Classifications

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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• • A—HUMAN NECESSITIES
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  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• • A—HUMAN NECESSITIES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
  • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
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  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system

Definitions

• the invention relates to methods and compositions for treating
• schizophrenia or bipolar disorder in particular, mania
• it relates to the use of a combination of a synaptic vesicle protein 2A (SV2A) inhibitor and an antipsychotic in treating a subject having or at risk for schizophrenia or bipolar disorder (in particular, mania).
• SV2A synaptic vesicle protein 2A
• Schizophrenia is a chronic psychiatric disorder, characterized by a wide spectrum of psychopathology, including positive symptoms such as aberrant or distorted mental representations (e.g., hallucinations, delusions), negative symptoms characterized by diminution of motivation and adaptive goal-directed action (e.g., anhedonia, affective flattening, avolition), and cognitive impairment. While abnormalities in the brain are proposed to underlie the full spectrum of psychopathology in schizophrenia, currently available antipsychotics are largely ineffective in treating cognitive impairments in schizophrenia patients.
• Cognitive impairments in schizophrenia involve both frontal and temporal lobe functions that include memory, attention, processing speed, and executive control.
• Recent observations, drawn from preclinical animal models and human neuroimaging studies, indicate that altered brain activity/excitability in the medial temporal lobe memory system may contribute to cognitive impairment and may also play a role in augmenting psychotic symptoms due to disinhibition of dopaminergic neurons.
• Cognitive deficits are increasingly recognized as a key clinical feature that can be detected in a prodromal phase and in remission, as well as during full expression of the illness but are not effectively treated by available antipsychotics. Because untreated features of schizophrenia, especially impaired cognition, predict long-term disability in patients (Green et al, Schizophr. Res. 2004, 72, 41-45), it is critical to develop effective therapies for the spectrum of this illness.
• a method for treating a subject suffering from schizophrenia or bipolar disorder (in particular, mania), or at risk thereof comprising the step of administering to said subject a therapeutically effective amount of an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof in combination with a therapeutically effective amount of an antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof.
• the methods of the present invention treat one or more positive and/or negative symptoms, as well as cognitive impairment, associated with schizophrenia.
• the methods of the present invention treat one or more symptoms, as well as cognitive impairment, associated with bipolar disorder (in particular, mania). In some embodiments of this invention, the methods of this invention prevent or slow the progression of cognitive impairment or bipolar disorder (in particular, mania) of schizophrenia in said subject.
• compositions of this aspect of the invention include those disclosed in, for example, United States (U.S.) Patent Application 12/580,464 (Pub. No. US-2010- 0099735), U.S. Patent Application 13/287,531 (Pub. No. US-2012-0046336), U.S. Patent Application 13/370,253 (Pub. No.US-2012-0214859), International Patent Application PCT/US2009/005647 (Pub. No. WO2010/044878), International Patent Application PCT/US 12/24556 (Pub. No. WO2012/109491), U.S.
• any SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof may be used in the methods and
• the SV2A inhibitor is selected from the group of SV2A inhibitors referred to in International Patent Applications WO2010/144712; WO2010/002869; WO2008/132139; WO2007/065595; WO2006/128693; WO2006/128692; WO2005/054188;
• the SV2A inhibitor is selected from the group consisting of levetiracetam, brivaracetam, and seletracetam or derivatives or analogs or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof.
• the SV2A inhibitor is levetiracetam or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof.
• the SV2A inhibitor is brivaracetam or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof.
• the SV2A inhibitor is seletracetam or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof.
• the antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof that is useful in the methods and compositions of this invention include both typical and atypical antipsychotics.
• the antipsychotics suitable for use in the present invention are selected from atypical antipsychotics, including, but not limited to, those disclosed in, for example, U.S. Patents 4,734,416; 5,006,528; 4,145,434; 5,763,476; 3,539,573; 5,229,382; 5,532,372; 4,879,288; 4,804,663; 4,710,500; 4,831,031; and 5,312,925, and EP Patents EP402644 and EP368388, and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
• atypical antipsychotics suitable for use in the present invention include, but are not limited to, aripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone, quetiapine, risperidone and ziprasidone, and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
• the antipsychotic of this invention is selected from aripiprazole (Bristol-Myers Squibb), olanzapine (Lilly) and ziprasidone (Pfizer), and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
• the antipsychotics suitable for use in the present invention are typical antipsychotics, including, but not limited to, acepromazine, benperidol, bromazepam, bromperidol, chlorpromazine, chlorprothixene, clotiapine, cyamemazine, diazepam, dixyrazine, droperidol, flupentixol, fluphenazine, fluspirilene, haloperidol, heptaminol, isopropamide iodide, levomepromazine, levosulpiride, loxapine, melperone, mesoridazine, molindone, oxypertine, oxyprothepine, penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone, pipotiazine, prochlorperazine, promazine, promethazine
• the antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof may be selected from compounds that are dopaminergic agents (such as dopamine Dl receptor antagonists or agonists, dopamine D 2 receptor antagonists or partial agonists, dopamine D3 receptor antagonists or partial agonists, dopamine D4 receptor antagonists), glutamatergic agents, N-methyl-D-aspartate (NMD A) receptor positive allosteric modulators, glycine reuptake inhibitors, glutamate reuptake inhibitor, metabotropic glutamate receptors (mGluRs) agonists or positive allosteric modulators (PAMs) (e.g., mGluR2/3 agonists or PAMs), glutamate receptor glur5 positive allosteric modulators (PAMs), Ml muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PA
• AMPA kainate receptor antagonists
• ampakines CX-516
• glutathione prodrugs noradrenergic agents (such as alpha-2 adrenergic receptor agonists or antagonists and catechol-O-methyl transferase (COMT) inhibitors)
• serotonin receptor modulators such as 5-HT 2 A receptor antagonists, 5-HT I A receptor partial agonists, 5-HT 2 c agonists, and 5-HT6 antagonists
• cholinergic agents such as alpha-7 nicotinic receptor agonists, alpha4-beta2 nicotinic receptor agonists, allosteric modulators of nicotinic receptors and acetylcholinesterase inhibitors, muscarinic receptor agonists and antagonists
• cannabinoid CB 1 antagonists neurokinin 3 antagonists, neurotensin agonists, monoamine oxidase (MAO) B inhibitors, PDE10 inhibitors, neuronal nitric oxide syntha
• the antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof that is useful in the methods and compositions of this invention include compounds that may be used to treat at least one sign or symptom of schizophrenia or bipolar disorder (in particular, mania).
• the antipsychotic is administered at a dose that is subtherapeutic as compared to the dose at which it is therapeutically effective when administered in the absence of the SV2A inhibitor.
• the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof can be administered at doses as disclosed, for example, in United States (U.S.) Patent Application 12/580,464 (Pub. No. US-2010-0099735), U.S. Patent Application 12/580,464 (Pub. No. US-2010-0099735), U.S. Patent
• the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof is administered at a daily dose of about 0.001 mg/kg to 5 mg/kg.
• the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof is administered every 12 or 24 hours at a daily dose of about 0.1 to 5 mg/kg, or about 1 to 2 mg/kg, or about 0.1 to 0.2 mg/kg, or about 0.01 to 2.5 mg/kg, or about 0.1 to 2.5 mg/kg, or about 0.4 to 2.5 mg/kg, or about 0.6 to 1.8 mg/kg, or about 0.04 to 2.5 mg/kg, or about 0.06 to 1.8 mg/kg, or about 0.01 to 1 mg/kg, or about 0.001 to 1 mg/kg, or about 0.5 mg/kg to 5 mg/kg, or about 0.05 mg/kg to 0.5 mg/kg; or at a daily dose of 0.0015 - 7 mg/kg, 0.0015 - 5 mg/kg, 0.01 - 5 mg/kg, 0.05 - 4.0 mg/kg, 0.05 - 2 mg/kg, 0.05 - 1.5 mg/kg, 0.1
• pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof is administered every 12 or 24 hours at a daily dose of about 0.1 to 0.2 mg/kg, or about 0.01 to 2.5 mg/kg, or about 0.1 to 2.5 mg/kg, or about 0.4 to 2.5 mg/kg, or about 0.6 to 1.8 mg/kg, or about 0.04 to 2.5 mg/kg, or about 0.06 to 1.8 mg/kg, or about 2.0 to 4.0 mg/kg, or about 2.0 to 3.0 mg/kg, or about 3.0 to 4.0 mg/kg, or about 0.2 to 0.4 mg/kg, or about 0.2 to 0.3 mg/kg, or about 0.3 to 0.4 mg/kg, or about 0.001 - 5 mg/kg, or about 0.001 - 0.5 mg/kg, or about 0.01 - 0.5 mg/kg.
• the SV2A inhibitor may be selected from the group consisting of levetiracetam, brivaracetam, and seletracetam or derivatives or analogs or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs, polymorphs, or prodrugs thereof, said SV2A inhibitor being administered every 12 or 24 hours at a daily dose selected from any of the above.
• a subtherapeutic amount of the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph, or prodrug thereof is used.
• subtherapeutic amount may be, for example, a daily dose of less than 7 mg/kg, less than 6 mg/kg, less than 5 mg/kg, less than 4 mg/kg, less than 3.8 mg/kg, less than 3.6 mg/kg, less than 3.4 mg/kg, less than 3.2 mg/kg, less than 3 mg/kg, less than 2.9 mg/kg, less than 2.8 mg/kg, less than 2.7 mg/kg, less than 2.6 mg/kg, less than 2.5 mg/kg, less than 2.4 mg/kg, less than 2.3 mg/kg, less than 2.2 mg/kg, less than 2.1 mg/kg, less than 2 mg/kg, less than 1.5 mg/kg, less than 1 mg/kg, less than 0.5 mg/kg, less than 0.1 mg/kg, less than 0.05 mg/kg, less than 0.01 mg/kg, or less than 0.0015 mg/kg; or less than 500 mg, less than 420 mg, less than 400 mg, less than 350 mg, less than 300 mg, less than 280 mg, less than 270 mg
• the SV2A inhibitors that can be used in the foregoing embodiments include, for example, levetiracetam, brivaracetam, and seletracetam or their pharmaceutically acceptable salt, hydrate, solvate or polymorph, or prodrug thereof.
• the SV2A inhibitor present in the composition of this invention is administered at a daily dose of 0.0015 to 7 mg/kg/day (which, given a typical human subject of 70 kg, is about 0.1 - 500 mg/day).
• Daily doses that may be used include, but are not limited to 0.0015 mg/kg, 0.002 mg/kg, 0.0025 mg/kg, 0.005 mg/kg, 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg, 0.06 mg/kg, 0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 1.2 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.8 mg/kg, 2.0 mg/kg, 2.2 mg/kg, 2.4 mg/kg, 2.5 mg/kg, 2.6 mg/kg, 2.8 mg/kg, 3.0 mg/kg, 3.5 mg/kg, 4.0 mg/kg, 4.5 mg/kg, 5.0 mg/kg, 6.0 mg/kg,
• the levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof is present in the composition of this invention in an amount of 0.7 - 50 mg, 0.7 - 75 mg, 0.7 - 100 mg, 0.7 - 150 mg, 0.7
• a subtherapeutic amount of the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph, or prodrug thereof is used.
• the SV2A inhibitors that can be used in the foregoing embodiments include, for example, levetiracetam, brivaracetam, and seletracetam or their pharmaceutically acceptable salt, hydrate, solvate or polymorph, or prodrug thereof.
• the SV2A inhibitor present in the composition of this invention is levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof and is administered at according to one of the daily dose ranges indicated as "+" listed in Table 1 or Table 2.
• the levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof is present in the composition of this invention in an amount of about 70 to 140 mg, or about 7 to 180 mg, or about 25 to 180 mg, or about 40 to 130 mg, or about 140 to 300 mg, or about 200 to 300 mg, or about 140 to 200 mg, or about 7 to 350 mg, about 70 - 350 mg, about 100 - 300 mg, or about 125 -250 mg.
• a subtherapeutic amount of levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph, or prodrug thereof is used.
• the SV2A inhibitor present in the composition of this invention is brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof and is administered at according to one of the daily dose ranges indicated as "+" listed in Tables 3-6.
• the brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof is present in the composition of this invention in an amount of about 7 to 15 mg, or about 0.7 to 180 mg, or about 2.5 to 180 mg, or about 4.0 to 130 mg, or about 14 to 30 mg, or about 0.1 - 35 mg, 0.5 - 35 mg, 0.75 - 35 mg, 1.0 - 35 mg, 1.5 - 35 mg, 2.0 - 35 mg, 0.1 - 30 mg, 0.1 - 25 mg, 0.1 - 20 mg, 0.1 - 15 mg, 0.1 - 10 mg, 0.1 - 5 mg, 0.1 - 2.5 mg, or 0.7 - 50 mg, 0.7 - 75 mg, 0.7 - 100 mg, 0.7 - 150 mg, 0.7 - 180 mg, 0.7 - 225 mg, 0.7 - 250 mg, 0.7 - 280 mg, 1.8 - 50 mg, 1.8 - 75 mg, 1.8 - 100 mg,
• a subtherapeutic amount of brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph, or prodrug thereof is used.
• the SV2A inhibitor present in the composition of this invention is seletracetam or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof and is administered at according to one of the daily dose ranges indicated as "+" listed in Tables 7-10.
• polymorph, or prodrug thereof is present in the composition of this invention in an amount of about 7 to 15 mg, or about 0.7 to 180 mg, or about 2.5 to 180 mg, or about 4.0 to 130 mg, or about 14 to 30 mg, or about 0.1 - 35 mg, 0.5 - 35 mg, 0.75 - 35 mg, 1.0 - 35 mg, 1.5 - 35 mg, 2.0 - 35 mg, 0.1 - 30 mg, 0.1 - 25 mg, 0.1 - 20 mg, 0.1 - 15 mg, 0.1 - 10 mg, 0.1 - 5 mg, 0.1 - 2.5 mg, or 0.7 - 50 mg, 0.7 - 75 mg, 0.7 - 100 mg, 0.7 - 150 mg, 0.7 - 180 mg, 0.7 - 225 mg, 0.7 - 250 mg, 0.7 - 280 mg, 1.8 - 50 mg, 1.8 - 75 mg, 1.8 - 100 mg, 1.8 - 150 mg, 1.8 - 180 mg, 0.7 - 225 mg, 0.7 - 250
• a subtherapeutic amount of seletracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph, or prodrug thereof is used.
• the SV2A inhibitor and the antipsychotic, or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or prodrugs are administered simultaneously, or sequentially, or in a single formulation, or in separate formulations packaged together.
• the SV2A inhibitor and the antipsychotic, or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or prodrugs are administered via different routes.
• “combination” includes administration by any of these formulations or routes of administration.
• the combined treatment has a longer or improved therapeutic effect in the subject than is attained by
• the combined treatment has a longer or improved therapeutic effect in the subject than is attained by
• a method of increasing the therapeutic index of an antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof in a method of treating schizophrenia or bipolar disorder (in particular, mania) in a subject in need or at risk thereof comprising administering an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof in combination with the antipsychotic or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof to said subject.
• the increase in the therapeutic index of the antipsychotic or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof is greater than the therapeutic index of the antipsychotic or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof when administered in the absence of the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof by at least about 1.5x, or 2. Ox, or 2.5x, or 3. Ox, or 3.5x, or 4. Ox, or 4.5x, or 5. Ox, or 5.5x, or 6. Ox, or 6.5x, or 7. Ox, or 7.5x, or 8. Ox, or 8.5x, or 9. Ox, or 9.5x, or lOx, or greater than about lOx.
• a method of increasing the therapeutic index of an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof in a method of treating schizophrenia or bipolar disorder (in particular, mania) in a subject in need or at risk thereof comprising administering the SV2A inhibitor or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof in combination with an antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof to said subject.
• the increase in the therapeutic index of the SV2A inhibitor or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof is greater than the therapeutic index of the SV2A inhibitor or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof when administered in the absence of the antipsychotic or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof by at least about 1.5x, or 2. Ox, or 2.5x, or 3. Ox, or 3.5x, or 4. Ox, or 4.5x, or 5. Ox, or 5.5x, or 6. Ox, or 6.5x, or 7. Ox, or 7.5x, or 8. Ox, or 8.5x, or 9. Ox, or 9.5x, or lOx, or greater than about lOx.
• a pharmaceutical composition for treating a subject suffering from schizophrenia or bipolar disorder (in particular, mania), or at risk thereof comprising an SV2A inhibitor and an antipsychotic or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or prodrugs thereof.
• the composition of this invention is for treating one or more positive and/or negative symptoms, as well as cognitive impairment, associated with schizophrenia.
• the composition of this invention is for treating one or more symptoms, as well as cognitive impairment, associated with bipolar disorder (in particular, mania).
• the composition is in a solid form (e.g., capsule or tablet).
• the composition is in a liquid form.
• the composition is in an aqueous solution. In some embodiments, the composition is in a suspension form. In some embodiments, the composition is in a sustained release form, or a controlled release form, or a delayed release form, or an extended release form. In some embodiments, the composition is in a unit dosage form. In other embodiments, the two components of the compositions are in separate delivery forms packaged together. In some embodiments, the composition is for oral administration. In some embodiments, the composition is in a unit dosage form. In some
• the composition is administered once daily. In some embodiments, the composition is administered twice daily.
• both the SV2A inhibitor or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof and the antipsychotic or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof are in an extended release form present in the composition.
• both the SV2A inhibitor or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof and the antipsychotic or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof are not in an extended release form present in the composition.
• the SV2A inhibitor or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof present in the composition is in an extended release form, while the antipsychotic or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof present in the composition is not in an extended release form.
