Title of Invention

NOVEL N-SPIRO SUBSTITUTED COMPOUNDS

Abstract

Abstract: Disclosed herein are novel N-Spiro substituted compounds, which are derivatives of the inhibitory neurotransmitter GABA (y-aminobutyric acid), represented by formula I, process for preparing these compounds and pharmaceutical use thereof as therapeutic agents in the treatment of epilepsy and neuropathic pain syndromes and their progression. Formula I wherein, n is 0,1,2 and 3 R is hydrogen, halo or straight or branched alkyl from 1 to 6 carbons. Ri is hydrogen or alkyl from 1 to 6 carbons, unsubstituted phenyl or halo, nitro, amino or alkyl substituted phenyl. R2 is hydrogen or alkyl from 1 to 6 carbons or unsubstituted phenyl or halo, nitro, amino or alkyl substituted phenyl, or Ri and R2 may form together unsubstituted isatinyl or halo or alkyl substituted isatinyl or cycloalkyl from 3 to 8 carbons.

Full Text

Technical field of the invention: The present invention relates to novel N-Spiro substituted compounds and intermediates thereof. More specifically the present invention relates to novel N-Spiro substituted derivatives of the inhibitory neurotransmitter GABA (-y-aminobutyric acid) represented by formula I, intermediates thereof, process for preparing these compounds and pharmaceutical use thereof, for the treatment of epilepsy and various neuropathic pain conditions. Wherein, n is 0,1,2 and 3; R is hydrogen, halo or straight or branched alkyl from 1 to 6 carbons; Ri is hydrogen or alkyl from 1 to 6 carbons, unsubstituted phenyl or halo, nitro, amino or alkyl substituted phenyl; . . R2 is hydrogen or alkyl from 1 to 6 carbons or unsubstituted phenyl or halo, nitro, amino or alkyl substituted phenyl; or Ri and R2 may form together unsubstituted isatinyl or halo or alkyl substituted isatinyl or cycloalkyl from 3 to 8 carbons. Background and prior art of the invention: Epilepsy is the most common primary neurological disorder known, affecting 0.4-0.8% of the population and up to 50 million people worldwide. It is a collective term given to a ■ group of syndromes that involve spontaneous, intermittent, abnormal electrical activity in the brain, which manifest as seizures. According to Treiman, D.M. epileptic seizures can be thought' of as paroxysmal, hypcrsynchrdnous, transient electrical discharges in the brain that result from too much '. excitation or too little inhibition in the area, in which the abnormal discharge starts :-(Treiman, D.M. Epilepsia, 2001, 42 (Suppl. 3), 8-12). The serendipitous discovery of ;' Phenobarbital, in 1912 marked the beginning of the modern pharmacotherapy of epilepsy. In the 70 years that ensued later, Phenytoin, Carbamazepine, Ethosuximide, Sodium. ;-valproate and a range of benzodiazepines became available and can be regarded as "established" antiepileptic drugs (AEDs). In the past decade, nine new agents have been licensed as add-on treatment for difficult-to-control type of epilepsies (Brodie, MJ. and Dichter, M.A.N. N. Engl. J. Med. 1996,334,168). Still more are under evaluation. A number of experimental and clinical sources provide strong support for a role of GABA in the mechanism and treatment of epilepsy. Some of the findings include 1) ■■ abnormalities of GABAergic function in various genetic and acquired animal models of epilepsy (Olsen et al. Proc. Natl. Acad. Sci. USA. 1985, 82, 67,01-6705); 2) GABA :' agonists suppress seizures and GABA antagonists produce seizures; 3) drugs that increase synaptic GABA by inhibiting GABA catabolism or reuptake, are effective !' anticonvulsants (Penry et al. Epilepsia, 1993, 34 (Suppl. 6), 67; Uthman et at. Arch. Neurol. 1998,55,56-62). Neuropathic pain can be described as pain associated with damage, or permanentL* alteration of the peripheral or central nervous system by Loughhead et al. in US 6262078 " Bl. It is a complex disorder resulting from injury to the nerve or to certain areas of the spinal cord or brain. In contrast to acute nociceptive pain (which! usually persists only.' while the injury is present), the cascade of events, that arise following peripheral nerve injury leads to a maintained abnormality in the sensory system, resulting in an abnormal -■ pain phenomenon that can be grossly debilitating. ri Neuropathic pain is commonly associated with several distinct characteristics. First, there ( are often abnormal or unfamiliar, unpleasant sensations, called dysesthesias, that include shooting, lacerating or burning pain, which occurs in the absence of ongoing tissues damage. Second, stimuli that are normally non painful often cause pain, a condition called 3 allodynia. Finally, neuropathic pain is characterized by hyperalgesia, a condition where the pain message from a normally noxious event is exacerbated, so that a much greater intensity of pain is felt (Munro et al. Trends in Pharmacol. Sci. 2003. 