HRP20030544A2 - Excitatory amino acid receptor antagonists - Google Patents

Description

Background of the invention

In the mammalian central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between neurotransmitters, released by the transmitting neuron, and surface receptors on the receiving neuron, which cause the excitation of that receiving neuron. L-glutamate, which is the most abundant neurotransmitter in the CNS, mediates the main excitatory pathways in mammals, and is called an excitatory amino acid (EAA). Receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors). See 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. Pharm. Sci., 11, 25 (1990). Excitatory amino acids are of great physiological importance because they play a role in various physiological processes, such as long-term potentiation (learning and memory), development of synaptic plasticity, motor control, breathing, cardiovascular regulation, and sensory perception.

Excitatory amino acid receptors are classified into two general types. Receptors that are directly related to the opening of cation channels in the cell membrane of neurons are called "ionotropic". This type of receptor is divided into at least three subtypes that are defined by the depolarizing action of the selective agonists N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (TO). Molecular biological studies have shown that AMPA receptors consist of subunits (GluR1 - GluR4), which can be assembled to form functional ion channels. Five kainate receptors have been identified that are classified as either high-affinity receptors (KA1 and KA2) or low-affinity receptors (composed of GluR5, GluR6, and/or GluR7 subunits). Bleakman et al., Molecular Pharmacology, 49, No. 4, 581, (1996).

Another general type of receptor is the "metabotropic" excitatory amino acid receptor coupled to a G-protein or other messenger. This second type is associated with multiple second messenger systems that lead to increased hydrolysis of phosphoinositides, activation of phospholipase D, increases or decreases in cAMP generation, and changes in ion channel function. Schoepp and Conn, Trends in Pharmacol. Sci., 14, 13 (1993).

It appears that both types of excitatory amino acid receptors not only mediate normal synaptic transmission down excitatory pathways, but also participate 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).

Increased or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss through a mechanism known as excitotoxicity.

This process has been proposed as a mediator of neuronal degradation in a range of neurological disorders and conditions. The medical consequences of such neuronal degradation make mitigation of these degenerative neurological processes an important goal of therapy. For example, excitatory amino receptor excitotoxicity has been shown to be involved in the pathophysiology of a number of neurological disorders, including the etiology of cerebral deficits secondary to cardiac bypass and graft surgery, stroke, cerebral ischemia, spinal cord lesions caused by trauma or inflammation, perinatal hypoxia, cardiac arrest , and hypoglycemic damage to neurons. In addition, excitotoxicity has been implicated in chronic neurodegenerative conditions including Alzheimer's disease, Huntington's chorea, hereditary ataxia, AIDS-related dementia, amyotrophic lateral sclerosis, idiopathic and drug-induced Parkinson's disease, as well as eye damage and retinopathy. Other neurological disorders associated with glutamate excitotoxicity and/or dysfunction include muscle spasticity including tremors, drug tolerance and withdrawal, brain edema, convulsive disorders including epilepsy, depression, anxiety and anxiety-related disorders such as post-traumatic stress syndrome, tardive dyskinesia, and psychoses associated with depression, schizophrenia, bipolar disorder, mania, and drug intoxication or drug dependence. (see generally United States Patent Nos. 5,446,051 and 5,670,516) Excitatory amino acid receptor antagonists may also be useful as analgesics and in the treatment or prevention of various forms of headache, including cluster headache, tension-type headache, and chronic daily headache. In addition, published European patent application WO98/45720 reports that excitatory amino acid receptor excitotoxicity is involved in the etiology of acute and chronic pain conditions including severe pain, intractable pain, neuropathic pain, post-traumatic pain.

It is also known that the trigeminal ganglia, and the nerve pathways associated with them, are associated with painful sensations in the head and face such as headache and, especially, migraine. Moskowitz (Cephalalgia, 12.5-7, (1992)) proposed that unknown triggers stimulate the trigeminal ganglia which then innervate blood vessels within the brain tissue, leading to the release of vasoactive neuropeptides from axons innervating the blood vessels. These neuropeptides initiate a series of events that lead to neurogenic inflammation of the meninges, resulting in pain. This neurogenic inflammation was stopped by sumatriptan at doses similar to those needed to treat acute migraine in humans. Nevertheless, such doses of sumatriptan are associated with contraindications resulting from the accompanying vasoconstrictive properties of sumatriptan. (see MacIntyre, P. D., et al., British Journal of Clinical Pharmacology, 34, 541-546 (1992); Chester, A. H., et al., Cardiovascular Research, 24, 932-937 (1990); Conner, H. E., et al. , European Journal of Pharmacology, 161,91-94 (1990)). Recently, it has been shown that all five members of the kainate subtype of ionotropic glutamate receptors are expressed in neurons of the trigeminal ganglion in rats, and particularly high levels of GluR5 and KA2 were observed. (Sahara et al., The Journal of Neuroscience, 17 (17), 6611 (1997)). In this light, migraine represents another neurological disorder that may be associated with glutamate receptor excitotoxicity.

The use of a neuroprotective agent, such as an excitatory amino acid receptor antagonist, is believed to be useful in the treatment or prevention of any of the aforementioned disorders and/or in reducing the amount of neurological damage resulting from these disorders. For example, studies have shown that AMPA receptor antagonists are neuroprotective in models of focal and global ischemia. The competitive AMPA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline) was found to be effective in preventing global and focal ischemic damage. Sheardown et al., Science, 247,571 (1900); Buchan et al., Neuroreport, 2,473 (1991); LePeillet et al., Brain Research, 571,115 (1992). The non-competitive AMPA receptor antagonist GKYI 52466 was shown to be an effective neuroprotective agent in a global ischemia model in rats. LaPeillet et al., Brain Research, 571,115 (1992). European Patent Application Publication No. 590789A1 and United States Patents No. 5,446,051 and 5,670,516 disclose that certain decahydroisoquinoline derivative compounds are precisely AMPA receptor antagonists and, as such, are useful in the treatment of a variety of disordered conditions, including painful and migraine headaches. WO98/45270 discloses that decahydroisoquinoline derivative compounds are selective iGluR5 receptor antagonists and are useful in the treatment of various types of pain, including; severe, chronic, unrelenting, and neuropathic pain.

In accordance with the present invention, Applicants have discovered novel compounds that are selective antagonists of the iGluR5 receptor subtype and, therefore, may be useful in the treatment of a variety of neurological disorders or neurodegenerative diseases, as discussed above. Such selective antagonists may answer the long-standing need for safe and effective treatment of neurological disorders, without associated side effects.

This improved the treatment of neurological disorders and neurodegenerative diseases.

The essence of invention

The present invention provides a compound of Formula I

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or a pharmaceutically acceptable salt or prodrug thereof.

In its preferred embodiment, the present invention provides a compound of Formula Ia

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in which

R1 and R2 each independently represent hydrogen, (C1-C20)alkyl, (C2-C6)alkenyl, (C1-C6)alkylaryl, (C1-C6)alkyl(C3-C10)cycloalkyl, (C1-C6) alkyl-N,N-C1-C6 dialkylamine, (C1-C6)alkyl-pyrrolidine, (C1-C6)alkyl-piperidine, or (C1-C6)alkyl-morpholine, provided that at least one of R1 and R2 is not hydrogen ,

or a pharmaceutically acceptable salt thereof.

In a particularly preferred embodiment, the present invention provides a D-(-)-α-hydroxyacetic acid salt of Formula I or Formula Ia, wherein Formula I and Formula Ia are as defined above.

In another aspect, the subject invention provides a method for treating or preventing a neurological disorder, or neurodegenerative condition, which involves 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. Examples of such neurological disorders, or neurodegenerative conditions, include: cerebral deficits resulting from cardiac bypass and graft surgeries; stroke; cerebral ischemia; lesions of the spinal cord caused by trauma or inflammation; perinatal hypoxia; cardiac arrest; hypoglycemic damage to neurons; Alzheimer's disease; Huntington's chorea; hereditary ataxias; AIDS-related dementia; amyotrophic lateral sclerosis; idiopathic and drug-induced Parkinson's disease; eye damage and retinopathy; muscle spasticity including tremors; tolerance and drug withdrawal; brain edema; convulsive disorders including epilepsy; depression; anxiety and anxiety-related disorders such as post-traumatic stress syndrome; tardive dyskinesia; psychoses associated with depression, schizophrenia, bipolar disorder, mania, and drug intoxication or drug dependence; headache, including cluster headache, tension-type headache, and chronic daily headache; 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 the treatment or prevention of migraine which comprises 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 the treatment or prevention of migraine which comprises administering to a patient in need thereof an effective amount of a D-(-)-α-hydroxyacetic acid salt of Formula I or Formula Ia.

The present invention also provides a process for the preparation of a compound of Formula Ia, which consists of combining a compound of structure (2)

[image]

wherein R2 is as described herein, Pg is a suitable nitrogen protecting group, and LgO is a suitable leaving group, with a suitable base in a suitable solvent, followed by addition of a compound of structure (3)

[image]

where R 1 is as defined herein, followed by oxidation to a compound of structure (5)

[image]

followed by halogenation and removal of the nitrogen protecting group.

