford the purified compound of formula (ii).

In Scheme IIa, step C, 6-methylidene-decahydroisoquinoline-3-carboxylate intermediate (Compound (ii)) is borohydride and subsequently oxidized to yield 6-hydroxymethyl-Deca as Compound (1). Hydroisoquinoline-3-carboxylate intermediate is obtained. For example, ethyl-6-methylidene-2-methoxycarbonyldecahydroisoquinoline-3-carboxylate is dissolved in THF and cooled to about -15 ° C with stirring under a nitrogen atmosphere. The 1M BH ₃ THF solution is added dropwise over 5-7 minutes and the reaction mixture is stirred at -10 to -12 ° C for about 2 hours. The reaction is then slowly treated with a suitable base such as lithium hydroxide or sodium hydroxide and then slowly with 30% H ₂ O ₂ over 15 minutes. The reaction mixture is allowed to warm to room temperature and then partitioned between ethyl acetate and 50% saturated sodium chloride solution. The aqueous layer is extracted with ethyl acetate, and the combined organics are washed with sodium bisulfite solution, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford compound (1).

Alternatively, 6-hydroxymethyl-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate intermediate (Compound (1)) can be prepared according to the synthetic route described in Scheme IIb. In Scheme Ilb, Step A, 6-oxo-decahydroisoquinoline-3-carboxylic acid is reacted with a compound of Formula R ² -Br, wherein R ² is as defined herein, to esterify the compound (ib) to obtain 6-oxo-decahydroisoquinoline-3-carboxylate intermediate. For example, 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid is dissolved in acetonitrile and treated with triamine and bromoethane. The reaction is heated at 50 ° C. for about 3 hours, cooled and partitioned between 50:50 ethyl acetate / heptane and 1N HCL. The organic phase is isolated, washed three times with water, saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the compound of formula (ib). This crude material is dissolved in 10% ethyl acetate / heptane and applied to a plug of silica gel (10 g in 10% ethyl acetate / heptane). The plug is eluted with 10% ethyl acetate / heptane, 15% ethyl acetate / heptane, and 25% ethyl acetate / heptane. The eluates are combined together and concentrated in vacuo to give the purified compound of formula (ib).

In Scheme IIb, step B, 6-oxo-decahydroisoquinoline-3-carboxylate intermediate compound (ib) is treated with methyltriphenylphosphonium bromide to compound (ii) 6-methylidene-decahydro Obtain isoquinoline-3-carboxylate. For example, 1 equivalent of 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate (compound (ib)) and about 1.4 equivalents of methyltriphenylphosphonium bromide in THF and DMF The slurry of is mechanically stirred under a nitrogen atmosphere and cooled to -10 ° C. A solution of 2.4 equivalents of potassium tert-butoxide in THF is added dropwise over 10 minutes. The slurry is allowed to warm to room temperature and stirred for 2.5 hours (by TLC confirming that the reaction is complete at this point). The reaction is partitioned between water and EtOAc and the layers are separated. The organic phase is extracted twice with water, the aqueous portions are combined together and washed 2-6 times with dichloromethane. The aqueous solution is made acidic by adding 6 M HCI solution, which is extracted 2-6 times with dichloromethane. The last three organic extracts are combined together, dried over sodium sulfate and concentrated under reduced pressure to give the compound of formula (ii).

In Scheme lb, step C, borohydride of 6-methylidene-decahydroisoquinoline-3-carboxylate intermediate (compound (ii)) is followed by the following procedure as described in Scheme IIa, step C. Oxidation yields 6-hydroxymethyldecahydroisoquinoline-3-carboxylate intermediate as compound (1).

The following preparations and examples illustrate the compounds and methods of the invention. Reagents and starting materials are readily available to those skilled in the art. These embodiments are merely illustrative and are not intended to limit the scope of the invention in any way. As used herein, the following terms have the meanings indicated: “iv” refers to intravenously; "po" represents oral; "ip" represents intraperitoneal; "eq" or "eqiv." represents an equivalent; "g" represents grams; "mg" represents milligrams; "L" represents liter; "mL" refers to milliliters; "μL" refers to microliters; "mol" represents mole; "mmol" refers to millimoles; "psi" represents pounds per square inch; "mmHg" refers to millimeters of mercury; "min" represents minutes; "h" or "hr" represents time; "° C" refers to degrees Celsius; "TLC" refers to thin layer chromatography; "HPLC" stands for high performance liquid chromatography; "R _f " stands for retardation factor; "R _t " represents the delay time; "δ" refers to parts per million from tetramethylsilane towards the downfield; "THF" refers to tetrahydrofuran; "DMF" refers to N, N-dimethylformamide; "DMSO" refers to dimethyl sulfoxide; "aq" refers to water solubility; "EtOAc" refers to ethyl acetate; "iPrOAc" refers to isopropyl acetate; "MeOH" refers to methanol; "MTBE" refers to tert-butyl methyl ether; "RT" represents room temperature; "K _i " is the dissociation constant of the enzyme-antagonist complex and represents the ligand binding index; And “ID ₅₀ ” and “ID ₁₀₀ ” refer to dosages of the administered therapeutic agents that produce 50% and 100% reductions in physiological response, respectively.