24, 555-557). At present, there are very few effective and well tolerated therapies for neuropathic pain. . The development of animal models and constant progress in understanding the basic pathophysiology of neuropathic pain has led to the introduction of adjuvant analgesics, such as AEDs (Laughlin et al. J. Pharmacol. Exp. Ther. 2002, 302, .1168-1175). Most of these agents are use-dependent inhibitors of Na+ channels. Some of the clinically used drugs include Phenytoin, Lamotrigine and Carbamazepine. According to Rani et al., increase in the 5-HT level affects the pain modulating system in the brain. Hence, apart from the conventionally used antidepressants, a growing interest in the use of selective serotonin-reuptake inhibitors (SSRIs), for the treatment of various pain syndromes is now seen (Rani et al. Anesih. Analg. 1996, 83, 371-375). Modulation of Ca:+ channels is another useful approach for the treatment of neuropathic pain. In particular, the modulation of N-type Ca2+ channels, which are expressed primarily in central and peripheral nervous tissues, has been the subject of greatest interest (Hu et al. Bioorg. Med. Chem. Lett. 1999, 9, 2151-2156). As a result of the above-mentioned pharmacological findings, world-wide research has:' focused on the development of derivatives of the inhibitory neurotransmitter GABA. Various GABA derivatives have been published in the patent and non-patent literature. ■P One of the pioneering efforts in the area of research on GABA analogues was the discovery that baclofen, a GABA analogue could be considered a prototype for GABAB receptor agonists. Baclofen was first synthesized in 1962, by the CIBA chemist Heinrich Keberle and was shown to exert potent muscle-relaxant and analgesic properties (Froestl et al. IL Farmaco, 2003, 58, 173-183). A report from Bowery et al. (Pharmacol. Rev., 54, 247-264, 2002) holds baclofen as an invaluable pharmacological tool in elucidating the role of GABAB receptors in several disorders including epilepsy, cognition, pain, and addiction. Other GABA analogs reported to have anticonvulsant activities include, cyclic amino acids such as Nipecotic acid, Guvacine, and homo-P-proline (Nielsen et al. J. Med. Chem. 1990, 33, 71-77). Gabapentin and Pregabalin are the recent marketed drugs having 4 anticonvulsant, anxiolytic-like and analgesic actions (Bryans et al. Med. Res. Rev. 1999, 19, 149-177). Gabapentin, which was developed earlier for the treatment of partial seizures, was also found to be active in the treatment of postherpetic neuralgia (a type of neuropathic pain) and in several preclinical models of neuropathic pain (Field et al. Br. J. Pharmacol. 1997, 121, 1513-1522). Pregabalin have shown promising antiepileptic and antinociceptive effects in various animal models of neuropathic pain in preclinical studies (Taylor et al. Epilepsy Res. 1993, 14, 11-15; Field et al. Br .J. Pharmacol. 1997, 121, 1513-1522) and has been approved for the treatment of various neuropathic pain conditions. A Spiro compound is a bicyclic organic compound with rings connected through just one atom. The rings can be different in nature or identical, the connecting atom is also called as the Spiro atom, most often a quaternary carbon (Spiro carbon). A number of Spiro compounds were found to have good CNS activity. It was envisaged that these privileged structures could be valuable alternative in the search for new receptor ligands. Structural analogues of Spiro[l,3-dioxane-2,3'-indolin]-2'-one, Spirb[l,3-dithiolane-2,3'-indolin]-2'-one, Spiro[indoline-3,2'-[ 1,3]- oxathiolan]-2-one, and 3,3-dimethoxyindolin-2-one were found to have good anticonvulsant activity (J. Med. Chem. 1988, 31, 1001-1005). r Spirocyclopropyl agents were found to have