In addition, the present invention provides pharmaceutical compositions of compounds of Formula I and Formula Ia, including pharmaceutically acceptable salts, and hydrates thereof, useful for the treatment of neurological disorders or neurodegenerative conditions, including, as an active ingredient, a compound of Formula I or Formula Ia in combination with a pharmaceutically acceptable carrier, diluent or excipient. This invention also encompasses new intermediates, and processes for the synthesis of compounds of Formula I and Formula Ia.

More specifically, the present invention provides pharmaceutical compositions useful for the treatment or prevention of migraine comprising, as an active ingredient, a D-(-)-α-phenylhydroxyacetic acid salt of Formula I or Formula Ia, in combination with one or more pharmaceutically acceptable carriers, diluents or excipients.

The present invention also provides the use of a compound of Formula I or Formula Ia for the preparation of medicaments for the treatment or prevention of a neurological disorder, or neurodegenerative condition.

More specifically, the present invention provides the use of a compound of Formula I or Formula Ia for the preparation of a medicament for the treatment or prevention of migraine.

Detailed description of the invention

The present invention provides compounds that act as selective iGluR5 receptor antagonists as well as pharmaceutically acceptable salts, prodrugs, and preparations thereof.

In addition, the present invention provides a method for treating a neurological disorder, or neurodegenerative condition. In particular, the present invention provides a method for the treatment of migraine which can be demonstrated by a special mechanism of action, the inhibition of neurogenic extravasation of dural proteins. By treating migraine with a compound or compounds that are selective antagonists of the iGluR5 receptor over other excitatory amino acid receptors, the neurogenic extravasation that mediates migraine is inhibited without the side effects of agents designed to optimize the 5-HT1-like mediated vasoconstrictive action of sumatriptan.

One skilled in the art will appreciate that all compounds useful in the methods of the present invention are available for formulating prodrugs. As used herein, the term "prodrug" refers to a compound of Formula I or a compound that has been structurally modified such that in vivo the drug is converted, for example, by hydrolytic, oxidative, reductive, or enzymatic cleavage, to the parent compound (e.g., carboxylic acid (drug), or what may also be the case the parent dicarboxylic acid) as given in Formula I. Such prodrugs may be, for example, metabolically unstable ester or diester derivatives of the parent compounds having a carboxylic acid group. It is to be understood that the present invention includes any such prodrug, such as metabolically unstable ester or diester derivatives of the compounds of Formula I. In all cases, the use of the compounds described herein as prodrugs is contemplated, and often preferred, and are therefore prodrugs of all compounds employed. covered here under the given names of compounds. Preferred prodrugs include diester derivatives of Formula I.

Conventional procedures for the selection and preparation of suitable prodrugs are well known to a person of ordinary skill in the art.

More specifically, examples of Formula I prodrugs that are intended to be included within the scope of the present invention are represented by Formula Ia below:

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R1 and R2 each independently represent hydrogen, (C1-C20)alkyl, (C2-C6)alkenyl, (C1-C6)alkylaryl, (C1-C6)-alkyl(C3-C10)cycloalkyl, (C1-C6 )alkyl-N,N-C1-C6 dialkylamine, (C1-C6)alkyl-pyrrolidine, (C1-C6)alkyl-piperidine, or (C1-C6)-alkyl-morpholine, provided that at least one of R1 and R2 not hydrogen

or a pharmaceutically acceptable salt thereof.

It is understood that the selective iGluR5 receptor antagonists of the present invention may exist as pharmaceutically acceptable salts and, as such, the salts are therefore included within the scope of the present invention. The term "pharmaceutically acceptable salt" as used herein refers to salts of the compounds provided, or used in the present invention, which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reacting the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or organic or inorganic base. Such salts are known as acid addition salts and base addition salts.

The skilled reader will appreciate that most or all of the compounds used in the present invention have the ability to form salts, and that salt forms are commonly used drugs, often because they are easier to crystallize and purify than the free bases. In all cases, the use of the drugs described herein in salt form is contemplated in this specification, and is often preferred, and pharmaceutically acceptable salts of all compounds are included by their names.

Commonly used acids for forming acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, α-hydroxyacetic acid, 1, 5-naphthalenedisulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.

Examples of such pharmaceutically acceptable salts are sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydroxyphosphate, dihydroxyphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyn-1,4-dioate, hexine-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, α-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, napadisilate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as D-(-)-α-hydroxyacetic acid, 1,5-naphthalenedisulfonic acid, maleic acid, and methanesulfonic acid.

Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in the preparation of the salts of the present invention therefore include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and similar to. Potassium and sodium salts are particularly preferred. It should be pointed out that the individual counterion that forms part of any salt from this invention usually does not have a critical role, if the salt is completely pharmacologically acceptable and if the counterion does not contribute to the unwanted properties of the salt as a whole. It is further clear that such salts can exist as hydrates.

As used herein, the term "stereoisomer" refers to a compound that is composed of the same atoms linked by the same bonds, but has different three-dimensional structures that are not interchangeable. Three-dimensional structures are called configurations. As used herein, the term "enantiomer" refers to two stereoisomers whose molecular structures are non-superimposable mirror images of each other. The term "chiral center" refers to a carbon atom to which four different groups are attached. As used herein, the term "diastereomers" refers to stereoisomers that are not enantiomers. Additionally, two diastereomers having different configurations at only one chiral center are referred to herein as "epimers". The terms "racemate", "racemate mixture" or "racemate modification" refer to a mixture of equal parts of enantiomers.

The term "enantiomeric enrichment" as used herein refers to an increase in the amount of one enantiomer compared to the other. A convenient method for expressing the achieved enantiomeric enrichment is the concept of enantiomeric excess, or "ee", which is obtained using the following equation:

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where E1 is the amount of the first enantiomer and E2 is the amount of the second enantiomer. Therefore, if the initial ratio of the two enantiomers is 50:50, as is the case in the racemate mixture in question, and the enantiomeric enrichment achieved is sufficient to reach the final ratio of 50:30, the ee, in relation to the first enantiomer, is 25%. Nevertheless, if the final ratio is 90:10, the ee, relative to the first enantiomer, is 80%. An ee greater than 90% is preferred, an ee greater than 95% is even more desirable, and an ee greater than 99% is particularly desirable. Enantiomeric enrichment will be readily determined by one skilled in the art using standard techniques and procedures, such as gas or high performance liquid chromatography on a chiral column. The selection of a suitable chiral column, eluent and conditions necessary to effect the separation of the enantiomeric pair is within the skill of one of ordinary skill in the art. Additionally, enantiomers of compounds of Formula I or Formula Ia can be resolved by one of ordinary skill in the art using conventional techniques well known in the art, such as those described in J. Jacques, et al., "Enantiomers, Racemates, and Resolutions." ", John Wiley and Sons, Inc., 1981.

The compounds of the present invention have one or more chiral centers and can exist in various stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers fall within the scope of the present invention.

The terms "R" and "S" are used herein as is customary in organic chemistry to denote a particular configuration of a chiral center. The term "R" (rectus) refers to such a configuration of the chiral center that has the groups arranged in order of priority (highest to second lowest) in a clockwise direction when looking down the bond to the group of lowest priority. The term "S" (sinister) refers to such a configuration of a chiral center that has a group arrangement in order of priority (highest to second lowest) in a counterclockwise direction when looking down the bond to the group of lowest priority. The priority of groups is based on their atomic number (in descending order of atomic number). A partial list of priorities and discussion of stereochemistry is found in "Nomenclature of Organic Compounds: Principles and Practice", (J. H. Fletcher, et al., eds., 1974) pages 103-120.

Individual stereoisomers and enantiomers of compounds of Formula I and Formula Ia can be prepared by one of ordinary skill in the art using well known techniques and processes, such as those provided in Eliel and Wilen, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc ., 1994, Chapter 7, Separation of Stereoisomers. Resolution. Racemization, and in Collet and Wilen, "Enantiomers, Racemates, and Resolutions", John Wiley & Sons, Inc., 1981. For example, individual stereoisomers and enantiomers can be prepared by stereospecific syntheses using enantiomerically and geometrically pure, or enantiomerically or geometrically enriched starting materials. In addition, individual stereoisomers and enantiomers can be separated and obtained by techniques such as chromatography on chiral stationary phases, enzymatic separation or fractional recrystallization of addition salts formed with reagents used for this purpose.

As used herein, the term "Pg" 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 the nitrogen group from undesirable reactions during synthetic procedures. The choice of the appropriate nitrogen protecting group to be used depends on the conditions to be used in the subsequent reaction steps in which protection is required, and is within the skill of one of ordinary skill in the art.

Commonly used nitrogen protecting groups are given in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981)). Suitable nitrogen protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, .alpha.-chlorobutyryl, benzoyl, 4- chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as 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, 1-(p-biphenylyl)-1-methylethoxycarbonyl, .alpha.,.alpha.-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t -butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, 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).

As used herein, the term "(C1-C4)alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.

As used herein, the term "(C1-C6)alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.

As used herein, the term "(C1-C10)alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 10 carbon atoms and includes, but is not limited to, 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.

As used herein, the term "(C1-C20) alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 20 carbon atoms and includes, but is not limited to, 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. It is understood that the terms "(C1-C4)alkyl", "(C1-C6)alkyl", and "(C1-C10)alkyl" are included under the definition of "(C1-C20)alkyl".