Preparation Example 1

[3S, 4aR, 6S, 8aR] -6-methylidene-2- (methoxycarbonyl) -1,2,3,4,4a, 5,6,7,8,8α-decahydroisoquinoline-3 Preparation of Carboxylic Acids

A slurry of 12.4 g (34.6 mmol) of methyltriphenylphosphonium bromide in 25 mL of THF was cooled to -10 to -12 ° C under a nitrogen atmosphere, and the syringe was stirred with 35 mL of sodium hexamethyldisilazide of 1M solution in THF. Treatment was over 6-8 minutes. The reaction mixture is then stirred at -10 to -12 [deg.] C. for 20 minutes and [3S, 4aR, 6S, 8aR] -6-oxo-2- (methoxycarbonyl) over 3-4 minutes via an inlet tube. 10.0 g (26.6 mmol) of 1,2,3,4,4a, 5,6,7,8,8α-decahydroisoquinoline-3-carboxylic acid (preliminarily 1 M solution in THE at 0-3 ° C.) Treated with 27 mL of sodium hexamethyldisilazide and stirred for 10 minutes), 20 mL of DMF was dissolved and cooled to 0-3 ° C under nitrogen atmosphere. Subsequently, the flask containing the Wittig reagent added to the reaction mixture was also washed with 3 mL of THF. The reaction mixture was then stirred at 0-3 ° C. for 5 minutes, then warmed to room temperature and stirred for an additional 3 hours. 100 mL of ethyl acetate and 50 mL of water were added with stirring, and then the layers were separated. The organic layer was extracted with 50 mL of water and the combined aqueous portions were washed 5 times with 75 mL of methylene chloride. The aqueous portion was then treated with 15 mL of 6M HCl and extracted three times with 50 mL of methylene chloride. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 6.59 g (98%) of the title compound as a yellow oil.

[3S, 4aR, 6S, 8aR] -6-methylidene-2- (methoxycarbonyl) -1,2,3,4,4a, 5,6,7,8,8α-decahydroisoquinoline-3 Alternative Synthesis of Carboxylic Acids

[3S, 4aR, 6S, 8aR] -6-oxo-2- (methoxycarbonyl) -1,2,3,4,4a, 5,6,7,8,8a in 150 mL THF and 25 mL DMF A slurry of 50.0 g (0.133 mol, 1.0 equivalent) of decahydroisoquinoline-3-carboxylic acid and 66.4 g (0.186 mol, 1.4 equivalent) of methyltriphenylphosphonium bromide was mechanically stirred under nitrogen atmosphere and brought to -10 ° C. Cooled. 187 mL (0.319 mol, 2.4 equiv) of 1.7 M potassium tert-butoxide solution in THF was added dropwise over 10 minutes. The gentle exothermic reaction through this addition increased the reaction temperature to 6 ° C. The slurry was warmed to room temperature and stirred for 2.5 hours (at this point TLC confirmed that the reaction was complete). The reaction was partitioned between 250 mL of water and 250 mL of EtOAc and the layers separated. The organic phase was extracted twice with 100 mL of water, the aqueous portions combined and washed 5 times with 300 mL of dichloromethane. The aqueous solution was acidified by addition of 50 mL of 6 M HCl solution and extracted three times with 150 mL of dichloromethane. The last three organic extracts were combined, dried over sodium sulfate and concentrated under reduced pressure to give 36.17 g of the title compound as a yellow film. The estimated potency of the product by proton NMR for the corrected yield of 32.2 g (95.6%) is 89% by weight (remaining remaining solvent).