anticonvulsant activity, when tested against pentylenetetrazole-induced seizures in mice. These agents effectively displaced j5[S]-tert-butylbicyclophosphorothionate (3S[S]-TBPS), a ligand for the picrotoxin binding site of the GABAA/chloride channel, from rat neuronal membranes and 'affected the GABA-mediated current in hippocampal neurons {J. Med. Chem. 1994, 37, 275-286). A series of Spiro analogues of Gabapentin, in which the GABA portion was subjected to conformational constraints, was synthesized in order to investigate the preferred binding conformation of the GABA moiety of Gabapentin. Conformktionally constrained analogues and Gabapentin had similar in vitro and in vivo biological activities at the Gabapentin binding site and in the carrageenan-induced thermal hyperalgesia model respectively. These results suggest that the GABA portion of Gabapentiri may adopt a binding conformation (Receveur et al. Bioorg. Med. Chem. Lett. 1999, 9, 2329 - 2324). i 2-Alkylamino-substituted-l,4-benzoxazinederivatives, a new class of potential neuroprotective agents were synthesized and examined for their intrinsic cytotoxicity and their capacity to inhibit oxidative stress-mediated neuronal degeneration in vitro 3,3- diphenyl-substituted-1,4-benzoxazinederivative, was found |to have potent neuroprotective activity without the manifestation of intrinsic cytotoxicity (J. Med. Chem. 2005,48, 1282-1286). [ Various GABA derivatives have been described earlier for the treatment of epilepsy and neuropathic pain. For example, Patent No(s). US 6833140 B2 (Cundy et al.) and US 6525096 Bl (Silverman et al.) disclose various optionally substituted derivatives of GABA, useful as agents for the treatment of epilepsy. r Baclofen, which could be considered as a prototype for GABAB receptor agonists, was shown to exert potent muscle-relaxant, analgesic and anticonvulsant properties (Froestl et al. IL Farmaco, 2003, 58, 173-183). Conformationally-restricted GABA analogs such as Nipecotic acid, Guvacine, and homo-Ji-proline were shown to have in vitro activity as inhibitors of [3H]-GABA uptake (Nielsen et al. J. Med Chem. 1990,-33, 71-77). In 1999, Bryans et ai. reported Gabapentin and Pregabalin as having anticonvulsant, anxiolytic-like, and analgesic actions (Bryans et al. Med. Res. Rev. 1999, 19, 149-177). These two molecules are currently being used for the treatment of neuropathic pain. US6642398 B2 (Belliotti et al., 2003) discloses a method, wherein the synthesis of mono and disubstituted 3-propyl y-aminobutyric acids was disclosed. In addition to the reported anticonvulsant activity, the compounds were proposed as effective in the treatment of hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, L neuropathological disorders, arthritis, sleep disorders, and gastric damage. In the same year, Belliotti et al. in their another patent US6627771 Bl patented another series of compounds, which are cycloalkyl derivatives of GABA and proved them as having improved activity in models of pain and epilepsy. The DBA/2 mouSe model was employed to test the protection offered by the compounds against sound-induced seizures. i The Spiro functionality has been known for a long time to be present in phytochemicals either in alkaloids, lactones or terpenoids. The Spirocyclic alkaloid (K)-histrionicotoxin isolated from skin extracts of the poison dart frog Dendrobais histrionius found in Columbia, is a very potent nicotinic receptor antagonist (Daly et al. Proc. Nail. Acad. Sci. U.S.A.I971, 68, 1870). The Spiro [pyrrolidin-3,30-indole] ring system is a recurring stnicturat motif in a number of natural products such as vinblastine and vincristine, that function as cytostatics and are of prime importance in cancer chemotherapy (cordell et al. The Alkaloids: Chemistry and Biology; Academic: San Diego, 1998; Vol. 5). Some Spiroheterocycles benzopyrans, which are aldose reductase inhibitors found to be useful as antidiabetics (Eggler et al. Chem. Absir. 