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

As used herein, the term "(C1-C4)Alkoxy" refers to an oxygen atom bearing a straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to, methyoxy, ethoxy, n -propoxy, isopropoxy, n-butoxy, and the like.

As used herein, the term "(C1-C6)Alkoxy" refers to an oxygen atom bearing a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to, methoxy, ethoxy, n- propoxy, 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 or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms having a (C 1 -C 6 )alkoxy group attached to an aliphatic chain.

As used herein, the terms "Halo", "Halide" or "Hal" refer to a chlorine, bromine, iodine or fluorine atom, unless otherwise indicated herein.

As used herein, the term "(C2-C6)alkenyl" refers to a straight or branched, monovalent, unsaturated aliphatic chain having from two to six carbon atoms. Typical C2-C6 alkenyl groups include 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 containing one or more fused or unfused phenyl rings and includes, for example, phenyl, 1- or 2-naphthyl, 1,2-dihydronaphthyl, 1,2, 3,4-tetrahydronaphthyl, and the like.

The term "substituted aryl" refers to an aryl group substituted with one or two subunits selected from the group consisting of halogen, hydroxy, cyano, nitro, (C1-C6)alkyl, (C1-C4)alkoxy, (C1-C6) alkyl(C3-C10)cycloalkyl, (C1-C6)alkylaryl, (C1-C6)alkoxycarbonyl, protected carboxy, carboxymethyl, hydroxymethyl, amino, aminomethyl, or trifluoromethyl groups.

As used herein, the term "(C1-C6)alkylaryl" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms having an aryl group attached to the aliphatic chain. The term "C1-C6alkylaryl" includes the following groups:

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and the like.

As used herein, the term "aryl(C1-C6)alkyl" refers to an aryl group having a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms attached to the aryl group. The term "aryl(C1-C6)alkyl" includes the following groups:

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and the like.

As used herein, the term "(C3-C10)cycloalkyl" refers to a saturated carbohydrate ring structure consisting of one or more fused or unfused rings containing from three to ten carbon atoms. Typical C3-C10 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamananyl, and the like.

As used herein, the term "C1-C6alkyl(C3-C10)cycloalkyl" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms having a (C3-C10)cycloalkyl group attached to the aliphatic chain. The term "C1-C6alkyl(C3-C10)cycloalkyl" includes the following groups:

[image]

and similar.

As used herein, the term "(C 1 -C 6 )alkoxycarbonyl" refers to a carbonyl group having a (C 1 -C 6 )alkyl group attached to the carbonyl carbon via an oxygen atom.

Examples of this group include t-buoxycarbonyl, methoxycarbonyl, and the like.

As used herein, the term "heterocycle" refers to a five- or six-membered ring containing from one to four heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen. Those skilled in the art will recognize the remaining ring atoms as carbon. Rings can be saturated or unsaturated. Examples of heterocyclic groups include thiophenyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, thiazolidinyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridiazinyl, triazinyl, imidazolyl, dihydropyrimidyl, tetrahydropyrimidyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, pyrimidinyl, imidazolidyl, morpholinyl, pyranyl, thiomorpholinyl, and the like. The term "substituted heterocycle" represents a heterocyclic group substituted with one or two subunits selected from the group consisting of halogen, hydroxy, cyano, nitro, oxo, (C1-C6)alkyl, (C1-C4)alkoxy, C1-C6alkyl(C3 -C 10 ) cycloalkyl, (C 1 -C 6 )alkylaryl, (C 1 -C 6 )alkoxycarbonyl, protected carboxy, carboxymethyl, hydroxymethyl, amino, aminomethyl, or trifluoromethyl groups.

As used herein, the term "N,N-C1-C6 dialkylamine" refers to a nitrogen atom substituted with two straight or branched, monovalent, saturated aliphatic chains having from 1 to 6 carbon atoms. The term "N,N-C1-C6 dialkylamine" also includes -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH2CH2CH2CH3)2, and the like.

As used herein, the term "C1-C6alkyl-N,N-C1-C6dialkylamine" refers to a straight or branched, monovalent, saturated aliphatic chain of from 1 to 6 carbon atoms having an N,N-C1-C6dialkylamine group attached to aliphatic chain. The term "C1-C6alkyl-N,N-C1-C6dialkylamine" includes the following groups:

[image]

and the like.

As used herein, the term "(C 1 -C 6 )alkyl-pyrrolidine" refers to a straight or branched, monovalent, saturated aliphatic chain having from 1 to 6 carbon atoms having a pyrrolidine attached to the aliphatic chain. The term "(C1-C6)alkyl-pyrrolidine" includes the following groups:

[image]

and the like.

As used herein, the term "(C 1 -C 6 )alkyl-piperidine" refers to a straight or branched, monovalent, saturated aliphatic chain having from 1 to 6 carbon atoms bearing a piperidine attached to the aliphatic chain. The term "(C1-C6)alkyl-piperidine" includes the following groups:

[image]

and the like.

As used herein, the term "(C1-C6)alkyl-morpholine" refers to a straight or branched, monovalent, saturated aliphatic chain having from 1 to 6 carbon atoms having a morpholine group attached to the aliphatic chain. The term "(C1-C6)alkyl-morpholine includes the following groups:

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and the like.

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The [image] tag refers to a link that protrudes backward relative to the page level.

As used herein, the term "iGluR5" refers to the kainate ionotropic glutamate receptor, subtype 5, of the larger group of excitatory amino acid receptors.

As used herein, the term "migraine" refers to a disorder of the nervous system characterized by recurrent attacks of pain in the head (not caused by abnormalities in brain structure such as those resulting from a tumor or stroke), gastrointestinal disturbances, and possible neurological symptoms such as which is visual distortion. Characteristic migraine headaches usually last for a day and are usually accompanied by nausea, vomiting, and photophobia.

Migraine can be a "chronic" condition, or an "acute" episode. The term "chronic", as used herein, means a condition of slow progression and long duration. As such, a chronic condition is treated when it is diagnosed and treatment continues throughout the course of the disease. In contrast, the term "acute" means an increase in the intensity of an event or attack, of short duration, followed by a period of remission. Therefore, migraine treatment addresses both acute events and chronic conditions. In an acute case, the compound is given at the moment of the onset of symptoms, and the administration is stopped when the symptoms disappear. As described above, a chronic condition is treated throughout the course of the disease.

As used herein, the term "patient" refers to a mammal, such as a mouse, gerbil, guinea pig, rat, dog, or human. It goes without saying, however, that the preferred patient is a human.

It is understood that the term "selective iGluR5 receptor antagonists" as used herein includes those excitatory amino acid receptor antagonists that selectively bind to the iGluR5 kainate receptor subtype, relative to the iGluR2 AMPA receptor subtype.

Preferably, the selective iGluR5 antagonist for use in accordance with the methods of the present invention has a binding affinity at least 10-fold greater for iGluR5 than for iGluR2, more preferably at least 100-fold greater. Selective iGluR5 receptor antagonists are readily available, or can be readily prepared by a person of ordinary skill in the art following known procedures. For example, WO 98/45270 provides examples of selective iGluR5 receptor antagonists and provides methods for synthesis.

As used herein, each of the terms "treating", "treating", or "treating" means reducing symptoms, removing the cause of the resulting symptoms either on a temporary or permanent basis, and preventing, slowing the onset of, or reversing the progression or severity of the resulting symptoms of said disorders. As such, the methods of this invention encompass both therapeutic and prophylactic applications.

As used herein, the term "effective amount" refers to an amount or dose of a compound which, upon single or repeated administration to a patient, provides the desired effect in a diagnosed or treated patient. The effective amount can be readily determined by the responsible diagnostician, as one skilled in the art, using known techniques and observing results obtained under analogous circumstances. In determining the effective amount or dose of a compound to be administered, the responsible diagnostician considers a number of factors, including but not limited to: the species of mammal; his size, age, and general health; degree of involvement or severity of migraine involved; individual patient's response; the particular compound being applied; route of application; bioavailability characteristics of the administered preparation; selected dosage regimen; parallel application of another treatment; and other relevant circumstances.

A typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of each compound used in the subject method of treatment. Preferably, daily doses will be from about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.

The preferred route of administration is oral administration of the compounds used in the present invention, either alone or in combination with compounds capable of acting as selective iGluR5 receptor antagonists. Oral administration, on the other hand, is not the only route of administration, nor the only preferred route of administration. Other preferred routes of administration include transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, or intrarectal routes. When the selective iGluR5 receptor antagonist is administered as a combination of compounds, one of the compounds may be administered by a single route of administration, such as orally, and the other may be administered by a transdermal, percutaneous, intravenous, intramuscular, intranasal, pulmonary, buccal, or intrarectal route, as certain circumstances require. The route of administration can be changed in any way, limited by the physical properties of the compounds and the suitability for the patient and for the person administering the drug.

The compounds used in the present invention can be used as pharmaceutical preparations and, therefore, pharmaceutical preparations containing compounds of Formula I or Formula Ia are important aspects of the present invention. Such preparations may have any physical form that is pharmaceutically acceptable, but pharmaceutical preparations for oral administration are particularly preferred. Such pharmaceutical preparations contain, as an active ingredient, an effective amount of a compound of Formula I or Formula Ia, including pharmaceutically acceptable salts, prodrugs, and hydrates thereof, the effective amount of which is related to the daily dose of the compound to be administered. Each dosage unit may contain a daily dose of a given compound, or may contain a fraction of a daily dose, such as half or a third of a dose. The amount of each compound placed in each dosage unit depends on the type of particular compound selected for therapy, and other factors such as the indication for which the compound is administered. The pharmaceutical compositions of the present invention can be formulated to provide a rapid, gradual, or delayed release of the active ingredient after administration to the patient, using well-known procedures.