• the antipsychotic or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof is in an immediate release form.
• the SV2A inhibitor or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof present in the composition is not in an extended release form, while the antipsychotic or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof present in the composition is in an extended release form.
• the SV2A inhibitor or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof is in an immediate release form.
• the extended release SV2A inhibitor or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof present in the composition does not affect the pharmacokinetics or the half-life clearance of the antipsychotics or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof present in the same composition.
• the extended release antipsychotics or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof present in the composition does not affect the pharmacokinetics or the half-life clearance of SV2A inhibitor or the
• the extended release form SV2A inhibitor includes without limitation a controlled release form, a prolonged release form, a sustained release form, a delayed release form, or a slow release form.
• the extended release form antipsychotics includes without limitation a controlled release form, a prolonged release form, a sustained release form, a delayed release form, or a slow release form.
• the SV2A inhibitor that can be used in the composition according to the foregoing embodiments include, without limitation, levetiracetam, brivaracetam, seletracetam and their pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof.
• the composition comprises levetiracetam, brivaracetam, seletracetam, or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof and an antipsychotic or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof.
• the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof in the composition is present in an amount of 0.07 - 350 mg, or 50 - 250 mg,
• the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof is present in an amount less than 500 mg, less than 350 mg, less than 300 mg, less than 250 mg, less than 200 mg, less than 150 mg, less than 110 mg, less than 100 mg, less than 70 mg, less than 50 mg, less than 35 mg, less than 10 mg, less than 7 mg, less than 5 mg, less than 3 mg, less than 1 mg, less than 0.7 mg, less than 0.5 mg, less than 0.1 mg, less than 0.07 mg, or less than 0.05 mg.
• the SV2A inhibitor is present in an amount of 0.07 - 60 mg, 0.07 - 350 mg, 25 - 60 mg, 25 - 125 mg, 50 - 250 mg, 5 - 140 mg, 0.7 - 180 mg, 125 - 240 mg, 3 - 50 mg, or 3 - 60 mg . In other embodiments of this aspect of the invention, the SV2A inhibitor is present in an amount of 0.05 - 35 mg.
• the SV2A inhibitor may be selected from the group consisting of levetiracetam, brivaracetam, and seletracetam or derivatives or analogs or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof, said SV2A inhibitor being present in an amount selected from any of the above.
• the effect of the treatment is measured by detecting the difference between the levels of reelin in the subject prior to and after the administration step.
• the effect of the treatment is measured by detecting the difference between the levels of somatostatin in the subject prior to and after the administration step.
• FIG. 1 depicts increased mRNA expression of the gene encoding SV2A in the dentate gyrus of the hippocampus of aged-impaired rats (AI) as compared to young rats (Y) and aged-unimpaired rats (AU).
• AI aged-impaired rats
• AU aged-unimpaired rats
• Normalized Affymetrix GeneChip probe set signal values (Y-axis), as a measure of mRNA expression, are plotted against learning indices of different rats, as a measure of cognitive impairment.
• FIG. 2 depicts the effects of administering levetiracetam on the spatial memory retention of six aged-impaired rats (AI) in a Morris Water Maze (MWM) test.
• AI aged-impaired rats
• MLM Morris Water Maze
• Three treatment conditions are employed: vehicle control, levetiracetam (5 mg/kg/day) and levetiracetam (10 mg/kg/day).
• the AI rats are trained for two consecutive days, with a one-time treatment prior to the training trials per day. 24 hours later, the AI rats are tested. The time the AI rats, 24 hours after treatment with the different conditions and two days of training, spent swimming in the target quadrant or the target annulus in a memory retention trial is used as a measure of spatial memory retention.
• the target quadrant refers to the quadrant of the maze (which is a circular pool) where the escape platform is placed during the training trials.
• the target annulus refers to the exact location of the escape platform during the training trials.
• FIG. 3 depicts the effects of administering levetiracetam on the spatial memory retention of ten aged-impaired rats (AI) in an eight-arm Radial Arm Maze (RAM) test.
• Six treatment conditions are employed: vehicle control, levetiracetam (1.25 mg/kg), levetiracetam (2.5 mg/kg), levetiracetam (5 mg/kg), levetiracetam (10 mg/kg) and levetiracetam (20 mg/kg).
• the RAM task used there is a one- hour delay between presentation of a subset of arms (5 arms available and 3 arms blocked) and completion of the eight-arm win-shift task (eight arms available). Rats are pre-treated 30 - 40 minutes before daily trials with a one-time
• the number of errors made by the rats after the delay is used as a measure of spatial memory retention. Errors are defined as instances when rats enter an arm from which food has already been retrieved in the pre-delay component of the trial or when rats re-visit an arm in the post-delay session that has already been visited. Paired t-tests are used to compare the number of errors between different doses of levetiracetam and vehicle control.
• FIG. 4 depicts the effects of administering levetiracetam or valproate separately on the spatial memory retention of ten aged-impaired rats (AI) in an eight-arm Radial Arm Maze (RAM) test.
• FIG. 5 depicts the effects of administering levetiracetam or valproate in combination on the spatial memory retention of ten aged-impaired rats (AI) in an eight-arm Radial Arm Maze (RAM) test.
• FIG. 6 shows an isobologram plotting levetiracetam dose against valproate dose.
• the diagonal straight line is the line of additivity, anchored on each axis by the lowest effective doses of valproate and levetiracetam when assessed individually.
• FIG. 7 depicts the experimental design of the human trials for levetiracetam treatment.
• FIG. 8 A depicts the average activity in the left CA3 of aMCI subjects with placebo treatment and age-matched control subjects with placebo treatment during the presentation of lure stimuli that the subject correctly identified as "similar.”
• FIG. 8B depicts the average activity in the left CA3 of aMCI subjects with placebo treatment or levetiracetam treatment (125 mg twice a day for two weeks) during the presentation of lure stimuli that the subject correctly identified as "similar.”
• FIG. 8C is a table of the data represented in FIGS. 8A and 8B.
• FIG. 9A depicts the average activity in the left entorhinal cortex of age- matched control subjects with placebo treatment and aMCI subjects with placebo treatment during the presentation of lure stimuli that the subject correctly identify as "similar.”
• FIG. 9B depicts the average activity in the left entorhinal cortex of the same aMCI subjects with placebo treatment or levetiracetam treatment (125 mg twice a day for two weeks) during the presentation of lure stimuli that the subject correctly identify as "similar.”
• FIG. 9C is a table of the data represented in FIGS. 9A and 9B.
• FIG. 10A depicts an example of the sequence of images shown to subjects in the explicit 3 -alternative forced choice task described in Example 2.
• FIG. 10B shows sample pairs of similar (“lure”) images.
• FIG. 11 shows the difference between the aMCI (placebo) subjects and age-matched control (placebo) subjects in their performance of the explicit 3- alternative forced choice task described in Example 2.
• Each bar represents the proportion of the subject responses (old, similar, or new) when presented with a lure image.
• FIG. 12 shows the difference between the same aMCI subjects with placebo treatment or with levetiracetam treatment (125 mg twice a day for two weeks) in their performance of the explicit 3 -alternative forced choice task described in Example 2.
• Each bar represents the proportion of the subjects responses (old, similar, or new) when presented with a lure image.
• FIG. 13 is a table of the data represented in FIGS. 11 and 12.
• FIG. 14A shows the difference between the age-matched control (placebo) subjects and the aMCI subjects treated with placebo or with levetiracetam (125 mg twice a day for two weeks) in their performance of the Buschke Selective reminding Test - Delayed Recall.
• FIG. 14B is a table of the data represented in FIG. 14A.
• FIG. 15A shows the difference between the control (placebo) subjects and the aMCI subjects treated with placebo or with levetiracetam (125 mg twice a day for two weeks) in their performance of the Benton Visual Retention Test.
• FIG. 15B is a table of the data represented in FIG. 15 A.
• FIG. 16A shows the difference between the control (placebo) subjects and the aMCI subjects treated with placebo or with levetiracetam (125 mg twice a day for two weeks) in their performance of the Verbal Paired Associates Test - Recognition.
• FIG. 16B is a table of the data represented in FIG. 16 A.
• FIG. 17A shows the difference between the control (placebo) subjects and the aMCI subjects treated with placebo or with levetiracetam (125 mg twice a day for two weeks) in their performance of the Verbal Paired Associates Test - Delayed Recall.
• FIG. 17B is a table of the data represented in FIG. 17A.
• FIG. 18A is a table showing the subject selection process for the human levetiracetam trial described in Example 2.
• FIG. 18B is a table showing the characteristics of the subjects selected for the human levetiracetam trial described in Example 2.
• FIG. 19 depicts the effects of administering brivaracetam on the memory performance of nine aged-impaired rats in an eight-arm Radial Arm Maze task.
• Doses of brivaracetam administered to the AI rats include 0.0625mg/kg, 0.125 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg and 4 mg/kg. Means and SEMs for the number of errors are shown as the y-axis.
• FIG. 20 depicts the effects of administering seletracetam on the memory performance of nine aged-impaired rats in an eight-arm Radial Arm Maze test.
• Doses of seletracetam administered to the AI rats include 0.0625mg/kg, 0.125 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg and 4 mg/kg. Means and SEMs for the number of errors are shown as the y-axis.
• FIG. 22 A and FIG. 22B depict the effects of levetiracetam on fMRI activities in Dentate Gyrus/CA3 region of aMCI patients at a dose of 62.5 mg BID and 250 mg BID.
• FIG. 23A and FIG. 23B show the difference between the aMCI
• FIG. 24A and FIG. 24B show the difference between the same aMCI subjects with placebo treatment or with levetiracetam treatment (62.5 mg BID and 250 mg BID) in their performance of the explicit 3 -alternative forced choice task described in Example 4.
• Each bar represents the proportion of the subjects responses (old, similar, or new) when presented with a lure image.
• FIG. 25 shows that administering levetiracetam at a dose of 10 mg/kg/day and vehicle in osmotic minipumps for four weeks in aged-impaired rats restores sematostatin in DG hilus.
• FIG. 26 shows that administering levetiracetam at a dose of 10 mg/kg/day and vehicle in osmotic minipumps for four weeks in aged-impaired rats restores reelin in Entorhinal Cortex (EC2).
• FIGS. 27A - 27C depict the levetiracetam blood plasma levels for the aMCI patients at a dose of 62.5 mg BID, 125 mg BID and 250 mg BID
• agent is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues.
• Agents include, for example, agents which are known with respect to structure, and those which are not known with respect to structure .
• a "patient”, “subject”, or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).
• Cognitive function or “cognitive status” refers to any higher order intellectual brain process or brain state, respectively, involved in learning and/or memory including, but not limited to, attention, information acquisition, information processing, working memory, short-term memory, long-term memory, anterograde memory, retrograde memory, memory retrieval, discrimination learning, decision-making, inhibitory response control, attentional set-shifting, delayed reinforcement learning, reversal learning, the temporal integration of voluntary behavior, expressing an interest in one's surroundings and self-care, speed of processing, reasoning and problem solving and social cognition.
• cognitive function may be measured, for example and without limitation, by the clinical global impression of change scale (CIBIC-plus scale); the Mini Mental State Exam (MMSE); the Neuropsychiatric Inventory (NPI); the Clinical Dementia Rating Scale (CDR); the Cambridge Neuropsychological Test Automated Battery (CANTAB); the Sandoz Clinical Assessment-Geriatric (SCAG), the Buschke Selective Reminding Test (Buschke and Fuld, 1974); the Verbal Paired Associates subtest; the Logical Memory subtest; the Visual
• cognitive function may be measured in various conventional ways known in the art, including using a Morris Water Maze
• MLM Microsoft Access to Browse Ratio
• Barnes circular maze a nursing woman
• elevated radial arm maze a nursing woman
• T maze a nursing woman
• cognitive function can be assessed by reversal learning, extradimensional set shifting, conditional discrimination learning and assessments of reward expectancy.
• Other tests known in the art may also be used to assess cognitive function, such as novel object recognition and odor recognition tasks.
• Cognitive function may also be measured using imaging techniques such as Positron Emission Tomography (PET), functional magnetic resonance imaging (fMRI), Single Photon Emission Computed Tomography (SPECT), or any other imaging technique that allows one to measure brain function.
• imaging techniques such as Positron Emission Tomography (PET), functional magnetic resonance imaging (fMRI), Single Photon Emission Computed Tomography (SPECT), or any other imaging technique that allows one to measure brain function.
• cognitive function may also be measured with electrophysiological techniques.
• “Promoting” cognitive function refers to affecting impaired cognitive function so that it more closely resembles the function of a normal, unimpaired subject. Cognitive function may be promoted to any detectable degree, but in humans preferably is promoted sufficiently to allow an impaired subject to carry out daily activities of normal life at the same level of proficiency as a normal, unimpaired subject. [0084] "Preserving" cognitive function refers to affecting normal or impaired cognitive function such that it does not decline or does not fall below that observed in the subject upon first presentation or diagnosis, or delays such decline.
• "Improving" cognitive function includes promoting cognitive function and/or preserving cognitive function in a subject.
• Cognitive impairment refers to cognitive function in subjects that is not as robust as that expected in a normal, unimpaired subject. In some cases, cognitive function is reduced by about 5%, about 10%, about 30%, or more, compared to cognitive function expected in a normal, unimpaired subject. In other cases, “cognitive impairment” in subjects affected by schizophrenia or bipolar disorder (in particular, mania) refers to cognitive function in subjects that is not as robust as that expected in normal, unimpaired subject.
• Schirhrenia refers to a chronic debilitating disorder, characterized by a spectrum of psychopathology, including positive symptoms such as aberrant or distorted mental representations (e.g., hallucinations, delusions), negative symptoms characterized by diminution of motivation and adaptive goal-directed action (e.g., anhedonia, affective flattening, avolition), and cognitive impairment. While abnormalities in the brain are proposed to underlie the full spectrum of psychopathology in schizophrenia, currently available antipsychotics are largely ineffective in treating cognitive impairments in patients.
• BP Bipolar disorder
• manic depressive disorder or “manic depressive illness” refers to a chronic psychological/mood disorder which can be characterized by significant mood changes including periods of depression and euphoric manic periods.
• BP may be diagnosed by a skilled physician based on personal and medical history, interview consultation and physical examinations.
• mania or “manic periods” or other variants refers to periods where an individual exhibits some or all of the following characteristics: racing thoughts, rapid speech, elevated levels of activity and agitation as well as an inflated sense of self-esteem, euphoria, poor judgment, insomnia, impaired concentration and aggression.
• Treating" a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
• beneficial or desired clinical results include, but are not limited to, preventing or slowing the progression of the disease or disorder, or alleviation, amelioration, or slowing the progression, of one or more symptoms associated with CNS disorders with cognitive impairment, such as schizophrenia or bipolar disorder (in particular, mania).
• Treating cognitive impairment refers to taking steps to improve cognitive function in a subject with cognitive impairment so that the subject's performance in one or more cognitive tests is improved to any detectable degree, or is prevented from further decline.
• that subject's cognitive function after treatment of cognitive impairment, more closely resembles the function of a normal, unimpaired subject.
• Treatment of cognitive impairment in humans may improve cognitive function to any detectable degree, but is preferably improved sufficiently to allow the impaired subject to carry out daily activities of normal life at the same level of proficiency as a normal, unimpaired subject.
• treating cognitive impairment refers to taking steps to improve cognitive function in a subject with cognitive impairment so that the subject's performance in one or more cognitive tests is improved to any detectable degree, or is prevented from further decline.
• that subject's cognitive function, after treatment of cognitive impairment more closely resembles the function of a normal, unimpaired subject.
• “treating cognitive impairment” in a subject affecting by schizophrenia or bipolar disorder (in particular, mania) refers to takings steps to improve cognitive function in the subject so that the subject's cognitive function, after treatment of cognitive impairment, more closely resembles the function of a normal, unimpaired subject.
• administering or "administration of a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art.
• a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitonealy, intravenously, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct).
• a compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow, or controlled release of the compound or agent.
• Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
• the administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug.
• a physician who instructs a patient to self-administer a drug, or to have the drug administered by another and/or who provides a patient with a prescription for a drug is
• a compound or an agent is administered orally, e.g., to a subject by ingestion, or intravenously, e.g., to a subject by injection.
• the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.
• SV2A inhibitor refers to any agent, substance or compound that binds to SV2A and reduces synaptic function by reducing pre-synaptic vesicle release (See, e.g., Noyer et al. 1995; Fuks et al. 2003; Lynch et al. 2004; Gillard et al. 2006; Custer et al, 2006; Smedt et al, 2007; Yang et al, 2007; Meehan,
• a substance, or a compound or an agent is an SV2A inhibitor even if it does not itself bind to SV2A, as long as it causes, or affects the ability of, another compound or agent to bind SV2A or reduce synaptic function by reducing pre-synaptic vesicle release.
• SV2A inhibitors include pharmaceutically acceptable salts of the inhibitors thereof. They also include hydrates, polymorphs, prodrugs, salts, and solvates of these inhibitors. [0094] "Antipsychotic", “antipsychotic agent”, “antipsychotic drug”, or
• antipsychotic compound refers to (1) a typical or an atypical antipsychotic; (2) an agent that is selected from dopaminergic agents, glutamatergic agents, NMDA receptor positive allosteric modulators, glycine reuptake inhibitors, glutamate reuptake inhibitor, metabotropic glutamate receptors (mGluRs) agonists or positive allosteric modulators (PAMs) (e.g., mGluR2/3 agonists or PAMs), glutamate receptor glur5 positive allosteric modulators (PAMs), Ml muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs), histamine H3 receptor antagonists, AMPA/kainate receptor antagonists, ampakines (CX-516), glutathione prodrugs, noradrenergic agents, serotonin receptor modulators, cholinergic agents, cannabinoid CB1 antagonists, neurokinin 3 antagonists, neurotensin, neuro
• Typical antipsychotics refer to conventional antipsychotics, which produce antipsychotic effects as well as movement related adverse effects related to disturbances in the nigrostriatal dopamine system.