1992, 116, 59214q). Several potent reductase inhibitors based on Spirosuccinimide, Spiropyridazine and Spiroazetidine have been reported for the prevention of secondary complications of diabetes (Malamas et al. J. Med. Chem. 1994,37,2059). :. US4181728 by Sarges et al. discloses Spiro-polycyclimidazolidinedione derivatives (2,,3,-dihydro-spiro[imidazolidine-4,4'-[4H]-Naptho[l,2-bJpyran]-2,5-dione, 2\3'- dihydro-spiro-[imidazolidine-4,4'-[4H]-Naptho[I,2-b]thiopyran]-2,5-dione, 2',3'- dihydro-spiro[imidazolidine-4,r-phenalene]-2,5-dione etc), which inhibit aldose reductase and were found to be useful therapeutic agents for the treatment of chronic diabetic complications. Bogeso et al. in their patent US5807855 discloses trans isomers of l-piperazino-1,2-dihydrbindene, when Spiro fused to the piperazine ring, showed potent antagonist action on dopamine Dl receptor and found to be useful in the CNS disorders, such as psychoses, -schizophrenia, anxiety, depression, sleep disturbances, migraine, Parkinson's disease and cocaine abuse. US4024263 by klioze .et al. discloses that l,3-dihydrospiro[isobenzofuran-l,4'-piperidine]s are useful as analgesics, anticonvulsants and antidepressants. These compounds exhibited unanticipated pharmacological activity and low toxicity levels. Ong et al. described methods for preparing Spiro[dibeiiz(b,f)oxepin-pi peri dine] s in their patent US4288623, which are useful as analgesics, tranquilizers and anticonvulsants. Similarly US4198418 by Martin et al. also reported- the same activities of Spiro[cyclohexane-l,P(3'H)-isobenzofuran] compounds. US4292245 discloses 3'-Phenylspiro[cyclohexane-l,r(3'H)-isobenzofuran]-4-one, useful as antidepressants, tranquillizers and anticonvulsants. US 4345081 by Ong et al. describes Spiro[indoline-3,4'-piperidine]s and related compounds. These compounds are useful as antidepressants, anticonvulsants and tranquilizers. Borenstein et al. reported Mannich bases of Spirosuccinimides; in their US patent 4925841, having anticonvulsant, sedative and antileukemic activities. US6043366 (Adam et al.) describes the process for the synthesis of I, 3, 8-Triazaspiro (4,5)decan-4-one derivatives. These compounds and their salts'are having valuable therapeutic properties, as they are agonists and/or antagonists of the Orphanin FQ receptor. They are useful for the treatment of memory and attention deficits, psychiatric, neurological and physiological disorders, amelioration of symptoms of anxiety and stress disorders, depression,' trauma, memory loss due to Alzheimer's disease' or other dementias, epilepsy and convulsions, acute and /or chronic pain conditions and metabolic disorders such as obesity. US7081463 B2 (Battista et al) discloses hydroxy alkyl1 substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives, acting on ORL-lG-protein coupled receptor, were claimed to be useful for the treatment of disorders and conditions such as anxiety, depression, panic, dementia, mania, bipolar disorder, substance abuse, neuropathic pain, chronic pain, acute pain, migraine, asthma, cough, psychosis, epilepsy; hypertension, obesity, Crohn's disease, attention deficit disorder, Alzheimer's disease etc. US7282515 B2 by Meese et al. described Azaspiro compounds and their use as medications for the treatment of chronic, chronic-phlogistic and/or neuropathic pain. 8 US 7338962 B2 by Dolle et al. described the invention relating to Spirocyclic heterocyclic derivatives (including derivatives of Spiro(2H-l-benzopyran-2,4'-piperidincs), pharmaceutical compositions containing these compounds and methods for their pharmaceutical use. The Spirocyclic heterocyclic derivatives are ligands of the 8 opioid receptor and are useful for treating and/or preventing pain, anxiety, gastrointestinal disorders and other 5 opioid receptor mediated conditions. US2004/0077616 (Bennani et al.) described spirocyclopropy lam ides, useful for treating epilepsy, bipolar disorder, psychiatric disorders, migraine, pain or movement disorders and also provide neuroprotection. US 2006/0252812 by Chafeev et al. discloses Spiro-oxindole compounds, useful in treating sodium channel mediated diseases or conditions, such as pain, as well as other diseases and conditions associated with the mediation of sodium channels. Rawson et al. in their patent US 2007/0129388 Al described spirocyclic derivatives, useful as PDE7 inhibitors and have a number of therapeutic applications, particularly in the treatment of pain, especially neuropathic pain. Objects of the present invention: The main object of the present invention is to provide novel N-Spiro substituted compounds, which