The compositions are preferably formulated into unit dosage forms, where each dose contains from about 1 to about 500 mg of each compound individually or in a single unit dosage form, more preferably from about 5 to about 300 mg (for example, 25 mg). The term "unit dosage form" refers to a physically discrete unit suitable as a single dose for a patient, each unit containing a predetermined amount of active material calculated to achieve the desired therapeutic effect, together with a suitable pharmaceutical carrier, diluent, or excipient.

The inert ingredients and the method of formulation of pharmaceutical preparations are conventional. Conventional formulation methods from pharmaceutical science can be used here. All common types of preparations can be used, including tablets, chewable tablets, capsules, solutions, parenteral solutions, intranasal sprays or powders, lozenges, suppositories, transdermal patches and suspensions. In general, the compositions contain from about 0.5% to about 50% of the compounds in total, depending on the dosages desired and the type of composition used. The amount of compound, on the other hand, is best defined as an "effective amount", that is, the amount of each compound that provides the desired dose to a patient in need of such treatment.

The activity of the compounds used in the present invention does not depend on the nature of the preparations, therefore the preparations were selected and formulated solely for their practicality and economy.

Capsules are prepared by mixing the compound with a suitable diluent and filling the appropriate amount of the mixture into the capsules. Common diluents include inert powders such as starch, powdered cellulose especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, cereal flour, and similar edible powders.

Tablets are prepared by direct compression, wet granulation, or dry granulation. Their formulations usually include diluents, binders, lubricants and disintegrators as well as the compound itself. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful. Typical binding agents in tablets are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also suitable, including acacia, alginates, methylcellulose, polyvinylpyrrolidine, and the like.

Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

Tablets are often coated with sugar, which serves as a flavoring agent and a means of sealing the surface. The compounds can also be formulated in the form of chewable tablets, using a large amount of a pleasant-tasting substance in the formulation, such as mannitol, which is currently a common practice.

Formulations similar to instant-dissolving tablets are now often used, in order for the patient to safely consume the dosage form, and to avoid difficulty swallowing solid objects that bothers some patients.

In a tablet formulation, a lubricant is often necessary to prevent the tablet and the embossing device from sticking to the paint. The lubricant is selected from such sliding solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.

Tablet disintegrators are substances that swell when wet to tear apart the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More specifically, for example, corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose can be used, as well as sodium lauryl sulfate. .

Enteric formulations are often used to protect the active ingredient from the highly acidic stomach contents. Such formulations are created by coating solid dosage forms with a polymer film that is insoluble in acidic environments and soluble in basic environments. Examples of films are cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.

When the compound is to be administered in suppository form, the usual bases can be used. Cocoa butter is the traditional base of suppositories, which can be modified by adding waxes that slightly raise its melting point. Suppository bases that mix with water are also widely used, and in particular they include polyethylene glycols of different molecular weights.

Transdermal stickers have become popular recently. They typically consist of a resinous composition in which the drug dissolves, or partially dissolves, and is held in contact with the skin by a film that protects the composition. Recently, many patents have appeared in this area. Other, more complicated preparations for stickers are also used, especially those that have a membrane with many pores through which drugs enter due to osmotic action.

The following table provides an illustrative list of formulations suitable for use with the compounds used in the present invention. What follows is provided to illustrate the invention only and should not be construed as limiting the subject invention in any respect.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

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The above-mentioned ingredients are mixed and filled into hard gelatin capsules in the amount of 460 mg.

Formulation 2

The tablet is prepared using the following ingredients listed below:

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The ingredients are mixed together into a uniform mixture and compressed into tablet form, each weighing 665 mg.

Formulation 3

The aerosol solution is prepared so that it contains the following components:

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The active ingredient was mixed with ethanol and the mixture was added to the Propellant 22 portion, cooled to -30°C and transferred to the filling device. The required amount was then filled into a stainless steel tank and diluted with the rest of the propellant. Parts with valves are then attached to the tank.

Formulation 4

The tablets, each containing 60 mg of the active ingredient, are prepared as follows:

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The active ingredient, starch, and cellulose were passed through a U.S. mesh size No. 45 and thoroughly mixed. A solution of polyvinylpyrrolidone was mixed with the resulting powders, which were then passed through a U.S. mesh size No. 14. The granules thus obtained were dried at 50°C and passed through a U.S. sieve of opening size No. 14. Sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a U.S. mesh No. 1 sieve. 60, were then added to the granules, which, after mixing, were compressed in a tablet machine to obtain tablets weighing 150 mg each.

Formulation 5

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

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The active ingredient, cellulose, starch and magnesium stearate were mixed together into a uniform mass, passed through sieve No. 45, and filled in hard gelatin capsules in the amount of 200 mg.

Formulation 6

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

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The active ingredient was passed through a U.S. mesh size No. 60 and suspended in glycerides of saturated fatty acids that have been previously dissolved with the help of the minimum necessary heat.

The mixture was then poured into a suppository mold with a nominal capacity of 2 g and cooled.

Formulation 7

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

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The drug was passed through a U. S. mesh size No. 45 and mixed with sodium carboxymethyl cellulose and syrup, resulting in a smooth paste. Benzoic acid solution, aroma and color were diluted with some water and added to the paste, while mixing.

Sufficient water was then added to achieve the desired volume.

Formulation 8

The intravenous formulation can be prepared as follows:

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It is clear to a person of ordinary skill in the art that the procedures described hereinabove can equally be applied to a method of treating neurological disorders or neurodegenerative conditions, particularly migraines, consisting of administering to the 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 procedures given in Scheme I. These schemes are not intended to limit the scope of the invention in any way. All substituents, unless otherwise indicated, are as previously defined. Reagents and starting materials are readily available to a person of ordinary skill in the art. For example, certain necessary starting materials can be prepared by a person of average skill in the art, if he follows the procedures given in United States Patents Nos. 5,356,902 (issued October 18, 1994) and 5,446,051 (issued August 29, 1995).

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In Scheme I, Step A, the 6-(hydroxymethyl)-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate of compound (1) (wherein Pg is a suitable nitrogen protecting group as defined herein above, with a methoxycarbonyl group being preferred) treated is under standard conditions with a compound of the formula Lg-Hal, where Lg is a suitable leaving group and Hal represents a chloro, bromo or iodine atom, to give a compound of structure (2). 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 a suitable organic base such as triethylamine and then about 1 to 2 equivalents of a compound of formula Lg - Hal. Examples of Lg-Hal include m-nitrobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, p-bromobenzenesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, and the like. (Additionally, one skilled in the art will appreciate that a halo atom such as chlorine, bromine, or iodine itself may also be used as a suitable leaving group in place of the LgO group.) The reaction mixture was warmed to room temperature and stirred for 5 a.m. to 8 p.m. Compound (2) was then isolated using standard procedures. For example, the reaction mixture was washed with water, the organic layer was separated and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude compound (2). Chromatography was then performed on a silica gel column with a suitable eluent such as 10-50% ethyl acetate/hexane to give the purified compound (2).

In Scheme I, Step B, compound (2) was treated under standard conditions with a pyrrolidine of structure (3) to give a compound of structure (4). For example, compound (2) is mixed with about 1-1.5 equivalents of 4-hydroxy-1-proline ethyl ester (R3 is ethyl) and 1-1.5 equivalents of potassium carbonate and heated to reflux in a suitable solvent as which is acetonitrile for about 60 - 70 hours. The reaction mixture was cooled to room temperature and the solvents were removed under vacuum. Compound (4) was then isolated using standard procedures such as extraction procedures. 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 were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give compound (4). Compound (4) can then be purified by chromatography on silica gel, with a suitable eluent such as 10-50% ethyl acetate/hexane or methanol/chloroform.

Alternatively, in Step B, the pyrrolidine of structure (3) can be mixed with a suitable resin filter cake and the resulting mixture treated with the compound of structure (2) to give the compound of structure (4). For example, Amberlite IRA 67 resin was treated with water, then mixed and filtered, and the filter cake was washed with a suitable solvent such as acetone until the water content of the wash was less than 5% by weight. The filter cake was mixed with 4-hydroxy-1-proline ethyl ester hydrochloride and acetone and the mixture was stirred at room temperature (RT) for about 1-2 hours. The mixture was then filtered and the filter cake was washed again with acetone. This filtered solution of hydroxyproline ethyl ester can be used directly. A thick solution of Amberlite IRA 67 resin in water was mixed, and the mixture was filtered. The filter cake was washed with a suitable solvent such as acetone until the water content of the wash was less than about 5% by weight. This second filter cake could then be mixed with the hydroxyproline ethyl ester solution from above and the compound (2) solution, and the mixture was heated at reflux. After about 24 hours, the reaction was cooled and filtered. The filter cake was washed with dichloromethane (about 300 ml) and the combined filtrates were concentrated in vacuo.