Preparation Example 2

[3S, 4aR, 6S, 8aR] -Ethyl-6-methylidene-2- (methoxycarbonyl) -1,2,3,4,4a, 5,6,7,8,8α-decahydroisoquinoline Preparation of 3-carboxylate

[3S, 4aR, 6S, 8aR] -6-methylidene-2- (methoxycarbonyl) -1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3 6.59 g (26.0 mmol, prepared in Preparation 1) of carboxylic acid were dissolved in 26 mL of acetonitrile and treated with 7.25 mL (52 mmol) of triethylamine and 5.82 mL (78 mmol) of bromoethane. The reaction was heated at 50 ° C. for about 3 hours, cooled and the reaction was partitioned between 100 ml of 50:50 ethyl acetate / heptane and 75 mL of 1N HCL. The organic phase was isolated and washed three times with 30 mL of water, 30 mL of saturated sodium bicarbonate, 30 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as an amber oil. This crude material was dissolved in 15 mL of 10% ethyl acetate / heptane and applied to a plug of 10 g of silica gel in 10% ethyl acetate / heptane. The plug was eluted with 10 mL of 10% ethyl acetate / heptane, 15 mL of 15% ethyl acetate / heptane, and 90 mL of 25% ethyl acetate / heptane. The eluates were combined and concentrated in vacuo to give 6.84 g (91%) of the title compound as a colorless oil.

Preparation Example 3

[3S, 4aR, 6S, 8aR] -Ethyl-6- (hydroxymethyl) -2- (methoxycarbonyl)-

Preparation of 1,2,3,4,4a, 5,6,7,8,8α-decahydroisoquinoline-3-carboxylate

[3S, 4aR, 6S, 8aR] -Ethyl-6-methylidene-2- (methoxycarbonyl) -1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline 2.0 g (7.11 mmol, prepared in Preparation 2) of -3-carboxylate was dissolved in 10 mL of THF and 2 mL of heptane and cooled to about -15 ° C with stirring under a nitrogen atmosphere. A 1M solution of 3.91 mmol of BH ₃ .THF in 3.91 mL of THF was added dropwise over 5-7 minutes and the reaction was stirred at -10 to -14 ° C for about 2-4 hours. The reaction was treated with 1.25 mL of ethanol over 2 minutes and then warmed to 20 ° C. The reaction was then slowly treated with 3.91 mL of 1 M LiOH solution, followed by slow addition of 30% H ₂ O ₂ (1.2 mL was added at a rate to keep the reaction temperature below 30 ° C.). The reaction mixture was stirred for 30-45 minutes at room temperature, then the reaction was partitioned between 12 mL of ethyl acetate and 14 mL of 10% sodium bisulfite solution. The organic layer was washed with 16 mL of 10% sodium bisulfite solution, 8 mL brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2.01 g of the title compound as a colorless oil.

Example 1

3S, 4aR, 6S, 8aR ethyl 6-(((2S) -2- (ethoxycarbonyl) -4,4-difluoropyrrolidinyl) methyl) -1,2,3,4,4a, 5 , 6,7,8,8α-decahydroisoquinoline-3-carboxylateD-(-)-mandelic acid

A.

Manufacture

[3S, 4aR, 6S, 8aR] -ethyl-6- (hydroxymethyl) -2- (methoxycarbonyl) -1,2,3,4,4a, 5,6,7,8 in 94 mL EtOAc A solution of 37.5 g (0.125 mol) and 35.0 mL (0.25 mol) of, 8α-decahydroisoquinoline-3-carboxylate and 35.0 mL (0.25 mol) of triethylamine was maintained at 0-2 ° C. (addition time: 30 minutes) in 94 mL of EtOAc. Add dropwise to 28.6 g (0.125 mol) of p-nitrobenzenesulfonyl chloride. The reaction was allowed to warm to room temperature and stirred for about 2.5 hours, then quenched by addition of 100 mL of water, 100 mL of 1M HCl and 20 mL of brine. The layers were separated and the organic phase was washed with 150 mL 1M NaHCO ₃ solution, 150 mL brine and dried over MgSO ₄ . Concentration in vacuo gave the title compound as 58.9 g (97%) of oil. ¹ H NMR (CDCl ₃ ) δ 8. 41 (2H, d), 8.05 (2H, d), 4.38 (t, 1H), 4.17 (m, 2H), 3.97 m, 2H), 3.69 (s, 3H), 3.39 (m, 2H), 2.12 ( m, 1H), 1.85 (m, 3H), 1.55 (m, 5H), 1.25 (m, 5H).

B.

Manufacture

334.7 g of Amberlite IRA 67 resin was treated with about 680 mL of water and stirred. The mixture was filtered and the filter cake was washed with acetone until the water content of the wash was less than 5% by weight. This filter cake was combined with hydroxyproline ethyl ester HCl, 72.7 g (0.372 mol) and 700 mL of acetone, and the mixture was stirred at room temperature for about 1-2 hours. The mixture was filtered and the filter cake was washed with 300 mL of acetone. A solution of this filtered hydroxyproline ethyl ester was used directly. A slurry of 465 g of Amberlite IRA 67 resin in about 900 mL of water was stirred and then the mixture was filtered. The filter cake was washed with acetone until the water content of the wash was less than 5% by weight. This filter cake was combined together with a solution of 100 g (0.206 mol) of the compound from Step A above in about 150 mL of the above hydroxyproline ethyl ester solution and EtOAc, and the mixture was heated to reflux. After about 24 hours, the reaction was cooled and filtered. The filter cake was washed with about 300 mL of dichloromethane, the combined filtrates were concentrated in vacuo and the residue was concentrated several times from dichloromethane to afford the title compound as an oil, which was used directly in the next step.