• extrapyramidal side effects include Parkinsonism, akathisia, tardive dyskinesia and dystonia. See Baldessarini and Tarazi in Goodman & Gilman's The Pharmacological Basis of Therapeutics 10 Edition, 2001, pp. 485-520.
• Atypical antipsychotics refer to antipsychotic drugs that produce antipsychotic effects with little or no EPS and include, but are not limited to, aripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone, quetiapine, risperidone and ziprasidone. "Atypical" antipsychotics differ from conventional antipsychotics in their pharmacological profiles.
• Atypical antipsychotic drugs are commonly referred to as
• atypical antipsychotics often display side effects, including, but not limited to, weight gain, diabetes (e.g., type II diabetes mellitus), hyperlipidemia, QTc interval prolongation, myocarditis, sexual side effects, extrapyramidal side effects and cataract.
• atypical antipsychotics do not represent a homogeneous class, given their differences in the context of both alleviation of clinical symptoms and their potential for inducing side effects such as the ones listed above.
• the common side effects of the atypical antipsychotics as described above often limit the antipsychotic doses that can be used for these agents.
• SV2A inhibitor and the antipsychotic, or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs are administered with a time separation of no more than about 15 minutes, and in some embodiments no more than about 10 minutes.
• the SV2A inhibitor and the antipsychotic, or their salts, hydrates, solvates, polymorphs or prodrugs may be contained in the same dosage (e.g., a unit dosage form comprising both the SV2A inhibitor and the antipsychotic) or in discrete dosages (e.g., the SV2A inhibitor or its salt, hydrate, solvate, polymorph, or prodrug is contained in one dosage form and the antipsychotic or its salt, hydrate, solvate, polymorph, or prodrug is contained in another dosage form).
• SV2A inhibitor and the antipsychotic are administered with a time separation of more than about 15 minutes, and in some embodiments more than about one hour, or up to 12-24 hours. Either the SV2A inhibitor or the antipsychotic may be administered first.
• the SV2A inhibitor and the antipsychotic, or their salts, hydrates, solvents, or polymorphs, for sequential administration may be contained in discrete dosage forms, optionally contained in the same container or package.
• a "therapeutically effective amount" of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended
• a therapeutic effect e.g. improving cognitive function in a subject in a subject suffering from a disease or disorder (e.g., schizophrenia or bipolar disorder (in particular, mania)), preventing or slowing the progression of a disease or disorder (e.g., schizophrenia or bipolar disorder (in particular, mania)), and/or alleviating, ameliorating, or slowing the progression of one or more symptoms associated with the disease or disorder (e.g., schizophrenia or bipolar disorder (in particular, mania)).
• the full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
• a therapeutically effective amount may be administered in one or more
• the precise effective amount needed for a subject will depend upon, for example, the subject's size, health and age, the nature and extent of the cognitive impairment, and the therapeutics or combination of therapeutics selected for administration, and the mode of administration. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.
• Subject therapeutic amount refers to an amount administered of an agent or compound of the invention that is less than the therapeutic amount, that is, less than the amount normally used when said agent or compound is administered alone (i.e., individually and in the absence of other therapeutic agents or compounds) to treat disorders, such as schizophrenia or bipolar disorder (in particular, mania).
• Analog is used herein to refer to a compound which functionally resembles another chemical entity, but does not share the identical chemical structure.
• an analog is sufficiently similar to a base or parent compound such that it can substitute for the base compound in therapeutic applications, despite minor structural differences.
• “Derivative” is used herein to refer to the chemical modification of a compound. Chemical modifications of a compound can include, for example, replacement of hydrogen by an alkyl, acyl, or amino group. Many other
• prodrug is art-recognized and is intended to encompass compounds or agents which, under physiological conditions, are converted into an SV2A inhibitor or an antipsychotic.
• a common method for making a prodrug is to select moieties which are hydrolyzed or metabolized under physiological
• the prodrug is converted by, for example, an enzymatic activity of the host animal to an SV2A inhibitor or an antipsychotic.
• aliphatic as used herein means a straight chained or branched alkyl, alkenyl or alkynyl. It is understood that alkenyl or alkynyl embodiments need at least two carbon atoms in the aliphatic chain. Aliphatic groups typically contains from 1 (or 2) to 12 carbons, such as from 1 (or 2) to 4 carbons.
• aryl as used herein means a monocyclic or bicyclic carbocyclic aromatic ring system.
• aryl as used herein can be a C5- C10 monocyclic or C8-C12 bicyclic carbocyclic aromatic ring system.
• Phenyl is an example of a monocyclic aromatic ring system.
• Bicyclic aromatic ring systems include systems wherein both rings are aromatic, e.g., naphthyl, and systems wherein only one of the two rings is aromatic, e.g., tetralin.
• heterocyclic as used herein means a monocyclic or bicyclic non-aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from O, N, NH, S, SO, or S0 2 in a chemically stable arrangement.
• heterocyclic as used herein can be a C5-C10 monocyclic or C8-C12 bicyclic non-aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from O, N, NH, S, SO, or S0 2 in a chemically stable arrangement.
• heterocyclyl one or both rings may contain said heteroatom or heteroatom groups.
• one of the two rings may be aromatic.
• a non-aromatic heterocyclic ring may optionally be fused to an aromatic carbocycle.
• heterocyclic rings include 3-lH-benzimidazol-2-one, 3-(l- alkyl)-benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2- tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4- morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1- pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2- tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3- piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1- piperidinyl, 2-piperidinyl, 3-piperidinyl,
• heteroaryl as used herein means a monocyclic or bicyclic aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from O, N, NH or S in a chemically stable arrangement.
• heteroaryl as used herein can be a C5-C10 monocyclic or C8-C12 bicyclic aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from O, N, NH or S in a chemically stable arrangement.
• heteroaryl as used herein can be a C5-C10 monocyclic or C8-C12 bicyclic aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from O, N, NH or S in a chemically stable arrangement.
• - one or both rings may contain said heteroatom or heteroatom groups.
• heteroaryl rings examples include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl
• cycloalkyl or cycloalkenyl refers to a monocyclic or fused or bridged bicyclic carbocyclic ring system that is not aromatic.
• cycloalkyl or cycloalkenyl as used herein can be a C5-C10 monocyclic or fused or bridged C8-C12 bicyclic carbocyclic ring system that is not aromatic.
• Cycloalkenyl rings have one or more units of unsaturation.
• Preferred cycloalkyl or cycloalkenyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, adamantyl and decalinyl.
• the carbon atom designations may have the indicated integer and any intervening integer.
• the number of carbon atoms in a (Cl-C4)-alkyl group is 1, 2, 3, or 4. It should be understood that these designation refer to the total number of atoms in the appropriate group.
• the total number of carbon atoms and heteroatoms is 3 (as in aziridine), 4, 5, 6 (as in morpholine), 7, 8, 9, or 10.
• “Pharmaceutically acceptable salt” is used herein to refer to an agent or a compound according to the invention that is a therapeutically active, non-toxic base and acid salt form of the compounds.
• the acid addition salt form of a compound that occurs in its free form as a base can be obtained by treating said free base form with an appropriate acid such as an inorganic acid, for example, a hydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclic, salicylic, p- aminosalicylic, pamoic and the like. See, e.g., WO 01
• Compounds containing acidic protons may be converted into their therapeutically active, non-toxic base addition salt form, e. g. metal or amine salts, by treatment with appropriate organic and inorganic bases.
• Appropriate base salt forms include, for example, ammonium salts, alkali and earth alkaline metal salts, e. g., lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e. g. N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
• said salt forms can be converted into the free forms by treatment with an appropriate base or acid.
• Compounds and their salts can be in the form of a solvate, which is included within the scope of the present invention. Such solvates include for example hydrates, alcoholates and the like. See, e.g., WO 01/062726.
• hydrate refers to a combination of water with a compound wherein the water retains its molecular state as water and is either absorbed, adsorbed or contained within a crystal lattice of the substrate compound.
• polymorph refers to different crystalline forms of the same compound and other solid state molecular forms including pseudo- polymorphs, such as hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water) of the same compound.
• pseudo- polymorphs such as hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water) of the same compound.
• pseudo- polymorphs such as hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water) of the same compound.
• Different crystalline polymorphs have different crystal structures due to a different packing of the molecules in the lattice. This results in a different crystal symmetry and/or unit cell parameters which directly influences its physical properties such the X-ray diffraction characteristics of crystals or powders.
• a different polymorph for example, will in general diffract at a different
• Crystalline polymorphic forms are of interest to the pharmaceutical industry and especially to those involved in the development of suitable dosage forms. If the polymorphic form is not held constant during clinical or stability studies, the exact dosage form used or studied may not be comparable from one lot to another. It is also desirable to have processes for producing a compound with the selected polymorphic form in high purity when the compound is used in clinical studies or commercial products since Impurities present may produce undesired toxicological effects. Certain polymorphic forms may exhibit enhanced thermodynamic stability or may be more readily manufactured in high purity in large quantities, and thus are more suitable for inclusion in pharmaceutical formulations. Certain
• polymorphs may display other advantageous physical properties such as lack of hygroscopic tendencies, improved solubility, and enhanced rates of dissolution due to different lattice energies.
• stereogenic center in their structure.
• This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45,11-30.
• the invention also relates to all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01/062726.
• the methods of this invention comprise administration of an SV2A inhibitor or a pharmaceutically acceptable salt thereof in combination with administration of an antipsychotic or a pharmaceutically acceptable salt thereof.
• the agents or compounds of the SV2A inhibitor or the antipsychotic and their pharmaceutically acceptable salts also include hydrates, solvates, polymorphs, and prodrugs of those agents, compounds, and salts.
• Animal models serve as an important resource for developing and evaluating treatments for CNS disorders with cognitive impairment.
• Features that characterize cognitive impairment in animal models typically extend to cognitive impairment in humans. Efficacy in such animal models is, thus, expected to be predictive of efficacy in humans.
• the extent of cognitive impairment in an animal model for a CNS disorder, and the efficacy of a method of treatment for said CNS disorder may be tested and confirmed with the use of a variety of cognitive tests.
• a Radial Arm Maze (RAM) behavioral task is one example of a cognitive test, specifically testing spacial memory (Chappell et al. Neuropharmacology 37: 481-487, 1998).
• the RAM apparatus consists of, e.g., eight equidistantly spaced arms. A maze arm projects from each facet of a center platform. A food well is located at the distal end of each arm. Food is used as a reward. Blocks can be positioned to prevent entry to any arm. Numerous extra maze cues surrounding the apparatus may also be provided. After habituation and training phases, spatial memory of the subjects may be tested in the RAM under control or test compound- treated conditions.
• subjects are pretreated before trials with a vehicle control or one of a range of dosages of the test compound.
• a subset of the arms of the eight-arm maze is blocked.
• Subjects are allowed to obtain food on the unblocked arms to which access is permitted during this initial "information phase" of the trial.
• Subjects are then removed from the maze for a delay period, e.g., a 60 second delay, a 15 minute delay, a one-hour delay, a two-hour delay, a six hour delay, a 24 hour delay, or longer) between the information phase and the subsequent "retention test," during which the barriers on the maze are removed, thus allowing access to all eight arms.
• Another cognitive test that may be used to assess the effects of a test compound on the cognitive impairment of a CNS disorder model animal is the Morris water maze.
• a water maze is a pool surrounded with a novel set of patterns relative to the maze.
• the training protocol for the water maze may be based on a modified water maze task that has been shown to be hippocampal-dependent (de Hoz et al, Eur. J. Neurosci., 22:745-54, 2005; Steele and Morris, Hippocampus 9: 118-36, 1999).
• the subject is trained to locate a submerged escape platform hidden underneath the surface of the pool.
• a subject is released in the maze (pool) from random starting positions around the perimeter of the pool.
• the starting position varies from trial to trial. If the subject does not locate the escape platform within a set time, the experimenter guides and places the subject on the platform to "teach" the location of the platform. After a delay period following the last training trial, a retention test in the absence of the escape platform is given to assess spatial memory.
• the subject's level of preference for the location of the (now absent) escape platform as measured by, e.g., the time spent in that location or the number of crossings of that location made by the mouse, indicates better spatial memory, i.e., treatment of cognitive impairment.
• the preference for the location of the escape platform under different treatment conditions can then be compared for efficacy of the test compound in treating CNS disorders with cognitive impairment.
• This invention provides methods and compositions for treating
• schizophrenia or bipolar disorder in particular, mania
• treatment comprises preventing or slowing the progression of schizophrenia or bipolar disorder (in particular, mania).
• Schizophrenia is characterized by a wide spectrum of psychopathology, including positive symptoms such as aberrant or distorted mental representations (e.g., hallucinations, delusions), negative symptoms characterized by diminution of motivation and adaptive goal-directed action (e.g., anhedonia, affective flattening, avolition), and cognitive impairment.
• treatment comprises alleviation, amelioration or slowing the progression of one or more positive and/or negative symptoms, as well as cognitive impairment, associated with schizophrenia.
• psychiatric diseases such as schizotypical and schizoaffective disorder, other acute- and chronic psychoses and bipolar disorder (in particular, mania), which have an overlapping symptomatology with schizophrenia.
• treatment comprises alleviation, amelioration or slowing the progression of one or more symptoms, as well as cognitive impairment, associated with bipolar disorder (in particular, mania).
• the methods and compositions may be used for human patients in clinical applications in treating schizophrenia or bipolar disorder (in particular, mania).
• the dose of the composition and dosage interval for the method is, as described herein, one that is safe and efficacious in those applications.
• Cognitive impairments are associated with schizophrenia. They precede the onset of psychosis and are present in non-affected relatives. The cognitive impairments associated with schizophrenia constitute a good predictor for functional outcome and are a core feature of the disorder. Cognitive features in schizophrenia reflect dysfunction in frontal cortical and hippocampal circuits. Patients with schizophrenia also present hippocampal pathologies such as reductions in hippocampal volume, reductions in neuronal size and dysfunctional hyperactivity. An imbalance in excitation and inhibition in these brain regions has also been documented in schizophrenic patients suggesting that drugs targeting inhibitory mechanisms could be therapeutic. See, e.g., Guidotti et al.,
• Methionine-treated mice exhibit deficient expression of GAD67 in frontal cortex and hippocampus, similar to those reported in the brain of postmortem schizophrenia patients. They also exhibit prepulse inhibition of startle and social interaction deficits (Tremonlizzo et al, PNAS, 99: 17095-17100, 2002).
• Another animal model of schizophrenia is methylaoxymethanol acetate (MAM)-treatment in rats. Pregnant female rats are administered MAM (20 mg/kg, intraperitoneal) on gestational day 17. MAM -treatment recapitulate a
• MAM-treated rats display a decreased density of parvalbumin-positive GABAergic interneurons in portions of the prefrontal cortex and hippocampus.
• MAM-treated rats display reduced latent inhibition.
• Latent inhibition is a behavioral phenomenon where there is reduced learning about a stimulus to which there has been prior exposure with any consequence. This tendency to disregard previously benign stimuli, and reduce the formation of association with such stimuli is believed to prevent sensory overload. Low latent inhibition is indicative of psychosis.
• Latent inhibition may be tested in rats in the following manner. Rats are divided into two groups. One group is pre- exposed to a tone over multiple trials.
• the other group has no tone presentation. Both groups are then exposed to an auditory fear conditioning procedure, in which the same tone is presented concurrently with a noxious stimulus, e.g. an electric shock to the foot. Subsequently, both groups are presented with the tone, and the rats' change in locomotor activity during tone presentation is monitored. After the fear conditioning the rats respond to the tone presentation by strongly reducing locomotor activity. However, the group that has been exposed to the tone before the conditioning period displays robust latent inhibition: the suppression of locomotor activity in response to tone presentation is reduced. MAM-treated rats, by contrast show impaired latent inhibition. That is, exposure to the tone previous to the fear conditioning procedure has no significant effect in suppressing the fear conditioning, ⁇ see Lodge et ah, J. Neurosci., 29:2344-2354, 2009) Such animal models of schizophrenia may be used to assay the effectiveness of the methods and compositions of the invention in treating schizophrenia or bipolar disorder (in particular, mania).
• a noxious stimulus e.g. an electric shock
• MAM-treated rats display a significantly enhanced locomotor response (or aberrant locomotor activity) to low dose D-amphetamine administration.
• the MAM-treated rats also display a significantly greater number of spontaneously firing ventral tegmental dopamine (DA) neurons.
• DA ventral tegmental dopamine
• MAM-treated rats in the above study may be suitable for use to assay the effectiveness of the methods and compositions of the present invention in treating schizophrenia or bipolar disorder (in particular, mania).
• the methods and compositions of this invention maybe evaluated, using MAM-treated animals, for their effects on the central
• hippocampus (vHipp) regulation on the elevated DA neuron population activity and on the hyperactive locomotor response to amphetamine in the MAM-treated animals.
• HPC hippocampal
• a benzodiazepine-positive allosteric modulator (PAM) selective for the a5 subunit of the GABAA receptor, SH-053-2'F-R-CH 3 , is tested for its effects on the output of the hippocampal (HPC).