The precipitate can be concentrated from dichloromethane several times to give compound (4) as an oil which can be used directly in the next step.

In Scheme I, Step C, compound (4) was oxidized under standard conditions to give a compound of structure (5). For example, a solution of dichloromethane was treated with phosphorus pentoxide and the reaction was allowed to cool to approximately -10°C. Dimethyl sulfoxide was added with stirring and the reaction mixture was then treated with a solution of compound (4) dissolved in dichloromethane. The reaction was heated to about 20-22°C for a period of about 4-5 hours, stirred for 8-20 hours, cooled to about 0°C, and then treated with triethylamine at a rate to maintain the reaction temperature below approximately 5°C. .

The reaction was allowed to warm to R.T., stirred for one hour, and then added to 0.1 M HCl solution at such a rate as to keep the reaction temperature below approximately 10°C. Compound (5) was then isolated using standard procedures. For example, additional dichloromethane was added to partition the reaction mixture. The aqueous layer was then extracted 2-6 times with dichloromethane and the organic phases were combined, washed with 1 M NaHCO3, dried over magnesium sulfate, then concentrated in vacuo to give compound (5). The crude material can then be purified by chromatography on silica gel with a suitable eluent such as 10-50% ethyl acetate in toluene or methanol/dichloromethane.

In Scheme I, Step D, compound (5) was fluorinated to give a compound of structure (6). For example, a solution of compound (5) in ethanol was dissolved in a suitable organic solvent such as 1,2-dichloroethane, treated with Deoxofluor ([bis-(2-methoxyethyl)amino]sulfur trifluoride) and stirred at R. T for from approximately 20 - 25 hours. The reaction mixture was then treated with concentrated NaHCO3 solution and stirred for 15 minutes. The layers were separated and the aqueous layer was extracted 2-6 times with toluene. The layers were separated again and the organic layers were combined, filtered, dried over Na 2 SO 4 , and then concentrated in vacuo to give a compound of structure (6). The crude material can then be purified by chromatography on silica gel with a suitable eluent such as (50:50) toluene/heptane and or 10-50% ethyl acetate in toluene.

In Scheme I, Step E, the compound of structure (6) was deprotected under standard conditions well known in the art to give the compound 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 a nitrogen atmosphere and treated with trimethylsilyl iodide. The reaction mixture was allowed to warm to room temperature and was stirred for 10-20 hours. The reaction was quenched by the addition of saturated aqueous NaHCO3. The aqueous layer was then extracted 2-6 times with dichloromethane. The organic phases were then combined, washed with 1 N sodium thiosulfate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to give the compound of Formula Ia. The material can then be purified by chromatography on silica gel with a suitable eluent such as methanol/dichloromethane to give the purified compound of Formula Ia.

In Scheme I, Step F, the compound of Formula Ia can optionally be hydrolyzed to the compound of Formula I under conditions well known in the art. For example, a compound of Formula Ia is dissolved in a suitable organic solvent such as methanol, and treated with an excess of a suitable base. Examples of suitable bases include aqueous lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like, with lithium hydroxide being preferred. The reaction was stirred for 10-20 hours. The reaction mixture is then neutralized to pH 6 with 1 N HCl and concentrated in vacuo to give the crude compound of Formula I. The material can then be purified using techniques well known in the art, such as chromatography with a suitable eluent.

In Scheme I, Step G, compound (6) can preferably be simultaneously deprotected and hydrolyzed to give the compound of Formula I. For example, a solution of compound (6) was dissolved in 6.0 N HCl, heated at reflux for 15 - 20 hours. The reaction mixture was then allowed to cool to room temperature and concentrated in vacuo to give the compound of Formula I. The compound of Formula I can then be purified by techniques well known in the art, such as cation exchange chromatography eluted with methanol/ water, then with 2 N ammonia in methanol or ethanol to give purified Formula I.

Additionally, one skilled in the art will recognize that a compound of Formula I can be esterified under standard conditions to give a compound of Formula Ia. For example, a compound of Formula I can be dissolved in a suitable organic solvent such as ethanol, and treated with an excess of a suitable acid. Examples of suitable acids include hydrochloric acid gas, aqueous sulfuric acid, p-toluene sulfonic acid, and the like, with hydrochloric acid gas being the preferred acid. The reaction mixture was heated to reflux for a suitable time. The reaction mixture can then be concentrated, for example, in vacuo, to give the crude compound of Formula Ia. This material can then be purified using techniques well known in the art, such as cation exchange chromatography, eluted with methanol/water, and then with 2 N ammonium in ethanol to give the purified compound of Formula Ia.

The compounds of Formula I and Formula Ia of the present invention can be chemically synthesized from the usual intermediate, 6-hydroxymethyl-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate. This intermediate can also be chemically synthesized from the intermediate 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid, the synthesis of which is described in United States Patents No. 4,902,695, No. 5,446,051, and No. 5,356,902 (the entire contents of which are incorporated herein by reference.)

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

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In Scheme IIa, Step A, 6-oxo-decahydroisoquinoline-3-carboxylic acid was treated with methyltriphenylphosphonium bromide to give 6-methylidine-decahydroisoquinoline-3-carboxylic acid of compound (i-a). For example, a thick solution of 1 equivalent of 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid and approximately 1.4 equivalents of methyltriphenylphosphonium bromide in THF and DMF was mechanically stirred under nitrogen and cooled to -10°C. A solution of potassium tert-butoxide (2.4 equiv in THF) was added dropwise over a period of 10 minutes. The thick solution was allowed to warm to room temperature and stirred for 2.5 hours (completed with TLC at that point). The reaction mixture was partitioned between water and EtOAc and the layers were separated. The organic phase was extracted 2 times with water and the aqueous parts were combined and washed 2-6 times with dichloromethane. The aqueous solution was prepared by acid addition of 6 M HCl solution and extracted 2-6 times with dichloromethane.

These last three organic extracts were combined, dried with sodium sulfate and concentrated under reduced pressure to give the compound of structure (i-a).

In Scheme IIa, Step B, the intermediate 6-methylidine-decahydroisoquinoline-3-carboxylic acid (compound (i-a)) was esterified by reaction with a compound of formula R2-Br (where R2 is as defined herein) to give 6-methylidine- decahydroisoquinoline-3-carboxylate intermediate of compound (ii). For example, 6-methylidine-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid was dissolved in acetonitrile and treated with triethylamine and bromoethane. The reaction was heated to 50°C for 3 hours, cooled and partitioned between 50:50 ethyl acetate/heptane and 1 N HCl. The organic phase was isolated and washed 3 times with water, saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the compound of structure (ii). The crude material was dissolved in 10% ethyl acetate/heptane and applied to a silica gel disk (10 g in 10% ethyl acetate/heptane).

The disk was eluted with 10% ethyl acetate/heptane, 15% ethyl acetate/heptane, and 25% ethyl acetate/heptane. The eluents were combined and concentrated in vacuo to give the purified compound of structure (ii).

In Scheme IIa, Step C, the 6-methylidine-decahydroisoquinoline-3-carboxylate intermediate (compound (ii)) was subjected to hydroboration, followed by oxidation to give the 6-hydroxymethyl-decahydroisoquinoline-3-carboxylate intermediate of compound (1) . For example, ethyl 6-methylidine-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate was dissolved in THF and cooled to about -15°C under nitrogen with stirring. A 1 M solution of BH3•THF was added dropwise over 5-7 minutes and the reaction mixture was stirred for 2 hours at -10 to -12°C. The reaction was then slowly treated with a suitable base, such as lithium or sodium hydroxide, and then slowly treated with 30% H 2 O 2 for 15 minutes. The reaction mixture was allowed to warm to room temperature and then partitioned between ethyl acetate and 50% saturated sodium chloride solution. The aqueous layer was extracted with ethyl acetate and the combined organic phases were washed with sodium bisulfite solution, brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give intermediate compound (1).

Alternatively, the 6-hydroxymethyl-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate intermediate (compound (1)) can be prepared according to the synthetic route described in Scheme IIb. In Scheme IIb, Step A, 6-oxo-decahydroisoquinoline-3-carboxylic acid was esterified by reaction with a compound of formula R2-Br (wherein R2 is as defined herein) to give 6-oxo-decahydroisoquinoline-3-carboxylate intermediate of compound (i-b). For example, 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid was dissolved in acetonitrile and treated with thiethylamine and bromoethane.

The reaction mixture was heated to 50°C for about 3 hours, cooled and partitioned between 50:50 ethyl acetate/heptane and 1 N HCl. The organic phase was isolated and washed 3 times with water, saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the compound of structure (i-b). This raw material was dissolved in 10% ethyl acetate/heptane and applied to a silica gel disc (10 g in 10% ethyl acetate/heptane). The disk was eluted with 10% ethyl acetate/heptane, 15% ethyl acetate/heptane, and 25% ethyl acetate/heptane. The eluents were combined and concentrated in vacuo to give the purified compound of structure (i-b).