C.

Manufacture

Approximately 230 mL of dichloromethane was treated with 117.2 g (0.825 mol) phosphite pentoxide and the mixture was cooled to about -10 ° C. 96.8 g (1.24 mol) of dimethyl sulfoxide were added to the mixture at a rate such that the reaction temperature was maintained at about 10 ° C. The reaction was stirred at about −10 ° C. and treated with a solution of the compound of Step B above in about 230 mL of dichloromethane so that the reaction temperature was maintained below about −10 ° C. The reaction was warmed to about 20-22 ° C. over several hours (4-5), stirred overnight, cooled to about 0 ° C. and 83.5 g of triethylamine at a rate such that the reaction temperature was maintained below 5 ° C. 0.825 mol). The reaction was warmed to rt and stirred for 1 h. The reaction was added to about 460 mL of the 0.1 M HCl solution (precooled to about 0-5 ° C) at a rate such that the reaction temperature was maintained below 10 ° C. An additional 460 mL of dichloromethane was added, the mixture was stirred for a while and the layers separated. The aqueous portion was extracted with about 460 mL of dichloromethane and the combined organic extracts were washed with about 460 mL of 1M NaHC0 ₃ . The layers were separated and the organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by chromatography using silica gel 60 and 35% EtOAc in toluene to give the title compound as 36.9 g (41% from 504476) of an oil. ¹ H NMR (CDC1 ₃ ) δ4. 39 (t, 1H), 4.18 (m, 4H), 3.72 (m, 1H), 3.70 (s, 3H), 3.40 (m, 3H), 3.00 (d, 1H), 2.40-2.69 (m, 4H) , 2.08 (m, 1H), 1.45-1.95 (m, 9H), 1.30 (m, 6H), 1.10 (m, 1H).

D.

Manufacture

A solution of 8.98 g (0.0205 mol) of the compound of Step C and 0.227 mL (0.0039 mol) of ethanol in 43 mL of 1,2-dichloroethane was added to deoxofluor ([bis- (2-methoxyethyl) amino] sulfur trifluor Lide, 6.5 mL, 0.0353 mol) and the reaction was stirred at rt for about 21 h. The reaction was treated with a saturated solution of NaHCO ₃ in 60 mL of water, then the mixture was stirred for 15 minutes. The layers were separated and the aqueous portion was extracted with about 45 mL of toluene. The layers were separated and toluene and 1, 2-dichloroethane solution were combined together and dried over Na ₂ SO ₄ . The desiccant was filtered off and the filter cake was washed with about 30 mL of toluene. The filtrate was concentrated in vacuo and the residue was dissolved in about 17 mL of 50:50 toluene: heptane and then the solution was applied to a silica gel 60 column (43 g in 50:50 toluene: heptane). The column was eluted with 50:50 toluene: about 230 mL heptane, about 430 mL toluene, 10% EtOAc in about 240 mL toluene and 20% EtOAc in about 86 mL toluene. Fractions of eluent including pure compound were combined and concentrated in vacuo to yield 5.79 g (61%) of the title compound as a syrup. ¹ H NMR (CDC1 ₃ ) δ4. 35 (m, 1H), 4.20 (m, 4H), 3.70 (s, 3H), 3.40 (m, 4H), 2.78 (m, 1H), 2.40-2.65 (m, 3H), 2.30 (m, 1H) , 2.15 (m, 1H), 1.70-1.95 (m, 4H), 1.45-1.65 (m, 4H), 1.30 (m, 6H), 1.10 (m, 2H).