are derivatives of the inhibitory neurotransmitter GABA of the formula 1 via novel intermediates, having pharmacological properties, including utility for the treatment of epilepsy and various neuropathic pain conditions. Another object of the present invention is to provide a simple process for the preparation of the compounds of the invention. In yet another object, the compounds of the invention have been screened for various pharmacological activities/properties such as anticonvulsive, antinociceptive activities 9 and for effectiveness in relieving the symptoms of physiological and neuropathic pain such as dynamic allodynia, cold allodynia, and mechanical hyperalgesia. Summary of the invention: In accordance with the present invention, there is provided novel N-Spiro substituted compounds. More particularly the present invention provides novel N-Spiro substituted derivatives of the inhibitory neurotransmitter GABA of the formula I, intermediates thereof, process for preparing theses compounds, and pharmaceutical use thereof as therapeutic agents in the treatment of epilepsy and neuropathic pain syndromes and their progression. Wherein, n is 0,1,2 and 3; ■ R is hydrogen, halo or straight or branched alkyl from 1 to 6 carbons; Ri is hydrogen or alkyl from 1 to 6 carbons, unsubstituted phenyl or halo, nitro, amino or alkyl substituted phenyl; R2 is hydrogen or alkyl from 1 to 6 carbons or unsubstituted phenyl or halo, nitro, amino or alkyl substituted phenyl; or R, and R2 may form together unsubstituted isatinyl or halo or alkyl substituted isatinyl or cycloalkyl from 3 to 8 carbons. Nomenclature: The naming and numbering of the compounds of the present invention is illustrated below. 10 For example a compound of formula (I (a) where R, is methyl and R2 is phenyl is named as 4-(7, 9-dioxo-8-azaspiro [4.5} dec-8-yl)-N-phcnylethylidene butanoic acid hydrazide. Brief Description of the Drawings: Figure-1 is a reaction scheme showing the method of preparation of compounds of formula A. Figure-2 is a reaction scheme showing the method of preparation of compounds of formula B. II Figure-3 is a reaction scheme showing the method of preparation of compounds of formula C. Figure-4 is a reaction scheme showing the method of preparation of compounds of formula D. Figure-5 is a reaction scheme showing the method of preparation of compounds of formula E. Figure-6 is a reaction scheme showing the method of preparation of compounds of formula I. Detailed description of the invention: The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. It is not intended to limit the invention to these particular embodiments. As described herein the term "compound" and "active ingredient" means same and are used in the following text interchangeably. According to the present invention, there are provided novel N-Spiro substituted compounds, of the formula I via novel intermediates, as therapeutic agents in the treatment of epilepsy and neuropathic pain syndromes and their progression. In a preferred embodiment, there are provided the novel N-Spiro substituted compounds, which are derivatives of the inhibitory neurotransmitter GABA of Formula I, R is hydrogen, halo or straight or branched alkyl from 1 to 6 carbons; Ri is hydrogen or alky! from 1 to 6 carbons, unsubstituted phenyl or halo, nitro, amino or alkyl substituted phenyl; R2 is hydrogen or alkyl from 1 to 6 carbons or unsubstituted phenyl or halo, nitro, amino or alkyl substituted phenyl; or Ri and R2 may form together unsubstituted isatinyl or halo or alkyl substituted isatinyl or cycloalkyl from 3 to 8 carbons. In another preferred embodiment, the present invention provides a process for the preparation of N-Spiro substituted derivatives of the inhibitory neurotransmitter GABA of the formula I, which comprises following intermediates/stages. The starting materials and reagents used in preparing these compounds are available from commercial suppliers such as Spectrochem and Aldrich Chemical Company. The intermediates may be characterized using conventional means, including physical constants and spectral data. (i)Preparation of a Compound of Formula (A): This step comprises reacting cyclic ketone with ethyl cyanoacetate at 0°C, in presence of excess of ammonia in ethanol and stored at 0-5°C for about 1 