In Scheme IIb, Step B, the 6-oxo-decahydroisoquinoline-3-carboxylate intermediate of compound (i-b) was treated with methyltriphenylphosphonium bromide to give the 6-methylidine-decahydroisoquinoline-3-carboxylate of compound (ii). For example, a concentrated solution of 1 equivalent of 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate (compound (i-b)) and approximately 1.4 equivalents of methyltriphenylphosphonium bromide in THF and DMF was stirred mechanically under a nitrogen atmosphere and cooled to - 10°C. A solution of potassium tert-butoxide (2.4 equiv in THF) was added dropwise over a period of 10 minutes. The thick solution was allowed to warm to room temperature and stirred for 2.5 hours (completed with TLC at that point). The reaction mixture was partitioned between water and EtOAc and the layers were separated. The organic phase was extracted 2 times with water and the aqueous parts were combined and washed 2-6 times with dichloromethane. The aqueous solution was acidified by the addition of 6 M HCl solution and extracted 2-6 times with dichloromethane. These last three organic extracts were combined, dried over sodium sulfate and concentrated under reduced pressure to give the compound of structure (ii).

In Scheme IIb, Step C, following the procedures as described above in Scheme IIa, Step C, the 6-methylidine-decahydroisoquinoline-3-carboxylate intermediate (compound (ii)) was subjected to hydroboration, followed by oxidation to give 6 -hydroxymethyl-decahydroisoquinoline-3-carboxylate intermediate of compound (1).

The following preparations and examples illustrate the compounds and methods of the present invention. Reagents and starting materials are readily available to a person of ordinary skill in the art. These examples are intended to be illustrative only and should not be construed to limit the scope of the invention in any way. As used herein, the following terms have the meanings indicated: "i.v." refers to intravenous; "per." refers to oral; "i.p." refers to intraperitoneal; "eq" or "equiv." refers to equivalents; "g" refers to grams; "mg" refers to milligrams; "l" refers to liters; "ml" refers to milliliters; "�l" refers to microliters; "mol" refers to moles; "mmol" refers to millimoles; "psi" refers to pounds per square inch; "mm Hg" refers to millimeters of mercury; "min" refers to minutes; "h" or "hr" refer to hours; "°C" refers to degrees Celsius; "TLC" refers to thin layer chromatography; "HPLC" refers to high performance liquid chromatography; "Rf" refers to the retention factor; "Rt" refers to retention time; "δ" refers to parts per million (ppm) downfield relative to tetramethylsilane; "THF" refers to tetrahydrofuran; "DMF" refers to N,N-dimethylformamide; "DMSO" refers to dimethyl sulfoxide; "aq" refers to aqueous; "EtOAc" refers to ethyl acetate; "iPrOAc" refers to isopropyl acetate; "MeOH" refers to methanol; "MTBE" refers to tert-butyl methyl ether; "RT" refers to room temperature; "Ki" refers to the dissociation constant of the enzyme-antagonist complex and serves as an indicator of ligand binding; and "ID50" and "ID100" refer to doses of a given medicinal substance that cause a 50% and 100% reduction in physiological response, respectively.

Preparation 1

Preparation of [3S,4aR,6S,8aR]-6-methylidine-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.

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A thick solution of methyltriphenylphosphonium bromide (12.4 g, 34.6 mmol) in THF (25 mL) was cooled to -10 to -12°C under nitrogen and treated with sodium hexamethyldisilazide (35 mL of a 1 M solution in THF ) through a syringe, lasting 6 to 8 minutes with mixing. The reaction mixture was then stirred for 20 minutes at -10 to -12°C and then 3S,4aR,6S,8aR-6-oxo-2-(methoxycarbonyl)-1,2,3 was added via cannula for 3-4 minutes. ,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (10.0 g, 26.6 mmol), [which was previously treated with sodium hexamethyldisilazide (27 ml of a 1 M solution in THE) at 0 - 3°C and stirred for 10 minutes], dissolved in DMF (20 ml) and cooled to 0 - 3°C, under a nitrogen atmosphere. This was followed by washing the vessel containing the Wittig reagent with THF (3 ml), which was also added to the reaction mixture. The reaction mixture was then allowed to stir for 5 minutes at 0-3°C, then allowed to warm to room temperature, and stirred for an additional 3 hours. Ethyl acetate (100 ml) and water (50 ml) were added with stirring and then the layers were separated. The organic layer was extracted with water (50 ml) and the combined aqueous portions were washed with methylene chloride (5 x 75 ml). The aqueous phase was then treated with 6 M HCl (15 ml) and extracted with methylene chloride (3 x 50 ml). The organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (6.59 g, 98%) as a yellow oil.

Alternative synthesis of [3S,4aR,6S,8aR]-6-methylidine-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.

A thick solution of [3S,4aR,6S,8aR]-6-oxo-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (50 .0 g, 0.133 mol, 1.0 equiv) and methyltriphenylphosphonium bromide (66.4 g, 0.186 mol, 1.4 equiv) in THF (150 ml) and DMF (25 ml) were stirred mechanically under a nitrogen atmosphere and cooled to -10°C. A solution of potassium tert-butoxide (187 ml of 1.7 M in THF, 0.319 mol, 2.4 equiv) was added dropwise over a period of 10 minutes. A slight exotherm during this addition results in an increase in the reaction temperature to 6°C. The thick solution was allowed to warm to room temperature and stirred for 2.5 hours (completed with TLC at that point). The reaction was partitioned between water (250 mL) and EtOAc (250 mL) and the layers were separated. The organic phase was extracted with water (2 x 100 ml) and the aqueous portions were combined and washed with dichloromethane (5 x 300 ml). The aqueous solution was acidified by the addition of 6 M HCl solution (50 ml) and extracted with dichloromethane (3 X 150 ml). These last three organic extracts were combined, dried over sodium sulfate and concentrated under reduced pressure to give the title compound as a yellow film (36.17 g). The estimated potency of the product by proton NMR is 89 wt % (the remainder is residual solvents) for a corrected yield of 32.2 g (95.6%).

Preparation 2

Preparation of [3S,4aR,6S,8aR]-ethyl-6-methylidine-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.

[image]

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

Preparation 3

Preparation of [3S,4aR,6S,8aR]-ethyl-6-(hydroxymethyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate .

[image]

[3S,4aR,6S,8aR]-Ethyl-6-methylidine-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (2, 0 g, 7.11 mmol, prepared in preparation 2) was dissolved in THF (10 ml) and heptane (2 ml) and cooled to about -15°C under nitrogen atmosphere with stirring. A 1 M solution of BH3•THF in THF (3.91 ml, 3.91 mmol) was added dropwise over a period of 5 - 7 minutes and the reaction was stirred for 2 - 4 hours at -10 to -14° C. The reaction was treated with ethanol (1.25 mL) for 2 minutes and then allowed to warm to 20°C. The reaction was then slowly treated with 1M LiOH solution (3.91 ml), followed by the slow addition of 30% H 2 O 2 (1.2 ml added at a rate to keep the reaction temperature below 30°C). The reaction mixture was allowed to stir at room temperature for 30-45 minutes and was then partitioned between ethyl acetate (12 ml) and 10% sodium bisulfite solution (14 ml). The organic layer was washed with 10% sodium bisulfite solution (16 mL), brine (8 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (2.01 g) as colorless oil.

EXAMPLE 1

3S, 4aR, 6S, 8aR Ethyl 6-(((2S)-2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-1,2,3,4,4a,5,6,7,8,8a -decahydroisoquinoline-3-carboxylate•D-(-)-�α-hydroxyacetic acid

[image]

A. Preparation

[image]

Solution of [3S,4aR,6S,8aR]-Ethyl-6-(hydroxymethyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (37.5 g, 0.125 mol) and triethylamine (35.0 mL, 0.25 mol) in EtOAc (94 mL) was added dropwise to a solution of p-nitrobenzenesulfonyl chloride (28.6 g, 0.125 mol) in EtOAc ( 94 ml) kept at 0 - 2°C (addition time: 30 min.). The reaction was allowed to warm to RT and was stirred for 2.5 hr and then quenched by the addition of water (100 ml), 1 M HCl (100 ml) and brine (20 ml). The layers were separated and the organic phase was washed with 1 M NaHCO 3 (150 ml), brine (150 ml) and dried over MgSO 4 . Concentration in vacuo afforded the title compound as an oil (58.9 g, 97%). 1H NMR (CDCl3) 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. Preparation

[image]

Amberlite IRA 67 resin (334.7 g) was treated with water (about 680 ml) and mixed.

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 mixed with hydroxyproline ethyl ester (HCl, 72.7 g, 0.372 mol) and acetone (700 mL) and the mixture was stirred at RT for approximately 1-2 hours. The mixture was filtered and the filter cake was washed with acetone (300 ml). This filtered solution of hydroxyproline ethyl ester is further used directly. A thick solution of Amberlite IRA 67 resin (465 g) in water (about 900 ml) was stirred and then the mixture was filtered. The filter cake was washed with acetone until the water content in the rinse was not less than 5% by weight. This filter cake was mixed with a solution of the hydroxyproline ethyl ester from above and a solution of the compound from Step A above (100 g, 0.206 mol) in EtOAc (about 150 ml) and the mixture was heated to reflux. After about 24 hours, the reaction was cooled and filtered. The filter cake was washed with dichloromethane (about 300 ml) and the combined filtrates were concentrated in vacuo and thus concentrated from dichloromethane several times to give the title compound in the form of an oil which was used directly in the next step.