E. 3S, 4aR, 6S, 8aR ethyl 6-(((2S) -2- (ethoxycarbonyl) -4,4-difluoropyrrolidinyl) methyl) -1,2,3,4,4a Preparation of 5,6,7,8,8α-decahydroisoquinoline-3-carboxylate (free base)

3S, 4aR, 6S, 8aR ethyl 6-(((2S) -2- (ethoxycarbonyl) -4,4-difluoropyrrolidinyl) methyl) -1,2,3,4,4a, 5 Preparation of 6,7,8,8α-decahydroisoquinoline-3-carboxylate-D-(-)-mandelate

A solution of 9.7 g (0.021 mol) of the compound of Step D in about 70 mL of dichloromethane and about 30 mL of toluene was cooled to 0-5 ° C and treated dropwise with 12.7 g (0.063 mol) of iodotrimethylsilane. The reaction was warmed to room temperature, stirred for about 16 hours and then concentrated in vacuo. The residue was concentrated several times with MTBE (methyl t-butyl ether), then dissolved in about 70 mL of MTBE and about 30 mL of toluene, about 100 mL of saturated NaHCO _3, about 100 mL of 1N sodium thiosulfate and about 100 water washed with mL. The organic layer was concentrated in vacuo, the residue concentrated several times with MTBE, dissolved in about 22 mL of toluene and then treated with a solution of 2.75 g (0.181 mol) of D-(-)-mandelic acid in about 33 mL of MTBE. It was. The mixture was stirred at room temperature for about 2 hours, then cooled to about -15 ° C and stirred for about 2 hours. D-(-)-mandelate was collected by filtration, washed with about 73 mL of cold MTBE (at about −15 ° C.) and dried to give 8.25 g (71%) of crystalline solid. ¹ H NMR (DMSOd ₅ ) δ 7.16-7.38 (m, 5H), 4.72 (s, 1H), 4.12 (m, 4H), 3.65 (m, 1H), 3.51 (m, 1H), 3.33 (m, 1H), 2.25-2.91 (m, 8H), 1.85 (m, 2H), 1.70 (m, 2H), 1.34-1.86 (m, 5H), 1.15-1.38 (m, 7H), 0.81 (m, 1H) .

Example 2

3S, 4aR, 6S, 8aR ethyl 6-(((2S) -2- (ethoxycarbonyl) -4,4-difluoropyrrolidinyl) methyl) -1,2,3,4,4a, 5 Preparation of 6,7,8,8α-decahydroisoquinoline-3-carboxylate and 1,5-naphthalene disulfonic acid

A solution of 1.1 g (3.05 mmol) of 1,5-naphthalenedisulfonic acid tetrahydrate in about 5 mL of refluxed ethanol was added to 3S, 4aR, 6S, 8aR ethyl 6 (((2S) -2- (ethoxy) in about 5 mL of ethanol. Carbonyl) -4,4-difluoropyrrolidinyl) methyl) -1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (above Example 1, which is the free base diester compound from Step E), was treated with 1.2 g (3.0 mmol) of solution, and the mixture was heated to reflux until crystals started to form (about 5 minutes). The reaction was cooled down and left at room temperature for about 3 days. The product was collected by filtration, washed three times with 5 mL of ethanol and dried (2.0 g, 96%). The product can be recrystallized from water or methanol.

Example 3

3S, 4aR, 6S, 8aR 6-(((2S) -2- (carboxylic acid) -4,4-difluoropyrrolidinyl) methyl) -1,2,3,4,4a, 5,6 Preparation of 7,7,8,8α-decahydroisoquinoline-3-carboxylic acid dihydrochloride

3S, 4aR, 6S, 8aR 6-(((2S) -2- (carboxylic acid) -4,4difluoropyrrolidinyl) methyl) -1,2,3,4,4a, 5,6, Preparation of 7,8,8α-decahydroisoquinoline-3-carboxylic acid (free base)

A mixture of 16.3 g (0.0353 mol) of the compound of Example 1, Step D and 170 mL of 6M HCl was heated to reflux and the distilled material from about 15 mL of the reaction was collected over 3 hours. The reaction was cooled, washed twice with 50 mL of dichloromethane, then treated with about 8 g of activated carbon and stirred at 60 ° C. for 30 minutes. The mixture was cooled and filtered through a pad of Hyflo. The filter cake was washed with about 50 mL of water and the aqueous filtrates were combined and concentrated in vacuo to give 14.2 g of a solid. 8.61 g (61% of this amount) of this solid was concentrated to 2-propanol and then treated with about 43 mL of 2-propanol and the mixture was heated at 50 ° C for 1 h. The mixture was cooled to about 0 ° C and stirred for 30 minutes. The solid was collected by filtration, washed with 20 mL of cold 2-propanol and dried to 7.5 g of a white powder, the dihydrochloride salt of the title compound. 2.5 g (33.3% of this amount) of this powder were treated with 11.9 mL of a 1N NaOH solution, and the solution was then concentrated in vacuo. The residue was concentrated to EtOH and then treated with 50:50 EtOH: EtOAc. The mixture was warmed to about 35 ° C., then cooled to RT, stirred for 1 h and then filtered. The filter cake was washed with 5 mL of 50:50 EtOH: EtOAc, and the combined filtrates were concentrated to give a foam. The foam was concentrated to EtOAc, then treated with 10 mL of EtOAc and stirred. The free base of the title compound was collected by filtration and dried to a powder (1.96 g, calibrated effective amount). Obtained calculation for free base: 1.96 g ÷ 0.333 ÷ 0.61 = 9.65 g or 79%. ¹ H NMR (D20 + DCl) □ 4. 55 (t, 1H), 4.07 (m, 1H), 3.83 (m, 1H), 3.65 (m, 1H), 3.25 (m, 1H), 2.95 (m, 4H), 2.59 (m, 1H), 1.89 (m, 3H), 1.77 (m, 1H), 1.65 (m, 1H), 1.46 (m, 3H), 1.35 (d, 1H), 1.20 (m, 1H), 0.84 (m, 1H).