week, followed by acidification with HC1 to yield free imide of Formula (A), wherein n is 0,1,2 and 3; R is hydrogen, hafo or straight or branched alkyi from 1 to 6 carbons. (ii)Preparation of a Compound of Formula (B): 14 Vr This Step comprises SOaking compound of formula (A) in sulphuric acid for about 8 hours, followed by addition of water and refluxing the mixture for 15 hours to yield crude reaction product, which was suspended in hot water; followed by addition of potassium bicarbonate and further acidification with concentrated hydrochloric acid to get 1,1-cycloalkane diacetic acid of formula (B), Formula (B) wherein n and R are as defined above. (iii) Preparation of a Compound of Formula (C): This step comprises refluxing 1,1-cycloalkane diacetic acid of formula (B) with acetyl chloride for 3 to 4 hours obtain compound of formula (C), Formula (C) wherein n and R are as defined above. (iv)Preparation of a Compound of Formula (D): This step comprises refluxing Compound of formula (C) and equimolar quantity of GABA (-y-aminobutyric acid) in toluene, in the presence of triethylamine for 3 to 4 hours to obtain compound of formula (D), Formula (E) wherein n and R are as defined above. (vi)Preparation of Compounds of Formula (I): This slep comprises refluxing compound (E) with the corresponding aldehyde or ketone for 4 hours to obtain respective acid hydrazones, Formula (I) wherein n and R are as defined above, Ri is hydrogen or alkyl from 1 to 6 carbons, unsubstituted phenyl or halo, nitro, amino or alkyl substituted phenyl, R2 is hydrogen or alkyl from 1 to 6 carbons or unsubstituted phenyl or halo, nitro, amino or alkyl substituted phenyl, or Ri and R2 may form together unsubstituted isatinyl or halo or alkyl substituted isatinyl or cycloalkyl from 3 to 8 carbons- Unless specified, the reactions described herein take place at atmospheric pressure over a temperature range from about 0°C to about I00°C. Pharmacological screening The compounds of formula I have been found to possess valuable pharmacological properties. They have been shown to be useful as anticonvulsants, after screening in the standard in vivo animal models of seizure. The tests used were the Maximal Electroshock Seizure (MES) threshold test and the subcutaneous Pentylenetetrazole-induced seizure threshold test (scPTZ) (Swinyard et al. FedProc. 1985, 44, 2629-2633). In particular, the compounds of formula I have also been shown to possess good activity in various experimental animal models of physiological and neuropathic pain. The models include, Acetic acid induced writhing model, Formalin induced flinching model, Chronic 17 Constriction Injury (CCl) model, Spinal Nerve Ligation (SNL) model, Infra Orbital Nerve Ligation model (ION) and Diabetic Neuropathy (DNP) model. In physiological pain models, pain was induced by using chemicals like acetic acid and formalin (Quinn H. Regional Anesthesia and Pain Medicine, 2002, 385-401; Steiner Hunskaar Pain, 30, 1987, 103-114 ). Diabetic Neuropathy was induced using intra¬peritoneal injection of Streptozotocin (Field el al, 1998, Pain, 80 1999, 391-398). Neuropathic surgery was done as previously described (Kim and Chung, Pain, 1992, 50, 355-363; Choi et al. Pain, 1994, 59, 369-376; Imamura et al. Brain Research, 1997, 116, 97-103). Behavioral signs of different components of neuropathic pain were measured as previously described in detail (Choi et al. Pain, 1994, 59, 369-376): spontaneous pain, dynamic allodynia, cold allodynia, and mechanical hyperalgesia. In-vivo Assays: The assays determine the effectiveness of compounds of formula I in relieving one of the symptoms of physiological and neuropathic pain in in-vivo models. In Acetic acid induced pain, intra-peritoneal injection of 3% acetic acid was given to mice (n=6), resulting in characteristic behaviors like hunching the back, licking the abdomen, tilting the pelvis, stretching, rubbing the abdomen against the floor etc. The numbers of responses were monitored for 30 minutes. In formalin test (n=6), the injection of a 1% formalin (0.025 ml) was given into subcutaneous tissues, typically the dorsal surface of the rodent paw, that gives flinches of paw in the early phase (0-5 min) and the late phase (10-30 min). Total time lifting, licking and biting were monitored. In