C. Preparation

[image]

Dichloromethane (about 230 ml) was treated with phosphorus pentoxide (117.2 g, 0.825 mol) and the mixture was cooled to about -10°C. Dimethyl sulfoxide (96.8 g, 1.24 mol) was added to the mixture at such a rate that the reaction temperature remained around -10°C. The reaction mixture was stirred at about -10°C and treated with a solution of the compound from Step B above in dichloromethane (about 230 mL) at such a rate that the reaction temperature remained below about -10°C. The reaction was warmed to about 20 - 22°C for several hours (4 - 5) and stirred overnight and then cooled to about 0°C and treated with triethylamine (83.5 g, 0.825 mol) at such a rate that the reaction temp. remained below 5°C. The reaction was allowed to warm to RT and stirred for 1 hour. The reaction was added to a 0.1 M HCl solution (about 460 ml pre-cooled to about 0-5°C) at such a rate that the reaction temperature remained below 10°C. Additional dichloromethane (about 460 ml) was added and the mixture was stirred briefly and the layers were separated. The aqueous portion was extracted with dichloromethane (ca. 460 ml) and the combined organic extracts were washed with 1 M NaHCO3 (ca. 460 ml). 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 an oil (36.9 g, 41% from 504476). 1H NMR (CDCl3) δ�4.39 (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. Preparation

[image]

A solution of the compound from Step C above (8.98 g, 0.0205 mol) and ethanol (0.227 mL, 0.0039 mol) in 1,2-dichloroethane (43 mL) was treated with Deoxofluor ([Bis-(2-methoxyethyl )amino]sulfur trifluoride, 6.5 ml, 0.0353 mol) and the reaction was stirred at RT for approximately 21 hours. The reaction was treated with a saturated solution of NaHCO 3 in water (60 ml) and the mixture was then stirred for 15 min. The layers were separated and the aqueous portion was extracted with toluene (about 45 ml). The layers were separated and the toluene and 1,2-dichloroethane solutions were mixed and dried over Na 2 SO 4 . The drying agent was filtered and the filter cake was washed with toluene (about 30 ml). The filtrate was then concentrated in vacuo and the precipitate was dissolved in 50:50 toluene:heptane (about 17 ml) 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:heptane (ca. 230 ml), toluene (ca. 430 ml), 10% EtOAc in toluene (ca. 240 ml), and 20% EtOAc in toluene (ca. 86 ml). The eluent fractions containing the pure compound were combined and concentrated in vacuo to give the title compound as a syrup (5.79 g, 61%). 1H NMR (CDCl3) δ�4.35 (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. Preparation of 3S, 4aR, 6S, 8aR Ethyl 6-(((2S)-2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-1,2,3,4,4a, 5,6,7, 8,8a-decahydroisoquinoline-3-carboxylate (free base)

[image]

Preparation of the salt 3S, 4aR, 6S, 8aR ethyl 6-(((2S)-2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-1,2,3,4,4a, 5,6,7,8 ,8a-decahydroisoquinoline-3-carboxylate•D-(-)-α-hydroxyacetic acid

[image]

A solution of the compound from Step D above (9.7 g, 0.021 mol) in dichloromethane (ca. 70 ml) and toluene (ca. 30 ml) was cooled to 0 - 5°C and treated dropwise with iodotrimethylsilane (12.7 g , 0.063 mol). The reaction was allowed to warm to RT and stirred for 16 h then concentrated in vacuo. The precipitate was concentrated from MTBE (methyl t-butyl ether) several times and then dissolved in MTBE (ca. 70 ml) and toluene (ca. 30 ml) and washed with saturated NaHCO3 (ca. 100 ml), 1 N sodium thiosulfate (ca. 100 ml), and water (about 100 ml). The organic layer was concentrated in vacuo and the precipitate was concentrated from MTBE several times and then dissolved in toluene (about 22 ml) and then treated with a solution of D-(-)-α-hydroxyacetic acid (2.75 g, 0.181 mol) in MTBE (about 33 ml). The mixture was stirred at RT for about 2 hours, then cooled to about -15°C and stirred for 2 hours. The D-(-)-�α-hydroxyacetic acid salt was collected by filtration, washed with cold MTBE (ca. 73 ml at ca. -15°C) and dried to a crystalline solid (8.25 g, 71%). 1H NMR (DMSOd6) 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

Preparation 3S, 4aR, 6S, 8aR Ethyl 6-(((2S)-2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-1,2,3,4,4a,5,6,7,8, 8a-decahydroisoquinoline-3-carboxylate•1,5-naphthalene disulfonic acid

[image]

A solution of 1,5-naphthalenedisulfonic acid tetrahydrate (1.1 g, 3.05 mmol) in refluxing ethanol (about 5 ml) was treated with a solution of 3S, 4aR, 6S, 8aR ethyl 6-(((2S)-2 -(ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (free base of the diester compound from Example 1, Step E , above) (1.2 g, 3.0 mmol) in ethanol (ca. 5 mL) and the mixture was heated at reflux until crystals began to form (ca. 5 min). The reaction was cooled and allowed to stand at RT for about 3 days. The product was collected by filtration, washed with ethanol (3 X 5 ml) and dried (2.0 g, 96%). The product can be recrystallized from water or methanol.

EXAMPLE 3

Preparation of 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•dihydrochloride

[image]

Preparation of 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 acids (free base)

[image]

A mixture of the compound from Example 1, Step D, above (16.3 g, 0.0353 mol) and 6 M HCl (170 ml) was heated to reflux and the distillate from the reaction (about 15 ml) was collected over a period of 3 hours. The reaction mixture was cooled and washed with dichloromethane (2 x 50 ml) then treated with activated carbon (about 8 g) and then stirred at 60°C for 30 min. The mixture was cooled and filtered through a pad of Hyflo. The filter cake was washed with water (about 50 ml) and the aqueous filtrates were combined and concentrated in vacuo to a solid (142 g). This solid (8.61 g, 61% of the amount obtained) was concentrated from 2-propanol and treated with 2-propanol (about 43 ml) and the mixture was heated to 50°C for 1 hour. The mixture was cooled to about 0°C and stirred for 30 min. The solid was collected by filtration, washed with cold 2-propanol (20 mL), and dried to give a white powder (7.5 g), which is the dihydrochloride salt of the title compound. This powder (2.5 g, 33.3% yield) was treated with 1 N NaOH solution (11.9 mL) and then the solution was concentrated in vacuo. The precipitate was concentrated from EtOH, then treated with 50:50 EtOH:EtOAc. The mixture was heated to about 35°C, then cooled to RT and stirred for 1 hour, then filtered. The filter cake was washed with 50:50 EtOH:EtOAc (5 mL) and the combined filtrates were concentrated until a foam was obtained. The foam was concentrated from EtOAc then treated with EtOAc (10 mL) and stirred. The free base of the title compound was collected by filtration and dried to a powder (1.96 g, weight corrected). Calculation of the yield for the free base: 1.96 g divided by 0.333 divided by 0.61 = 9.65 g or 79%. 1H NMR (D2O + DCl) δ 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

In order to determine that the iGluR5 subtype of the receptor mediates neurogenic protein extravasation, a functional characteristic of migraine, the binding affinity of the mentioned compounds to the iGluR5 receptor was first measured using standard methods. For example, the activity of compounds that act as iGluR5 receptor antagonists can be determined using radiolabeled ligand binding studies on the cloned and expressed human iGluR5 receptor (Korczak et al., 1994, Recept. Channels 3; 41-49), and electrophysiological current recordings using whole-cell voltage clamps in isolated rat neurons from the dorsal basal ganglia (Bleakman et al., 1996, Mol. Pharmacol. 49; 581-585). The selectivity of compounds that act on the iGluR5 receptor subtype can be determined by comparing the action of antagonists on the iGluR5 receptor, with the action of antagonists on other AMPA and kainate receptors. Methods that are useful for such comparative studies include: receptor-ligand binding studies and electrophysiological recordings, with whole-cell voltage clamp, functional activities of human GluR1, GluR2, GluR3 and GluR4 receptors (Fletcher et al., 1995, Recept. Channels 3; 21-31); receptor-ligand binding studies and whole-cell voltage-clamp electrophysiological recordings of the functional activities of human GluR6 receptors (Hoo et al., Recept. Channels 2; 327-338); and whole-cell voltage-clamp electrophysiological recordings of functional activity on AMPA receptors and isolated cerebellar Purkinje neurons (Bleakman et al., 1996, Mol. Pharmacol. 49; 581-585) and other tissues expressing AMPA receptors (Fletcher and Lodge, 1996, Pharmacol. Ther. 70; 65-89).

A. Binding affinity profiles of iGluR5 antagonists

Cell lines (HEK 293 cells) stably transfected with human iGluR receptors were used. 3[H] AMPA turnover with increasing antagonist concentrations was measured in cells expressing iGluR1, iGluR2, iGluR3, and iGluR4, while 3[H] kainate (KA) turnover was measured in cells expressing iGluR5, iGluR6, iGluR7, and KA2. Estimated antagonist binding activity (Ki) in �M is, for example, determined for Compounds of Formula I or Formula Ia. As an indicator of selectivity, the ratio of binding affinity for the iGluR2 AMPA receptor subtype, in relation to the binding affinity for the iGluR5 kainate receptor subtype (Ki on iGluR2/Ki on iGluR5) was also determined. The compounds provided in the present invention show higher binding affinity for iGluR5 (lower Ki) than those for iGluR2, preferably at least 10 times higher for iGluR5 than for iGluR2, more preferably at least 100 times.