Example 4

The binding affinity of the panel compound to the iGluR ₅ receptor was measured using standard methods to establish that the iGluR ₅ receptor subtype first mediates the neuronal protein extravasation, a functional characteristic of migraine headaches. For example, the activity of a compound that acts on iGluR ₅ receptor antagonists is characterized by radiolabeled ligand binding studies (Korczak et al., 1994, Recept. Channel 3; 41-49), and severity in cloned and expressed human iGIuR ₅ receptors. Total cell voltage clamp electrophysiological recordings of currents in dorsal root ganglion neurons of properly isolated mice can be determined (Bleakman et al., 1996, Mol. Pharmacol. 49; 581-585). Then, iGluR ₅ selectivity of compounds acting on the receptor subtype can be determined by comparing antagonist activity and other AMPA and antagonist activity at the iGluR ₅ receptor from the receptor chi carbonate. Useful methods for these comparative studies include receptor-ligand binding studies on functional activity at human GluR ₁ , GluR ₂ , GluR ₃ and GluR ₄ receptors and whole cell voltage clamp electrophysiological recordings (Fletcher et al., 1995, Recept. Channel 3; 21-31); Receptor-ligand binding studies on functional activity at human GluR ₆ receptors and whole cell voltage clamp electrophysiological recordings (Hoo et al., Recept. Channel 2; 327-338); And expressing whole cell voltage clamp electrophysiological records (Bleakman et al., 1996, Mol. Pharmacol. 49; 581- 585) and AMPA receptors for functional activity at AMPA receptors in severely isolated cerebellar Perkinje neurons. Whole cell voltage clamp electrophysiological recordings of functional activity in other tissues (Fletcher and Lodge, 1996, Pharmacol. Ther. 70; 65-89).

A. iGluR ₅ antagonist binding affinity profile

Cell lines stably transfected with human iGluR receptors (HEK293 cells) are used. By increasing the concentration of the antagonist, the displacement of ³ [H] AMPA is measured in iGluR ₁ , iGluR ₂ , iGluR ₃ , and iGluR ₄ expressing cells, while the displacement of ³ [H] catenate (KA) is measured in iGluR ₅ , iGluR ₆ , iGluR ₇ , and KA2-expressing cells. Presumed antagonist binding activity (K _i ) (μM) is determined for compounds of formula (I) or formula (Ia), for example. Furthermore, it was determined as an indication of the selectivity, iGluR ₂ AMPA receptor ratio (K _i in K _i / iGluR ₅ at iGluR ₂₎ a binding affinity for iGluR ₅ Kai carbonate receptor binding affinity for subtypes of the subtype. Compounds provided by the present invention is higher and a binding affinity to the iGluR ₅ than the binding affinity to the iGluR ₂ (K _i no low), preferably at least 10 times, more preferably than the binding affinity to the iGluR ₂ More than 100-fold higher binding affinity for iGluR ₅ .

Example 5

The following animal models can be used to determine the ability of a compound of Formula (I) or Formula (Ia) to inhibit protein extravasation, a representative functional analysis of the neuronal mechanism of migraine.

Animal Models of Dural Protein Extravasation

A. Harlan Sprague-Dawley rats (225-325 g) or guinea pigs (225-325 g) from Charles River Laboratories intraperitoneally with sodium pentovalbital (65 mg / kg or 45 mg / kg, respectively) is administered and anesthetized, placed in a stereotactic frame (David Kopf Instruments) and fixed to -3.5 mm (rat) or -4.0 mm (guinea pig). After midline sagittal scalp incision, two pairs of bilateral lateral holes are drilled through the skull (6 mm to the back in rats, 2.0 and 4.0 mm to the side; 4 mm to the back and 3.2 and 5.2 mm to the side in guinea pigs, all Figures are based on parietal). A pair of stainless steel stimulation electrodes (Rhodes Medical Systems, Inc.) that excite the insulated electrode except the tip is lowered 9 mm (rat) or 10.5 mm (guinea pig) from the hard membrane through the hole in both hemispheres. send.