• the effect of SH-053-2 - Pv-CH 3 on the hyperactive locomotor response to amphetamine in MAM-treated animals is also examined.
• the a5GABAAR PAM reduces the number of spontaneously active DA neurons in the ventral tegmental area (VTA) of MAM rats to levels observed in saline-treated rats (control group), both when
• MAM-treated rats in the above study may be suitable for use in the present invention to assay the effectiveness of the methods and compositions of the invention in treating schizophrenia or bipolar disorder (in particular, mania).
• the methods and compositions of this invention maybe evaluated, using MAM-treated animals, for their effects on the output of the hippocampal (HPC) and on the hyperactive locomotor response to amphetamine in the MAM-treated animals.
• Apomorphine-induced climbing (AIC) and stereotype (AIS) in mice is another animal model useful in this invention.
• Agents are administered to mice at a desired dose level (e.g., via intraperitoneal administration).
• a desired dose level e.g., via intraperitoneal administration.
• experimental mice are challenges with apomorphine (e.g., with 1 mg/kg sc).
• apomorphine e.g., with 1 mg/kg sc
• the sniffing-licking- gnawing syndrome stereotyped behavior
• climbing behavior induced by apomorphine are scored and recorded for each animal. Readings can be repeated every 5 min during a 30-min test session. Scores for each animal are totaled over the 30-min test session for each syndrome (stereotyped behavior and climbing).
• the efficacy of the methods and compositions of this invention in treating schizophrenia may also be assessed in animal models of schizophrenia or bipolar disorder (in particular, mania), as well as human subjects with schizophrenia, using a variety of cognitive tests known in the art, as discussed above.
• schizophrenia or bipolar disorder in particular, mania
• human subjects with schizophrenia using a variety of cognitive tests known in the art, as discussed above.
• SV2A synaptic vesicle protein-2
• SV2B synaptic vesicle protein-2
• SV2C synaptic vesicle protein-2
• SV2A is the most widely distributed family member, being expressed ubiquitously in the brain.
• the proteins are integral membrane proteins and have a low-level homology (20-30%) to the twelve transmembrane family of bacterial and fungal transporter proteins that transport sugar, citrate, and xenobiotics (Bajjalieh et al., Science. 257: 1271-1273. (1992)).
• SV2 family proteins are present in the brain and endocrine cells, and further are present in all synaptic and endocrine vesicles. SV2 proteins are reported to play a role in normal synaptic function, and functions in a maturation step of primed vesicles that converts the vesicles into a Ca( 2+ )- and synaptotagmin-responsive state (Sudhof et al, 2009). Functionally, SV2 proteins are reported to enhance synaptic currents and increase the probability of transmitter release by maintaining the size of the readily releasable pool of vesicles (Custer et al, 2006).
• SV2A inhibitor refers to any agent, substance or compound that binds to SV2A and reduces synaptic function by reducing pre-synaptic vesicle release (See, e.g., Noyer et al. 1995; Fuks et al. 2003; Lynch et al. 2004; Gillard et al. 2006; Custer et al, 2006; Smedt et al, 2007; Yang et al, 2007; Meehan,
• a substance, or a compound or an agent is an SV2A inhibitor even if it does not itself bind to SV2A, as long as it causes, or affects the ability of, another compound or agent to bind SV2A or reduce synaptic function by reducing pre-synaptic vesicle release.
• SV2A inhibitors include pharmaceutically acceptable salts of the inhibitors thereof. They also include hydrates, polymorphs, prodrugs, salts, and solvates of these inhibitors.
• SV2A inhibitors or pharmaceutically acceptable salts, hydrates, solvates, polymorphs and prodrugs thereof that are useful in the methods and compositions of this invention are those disclosed, for example, United States (U.S.) Patent Application 12/580,464 (Pub. No. US-2010-0099735), U.S. Patent Application 13/287,531 (Pub. No. US-2012-0046336), U.S. Patent Application 13/370,253 (Pub. No.US-2012-0214859), International Patent Application
• any SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof may be used in the methods and
• the SV2A inhibitor is selected from the group of SV2A inhibitors referred to in International Patent Applications WO2010/144712; WO2010/002869; WO2008/132139;
• Other SV2A inhibitors may also be used in this invention. Applicants also refer to methods of preparing these compounds found in the documents cited above. Other synthetic methods may also be used. These methods are well known to those skilled in the art.
• the SV2A inhibitor is selected from the group consisting of levetiracetam, brivaracetam, and seletracetam or derivatives or analogs or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, or prodrugs thereof.
• the SV2A inhibitor is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
• levetiracetam or salts solvates, hydrates, polymorphs or prodrugs thereof.
• Levetiracetam refers to the International Union of Pure and Applied Chemistry (IUPAC) name of the compound (2S)-2-(2-oxopyrrolidin-l-yl) butanamide).
• Levetiracetam is a widely used antiepileptic drug. Levetiracetam binds to a specific site in the CNS: the synaptic vesicle protein 2A (SV2A) (See. e.g., Noyer et al. 1995; Fuks et al. 2003; Lynch et al. 2004; GiUard et al. 2006) and has further been shown to directly inhibit synaptic activity and neurotransmission by inhibiting presynaptic neurotransmitter release (Yang et al., 2007).
• SV2A synaptic vesicle protein 2A
• SV2A inhibitors useful for the methods and compositions of this invention are the following:
• X is-CA ⁇ R or-CA ⁇ R 7 or-CA ⁇ R 8 or CN ;
• a 1 and A 2 are independently oxygen, sulfur or-NR 9 ;
• R 1 is hydrogen, alkyl, aryl or-CH 2 -R la wherein R la is aryl, heterocycle, halogen, hydroxy, amino, nitro or cyano;
• R 2 , R 3 and R 4 are the same or different and each is independently hydrogen, halogen, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azido, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle, or an oxy derivative, thio derivative, amino derivative, acyl derivative, sulfonyl derivative or sulfmyl derivative;
• R 2a , R 3a and R 4a are the same or different and each is independently hydrogen, halogen, alkyl, alkenyl, alkynyl or aryl;
• R 5 , R 6 , R 7 and R 9 are the same or different and each is independently hydrogen, hydroxy, alkyl, aryl, heterocycle or an oxy derivative;
• R 8 is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle or a thio derivative
• R 2 , R 3 , R 4 , R 2a , R 3a and R 4a is other than hydrogen; and that when the compound is a mixture of all possible isomers, X is-CONR 5 R 6 , A 2 is oxygen and R 1 is hydrogen, methyl, ethyl or propyl then substitution on the pyrollidine ring is other than mono-, di-, or tri- methyl or mono-ethyl; and that when R 1 , R 2 , R 4 , R 2a , R 3a and R 4a are each hydrogen, A 2 is oxygen and X is CONR 5 R 6 then R 3 is different from carboxy, ester, amido, substituted oxo-pyrrolidine, hydroxy, oxy derivative, amino, amino derivatives, methyl, naphthyl, phenyl optionally substituted by oxy derivatives or in the para position by an halogen atom.
• R 11 and R 12 are the same or different and each is independently amido, alkyl, alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl, heterocycle or an oxy derivative, thio derivative, acyl derivative, amino derivative, sulfonyl derivative, or sulfmyl derivative, each optionally substituted with any suitable group, including, but not limited to, one or more moieties selected from lower alkyl or other groups as described below as substituents for alkyl.
• oxy derivative as used herein is defined as including -O-R 11 groups wherein R 11 is as defined above except for "oxy derivative".
• Non- limiting examples are alkoxy, alkenyloxy, alkynyloxy, acyloxy, oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy,
• arylsulfinyloxy aryloxy, aralkoxy or heterocyclooxy such as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2-naphthyloxy, 2-pyridyloxy, methylenedioxy, carbonate.
• thio derivative as used herein, is defined as including-S-R 11 groups wherein R 11 is as defined above except for "thio derivative".
• Non- limiting examples are alkylthio, alkenylthio, alkynylthio and arylthio.
• amino derivative as used herein, is defined as including-NHR 11
• Non-limiting examples are mono- or di-alkyl-, alkenyl-, alkynyl- and arylamino or mixed amino.
• acyl derivative represents a radical derived from carboxylic acid and thus is defined as including groups of the formula R u -CO-, wherein R 11 is as defined above and may also be hydrogen.
• R 11 is as defined above and may also be hydrogen.
• Non- limiting examples are formyl, acetyl, propionyl, isobutyryl, valeryl, lauroyl,
• heptanedioyl cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl, furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl, oxamoyl.
• sulfonyl derivative as used herein, is defined as including a group of the formula -SO2-R 11 , wherein R 11 is as defined above except for “sulfonyl derivative".
• R 11 is as defined above except for “sulfonyl derivative”.
• Non-limiting examples are alkylsulfonyl,
• alkenylsulfonyl alkynylsulfonyl and arylsulfonyl.
• sulfinyl derivative as used herein, is defined as including a group of the formula -SO-R 11 , wherein R 11 is as defined above except for "sulfinyl derivative".
• R 11 is as defined above except for "sulfinyl derivative”.
• Non- limiting examples are alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.
• alkyl is defined as including saturated, monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof and containing 1-20 carbon atoms, preferably 1-6 carbon atoms for non-cyclic alkyl and 3-6 carbon atoms for cycloalkyl (in these two preferred cases, unless otherwise specified, "lower alkyl”).
• Alkyl moieties may optionally be substituted by 1 to 5 substituents independently selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfmyl derivative, alkylamino, carboxy, ester, ether, amido, azido, cycloalkyl, sulfonic acid, sulfonamide, thio derivative, oxyester, oxyamido, heterocycle, vinyl, Cl-5-alkoxy, C6-10- aryloxy and C6-10-aryl.
• substituents independently selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfmyl derivative, alkylamino, carboxy, ester, ether, amido, azi
• Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter- butyl, and 2,2,2-trimethylethyl each optionally substituted by at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro and cyano, such as trifluoromethyl, trichloromethyl, 2,2,2- trichloroethyl, 1 , 1 -dimethyl-2,2-dibromoethyl, 1 , 1 -dimethyl-2,2,2- trichloroethyl.
• alkyl, alkenyl and alkynyl represent straight- or branched chains, Cl-12, preferably Cl-4-alkylene or C2-12-, preferably C2-4-alkenylene or -alkynylene moieties respectively.
• Groups where branched derivatives are conventionally qualified by prefixes such as "n”, “sec”, “iso” and the like are in the n- form unless otherwise stated.
• aryl as used herein, is defined as including an organic radical derived from an aromatic hydrocarbon consisting of 1-3 rings and containing 6- 30 carbon atoms by removal of one hydrogen, such as phenyl and naphthyl each optionally substituted by 1 to 5 substituents independently selected from halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfmyl, alkylamino, carboxy, ester, ether, amido, azido, sulfonic acid, sulfonamide, alkylsulfonyl, alkylsulfmyl, alkylthio, oxyester, oxyamido, aryl, Cl-6-alkoxy, C6-10-aryloxy, Cl-6-alkyl, Cl-6-haloalkyl.
• Aryl radicals are preferably monocyclic containing 6-10 carbon atoms.
• Preferred aryl groups are phenyl and naphthyl each optionally substituted by 1 to 5 substituents independently selected from halogen, nitro, amino, azido, Cl-6-alkoxy, CI -6- alkylthio, Cl-6- alkyl, Cl-6-haloalkyl and phenyl.
• halogen includes an atom of CI, Br, F, I.
• hydroxy represents a group of the formula -OH.
• thiol represents a group of the formula -SH.
• cyano represents a group of the formula -CN.
• nitro represents a group of the formula -N0 2 .
• nitrooxy represents a group of the formula - ON0 2 .
• amino represents a group of the formula -NH 2 .
• azido represents a group of the formula -N 3 .
• carboxy represents a group of the formula - COOH.
• sulfonic acid represents a group of the formula - S0 3 H.
• sulfonamide represents a group of the formula - S0 2 NH 2 .
• ester as used herein is defined as including a group of formula - COO-R 11 wherein R 11 is as defined above except oxy derivative, thio derivative or amino derivative.
• ether is defined as including a group selected from CI -50- straight or branched alkyl, or C2-50- straight or branched alkenyl or alkynyl groups or a combination of the same, interrupted by one or more oxygen atoms.
• amido is defined as including a group of formula -CONH 2 or- CONHR 11 or -CONR n R 12 wherein R 11 and R 12 are as defined above.
• heterocycle as used herein is defined as including an aromatic or non aromatic cyclic alkyl, alkenyl, or alkynyl moiety as defined above, having at least one O, S and/or N atom interrupting the carbocyclic ring structure and optionally, one of the carbon of the carbocyclic ring structure may be replaced by a carbonyl.
• aromatic as used herein is defined as including an aromatic or non aromatic cyclic alkyl, alkenyl, or alkynyl moiety as defined above, having at least one O, S and/or N atom interrupting the carbocyclic ring structure and optionally, one of the carbon of the carbocyclic ring structure may be replaced by a carbonyl.
• heterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl, quinolizinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl, indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl, 1, 2, 4-thiadiazolyl, thieno (2,3-b) furanyl, furopyranyl,
• benzothiazolyl or benzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenothiazinyl, furazanyl, isochromanyl, indolinyl, xanthenyl, hypoxanthinyl, pteridinyl, 5- azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,
• Non-limiting examples of non aromatic heterocycles are tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholino, morpholinyl, 1-oxaspiro (4.5) dec-2-yl, pyrrolidinyl, 2-oxo-pyrrolidinyl, sugar moieties (i.e.
• heterocycle also includes bicyclic, tricyclic and tetracyclic, spiro groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or another monocyclic heterocyclic ring or where a monocyclic heterocyclic group is bridged by an alkylene group, such as quinuclidinyl, 7-azabicyclo (2.2.1)heptanyl, 7- oxabicyclo (2.2.1) heptanyl, 8- azabicyclo (3.2.1)octanyl.
• alkylene group such as quinuclidinyl, 7-azabicyclo (2.2.1)heptanyl, 7- oxabicyclo (2.2.1) heptanyl, 8- azabicyclo (3.2.1)octanyl.
• X are -COO R 7 or -CONR 5 R 6 , wherein R 5 , R 6 and R 7 are preferably hydrogen, Cl-4-alkyl, phenyl or alkylphenyl.
• X is carboxy or -CONR 5 R 6 , wherein R 5 and R 6 are preferably hydrogen, Cl-4-alkyl, phenyl or alkylphenyl, especially -CONH 2 .
• a 1 and A 2 are each oxygen.
• R 1 is hydrogen, alkyl, especially CI -12 alkyl, particularly lower alkyl or aryl especially phenyl.
• R 1 groups are methyl, ethyl, propyl, isopropyl, butyl, iso- or ter-butyl, 2,2,2-trimethylethyl each optionally attached via a methylene bridge or the same substituted by at least one halogen atom such as
• R 1 as ethyl is especially preferred.
• R 2 and R 2a are independently hydrogen, halogen or alkyl, especially lower alkyl.
• R 2 and R 2a groups are independently hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2- trimethylethyl or the same substituted by at least one halogen atom such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, l,l-dimethyl-2,2- dibromoethyl, 1 , 1 -dimethyl -2,2,2-trichloroethyl.
• R 2 and R 2a are hydrogen.
• R 3a , R 4 and R 4a are independently hydrogen, alkyl, especially methyl or ethyl or aryl especially phenyl or aralkyl, especially benzyl.
• R 3a , R 4 and R 4a groups are independently hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2- trimethylethyl or the same substituted by at least one halogen atom such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, l,l-dimethyl-2, 2- dibromoethyl, 1 , 1 -dimethyl -2,2,2-trichloroethyl.
• R 4 and R 4a are hydrogen.
• R 3a is particularly hydrogen or alkyl, especially lower alkyl and is most preferably hydrogen.
• R 3 is hydrogen, Cl-12-alkyl, especially Cl-6-alkyl, each optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato or alkoxy and attached to the ring either directly or via a thio, sulfinyl, sulfonyl, carbonyl or oxycarbonyl group and optionally, a Cl-4-alkylene bridge, particularly methylene ; C2-6-alkenyl or -alkynyl, especially C2-3-alkenyl or-alkynyl each optionally substituted by one or more halogens ; azido ; cyano ; amido ; carboxy ; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1- oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimi
• R 3 is Cl-6-alkyl optionally substituted by one or more substituents selected from halogen, thiocyanato, azido, alkoxy, alkylthio, phenylsulfonyl ; nitrooxy ; C2-3- alkenyl or-alkynyl each optionally substituted by one or more halogens or by acetyl ; tetrazolyl, pyridyl, furyl, pyrrolyl, thiazolyl or thienyl ; or phenyl or phenylalkyl each optionally substituted by one or more substituents selected from halogen, Cl-6-alkyl, CI -6 haloalkyl, Cl-6-alkoxy, amino, azido, phenyl and nitro and each attached to the ring either directly or via a sulfonyloxy and optionally additionally a Cl-4-alkylene bridge, particularly methylene.
• substituents selected from
• R 3 groups are hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least one halogen atom such as trifluoromethyl,
• R 3 is especially Cl-4-alkyl optionally substituted by one or more substituents selected from halogen, thiocyanato or azido; C2-5-alkenyl or- alkynyl, each optionally substituted by one or more halogens; thienyl; or phenyl optionally substituted by one or more substituents selected from halogen, Cl-6-alkyl, CI -6 haloalkyl or azido.
• R 3 groups are CI -6 alkyl and C2-6 haloalkenyl.
• R 5 and R 6 are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl, especially hydrogen or methyl.
• R 5 and R 6 are hydrogen.