rat model of diabetic neuropathy (n=4), 50 mg/kg of Streptozotocin was given to induced neuropathy and behavioral tests like heat hyperalgesia, cold allodynia and radiant heat induced tail flicking were performed from 9Ih day onwards. For neuropathic surgery models (CCl, SNL and ION), rats of 150-200g were taken and a total number of four rats (n=4) were assigned to each group. Briefly, the rats were 18 anesthetized with an intra-peritoneal dose of pentobarbital sodium (65 mg/kg) with additional doses of anesthetic given as needed. In the CCI (Chronic Constriction Injury) model, a 3 cm incision was made on the lateral aspect of the left hindlimb (ipsilateral) at the mid-thigh level, with the right hindlimb serving as the control (contralateral). The left paraspinal muscles were then separated from the spinous processes and the left sciatic nerve was exposed just above the trifurcation point. Four loose ligatures were then made with a 4-0 silk thread along the sciatic nerve each with a 1-2 mm spacing in between. The wound was then closed by suturing the muscle using catgut with a continuous suture pattern. Finally, the skin was sutured using silk thread with horizontal-mattress suture pattern. The animal was then transferred to its home-cage and left for recovery. In the SNL (Spinal Nerve Ligation) model, the L5 spinal nerve was exposed at the level of the dorsal root ganglion, and ligated tightly with a 4-0 silk thread. Only one tight ligature was made in this model. ION (Infra Orbital Nerve) model, which mimics the human secondary trigeminal neuralgia, was performed by making an incision of approximately 1 cm, along the gingivobuccal margin and exposing infra orbital nerve (ION) branch of the trigeminal nerve. Two loose ligations of infra orbital nerve branch leading to chronic constriction injury were made using 4-0 chromic gut suture. Hemostasis was confirmed and the wound was closed. In all these models a sham-operated group was maintained wherein the nerve was exposed, but no manipulation was made on the nerve. The rats demonstrating unilateral mononeuropathy were assessed for allodynia and hyperalgesia sensitivity. Behavioral tests were performed both on the 9* and the 14th day post-surgery. In an another preferred embodiment, the invention discloses a pharmaceutical composition, which comprises an effective amount of a novel N-spiro substituted derivative of y-aminobutyric acid of formula (1) of the present invention in association with at least one pharmaceutical acceptable carrier or adjuvant known in art. The quantity of the compound used in pharmaceutical compositions of the present invention will vary depending upon the body weight of the patient and the mode of administration and can be of any effective amount to achieve the desired therapeutic effect. In another embodiment of the invention, the compounds of formula (1) are administered orally or parenterally, for the treatment or prevention of epilepsy and neuropathic pain syndromes. 'Accordingly, the effective amount as used above is an amount ranging from about 1 mg/kg to 300 mg/kg. Furthermore, A non-neurotoxic anticonvulsant composition, highly effective in the scPTZ (subcutaneous Pentylenetetrazol), scSTY or ipPIC tests (subcutaneous Strychnine and intra-peritoneal Picrotoxin-induced seizure tests) and comprising an anticonvulsive effective amount of the compound of formula (I), as the active ingredient, is provided by the present invention. Still in an another embodiment, use of the novel N-spiro substituted derivative of y-aminobutyric acid of formula (I), for the preparation of medicament useful for the treatment or prevention of epilepsy and various neuropathic pain conditions such, as acute and/or chronic convulsive disorders, neuropathic pain syndromes; and for slowing or delaying the progression of neuropathic pain syndromes and convulsive disorders, is provided by the invention. Further, the use of these novel compounds of formula (I) is provided for the manufacture of a medicament for the treatment of a disorder or condition selected from the group consisting of diseases and conditions in which pain predominates, including acute pain, chronic pain, neuropathic pain, including soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculoskeletal pain, particularly