B. The femoral vein is exposed and the dose of test compound is injected intravenously (iv) in a dose volume of 1 ml / Kg or, alternatively, the test compound is orally gavaged in a volume of 2.0 ml / Kg. Administration. In addition, about 7 minutes after this intravenous injection, a 50 mg / Kg dose of the fluorescent dye Evans Blue is injected intravenously. Evans Blue complexes with proteins in the blood and functions as a marker for protein extravasation. Exactly 10 minutes after injection of the test compound, the left trigeminal ganglion was removed at 1.0 mA current intensity (5 Hz, 4) using model 273 potentiostat / galvanostat (EG & G Princeton Applied Research). msec period) for 3 minutes.

C. After 15 minutes after stimulation, animals are euthanized by large bleeding with 20 mL of saline. The top of the skull is removed to facilitate the collection of the dura mater. The membrane sample is removed from both hemispheres, washed with water and flattened onto the microscope slide. Once dry, the tissue is covered using a 70% glycerol / water solution.

D. A fluorescence microscope (Zeiss) equipped with a monochromator and spectrophotometer is used to determine the amount of Evans blue dye in each sample. An excitation wavelength of approximately 535 nm is used and emission intensity is determined at 600 nm. The microscope is equipped with a motorized stage and is also interfaced with a personal computer. This facilitates computer controlled movement of the stage using fluorescence measurements at 25 points (500 mm steps) on each dural sample. The mean and standard error of the measurements are determined by computer.

E. Extravasation induced by electrical stimulation of the trigeminal ganglia has an ipsilateral effect (ie occurs only in the dura membrane on the side where the trigeminal ganglion is stimulated). This allows the other half of the hard membrane (not stimulated) to be used as a control. The ratio of extravasation in the dura membrane from the stimulated side to the extravasation from the unstimulated side (“extravascular outflow ratio”) is calculated. Control animals that received saline only had an extravasation ratio of approximately 2.0 in rats and approximately 1.8 in guinea pigs. In contrast, the extravasation ratio of the compound which completely prevents extravasation in the dura mater from the stimulated side is approximately 1.0.

F. A dose-response curve can be generated for each of the compounds of Formula (I) and Formula (Ia), and then a dose that inhibits extravasation (ID ₅₀ ) or a dose that inhibits 100% (ID ₁₀₀₎ ) Can approximate the dosage. Compound 3S, 4aR, 6S, 8aR ethyl 6-(((2S) -2- (ethoxycarbonyl) -4,4-difluoropyrrolidinyl) methyl) -1,2,3,4,4a, 5,6,7,8,8α-decahydroisoquinoline-3-carboxylate dihydrochloride gives an ID ₁₀₀ of approximately 0.01 ng / Kg when administered orally to rats.

Claims (27)