• R 7 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or tert-butyl, 2,2,2-trimethylethyl, methoxy, ethoxy, phenyl, benzyl or the same substituted by at least one halogen atom such as trifluoromethyl, chlorophenyl.
• R 7 is hydrogen, methyl or ethyl especially hydrogen.
• R 8 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl, phenyl, benzyl or the same substituted by at least one halogen atom such as trifluoromethyl, chlorobenzyl.
• R 8 is hydrogen or methyl.
• Combinations of one or more of these preferred compound groups are especially preferred.
• a particular group of compounds of formula I comprises those wherein,
• a 2 is oxygen
• X is-CONR 5 R 6 or-COOR 7 or-CO-R 8 or CN ;
• R 1 is hydrogen or alkyl, aryl, halogen, hydroxy, amino, nitro, cyano;
• R 2 , R 3 , R 4 are the same or different and each is independently hydrogen or halogen, hydroxy, amino, nitro, cyano, acyl, acyloxy, a sulfonyl derivative, a sulfmyl derivative, an amino derivative, carboxy, ester, ether, amido, sulfonic acid, sulfonamide,,, alkoxycarbonyl,,, a thio derivative,, alkyl, alkoxy, oxyester, oxyamido, aryl,, an oxy derivative, heterocycle, vinyl and R 3 may additionally represent C2-5 alkenyl, C2-5 alkynyl or azido each optionally substituted by one or more halogen, cyano, thiocyano, azido,, cyclopropyl, acyl and/or phenyl ; or phenylsulfonyloxy whereby any phenyl moiety may be substituted by one or more halogen
• R 2a , R 3a and R 4a are hydrogen
• R 5 , R 6 , R 7 are the same or different and each is independently hydrogen, hydroxy, alkyl, aryl, heterocycle or oxy derivative;
• R 8 is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle, alkylthio or thio derivative.
• R 1 is preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl ; most preferably methyl, ethyl or n-propyl.
• R 2 and R 4 are preferably independently hydrogen or halogen or methyl, ethyl, propyl, isopropyl, butyl, isobutyl ; and, most preferably, are each hydrogen.
• R 3 is preferably CI -5 alkyl, C2-5 alkenyl, C2-C5 alkynyl, cyclopropyl, azido, each optionally substituted by one or more halogen, cyano, thiocyano, azido, alkylthio, cyclopropyl, acyl and/or phenyl ; phenyl ; phenylsulfonyl ; phenylsulfonyloxy, tetrazole, thiazole, thienyl, furyl, pyrrole, pyridine, whereby any phenyl moiety may be substituted by one or more halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and/
• X is preferably -COOH or -COOMe or -COOEt or -CONH 2 ; most preferably -CONH 2 .
• a further particular group of compounds of formula I comprises those wherein,
• X is-CA 1 NH 2 ,-CA 1 NHCH 3 or-CA ⁇ (CH 3 ) 2 ;
• R 1 is alkyl or phenyl
• R 3 is alkyl, alkenyl, alkynyl, cyano, isothiocyanato, ether, carboxyl, amido, aryl, heterocycle ; or
• R 3 is CH 2 R 10 wherein R 10 is hydrogen, cycloalkyl, oxyester,
• oxyalkylsulfonyl oxyarylsufonyl, aminoalkylsulfonyl, aminoarylsulfonyl, nitrooxy, cyano, isothiocyanato, azido, alkylthio, arylthio, alkylsulfmyl, alkylsulfonyl, heterocycle, aryloxy, alkoxy or trifluoroethyl;
• R 3a is hydrogen, alkyl or aryl (especially with the proviso that when R 3a is hydrogen, R 3 other than methyl);
• R 3 R 3a form a cycloalkyl
• R 2 , R 2a , R 4 and R 4a are each hydrogen.
• R 1 is preferably alkyl especially CI -12- more particularly Cl-6-alkyl and is most preferably ethyl;
• R 2 , R 2a , R 3a and R 4a are preferably hydrogen
• R 3 is preferably selected from hydrogen; Cl-12-alkyl, especially Cl-6- alkyl, each optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato or alkoxy and attached to the ring either directly or via a thio, sulfinyl, sulfonyl, carbonyl or oxycarbonyl group and optionally additionally a Cl-4-alkylene bridge, particularly methylene; C2-6- alkenyl or-alkynyl, especially C2-3-alkenyl or-alkynyl, each optionally substituted by one or more halogens ; azido ; cyano ; amido ; carboxy ;
• R 3a is preferably hydrogen or Cl-4-alkyl ;
• R 4 and R 4a are preferably, independently hydrogen, Cl-4-alkyl, phenyl or benzyl.
• a further group of compounds of formula I comprises those in racemic form wherein, when X is-CONR 5 R 6 and R 1 is hydrogen, methyl, ethyl or propyl, then substitution on the pyrrolidine ring is other than mono-, di-, or tri-methyl or mono-ethyl.
• a further group of compound of formula I comprises those in racemic form wherein, when X is-CONR 5 R 6 and R 1 is hydrogen or Cl-6-alkyl, C2-6-alkenyl or- alkynyl or cycloalkyl, each unsubstituted, then substitution in the ring is other than by alkyl, alkenyl or alkynyl, each unsubstituted.
• a further particular group of compounds of formula I (Compounds IE) comprises those wherein,
• X is-CA 1 NH 2 ;
• R 1 is H ;
• R 3 is azidomethyl, iodomethyl, ethyl optionally substituted by 1 to 5 halogen atoms, n- propyl optionally substituted by 1 to 5 halogen atoms, vinyl optionally substituted by one or two methyl, and/or 1 to 3 halogen atoms, acetylene optionally substituted by Cl-4-alkyl, phenyl or halogen ;
• R 3a is hydrogen or halogen, preferably fluorine ;
• R 2 , R 2a , R 4 and R 4a are each hydrogen ;
• a further particular group of compounds of formula I (Compounds IF) comprises those wherein,
• X is-CA 1 NH 2 ;
• R 3 is Cl-6-alkyl, C2-6-alkenyl or C2-6-alkynyl optionally substituted by azido, oxynitro, 1 to 6 halogen atoms ;
• R 3a is hydrogen or halogen, preferably fluorine ;
• R 2 , R 2a , R 4 and R 4a are each hydrogen ; as their racemates or in enantiomerically enriched form, preferably the pure enantiomers.
• compounds useful in the methods and compositions of this invention are selected from the group consisting of:
• compounds useful in the methods and compositions of this invention are selected from the group consisting of :
• a 1 represents an oxygen or a sulfur atom
• X is-CONR 7 R 8 ,-COOR 9 ,-CO-R 10 or CN;
• R 1 when existent, R 2 , R 3 , R 4 and R 5 are the same or different and each is independently hydrogen, halogen, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azido, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle, or an oxy derivative, thio derivative, amino derivative, acyl derivative, sulfonyl derivative or sulfmyl derivative, provided that at least one of the substituents R chosen from R 1 when existent, R 2 , R 3 , R 4 or R 5 is not hydrogen;
• R 6 is hydrogen, alkyl, aryl or-CH 2 -R 6a wherein R 6a is aryl, heterocycle, halogen, hydroxy, amino, nitro or cyano;
• R 7 , R 8 and R 9 are the same or different and each is independently hydrogen, hydroxy, alkyl, aryl, heterocycle or an oxy derivative
• R 10 is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle or a thio derivative
• At least one substituent R 1 to R 5 is different from hydrogen.
• Some non- substituted compounds are referred to in US Patent No. 5,468,733 and 5,516, 759.
• US Patent No. 5,468,733 refers to non-ring substituted 2-oxo-l-pyrrolidinyl and 2-oxo-l-piperidinyl derivatives as inhibitors of the oncogene Ras protein.
• these compounds block the ability of Ras to transform normal cells to cancer cells, and therefore can be included in several chemotherapeutic compositions for treating cancer.
• US Patent No. 5,516,759 refers to non-ring substituted 2-oxo-l- pyrrolidinyl, 2-oxo-l- piperidinyl and azepanyl derivatives present at the N- terminus of dodecapeptides possessing LHRH (luteinizing hormone-releasing hormone) antagonistic activity.
• LHRH antagonists are useful in the treatment of a variety of conditions in which suppression of sex steroids plays a key role including contraception, delay of puberty, treatment of benign prostatic hyperplasia a. o.
• R 11 and R 12 are the same or different and each is independently amido, alkyl, alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl. heterocycle or an oxy derivative, thio derivative, acyl derivative, amino derivative, sulfonyl derivative, or sulfinyl derivative, each optionally substituted with any suitable group, including, but not limited to, one or more moieties selected from lower alkyl or other groups as described below as substituents for alkyl.
• oxy derivative is defined as including-O-R 11 groups wherein R 11 is as defined above except for "oxy derivative".
• Non- limiting examples are alkoxy, alkenyloxy, alkynyloxy, acyloxy, oxyester, oxyamido, alkylsulfonyloxy, alkylsulfmyloxy, arylsulfonyloxy,
• arylsulfmyloxy aryloxy, aralkoxy or heterocyclooxy such as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2-naphthyloxy, 2-pyridyloxy, methylenedioxy, carbonate.
• thio derivative is defined as including-S-R 11 groups wherein R 11 is as defined above except for "thio derivative".
• Non- limiting examples are alkylthio, alkenylthio, alkynylthio and arylthio.
• amino derivative as used herein, is defined as including-NHR 11
• R and R are as defined above.
• Non-limiting examples are mono- or di-alkyl-, alkenyl-, alkynyl-and arylamino or mixed amino.
• acyl derivative represents a radical derived from carboxylic acid and thus is defined as including groups of the formula R u -CO-, wherein R 11 is as defined above and may also be hydrogen.
• R 11 is selected from hydrogen, Cl-12 alkyl, C2-12 alkenyl, C2-12 alkenyl, heterocyle and aryl.
• Non- limiting examples are formyl, acetyl, propionyl, isobutyryl, valeryl, lauroyl,
• heptanedioyl cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl, furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl, oxamoyl.
• sulfonyl derivative is defined as including a group of the formula -SO 2 -R 11 , wherein R 11 is as defined above except for "sulfonyl derivative".
• R 11 is as defined above except for "sulfonyl derivative”.
• Non-limiting examples are alkylsulfonyl,
• alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.
• sulfmyl derivative is defined as including a group of the formula -SO-R 11 , wherein R 11 is as defined above except for "sulfmyl derivative".
• Non- limiting examples are alkylsulfmyl, alkenylsulfinyl, alkynylsulfmyl and arylsulfmyl.
• alkyl is defined as including saturated, monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof and generally containing 1-20 carbon atoms, most often 1 to 12 carbon atoms, preferably 1-7 carbon atoms for non-cyclic alkyl and 3-7 carbon atoms for cycloalkyl (in these two preferred cases, unless otherwise specified, "lower alkyl”), each optionally substituted by, preferably 1 to 5, substituents independently selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfmyl derivative, alkylamino, carboxy, ester, ether, amido, azido, cycloalkyl, sulfonic acid, sulfonamide, thio derivative, alkylthio, oxyester, oxyamido, heterocycle
• alkyl groups containing 1 to 7 carbon atoms each optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio, cyclopropyl, acyl and phenyl.
• substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio, cyclopropyl, acyl and phenyl.
• CI -4 alkyl and C3-7 cycloalkyl each optionally substituted by one or more hydroxy, halogen, lower alkyl or/and azido.
• alkyl groups are hydroxymethyl, propyl, butyl, 2, 2,2- trifluoroethyl, 2- bromo-2,2-difluoroethyl, 2-chloro-2,2-difluoroethyl, 3,3,3- trifluoropropyl, cyclopropylmethyl, iodomethyl, azidomethyl, 2,2- difluoropropyl, 2-iodo-2,2-difluoroethyl.
• lower alkyl refers to Ci to C 7 saturated straight, branched or cyclic hydrocarbon.
• Non limiting examples are methyl, ethyl, propyl, isopropyl, butyl, tertiobutyl, pentyl, cyclopropyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methypentyl, 2,2-dimethylbutyl, optionally substituted with any suitable group, including but not limited to one or more moieties selected from groups as described above for the alkyl groups.
• lower alkyl is methyl.
• alkenyl is defined as including both branched and unbranched, unsaturated hydrocarbon radicals having at least one double bond, and being optionally substituted by at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, thiocyanato, azido, alkylthio, cycloalkyl, acyl, nitro, cyano, aryl and heterocycle.
• Most preferred is vinyl, optionally substituted by one or more halogen or/and lower alkyl, and especially 2,2- difluorovinyl, 2,2-dibromovinyl and 2,2- dichlorovin
• Preferred alkynyl groups are C2-12 alkynyl, especially C2-6 alkynyl, optionally being substituted by one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, acyl, aryl such as phenyl and alkyl, preferably cycloalkyl.
• ethynyl, propynyl and butynyl optionally substituted by lower alkyl or/and halogen, and especially 1 -propynyl, cyclopropylethynyl, 3- methyl-1 -butynyl and 3,3,3- trifluoro-1 -propynyl.
• alkyl, alkenyl and alkynyl represent straight- or branched chains, Cl-12, preferably Cl-4-alkylene or C2-12-, preferably C2-4-alkenylene or- alkynylene moieties respectively.
• Groups where branched derivatives are conventionally qualified by prefixes such as "n”, “sec”, “iso” and the like are in the n- form unless otherwise stated.
• aryl is defined as including an organic radical derived from an aromatic hydrocarbon consisting of at least one ring, most often 1 to 3 rings and generally containing 6-30 carbon atoms by removal of one hydrogen, such as phenyl and naphthyl, each optionally substituted by one or more substituents independently selected from halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amido, azido, sulfonic acid, sulfonamide, alkylsulfonyl, alkylsulfmyl, Cl-6-alkylthio, oxyester, oxyamido, aryl, Cl-6-alkoxy, C6-10- aryloxy, Cl-6-alkyl, Cl-6-haloalkyl.
• Aryl radicals are preferably monocyclic or bicyclic containing 6-10 carbon atoms.
• Preferred aryl groups are phenyl and naphthyl each optionally substituted by one or more substituents independently selected from halogen, nitro, amino, azido, Cl-6-alkoxy, Cl-6-alkyl, Cl-6- haloalkyl, sulfonyl and phenyl.
• Preferred aryl is phenyl, optionally substituted by one or more halogen, lower alkyl, azido or nitro, such as 3-chlorophenyl and 3-azidophenyl.
• halogen includes an atom of CI, Br, F, I.
• hydroxy represents a group of the formula -OH.
• thiol represents a group of the formula -SH.
• cyano represents a group of the formula -CN.
• nitro represents a group of the formula -N0 2 .
• nitrooxy represents a group of the formula - ON0 2 .
• amino represents a group of the formula -NH 2 .
• azido represents a group of the formula -N 3 .
• carboxy represents a group of the formula - COOH.
• sulfonic acid represents a group of the formula - S0 3 H.
• sulfonamide represents a group of the formula - S0 2 NH 2 .
• esters as used herein, is defined as including a group of formula -COO-R 11 wherein R 11 is as defined above except oxy derivative, thio derivative or amino derivative.
• esters of formula -COOR 11 wherein R 11 is selected from Cl-12 alkyl, C2-12 alkenyl, C2-12 alkynyl and aryl. Most preferred are esters where R 11 is a lower alkyl, especially methyl.
• ether is defined as including a group selected from CI -50- straight or branched alkyl, or C2-50-straight or branched alkenyl or alkynyl groups or a combination of the same, interrupted by one or more oxygen atoms.
• amido is defined as including a group of formula -CONH 2 or - CONHR 11 or -CONR u R 12 wherein R 11 and R 12 are as defined above.
• heterocycle is defined as including an aromatic or non aromatic cyclic alkyl, alkenyl, or alkynyl moiety as defined above, having at least one O, S and/or N atom interrupting the carbocyclic ring structure and optionally, one of the carbon of the carbocyclic ring structure may be replaced by a carbonyl, and optionally being substituted with any suitable group, including but not limited to one or more moieties selected from lower alkyl, or other groups as described above for the alkyl groups.
• Non- limiting examples of heterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, triazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl, quinolizinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl, indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl, 1,2,4-thiadiazolyl, thiomorpholinyl, thieno (2,3-b) furanyl, furopyranyl, benzofuranyl, benzoxepinyl, isooxazolyl, oxazolyl, thianthreny
• phthalazinyl quinoxalinyl, 1-oxidopyridyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenothiazinyl, furazanyl, benzodioxolyl, isochromanyl, indolinyl, xanthenyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholino, morpholinyl, 1-oxaspiro (4.5) dec-2-yl, pyrrolidinyl, 2-ox
• heterocycle also includes bicyclic, tricyclic and tetracyclic, spiro groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or another monocyclic heterocyclic ring or where a monocyclic heterocyclic group is bridged by an alkylene group, such as quinuclidinyl, 7-azabicyclo (2.2.1) heptanyl, 7- oxabicyclo (2.2.1) heptanyl, 8-azabicyclo (3.2.1) octanyl.
• alkylene group such as quinuclidinyl, 7-azabicyclo (2.2.1) heptanyl, 7- oxabicyclo (2.2.1) heptanyl, 8-azabicyclo (3.2.1) octanyl
• the heterocycle is preferably selected from triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1- oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and piperazinyl, each optionally substituted by one or more substituents selected from halogen, alkyl, substituted alkyl, alkoxy, nitro, amino, acyl and phenyl.
• the heterocycle is selected from tetrazolyl, pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, each optionally substituted by one or more substituents selected from halogen, alkyl, halogen substituted alkyl, acyl, alkoxy, nitro, amino and phenyl, and especially from 2-and 3- thienyl, optionally substituted by one or more halogen, acyl such as formyl, cyano and/or lower alkyl, such as methyl.