EXAMPLE 5

The following animal model can be used to determine the ability of compounds of Formula I or Formula Ia to inhibit protein extravasation, which is an example of a functional test of the neuronal mechanism of migraine.

Animal model for extravasation of dural proteins

A. Harlan Sprague-Dawley rats (225 - 325 g) or Charles River Laboratories guinea pigs (225 - 325 g) were intraperitoneally anesthetized with sodium pentobarbital (65 mg/kg and 45 mg/kg, respectively) and placed in a stereotaxic frame (David Kopf Instruments) with the notch scale set at -3.5 mm for rats or -4.0 mm for guinea pigs. After a central sagittal scalp incision, two pairs of bilateral holes were drilled through the skull (6 mm posterior, 2.0 and 4.0 mm lateral in rats; 4 mm posterior and 3.2 and 5.2 mm lateral in guinea pigs, all coordinates are relative to bregma).

Pairs of stainless steel stimulating electrodes, insulated except at the tips (Rhodes Medical Systems, Inc.), were lowered through holes in both hemispheres to a depth of 9 mm (rats) or 10.5 mm (guinea pigs) from the dura.

B. The femoral vein was exposed, and a dose of the test compound was injected intravenously (i.v.) at a dosing volume of 1 ml/kg or, alternatively, the test compound was given orally (p.o.) via a gastric tube in a volume of 2.0 ml / kg. Approximately 7 minutes after the i.v. injection, a 50 mg/kg dose of Evans Blue fluorescent dye was also injected intravenously. Evans Blue complexes with blood proteins serve as a marker for protein extravasation. Exactly 10 minutes after injection of the test compound, the left trigeminal ganglion was stimulated for 3 minutes at a current of 1.0 mA (5 Hz, 4 msec duration) with a potentiostat/galvanostat Model 273 device (EG&G Princeton Applied Research).

C. Fifteen minutes after stimulation, the animals were euthanized by exsanguination with 20 ml of saline. The top of the skull was removed to facilitate collection of the dural membranes. Membrane samples were taken from both hemispheres, washed with water, and spread on microscope slides. When they were dry, the tissues were covered with a 70% glycerol/water solution.

D. A fluorescence microscope (Zeiss) equipped with a grating monochromator and a spectrophotometer was used to quantify the amount of Evans Blue dye in each sample.

An excitation wavelength of approximately 535 nm was used and the emission intensity was determined at 600 nm. The microscope is equipped with a motorized stand and is also connected to a personal computer. This facilitated computer control of the stage movements, with fluorescence measurement at 25 points (500 mm step) on each dura sample. The mean value and standard deviation of the measurements were determined using a computer.

E. Extravasation caused by electrical stimulation of the trigeminal ganglion has an ipsilateral effect (that is, it occurs only on the side of the dura where the trigeminal ganglion is stimulated). This allows the other (unexcited) half of the dura to be used as a control. The ratio ("extravasation ratio") of the amount of extravasation in the dura on the stimulated side, in relation to the amount of extravasation on the non-stimulated side, was calculated. In control animals, given only the saline dose, extravasation ratios of approximately 2.0 in rats and approximately 1.8 in guinea pigs were obtained.

In contrast, a compound that completely prevents extravasation into the dura from the excited side achieves an extravasation ratio of approximately 1.0.

F. Dose response curves can be generated for each of the compounds of Formula I and Formula Ia and doses that inhibit extravasation by 50% (ID50) or 100% (ID100) can be approximated. 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 ID100 of approximately 0.01 ng/Kg when administered orally to rats.

Claims (27)

1. Pharmaceutically acceptable salt of the compound of the formula: [image] or a prodrug thereof, characterized in that the pharmaceutically acceptable salt is selected from the group consisting of a salt of D-(-)-α-phenylhydroxyacetic acid or a salt of 1,5-naphthalene disulfonic acid. 2. Pharmaceutically acceptable salt according to Claim 1, characterized in that it is a salt of D-(-)-α-phenylhydroxyacetic acid. 3. Pharmaceutically acceptable salt according to Claim 1, characterized in that it is a salt of 1,5-naphthalene disulfonic acid. 4. A compound characterized by the fact that 3S, 4aR, 6S, 8aR is 6-(((2S)-2-(carboxylic acid)-4,4-difluoropyrrolidinyl)methyl)-1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid•D-(-)-α-phenylhydroxyacetic acid. 5. Compound, characterized in that 3S, 4aR, 6S, 8aR is 6-(((2S)-2-(carboxylic acid)-4,4-difluoropyrrolidinyl)methyl)-1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid•1,5-naphthalene disulfonic acid. 6. Pharmaceutically acceptable salt of a compound of the formula: [image] indicated by that R1 and R2 each independently represent hydrogen, (C1-C20)alkyl, (C2-C6)alkenyl, (C1-C6)alkylaryl, (C1-C6)alkyl(C3-C10)cycloalkyl, (C1-C6) alkyl-N,N-C1-C6 dialkylamine, (C1-C6)alkyl-pyrrolidine, (C1-C6)alkyl-piperidine, or (C1-C6)alkyl-morpholine, provided that at least one of R1 and R2 is not hydrogen ; wherein the pharmaceutically acceptable salt is selected from the group consisting of a salt of D-(-)-α-phenylhydroxyacetic acid or a salt of 1,5-naphthalene disulfonic acid. 7. A pharmaceutically acceptable salt according to Claim 6, characterized in that R 1 and R 2 are each independently (C 1 -C 20 )alkyl. 8. A pharmaceutically acceptable salt according to Claim 7, characterized in that R 1 and R 2 are each independently (C 1 -C 6 )alkyl. 9. Pharmaceutically acceptable salt according to Claim 8, characterized in that it is a salt of D-(-)-α-phenylhydroxyacetic acid. 10. Pharmaceutically acceptable salt according to Claim 8, characterized in that it is a salt of 1,5-naphthalene disulfonic acid. 11. Compound, characterized in that 3S, 4aR, 6S, 8aR is Ethyl 6-(((2S)-2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylate•D-(-)-α-phenylhydroxyacetic acid. 12. Compound, characterized in that 3S, 4aR, 6S, 8aR is Ethyl 6-(((2S)-2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylate•1,5-naphthalene disulfonic acid. 13. A method for the treatment of a neurological disorder or a neurodegenerative disease characterized by the fact that it consists of administering to a patient who is in need of it, an effective amount of a pharmaceutically acceptable salt in accordance with Claim 1. 14. The method according to Claim 13, characterized in that the neurological disorder is migraine. 15. The method according to Claim 14, characterized in that 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-(-)-α-phenylhydroxyacetic acid. 16. The method according to Claim 14, characterized in that the pharmaceutically acceptable salt is 3S, 4aR, 6S, 8aR Ethyl 6-(((2S)-2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-1, 2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate•1,5-naphthalene disulfonic acid. 17. A method for the treatment of a neurological disorder or a neurodegenerative disease, characterized in that an effective amount of a pharmaceutically acceptable salt is administered to a patient in need thereof in accordance with Claim 6. 18. The method according to Claim 17, characterized in that the neurological disorder is migraine. 19. The method according to Claim 17, characterized in that 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-(-)-α-phenylhydroxyacetic acid. 20. The method according to Claim 17, characterized in that the pharmaceutically acceptable salt is 3S, 4aR, 6S, 8aR Ethyl 6-(((2S)-2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-1, 2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate•1,5-naphthalene disulfonic acid. 21. A pharmaceutical composition, characterized in that it consists of an effective amount of a pharmaceutically acceptable salt according to Claim 1, in combination with a pharmaceutically acceptable carrier, diluent or excipient. 22. A pharmaceutical composition, characterized in that it consists of an effective amount of a pharmaceutically acceptable salt according to Claim 6, in combination with a pharmaceutically acceptable carrier, diluent or excipient. 23. Use of the compound according to Claim 1, characterized in that the compound is used for the production of a medicament for the treatment of migraine. 24. Use of the compound according to Claim 6, characterized in that the compound is used for the production of a medicament for the treatment of migraine. 25. Use of the compound according to Claim 1, characterized in that it is used for the treatment of migraine. 26. Use of a compound according to Claim 6, characterized in that it is used for the treatment of migraine. 27. Process for the preparation of a compound of the formula: [image] indicated that: R1 and R2 each independently represent hydrogen, (C1-C20)alkyl, (C2-C6)alkenyl, (C1-C6)alkylaryl, (C1-C6)alkyl(C3-C10)cycloalkyl, (C1-C6) alkyl-N,N-C1-C6 dialkylamine, (C1-C6)alkyl-pyrrolidine, (C1-C6)alkyl-piperidine, or (C1-C6)alkyl-morpholine, provided that at least one of R1 and R2 is not hydrogen , which involves combining a compound of structure (2) [image] wherein R2 is as defined above, Pg is a suitable nitrogen protecting group, and LgO is a suitable leaving group, with a suitable base in a suitable solvent, followed by addition of a compound of structure (3) [image] where R 1 is as defined above, followed by oxidation to a compound of structure (5) [image] followed by halogenation and removal of the nitrogen protecting group.