A pharmaceutically acceptable salt of a compound of formula or a prodrug thereof selected from the group consisting of D-(-)-mandelate or 1,5-naphthalene disulfonate. The pharmaceutically acceptable salt of claim 1, which is D-(-)-mandelate. The pharmaceutically acceptable salt of claim 1, which is 1,5-naphthalene disulfonate. 3S, 4aR, 6S, 8aR 6-(((2S) -2- (carboxylic acid) -4,4-difluoropyrrolidinyl) methyl) -1,2,3,4,4a, 5,6 , 7,8,8a-decahydroisoquinoline-3-carboxylic acid. D-(-)-mandelic acid. 3S, 4aR, 6S, 8aR 6-(((2S) -2- (carboxylic acid) -4,4-difluoropyrrolidinyl) methyl) -1,2,3,4,4a, 5,6 , 7,8,8α-decahydroisoquinoline-3-carboxylic acid. 1,5-naphthalene disulfonic acid. A pharmaceutically acceptable salt of a compound of the formula: selected from the group consisting of D-(-)-mandelate or 1,5-naphthalene disulfonate. Wherein R ¹ and R ² are each independently hydrogen, (C ₁ -C ₂₀ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkylaryl, (C ₁ -C ₆ ) Alkyl (C ₃ -C ₁₀ ) cycloalkyl, (C ₁ -C ₆ ) alkyl-N, NC ₁ -C ₆ dialkylamine, (C ₁ -C ₆ ) alkyl-pyrrolidine, (C ₁ -C ₆ ) Alkyl-piperidine or (C ₁ -C ₆ ) alkyl-morpholine, provided that at least one of R ¹ and R ² is other than hydrogen) The pharmaceutically acceptable salt of claim 6, wherein R ¹ and R ² are each independently (C ₁ -C ₂₀ ) alkyl. 8. The pharmaceutically acceptable salt of claim 7, wherein R ¹ and R ² are each independently (C ₁ -C ₆ ) alkyl. 9. The pharmaceutically acceptable salt of claim 8 which is D-(-)-mandelate. 9. The pharmaceutically acceptable salt of claim 8 which is 1,5-naphthalene disulfonate. 3S, 4aR, 6S, 8aR ethyl 6-(((2S) -2- (ethoxycarbonyl) -4,4-difluoropyrrolidinyl) methyl) -1,2,3,4,4a, 5 , 6,7,8,8α-decahydroisoquinoline-3-carboxylate.D-(-)-mandelic acid. 3S, 4aR, 6S, 8aR ethyl 6-(((2S) -2- (ethoxycarbonyl) -4,4-difluoropyrrolidinyl) methyl) -1,2,3,4,4a, 5 , 6,7,8,8α-decahydroisoquinoline-3-carboxylate.1,5-naphthalene disulfonic acid. A method of treating a neurological disorder or neurodegenerative disease comprising administering to a patient in need thereof an effective amount of a pharmaceutically acceptable salt according to claim 1. The method of claim 13, wherein the neurological disorder is migraine. The pharmaceutically acceptable salt of claim 14, wherein the pharmaceutically acceptable salt is 3S, 4aR, 6S, 8aR 6-(((2S) -2- (carboxylic acid) -4,4-difluoropyrrolidinyl) methyl)- 1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid. D-(-)-mandelic acid. The method of claim 14, wherein the pharmaceutically acceptable salt is 3S, 4aR, 6S, 8aR ethyl 6-(((2S) -2- (ethoxycarbonyl) -4,4-difluoropyrrolidinyl) methyl ) -1,2,3,4,4a, 5,6,7,8,8α-decahydroisoquinoline-3-carboxylate. 1,5-naphthalene disulfonic acid. A method of treating a neurological disorder or neurodegenerative disease comprising administering to a patient in need thereof an effective amount of a pharmaceutically acceptable salt according to claim 6. 18. The method of claim 17, wherein the neurological disorder is migraine. 18. The composition of claim 17, wherein the pharmaceutically acceptable salt is 3S, 4aR, 6S, 8aR 6-(((2S) -2- (carboxylic acid) -4,4-difluoropyrrolidinyl) methyl)- 1,2,3,4,4a, 5,6,7,8,8α-decahydroisoquinoline-3-carboxylic acid. D-(-)-mandelic acid. 18. The method of claim 17, wherein the pharmaceutically acceptable salt is 3S, 4aR, 6S, 8aR ethyl 6-(((2S) -2- (ethoxycarbonyl) -4,4-difluoropyrrolidinyl) methyl ) -l, 2,3,4,4a, 5,6,7,8,8α-decahydroisoquinoline-3-carboxylate.1,5-naphthalene disulfonic acid. A pharmaceutical composition comprising an effective amount of the pharmaceutically acceptable salt of claim 1 together with a pharmaceutically acceptable carrier, diluent, or excipient. A pharmaceutical composition comprising an effective amount of the pharmaceutically acceptable salt of claim 6 together with a pharmaceutically acceptable carrier, diluent, or excipient. Use of the compound of claim 1 for the preparation of a medicament for the treatment of migraine. Use of a medicament for the treatment of migraine of a compound of claim 6. Use of the compound of claim 1 for the treatment of migraine headaches. Use of the compound of claim 6 for the treatment of migraine headaches. In a suitable solvent, the compound of formula (2) and the appropriate base are combined together, followed by addition of the compound of formula (3), followed by oxidation with a compound of formula (5), followed by halogenation and removal of the nitrogen protecting group Method for producing a compound of the formula Wherein R ¹ and R ² are each independently hydrogen, (C ₁ -C ₂₀ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkylaryl, (C ₁ -C ₆ ) Alkyl (C ₃ -C ₁₀ ) cycloalkyl, (C ₁ -C ₆ ) alkyl-N, NC ₁ -C ₆ dialkylamine, (C ₁ -C ₆ ) alkyl-pyrrolidine, (C ₁ -C ₆ ) Alkyl-piperidine or (C ₁ -C ₆ ) alkyl-morpholine, provided that at least one of R ¹ and R ² is other than hydrogen) <Formula 2> Where R ² is as defined herein, Pg is a suitable nitrogen protecting group and LgO is a suitable leaving group <Formula 3> Wherein R ¹ is as defined herein <Formula 5>