• R substituent refers to R 1 , R 2 , R 3 , R 4 or R 5 , independently.
• a compound of formula I is as defined above wherein n represents 0.
• the compound of formula I is as defined above wherein n represents 1.
• R substituent(s) is/are hydrogen.
• compounds of formula I are as defined above wherein A 1 represents an oxygen atom.
• a 1 represents an oxygen atom.
• compounds of formula I are as defined above wherein X is CONR 7 R 8 , especially CONH 2 .
• X is CONR 7 R 8 , especially CONH 2 .
• compounds of formula I are as defined above wherein R 6 represents hydrogen, CI -4 alkyl, or a CH 2 -R 6a group wherein R 6a represents a heterocycle. Most preferably R 6 is a C 1-4 alkyl, especially ethyl. When R 6 is ethyl we refer to 2- (2-oxo (or thioxo)- 1- piperidinyl) butanamide or 2- (2-oxo (or thioxo)- 1 -azepanyl) butanamide derivatives.
• compounds of formula I are as defined above wherein the carbon atom to which R 6 is attached is of the S configuration.
• R 6 is ethyl
• A is oxygen
• X is CONR 7 R 8 we refer then to (2S)-2-(2-oxo-l-piperidinyl) butanamide or (2S)-2- (2-oxo- 1- azepanyl) butanamide derivatives.
• R 1 when existent, R 2 when n 0 and R 5 are hydrogen;
• R 6 is hydrogen, alkyl, aryl or-CH 2 -R 6a wherein R 6a is aryl, heterocycle, halogen, hydroxy, amino, nitro or cyano;
• Cl-12 alkyl each optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkyltio, cycloalkyl, acyl, aryl and heterocycle;
• C2-12 alkenyl each optionally substituted by one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryl and acyl;
• C2-12 alkynyl each optionally substituted by one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryl and acyl ; acyl derivative of formula -CO-R 11 , wherein R 11 is selected from Cl-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, heterocycle and aryl;
• heterocycle selected from triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1- oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and piperazinyl, each optionally substituted by one or more substituents selected from halogen, alkyl, substituted alkyl, alkoxy, nitro, amino, acyl and phenyl;
• aryl each optionally substituted by one or more substituents selected from CI -6 alkyl, CI -6 haloalkyl, CI -6 alkoxy, CI -6 alkylthio, amino, azido, sulfonyl, aryl and nitro.
• CI -7 alkyl each optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkyltio, cyclopropyl, acyl and phenyl;
• C2-6 alkenyl each optionally substituted by one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl, phenyl and acyl ;
• C2-6 alkynyl each optionally substituted by one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl, phenyl and acyl;
• heterocycle selected from tetrazolyl, pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, each optionally substituted by one or more substituents selected from halogen, alkyl, halogen substituted alkyl, acyl, alkoxy, nitro, amino and phenyl;
• phenyl each optionally substituted by one or more substituents selected from CI -6 alkyl, halogen substituted alkyl, halogen, alkoxy, amino, azido, sulfonyl, phenyl and nitro.
• the compound is as defined above wherein at least one of the R substituents chosen from the group
• the compound is as defined above wherein R 1 , R 2 , R 4 and R 5 are hydrogen.
• the compound is as defined above wherein R 1 , R 2 , R 3 and R 5 are hydrogen.
• compounds useful in the methods and compositions of this invention are selected from the group consisting of:
• R 1 is hydrogen
• R 2 is hydrogen or Cl-20-alkyl
• R 3 is hydrogen, Cl-20-alkyl, C4-8-cycloalkyl, C5-8-cycloalkenyl, aryl, aromatic or non aromatic heterocycle, Cl-20-alkoxy, or a group of formula - W-R 8 , R 3a is hydrogen, Cl-20-alkyl or a group of formula : or NR R is a roup of formula
• R 4 is hydrogen
• R 5 is hydrogen; nitro; halogen; azido; cyano; -S-Cl-4-alkyl; -SO-C1-4- alkyl; -S0 2 -Cl-4-alkyl; -SONH 2 ; Cl-20-alkyl unsubstituted or substituted by halogen; or Cl-20-alkoxy unsubstituted or substituted by halogen,
• R 6 is hydrogen, Cl-20-alkyl or halogen
• R 7 is hydrogen, C l-20-alkyl or halogen
• X is O, S or NH
• R 8 is aryl or heterocycle
• R 9 , R 10 , R 10a and R 11 are independently selected from hydrogen, Cl-4-alkyl, halogen, hydroxy or methoxycarbonyl,
• R 10 and R 10a together form a C3-6-alkylene
• R 12 is hydrogen, Cl-4-alkyl, halogen or hydroxy
• R 13 is hydrogen
• CR 12 R 13 is dioxolanyl
• R 14 is aryl, heterocycle or a group of formula -V-R 15 ,
• V is Ci_i 2 -alkylene
• R 15 is aryl or heterocycle
• n 1 to 4
• n 0 or 1
• at least one of R 5 , R 6 or R 7 is different from hydrogen when R 2 is hydrogen
• R 3 is H or 2, 6-diisopropylphenyl
• R 3a is H.
• the compound has the formula I or a pharmaceutically acceptable salt thereof or stereoisomeric forms thereof,
• R 1 is hydrogen
• R 2 is hydrogen or Cl-20-alkyl
• R 3 is hydrogen, Cl-20-alkyl, C4-8-cycloalkyl, C5-8-cycloalkenyl, aryl, aromatic or non aromatic heterocycle, Cl-20-alkoxy, or a group of formula W-R 8 ,
• R 3a is hydrogen, Cl-20-alkyl or a group of formula: or 3 R 3a is a group of formula
• R is hydrogen
• R 5 is hydrogen; nitro; halogen; Cl-20-alkyl unsubstituted or substituted by halogen; or Cl-20-alkoxy unsubstituted or substituted by halogen,
• R 6 is hydrogen, Cl-20-alkyl or halogen
• R 7 is hydrogen, Cl-20-alkyl or halogen
• R 8 is aryl or heterocycle
• R 9 , R 10 , R 10a and R u are independently selected from hydrogen, Cl-4-alkyl, halogen, hydroxy or methoxycarbonyl,
• R 10 and R 10a together form a C3-6-alkylene
• R 12 is hydrogen, Cl-4-alkyl, halogen or hydroxy
• R 13 is hydrogen
• CR 12 R 13 is dioxolanyl
• R 14 is aryl, heterocycle or a group of formula -V-R 15 ,
• V is Cl-12-alkylene
• R 15 is aryl or heterocycle
• n 1 to 4
• n 0 or 1
• R 5 , R 6 or R 7 is different from hydrogen when R 2 is hydrogen, R 3 is H or 2,6-diisopropylphenyl, and R 3a is H.
• alkyl is defined as including saturated, monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof and containing 1-20 carbon atoms, preferably 1-6 carbon atoms and more preferably 1-4 carbon atoms for non-cyclic alkyl and 3- 8 carbon atoms for cycloalkyl. Alliyl moieties may optionally be substituted by 1 to 5 substituents independently selected from halogen, hydroxy, alkoxy, alkoxycarbonyl, ester or alkylamino.
• Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, n-butyl, 2- fluoroethyl, 3-hydroxypropyl, 3-hydroxy-2, 2-dimethylpropyl, l-(hydroxymethyl) propyl, 3,3, 3-trifluoro-2- hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl and 3- (dimethylamino) propyl.
• cycloalkyl refers to a monovalent group of 3 to 18 carbon atoms, preferably 4-8 carbon atoms, derived from a saturated cyclic or polycyclic hydrocarbon which may be substituted by any suitable group including but not limited to one or more moieties selected from groups as described above for the alkyl groups. Preferred cycloalkyl group is cycloheptyl.
• alkylene represents a divalent alkyl group, having straight or branched moieties, containing 1-12 carbon atoms, preferably
• alkylene groups are methylene, ethylene, hydroxy ethylene, trimethylene or propylene.
• cycloalkenyl is defined as a cyclic unsaturated hydrocarbon radical having at least one double bond, containing 4-20 carbon atoms, preferably 5-8 carbon atoms, and being optionally substituted with any suitable group, including but not limited to one or more moieties selected from groups as described above for the alkyl groups.
• Preferred cycloalkenyl group is 6- (hydroxymethyl) cyclohex-3-en-l-yl.
• aryl is defined as including an organic radical derived from an aromatic hydrocarbon consisting of 1-3 rings and containing 6- 30 carbon atoms by removal of one hydrogen, such as phenyl and naphthyl each optionally substituted by 1 to 5 substituents independently selected from halogen, hydroxy, nitro, Cl-6-alkyl, Cl-6-alkoxy, Cl-6-alkylsulfonyl, trifluoromethylthio or pyridinylalkyl.
• Aryl radicals are preferably phenyl radicals.
• Preferred aryl groups are phenyl, 3-hydroxyphenyl, 3 -fluorophenyl, 3- methylphenyl, 4-methylphenyl, 4- hydroxyphenyl, 4-hydroxy-3- methoxyphenyl, 3-(2-pyridin-2-ylethyl) phenyl, 3,4- dimethylphenyl, 4-tert- butylphenyl, 4-methylsulfonylphenyl, 2-nitrophenyl, 2-chloro- 6-fluorophenyl,
• halogen includes an atom of CI, Br, F, I.
• nitro represents a group of the formula -N0 2 .
• hydroxy represents a group of the formula -OH.
• alkoxy represents a group of formula -OR b wherein R b is an alkyl group, as defined above.
• esters represents a group of formula -COOR wherein R c is an alkyl group or an aryl group, as defined above.
• alkoxycarbonyl represents a group of formula - COOR d wherein R d is an alkyl group, as defined above.
• amino represents a group of the formula -NH 2 .
• alkylamino represents a group of formula - NHR e or -NR e R f wherein R e and R f are alkyl group as defined above.
• alkylsulfonyl as used herein is defined as representing a group of formula -S0 2 -R g , wherein R g is Cl-4-alkyl.
• heterocycle as used herein is defined as including an aromatic or non aromatic cycloalkyl or cycloalkenyl moiety as defined above, having at least one O, S and/or N atom interrupting the carbocyclic ring structure and optionally, one of the carbon of the carbocyclic ring structure may be replaced by a carbonyl.
• Non-limiting examples of aromatic heterocycles are pyrazolyl, furyl, imidazolyl, triazolyl, oxazolyl, pyridinyl, pyrrolyl, thienyl, isothiazolyl, benzimidazolyl, tetrazolyl, isooxazolyl, oxazolyl, thiazolyl, 1,2, 4-thiadiazolyl, oxadiazole, pyridazinyl, pyrimidinyl, pyrazinyl, isoindolyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, quinazolinyl, quinolizinyl, naphthyridinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, indolyl, indolizinyl, purinyl
• Non-limiting examples of non aromatic heterocycles are tetrahydrofuranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholinyl,
• thiomorpholinyl pyrrolidinyl, thiazolidinyl, indolinyl, tetrahydrobenzazocmyl, dihydroisochromenyl, tetrahydropyranyl, oxooctahydroquinolinyl, dioxolanyl, 1-oxaspiro (4.5) dec-2-yl, pyrrolidinyl, 2-oxo-pyrrolidinyl, 8-thiabicyclo [3.2.
• cyclooctanyl 1 ,4-dithiepanyl, tetrahydro-2H-thiopyranyl, azepanyl and azocanyl, optionally substituted by 1 to 5 substituents independently selected from halogen, hydroxy, thiol, amino, nitro, cyano, azido, Cl-6-alkoxy, Cl-6- alkylthio, Cl-6-alkyl, Cl-6-haloalkyl, formyl or ester.
• More preferred non aromatic heterocycles are tetrahydrofuranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, thiazolidinyl, indolinyl, tetrahydro-l-benzazocin-1 (2H)-yl, 3, 4-dihydro-lH-isochromen-l- yl, tetrahydropyranyl, oxooctahydroquinolinyl and dioxolanyl.
• heterocycle also includes bicyclic, tricyclic and tetracyclic, spiro groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cycloalkyl ring, a cycloalkenyl ring or another monocyclic heterocyclic ring or where a monocyclic heterocyclic group is bridged by an alkylene group, such as quinuclidinyl, 7-azabicyclo (2.2.1)heptanyl, 7-oxabicyclo (2.2.1)heptanyl and 8- azabicyclo (3.2.1)octanyl.
• pyridinylalkyl represents a group of formula - R h - pyridinyl in which R h is Cl-4-alkylene.
• cyano as used herein, represents a group of the formula -CN.
• R 2 is hydrogen or Cl-4-alkyl.
• R 2 is hydrogen, methyl or ethyl. More preferably, R 2 is hydrogen or methyl.
• R 3 is hydrogen; Cl-6-alkyl unsubstituted or substituted by 1 to 5 substituents selected from halogen, hydroxy, alkoxy, alkoxycarbonyl or alkylamino; C5-7-cycloalkyl; (hydroxymethyl) cyclohexenyl; phenyl unsubstituted or substituted by 1 to 5 substituents selected from halogen, Cl-4- alkyl, hydroxy, methoxy, nitro, methylsulfonyl, trifluoromethylthio or pyridinylalkyl ; pyridinyl unsubstituted or substituted by methoxy; triazolyl; Cl-4-alkoxy ; or a group of formula -W-R 8 wherein:
• R 8 is phenyl unsubstituted or substituted by 1 to 5 substituents selected from halogen, Cl-4-alkyl, hydroxy, methoxy, nitro, methylsulfonyl or trifluoromethylthio; furyl unsubstituted or substituted by methyl; pyrazolyl; pyridinyl; morpholinyl ; tetrahydrobenzazocmyl; piperidinyl unsubstituted or substituted by methyl; dihydroisochromenyl or dihydroimidazolyl.
• R 3 is hydrogen, n-butyl, cycloheptyl, 2-fluoroethyl, 3- hydroxypropyl, 3-hydroxy-2, 2-dimethylpropyl, l-(hydroxymethyl) propyl, 3,3, 3- trifiuoro-2-hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl, 3- (dimethylamino) propyl, 6-(hydroxymethyl) cyclohex-3-en-l-yl, 3- hydroxyphenyl, 3- fluorophenyl, 3- (2-pyridin-2-ylethyl) phenyl, 3, 4- dimethylphenyl, 4-tert-butylphenyl, benzyl, 4-hydroxy-3-methoxybenzyl, 4- methylsulfonylbenzyl, 2-nitrobenzyl, 2-chloro- 6-fiuorobenzyl, 2- [(trifiuoromethyl) thio] benzyl
• R 3a is hydrogen, Cl-4-alkyl or a group of formula
• R 3a is hydrogen, methyl or tetrahydrofuran-2-ylmethyl. More preferably, R 3a is hydrogen.
• NR 3 R 3a is piperidinyl unsubstituted or substituted by hydroxy; thiomorpholinyl; thiazolidinyl unsubstituted or substituted by Cl- 4- alkoxycarbonyl ; 2, 5-dihydro-lH-pyrrol-l-yl ; 1, 4-dioxa-8-azaspiro [4.5] dec-8- l; 4- oxooctahydro-l(2H)-quinolinyl; or a group of formula
• R is pyridinyl ; phenyl unsubstituted or substituted by halogen, hydroxy, Cl-4-alkyl ; or a group of formula -V-R 15 wherein V is unsubstituted
• NR 3 R 3a is 4-pyridin-2-ylpiperazin-l-yl, 4-(3- methylphenyl) piperazin-l-yl, 4- (4-hydroxyphenyl) piperazin-l-yl, 4- (2- phenylethyl) piperazin-l-yl, 4- (2-morpholin-4-ylethyl) piperazin-l-yl, 3- hydroxypiperidin- 1 -yl, thiomorpholin-4-yl, 4-methoxycarbonyl- 1 ,3-thiazolidin- 3-yl, 2, 5-dihydro-lH-pyrrol-l-yl, 1, 4-dioxa-8-azaspiro [4.5] dec-8-yl or 4- oxooctahydro- 1 (2H)-quinolinyl.
• R 5 is hydrogen, nitro, halogen, Cl-4-alkyl, unsubstituted or substituted by halogen, or Cl-4-alkoxy unsubstituted or substituted by halogen.
• R 5 is hydrogen, methyl, ethyl, trifluoromethyl
• R 5 is halogen or trifluoromethyl.
• R 6 is hydrogen, Cl-6-alkyl or halogen.
• R 6 is hydrogen, methyl or CI. More preferably, R 6 is hydrogen. Generally, R 7 is hydrogen, methyl or halogen.
• R 7 is hydrogen, methyl, Br, F or CI. More preferably, R 7 is hydrogen, Br or F.
• Combinations of one or more of these preferred compound groups are especially preferred.
• the compound has the formula I or a
• R 1 is hydrogen
• R 2 is hydrogen or Cl-4-alkyl
• R 3 is hydrogen; Cl-6-alkyl unsubstituted or substituted by 1 to 5 substituents selected from halogen, hydroxy, alkoxy, alkoxycarbonyl or alkylamino ; C5-7-cycloalkyl ; (hydroxymethyl) cyclohexenyl; phenyl unsubstituted or substituted by 1 to 5 substituents selected from halogen, Cl-4- alkyl, hydroxy, methoxy, nitro, methylsulfonyl, trifluoromethylthio or pyridinylalkyl ; pyridinyl unsubstituted or substituted by methoxy; triazolyl; Cl-4-alkoxy ; or a group of formula- W-R 8 ,
• R 3a is hydrogen, Cl-4-alkyl or a group of formula
• NR 3 R 3a is piperidinyl unsubstituted or substituted by hydroxy
• thiomorpholinyl thiazolidinyl unsubstituted or substituted by Cl-4- alkoxycarbonyl ; 2,5-dihydro-lH-pyrrol-l-yl; l,4-dioxa-8-azaspiro [4.5] dec-8- yl; 4-oxooctahydro-l(2H)-quinolinyl ; or a group of formula
• R 4 is hydrogen
• R 5 is hydrogen; nitro; halogen; Cl-4-alkyl, unsubstituted or substituted by halogen; or Cl-4-alkoxy unsubstituted or substituted by halogen,
• R6 is hydrogen, Cl-6-allyl or halogen
• R7 is hydrogen, methyl or halogen
• R8 is phenyl unsubstituted or substituted by 1 to 5 substituents selected from halogen, Cl-4-alkyl, hydroxy, methoxy, nitro, methylsulfonyl or trifluoromethylthio ; furyl unsubstituted or substituted by methyl; pyrazolyl; pyridinyl ; morpholinyl; tetrahydrobenzazocmyl ; piperidinyl unsubstituted or substituted by methyl ; dihydroisochromenyl or dihydroimidazolyl,
• R 14 is pyridinyl; phenyl unsubstituted or substituted by halogen, hydroxy, Cl-4-alkyl ; or a group of formula- V-R 15 ,
• V is unsubstituted C 1 -4-alkylene
• R 15 is phenyl or morpholinyl
• n 1 to 4, and at least one of R 5 , R 6 or R 7 is different from hydrogen when R 2 is hydrogen, R 3 is H or 2,6-diisopropylphenyl, and R 3a is H.
• the compound has the formula I or a pharmaceutically acceptable salt thereof or stereoisomeric forms thereof,
• R 1 is hydrogen
• R 2 is hydrogen, methyl or ethyl
• R 3 is hydrogen, n-butyl, cycloheptyl, 2-fluoroethyl, 3-hydroxypropyl, 3- hydroxy-2,2- dimethylpropyl, l-(hydroxymethyl) propyl, 3,3, 3-trifluoro-2- hydroxypropyl, 3- ethoxypropyl, 2-ethoxy-2-oxoethyl, 3- (dimethylamino) propyl, 6- (hydroxymethyl) cyclohex-3-en-l-yl, 3-hydroxyphenyl, 3- fluorophenyl, 3- (2-pyridin-2-ylethyl) phenyl, 3,4-dimethylphenyl, 4-tert- butylphenyl, benzyl, 4-hydroxy-3- methoxybenzyl, 4-methylsulfonylbenzyl, 2- nitrobenzyl, 2-chloro-6-fluorobenzyl, 2- [(trifluoromethyl)thio] benzyl, 2- hydroxy-2-pheny
• R 3a is hydrogen, methyl or tetrahydrofuran-2-ylmethyl, or NR 3 R 3a 4- pyridin-2-ylpiperazin-l-yl, 4-(3-methylphenyl) piperazin-l-yl, 4-(4- hydroxyphenyl) piperazin-l-yl, 4-(2-phenylethyl) piperazin-l-yl, 4-(2- morpholin-4- ylethyl) piperazin-l-yl, 3-hydroxypiperidin-l-yl, thiomorpholin- 4-yl, 4- methoxycarbonyl-1, 3-thiazolidin-3-yl, 2, 5-dihydro-lH-pyrrol-l-yl, l,4-dioxa-8- azaspiro [4.5]dec-8-yl or 4-oxooctahydro-l(2H)-quinolinyl,
• R 4 is hydrogen
• R5 is hydrogen, methyl, ethyl, trifluoromethyl, trifluoromethoxy, n-propyl, isopropyl, nitro or halogen,
• R 6 is hydrogen, methyl or CI
• R 7 is hydrogen, methyl, Br, F or CI
• R 5 , R 6 or R 7 is different from hydrogen when R 2 is hydrogen, R 3 is H or 2,6-diisopropylphenyl, and R 3a is H.
• R 2 is hydrogen or methyl
• R 3 is hydrogen
• R 3a is hydrogen
• R 5 is halogen or trifluoromethyl
• R 6 is hydrogen
• R 7 is hydrogen, Br or F.
• R 2 when R 2 is Cl-20-alkyl, the carbon atom to which R 2 is attached is preferably in the "S"-configuration.
• compounds useful in the methods and compositions of this invention are selected from the group consisting of: 2-(5-iodo-2-oxo- 2,3-dihydro-lH-indol-l- yl) acetamide ; 2- (5-chloro-2-oxo-2, 3-dihydro-lH- indol-l-yl) acetamide ; 2- (5, 7-dibromo- 2-oxo-2, 3-dthydro-lH-indol-l-yl) acetamide ; 2-(5-nitro-2 -oxo-2, 3-dihydro-lH-indol-l- yl) acetamide ; 2-(5- methyl-2-oxo-2,3-dihydro-lH-indol-l-yl) acetamide; 2- (5-chloro-2- oxo-2, 3- dihydro-lH-indol-l-yl) acet
• compounds useful in the methods and compositions of this invention are selected from the group consisting of: 2-(5-iodo-2-oxo- 2,3-dihydro-lH-indol-l- yl) acetamide ; 2- (5-chloro-2-oxo-2, 3-dihydro-lH- indol-l-yl) acetamide ; 2- (5, 7-dibromo- 2-oxo-2, 3-dihydro-lH-indol-l- yl)acetamide ; (2S)-2-(5-chloro-2-oxo-2,3-dihydro-lH- indol-l-yl)
• compositions of this invention are selected from the group consisting of: 2- (5- chloro-2-oxo-2, 3-dihydro-lH-indol-l-yl) acetamide and (2S) -2- (5-chloro-2- oxo-2, 3-dihydro-lH-indol-l-yl) propanamide.
• R is hydrogen, Ci_ 2 o alkyl, C3-8 cycloalkyl, halogen, hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, guanidine, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfmyl, arylsulfinyl, aryl or heterocycle;
• R 2 is hydrogen, Ci_ 2 o alkyl, alkoxy, amino, halogen, hydroxy, ester, amido, nitro, cyano, carbamate, or aryl;
• R 3 is hydrogen, Ci_ 2 o alkyl, alkoxy, amino, halogen, hydroxy, ester, amido, nitro, cyano, carbamate, or aryl;
• R 2 and R 3 can form together with the imidazole ring the following 1H- benzimidazole cycle
• R 4 is hydrogen, Ci_ 2 o alkyl, C 2 _i 2 alkenyl, C 2 _i 2 alkynyl, aryl, azido, alkoxy carbonylamino, arylsulfonyloxy or heterocycle;
• R 4a is hydrogen or Ci_ 20 alkyl
• R 4 and R 4a can form together a C 3 _ 8 cycloalkyl
• R 5 is hydrogen
• R 4 , R 4a and R 5 can form together with the 2-oxo-l -pyrrolidine ring the following l ,3-dihydro-2H-indol-2-one cycle
• R 6 is hydrogen or Ci_ 2 o alkyl
• R 7 is hydrogen
• R 6 and R 7 are linked together to form a C 3 _ 6 cycloalkyl
• R 8 is hydrogen, halogen, nitro, cyano, Ci_ 20 alkyl or alkoxy;
• R 9 is hydrogen, Ci_ 2 o alkyl, halogen, hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfmyl or arylsulfinyl;
• R 10 is hydrogen, Ci_ 20 alkyl, halogen, hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfmyl or arylsulfinyl;
• R 11 is hydrogen, halogen, nitro, cyano, Ci_ 2 o alkyl or alkoxy;
• R 12 is hydrogen or halogen
• R is hydrogen, nitro, halogen, heterocycle, amino, aryl, Ci_ 2 o alkyl unsubstituted or substituted by halogen, or alkoxy unsubstituted or substituted by halogen;
• R 14 is hydrogen, Ci_ 20 alkyl or halogen
• R 15 is hydrogen, Ci_ 2 o alkyl or halogen
• R 4 is different from hydrogen when represents a group of formula
• the asterisk * indicates the point of attachment of the substituents.
• the compounds have the formula I, their tautomers, geometrical isomers (including cis and trans, Z and E isomers), enantiomers, diastereoisomers and mixtures thereof (including all possible mixtures of stereoisomers), or pharmaceutically acceptable salts thereof,
• R 1 is hydrogen, Ci_ 2 o alkyl, C3-8 cycloalkyl, halogen, hydroxy, ester, amido, cyano, nitro, amino, guanidine, alkylthio, alkylsulfonyl, alkylsulfmyl, aryl or heterocycle;
• R 2 is hydrogen, Ci_ 20 alkyl, halogen, cyano, ester, carbamate or amido;
• R 3 is hydrogen, cyano, Ci_ 2 o alkyl, halogen or ester; or R 2 and R ? can form together with the imidazole ring the following benzimidazole cycle
• R 4 is hydrogen, Ci_ 2 o alkyl, C 2-12 alkenyl or aryl;
• R 4a is hydrogen
• R 5 is hydrogen
• R 4 , R 4a and R 5 can form together with the 2-oxo-l -pyrrolidine ring the following l ,3-dihydro-2H-indol-2-one cycle
• R 6 is hydrogen or Ci_ 2 o alkyl
• R 7 is hydrogen; or R 6 and R 7 are linked together to form a C3-6 cycloalkyl; R 8 is hydrogen;
• R 9 is hydrogen, Ci_ 2 o alkyl, halogen or alkoxy
• R 10 is hydrogen, Ci_ 2 o alkyl, halogen or cyano
• R 11 is hydrogen
• R 12 is hydrogen or halogen
• R 13 is hydrogen, halogen, heterocycle or Ci_ 2 o alkyl
• R 14 is hydrogen
• R 15 is hydrogen; with the proviso that R 4 is different from hydrogen when
• alkyl represents saturated, monovalent hydrocarbon radicals having straight (unbranched) or branched or cyclic or combinations thereof and containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more pre preferred alkyl groups have 1-3 carbon atoms.
• Alkyl moieties may optionally be substituted by 1 to 5 substituents independently selected from the group consisting of halogen, hydroxy, cyano, azido, aryloxy, alkoxy, alkythio, alkanoylamino, arylcarbonylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl or aryl.
• alkyl groups in the present case, are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, 1-ethylpropyl, n-heptyl, 2,4,4-trimethylpentyl, n-decyl, chloromethyl, trifluoromethyl, 2-bromo-2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3- trifluoropropyl, hydroxymethyl, cyanomethyl, azidomethyl,
• alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, 1- ethylpropyl, 2,4,4-trimethylpentyl, chloromethyl, trifluoromethyl, 2,2,2- trifluoroethyl, hydroxymethyl, cyanomethyl, azidomethyl,
• alkyl groups are methyl, ethyl, n-propyl, i- propyl, n-butyl, azidomethyl or trifluoromethyl. Most preferred alkyl groups are methyl or n-propyl.
• cycloalkyl represents a monovalent group of 3 to 8 carbon atoms, usually 3-6 carbon atoms derived from a saturated cyclic hydrocarbon, which may be substituted by any suitable group including but not limited to one or more moieties selected from groups as described above for the alkyl groups.
• Preferred cycloalkyl groups are cyclopropyl and cyclohexyl.
• alkenyl represents straight, branched or cyclic unsaturated hydrocarbon radicals or combinations thereof having at least one carbon-carbon double bond, containing 2-12 carbon atoms, preferably usually 2-4 carbon atoms.
• Alkenyl groups are being optionally substituted with any suitable group, including but not limited to one or more moieties selected from groups as described above for the alkyl groups.
• an alkenyl group is ethenyl (vinyl) optionally substituted by 1 to 3 halogens.
• Preferred alkenyl group in the present case, is 2, 2-difluorovinyl.
• alkynyl represents straight, branched or cyclic hydrocarbon radicals or combinations thereof containing at least one carbon- carbon triple bond, containing 2-12 carbon atoms, preferably 2-6 carbon atoms, and being optionally substituted by any suitable group, including but not limited to one or more moieties selected from groups as described above for the alkyl groups.
• an alkynyl group is a halogenoalkynyl group
• Groups qualified by prefixes such as "s”, “i”, “t” and the like are branched derivatives.
• aryl as used herein, is defined as phenyl optionally substituted by 1 to 4 substituents independently selected from halogen, cyano, alkoxy, alkylthio, Ci_ 3 alkyl or azido, preferably halogen or azido.
• aryl groups in the present case are phenyl, 3-chlorophenyl, 3 -fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4- fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5- trifluorophenyl, 3,4,5-trifluorophenyl, 3-azido-2,4-difluorophenyl or 3-azido- 2,4,6-trifluorophenyl.
• aryl groups are phenyl, 3-chlorophenyl, 3- fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5- difluorophenyl, 3-chloro-4-fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5- trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl or 3-azido-2,4- difluorophenyl.
• aryl groups are phenyl, 3-chlorophenyl, 3- fluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl.
• heterocycle is defined as including an aromatic or non aromatic cycloalkyl moiety as defined above, having at least one O, S and/or N atom interrupting the carbocyclic ring structure.
• Heterocyclic ring moieties can be optionally substituted by alkyl groups or halogens and optionally, one of the carbon of the carbocyclic ring structure may be replaced by a carbonyl.
• heterocycles are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-tetrahydrofuranyl, lH-pyrrol-2-yl, 1 -methyl- 1H- pyrrol-2-yl, lH-pyrazol-2-yl, lH-pyrazol-3-yl, 4-chloro-l -methyl- lH-pyrazol- 3-yl, 5 -chloro- 1,3 -dimethyl- lH-pyrazol-4-yl, l,2,3-thiadiazol-4-yl, 3,5- dimethyl-4-isothiazyl, lH-imidazol-2-yl, 1 -methyl- lH-imidazol-2-yl, 4- methyl-lH-imidazol-5-yl, or 2-methyl-l,3-thiazol-4-yl.
• Preferred heterocycles are lH-imidazol-2-yl, l,2,3-thiadiazol-4-yl, lH-pyrazol-3-yl, 2-furyl, 3-furyl, 2-thienyl, 1 -methyl- lH-pyrrol-2-yl, lH-pyrrol-2-yl.
• halogen includes an atom of chlorine, bromine, fluorine, iodine. Usually halogens are chlorine, bromine and fluorine. Preferred halogens are fluorine, bromine and chlorine.
• hydroxy represents a group of formula—OH.
• alkoxy represents a group of formula -OR a wherein R a is an alkyl group, as defined above. Preferred alkoxy group is methoxy.
• aryloxy represents a group of formula— OR b wherein R b is an aryl group, as defined above. Preferred aryloxy group is phenoxy.
• ester represents a group of formula— COOR c wherein R c is an alkyl group or aryl group, as defined above. Preferred ester group is methoxy carbonyl.
• ester represents a group of formula— CONH 2 .
• amino represents a group of formula ⁇ NH 2 .
• amino acid represents an alkylamino or an arylamino group, wherein the terms “alkyl” and “aryl” are defined as above.
• cyano represents a group of formula --CN.
• nitro represents a group of formula -N0 2 .
• azido represents a group of formula ⁇ N 3 .
• alkylthio represents a group of formula— SR d wherein R d is an alkyl group, as defined above.
• Preferred alkylthio group is methylthio.
• alkylsulfonyl group is methylsulfonyl.
• alkylsulfinyl represents a group of formula - f f
• R is an alkyl group, as defined above.
• Preferred alkylsulfinyl group is methylsulfmyl.
• arylthio represents a group of formula— SR g wherein R g is an aryl group, as defined above.
• arylsulfinyl represents a group of the formula— S ⁇ C ⁇ R 1 wherein R 1 is an aryl group, as defined above.
• N(H)C(0)OR J wherein R J is an alkyl or an aryl, as defined above.
• carbamate groups are (propoxycarbonyl)amino or (benzyloaxycarbonyl)amino.
• Preferred carbamate group is (benzyloaxycarbonyl)amino.
• Preferred (arylcarbonyl)amino is benzoylamino.
• R 1 is hydrogen; C 1-10 alkyl unsubstituted or substituted by halogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; hydroxy; C3-6 cycloalkyl; halogen; ester; amido; nitro; cyano; amino; phenyl; alkylthio;
• R 1 is hydrogen; methyl; ethyl; i-propyl; n- propyl; cyclopropyl; n-butyl; i-butyl; t-butyl; 1-ethylpropyl; 2,4,4- trimethylpentyl; hydroxymethyl; chloromethyl; trifluoromethyl; 2,2,2- trifluoroethyl; cyanomethyl; 2-(methylthio)ethyl; chloro; bromo; nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio; methylsulfmyl;
• R 1 is hydrogen; methyl; ethyl; i-propyl; n-propyl; n-butyl; methylthio; nitro; cyano; amino; chloro or lH-pyrrol-2-yl.
• R 1 is hydrogen; methyl; methylthio; nitro; cyano; amino or chloro.
• R 2 is hydrogen; Ci_ 4 alkyl unsubstituted or substituted by hydroxy, alkanoylamino or benzoylamino; halogen; ester; cyano; alkyl carbamate; [(N- methoxy-N-methyl)amino]carbonyl.
• R 2 is hydrogen; methyl;
• R 2 is hydrogen; chloro or cyano.
• R 3 is hydrogen; Ci_ 4 alkyl unsubstituted or substituted by hydroxy; halogen; ester or cyano.
• R 3 is hydrogen; hydroxymethyl; chloro; cyano. More preferably, R 3 is hydrogen or cyano. Most preferred R 3 is hydrogen.
• R 4 is hydrogen; Ci_ 4 alkyl unsubstituted or substituted by halogens; C 2 _ 4 alkenyl substituted by halogens or phenyl group unsubstituted or substituted by azido or/and halogens.
• R 4 is hydrogen; n-propyl; 2,2- difluoro vinyl; phenyl; 3-chlorophenyl; 3 -fluorophenyl; 4-chlorophenyl; 4- fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5- trifluorophenyl; 3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trifluorophenyl.
• R 4 is hydrogen; n-propyl; 2,2-difluorovinyl; phenyl; 3- chlorophenyl; 3 -fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5- difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4- trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5- trifluorophenyl or 3-azido-2,4-difluorophenyl.
• R 4 is n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3 -fluorophenyl; 3,5-difluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5- trifluorophenyl or 3-azido-2,4-difluorophenyl.
• R 4a is hydrogen
• R 5 is hydrogen
• R 6 is hydrogen or Ci_i 0 alkyl unsubstituted or substituted by hydroxy or azido.
• R 6 is hydrogen or azidomethyl. More preferably R 6 is hydrogen.
• R 7 is hydrogen
• R 6 and R 7 are linked to form a
• R 2 and R 3 can form together with the imidazole ring the following lH-benzimidazole cycle
• R 8 is hydrogen
• R 9 is hydrogen; halogen; Ci_ 3 alkyl or alkoxy.
• R 9 hydrogen; methyl; chloro or methoxy. More preferred R 9 is hydrogen.
• R 10 is hydrogen; halogen; cyano; Ci_ 3 alkyl unsubstituted or substituted by halogens; or alkoxy.
• R 10 is methyl; hydrogen; trifluoromethyl; fluoro; cyano or methoxy. More preferred R is hydrogen; trifluoromethyl; fluoro or cyano.
• R 11 is hydrogen
• R 4 , R 4a and R 5 can form together with tl 2-oxo-l -pyrrolidine ring the following l,3-dihydro-2H-indol-2-one cycle
• R 12 is hydrogen or halogen.
• R 12 is hydrogen; chloro or fluoro. More preferred R 12 is hydrogen.
• R 13 is hydrogen; Ci_ 3 alkyl; halogen or thiazolyl unsubstituted or substituted by alkyl groups, such as methylthiazolyl.
• R 13 is hydrogen; chloro; bromo or methyl.
• Most preferred R 13 is chloro; bromo or methyl.
• R 14 is hydrogen.
• R 15 is hydrogen
• Combinations of one or more of these preferred compound groups are especially preferred.
• the compounds of formula I, or pharmaceutically acceptable salts thereof are those wherein
• R 1 is selected from hydrogen; C 1-10 alkyl unsubstituted or substituted by halogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; C 3 _ 6 cycloalkyl; halogen; ester; amido; nitro; cyano; amino; phenyl; alkylthio; alkylsulfonyl; alkylsulfmyl; heterocycle unsubstituted or substituted by alkyl group; or guanidine;
• R 2 is selected from hydrogen; Ci_ 4 alkyl unsubstituted or substituted by hydroxy, alkanoylamino or benzoylamino; halogen; ester; cyano; alkyl carbamate or [(N-methoxy-N-methyl)amino]carbonyl.
• R is selected from hydrogen; C 1-4 alkyl unsubstituted or substituted by hydroxy; halogen; ester or cyano;
• R 4 is selected from hydrogen; Ci_ 4 alkyl unsubstituted or substituted by halogens; C 2-4 alkenyl substituted by halogens or phenyl group unsubstituted or substituted by azido or /and halogens;
• R 4a is hydrogen
• R 5 is hydrogen
• R 6 is selected from hydrogen or C 1-10 alkyl unsubstituted or substituted by hydroxy or azido;
• R 7 is hydrogen
• R 6 and R 7 can be linked to form a cyclopropyl
• R 2 and R 3 can form together with the imidazole ring the following 1H- benzimidazole cycle
• R 8 is hydrogen
• R 9 is selected from hydrogen; halogen; Ci_ 3 alkyl; alkoxy;
• R 10 is selected from hydrogen; halogen; cyano or Ci_ alkyl unsubstituted or substituted by halogens; or alkoxy;
• R 11 is hydrogen
• R 4 , R 4a and R 5 can form together with the 2-oxo-l -pyrrolidine ring the following l,3-dihydro-2H-indol-2-one cycle
• R 12 is selected from hydrogen or halogen
• R 13 is selected from hydrogen; Ci_ 3 alkyl; halogen; thiazolyl unsubstituted or substituted by alkyl groups, such as methylthiazolyl;
• R 14 is hydrogen
• R 15 is hydrogen
• R 1 is selected from hydrogen; methyl; ethyl; i-propyl; n-propyl;
• R 2 is selected from hydrogen; methyl; hydroxymethyl;
• R 3 is selected from hydrogen; hydroxymethyl; chloro; cyano; or R 2 and R 3 can form together with the imidazole ring the following 1H- benzimidazole cycle
• R 8 is hydrogen
• R 9 is selected from hydrogen; methyl; choro; methoxy;
• R 10 is selected from methyl; hydrogen; trifluoromethyl; fluoro; cyano; or methoxy;
• R 11 is hydrogen
• R 4 is selected from hydrogen; n-propyl; 2,2-difluorovinyl; phenyl; 3- chlorophenyl; 3 -fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5- difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4- trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5- trifluorophenyl; 3-azido-2,4-difluorophenyl; or 3-azido-2,4,6-trifluorophenyl.
• R 4 , R 4a and R 5 can form together with the 2-oxo-l -pyrrolidine ring the following l,3-dihydro-2H-indol-2-one cycle
• R 12 is selected from hydrogen; chloro; fluoro;
• R 13 is selected from hydrogen; chloro; bromo; methyl;
• R 14 is hydrogen
• R 6 is selected from hydrogen; azidomethyl
• R 7 is hydrogen; or R 6 and R 7 are linked to form a cyclopropyl;
• the compounds of formula I, or pharmaceutically acceptable salt thereof are those wherein
• R 1 is selected from hydrogen; methyl; ethyl; i-propyl; n-propyl; n-butyl; methylthio; nitro; cyano; amino; chloro; or lH-pyrrol-2-yl;
• R 2 is selected from hydrogen; chloro; cyano;
• R is selected from hydrogen; cyano;
• R 2 and R 3 can form together with the imidazole ring the following 1H benzimidazole cycle
• R is hydrogen
• R 9 is hydrogen
• R 10 is selected from hydrogen; trifluoromethyl; fluoro; cyano;
• R 11 is hydrogen
• R 4 is selected from hydrogen; n-propyl; 2,2-difluorovinyl; phenyl; 3- chlorophenyl; 3 -fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5- difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4- trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5- trifluorophenyl; or 3-azido-2,4-difluorophenyl;
• R 4a is hydrogen
• R 5 is hydrogen
• R 4 , R 4a and R 5 can form together with the 2-oxo-l -pyrrolidine ring the following l,3-dihydro-2H-indol-2-one cycle
• R 12 is hydrogen
• R 13 is selected from methyl; chloro; bromo;
• R 14 is hydrogen
• R 6 is hydrogen
• R 7 is hydrogen
• the compounds of formula I, or pharmaceutically acceptable salt thereof are those wherein R 1 is selected from hydrogen; methyl; methylthio; nitro; cyano; amino; chloro;
• R 2 is selected from hydrogen; chloro; cyano;
• R 3 is hydrogen
• R 4 is selected from n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3- fluorophenyl; 3,5-difluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl; 3-azido-2,4-difluorophenyl;
• R 4a is hydrogen
• R 5 is hydrogen
• R 4 , R 4a and R 5 can form together with the 2-oxo-l -pyrrolidine ring the following l,3-dihydro-2H-indol-2-one cycle
• R 12 is hydrogen
• R 13 is selected from chloro; bromo; methyl
• R 14 is hydrogen
• R 6 is hydrogen
• R 7 is hydrogen
• compounds useful in the methods and compositions of this invention are selected from the group consisting of: 1 -(1 H-imidazol- 1- ylmethyl)pyrrolidin-2-one; 1-(1 H-imidazol- l-ylmethyl)-4-phenylpyrrolidin-2- one; 4-(3-azido-2,4,6-trifluorophenyl)- 1 -( 1 H-imidazol- 1 -ylmethyl)pyrrolidin- 2— one; 1-(1 H-imidazol- l-ylmethyl)-4-propylpyrrolidin-2-one; (-)-4-(3-azido- 2,4-difluorophenyl)- 1 -( 1 H-imidazol- 1 -ylmethyl)pyrrolidin-2- -one; (+)-4-(3 - azido-2,4-difluorophenyl)- 1 -( 1 H-imidazol- 1 - 1 -
• compounds useful in the methods and compositions of this invention are selected from the group consisting of: 1 -(1 H-imidazol- 1- ylmethyl)pyrrolidin-2-one, 1 -( 1 H-imidazol- 1 -ylmethyl)-4-phenylpyrrolidin-2- one; 1-(1 H-imidazol- l-ylmethyl)-4-propylpyrrolidin-2-one; (-)-4-(3-azido-2,4- difluorophenyl)- 1 -( 1 H-imidazol- 1 -ylmethyl)pyrrolidin-2- -one; (+)-4-(3 -azido- 2,4-difluorophenyl)- 1 -(1 H-imidazol- 1 -ylmethyl)pyrrolidin-2-one; 1 -[(2-ethyl- 1 H-imidazol- 1 -yl)methyl] -4-propylpyrrol
• compounds useful in the methods and compositions of this invention are selected from the group consisting of: 1 -(1 H-imidazol- 1- ylmethyl)-4-phenylpyrrolidin-2-one; 1 -( 1 H-imidazol- 1 -ylmethyl)-4- propylpyrrolidin-2-one; (-)-4-(3-azido-2,4-difluorophenyl)-l-(lH-imidazol-l- ylmethyl)pyrrolidin-2- -one; (+)-4-(3 -azido-2,4-difluorophenyl)- 1 -( 1 H- imidazol- 1 -ylmethyl)pyrrolidin-2-one; 4-(2,2-difluorovinyl)- 1 -( 1 H-imidazol- 1 - ylmethyl)pyrrolidin-2-on- e; 4-(3-chlorophenyl)-l-(
• compounds useful in the methods and compositions of this invention are selected from the group consisting of: (-)-4-(3-azido-2,4- difluorophenyl)- 1 -( 1 H-imidazol- 1 -ylmethyl)pyrrolidin-2- -one; (+)-4-(3 -azido- 2,4-difluorophenyl)- 1 -( 1 H-imidazol- 1 -ylmethyl)pyrrolidin-2-one; 4-(3 -azido- 2,4-difluorophenyl)- 1 -( 1 H-imidazol- 1 -ylmethyl)pyrrolidin-2-one .
• R 1 is hydrogen or Ci_ 6 alkyl
• R 2 is hydrogen or Ci_ 4 alkyl
• R 3 is a group of formula -CHR 5 R 6 or a benzyl group
• R 4 is Ci_8 alkyl optionally substituted by alkoxycarbonyl, C3-6 cycloalkyl, aryl or heterocycle;
• R 5 is C2-4 alkyl
• R 6 is C2-4 alkyl, amido or -COOR 7 ;
• R is CI -4 alkyl;
• R 4 is Ci_g alkyl optionally substituted by alkoxycarbonyl.
• R 4 is Ci_g alkyl optionally substituted by C3-6 cycloalkyl, aryl or heterocycle.
• alkyl is a group which represents saturated, monovalent hydrocarbon radicals having straight (unbranched) or branched moieties, or combinations thereof, and containing 1-8 carbon atoms, preferably
• alkyl moieties may optionally be substituted by 1 to 5 substituents independently selected from the group consisting of hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl, acyl, aryl or heterocycle. Alkyl moieties may be optionally substituted by a cycloalkyl as defined hereafter.
• Preferred alkyl groups are methyl, cyanomethyl, ethyl, 2-ethoxy-2-oxoethyl, 2- methoxyethyl, n-propyl,
• More preferred alkyl groups are methyl, ethyl, cyanomethyl, 2-methoxy ethyl, n-propyl, 3- hydroxypropyl, 2-propynyl, n-butyl, 3-pentyl, n-hexyl, benzyl, 3-bromobenzyl, 3- methoxybenzyl, 3- nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl or (5-nitro- 2- furyl)methyl.
• Most preferred alkyl groups are methyl, ethyl, 3-methoxybenzyl,
• cycloalkyl represents a monovalent group of 3 to 8, preferably 3 to 6 carbon atoms derived from a saturated cyclic
• hydrocarbon which may be substituted by any suitable group including but not limited to one or more moieties selected from groups as described above for the alkyl groups.
• Preferred cycloalkyl group is cyclohexyl.
• aryl as used herein, is defined as a phenyl group optionally substituted by 1 to 4 substituents independently selected from halogen, amino, nitro, alkoxy or aminosulfonyl.
• Preferred aryl groups are phenyl, 2- bromophenyl, 3-bromophenyl, 4- bromophenyl, 3-methoxyphenyl, 3- nitrophenyl, 3-aminophenyl or 4-(aminosulfonyl)phenyl.
• phenyl represents an aromatic hydrocarbon group of formula -C 6 H 5 .
• benzyl group represents a group of formula - CH 2 -aryl.
• Preferred benzyl groups are benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3- methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl or 4- (aminosulfonyl)benzyl.
• More preferred benzyl groups are benzyl, 3- bromobenzyl, 3 -methoxybenzyl, 3-nitrobenzyl or 3- aminobenzyl.
• Most preferred alkyl groups are 3 -methoxybenzyl or 3-nitrobenzyl.
• halogen represents an atom of fluorine, chlorine, bromine, or iodine. Preferred halogen is bromine.
• hydroxy represents a group of formula -OH.
• cyano represents a group of formula -CN.
• amino represents a group of formula -NH 2 .
• ethynyl represents a group of formula -C ⁇ CH.
• alkoxy represents a group of formula -OR a wherein R a is an alkyl group, as defined above. Preferred alkoxy group is methoxy.
• nitro represents a group of formula -N0 2 .
• alkoxycarbonyl (or ester) represents a group of formula -COOR 0 wherein R c is an alkyl group; with the proviso that R c does not represent an alkyl alpha-substituted by hydroxy.
• Preferred alkoxycarbonyl group is ethoxycarbonyl.
• heterocycle represents a 5-membered ring containing one or two heteroatoms selected from O or N.
• the heterocycle may be substituted by one or two Ci_ 4 alkyl or nitro.
• Preferred heterocycles are (3, 5-dimethylisoxazol-4-yl) or (5-nitro- 2-furyl). Most preferred heterocycle is (5- nitro-2-furyl).
• R 1 is hydrogen or Ci_ 6 alkyl.
• R 1 is hydrogen or Ci_ 6 alkyl optionally substituted by hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl or acyl.
• R 1 is hydrogen, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl, 2- methoxy ethyl, n- propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-pentyl or n-hexyl.
• R 1 is hydrogen, methyl, cyanomethyl, 2- methoxyethyl, n-propyl, 3-hydroxypropyl or 2- propynyl.
• R 1 is hydrogen.
• R 2 is hydrogen or Ci_ 4 alkyl. Usually R 2 is hydrogen or unsubstituted Ci_ 4 alkyl. Preferably R 2 is hydrogen, methyl or n-butyl. More preferably, R 2 is methyl.
• R 3 is a group of formula -CHR 5 R 6 or a benzyl group.
• R 3 is 3-pentyl, l-(aminocarbonyl)propyl, l-(ethoxycarbonyl)propyl or 3- bromobenzyl.
• R 3 is l-(ethoxycarbonyl)propyl.
• R 4 is Ci_g alkyl optionally substituted by alkoxycarbonyl, C3-6 cycloalkyl, aryl or heterocycle.
• R 4 is Ci_ 8 alkyl optionally substituted by cyclohexyl, phenyl, bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl, aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl or ethoxycarbonyl.
• R 4 is n-butyl, i-butyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2- bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3- methoxybenzyl, 3-nitrobenzyl, 3- aminobenzyl, 4-(aminosulfonyl)benzyl, 1- phenylethyl, 2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2- furyl)methyl or l-(ethoxycarbonyl)propyl.
• R 4 is n- butyl, n- hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3- aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl or 1 - (ethoxycarbonyl)propyl. Most preferably R 4 is 3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl.
• R 5 is C 2 _ 4 alkyl. Usually R 5 is unsubstituted C 2 _ 4 4 alkyl.
• R 5 is ethyl.
• R 6 is C 2 _ 4 alkyl, amido or -COOR 7 .
• R 6 is unsubstituted C 2 _4 alkyl, amido or -COOR 7 .
• R 6 is ethyl, amido or ethoxycarbonyl. Most preferably R 6 is ethoxycarbonyl.
• R 7 is Ci_ 4 alkyl. Usually R 7 is unsubstituted Ci_ 4 alkyl.
• R 7 is ethyl
• the compounds are those having formula I, and their enantiomers, diastereoisomers and mixtures thereof (including all possible mixtures of stereoisomers), or pharmaceutically acceptable salts thereof,
• R 1 is hydrogen, Ci_ 6 alkyl optionally substituted by hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl or acyl;
• R 2 is hydrogen or unsubstituted Ci_ 4 alkyl
• R 3 is a group of formula -CHR 5 R 6 or a benzyl group
• R 4 is Ci_8 alkyl optionally substituted by cyclohexyl, phenyl, bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl, aminosulfonylphenyl, 3,5- dimethylisoxazol-4-yl, 5-nitro-2-furyl or ethoxycarbonyl;
• R 5 is unsubstituted C 2 _ 4 alkyl
• R 6 is unsubstituted C 2 _ 4 alkyl, amido or -COOR 7 ;

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