after trauma, spinal pain, dental pain, myofacial pain syndromes; deep and visceral pain such as heart pain, muscle pain, eye pain; orofacial pain, for example, odontalgia, abdominal pain; gynaecological pain, for example, dysmenorrhea, and labor pain; pain associated 20 with nerve and root damage including pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, atypical facial pain, nerve root damage, and arachnoiditis; pain associated with carcinoma, often referred to as cancer pain; central nervous system pain, such as pain due to spinal cord or brain stem damage; low back pain such as sciatica; headache, including migraine, acute or chronic tension headache, cluster headache and maxillary sinus pain; ankylosing spondylitis, gout; post- operative pain; and scar pain. Furthermore, the use of novel N-Spiro substituted derivatives of the inhibitory neurotransmitter GABA of formula (I) for the treatment of chronic or debilitating conditions selected from the group consisting of painful diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, post-stroke pain, neuropathies-associated pain such as in idiopathic or post-traumatic neuropathy and mononeuritis, HIV/AIDS-associated neuropathic pain, cancer-associated neuropathic pain, spinal cord injury-associated pain, complex regional pain syndrome, fibromyalgia-associated neuropathic pain, lumbar and cervical pain, phantom limb syndrome and other chronic and debilitating condition-associated pain syndromes, is provided. The invention further provides a method for treating or preventing epilepsy, neuropathic pain syndromes and associated hyperalgesia in mammals, which comprises administering an effective amount of the compound of formula (I), in association with pharmaceutical acceptable carrier or adjuvant. The following examples are given to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof. Examples: Example 1 General Procedure for preparation of Compounds of Formula 1(a) (i)Preparation of a Compound of Formula (A), wherein n=0, R=H: 21 cyclopentanone (30 gm, 356.6 mmole) and ethyl cyanoacetate (85gm, 75.221 mmoles) were treated at 0°C with an excess of ammonia in ethanol and the mixture was stored at 0-5°C in a stopper bottle for a period of 1 week. The precipitated ammonium salt was filtered off, pressed and washed several times with alcohol. After the filter cake had stopped dripping, the solid ammonium salt was dissolved in large amount of boiling water; the solution was filtered while hot. and acidified with HCI. The free imide was filtered, washed with water and dried to obtain imide of compound A. (60%, 179-181°C) (ii)Preparation of a Compound (1,1-cyclopentane diacetic acid) of Formula (B), wherein n=0, R=H: Compound (A) (30 gm, 161.29 mmoles) was soaked in sulphuric acid (four times the weight of imide). After standing for 8 hours, water (three times the weight of imide) was added with frequent shaking. The mixture was heated under reflux for 15 hours with intermittent shaking, until frothing had ceased. After the mixture was allowed to cool to room temperature, water was added to dilute the reaction mixture. The crude acid together with charred material was filtered off and washed well with water. The crude reaction product was then suspended in hot water and sufficient potassium bicarbonate was added to dissolve all the acid. After boiling with charcoal, the solution was filtered, acidified with concentrated hydrochloric acid. The precipitate was filtered off, washed with water and dried. (45%, 175-177°C) (iii) Preparation of a Compound of Formula (C), wherein n=0,R=H: Compound (B) (20 gm, 0.107 moles) was mixed with 3 times its weight of acetyl chloride and refluxed for 3 to 4 hours. The reaction mixture was cooled to room temperature and crushed ice was added to the reaction mixture. The precipitated solid was filtered off and washed several times with water and dried to obtain compound of formula C. (45%, 62-64° C) (rv)Preparation of a Compound of Formula (D), wherein n=Q, R=H: Compound (C) (10 gm, 59.52 mmoles) and GABA (6 gm, 58.252 mmoles) were refluxed in toluene in the presence of triethylamine for 3 to 4 hours in Dean-stark apparatus. The organic solvents were removed in vacuo, water was added to the reaction mixture and 22 acidified with concentrated hydrochloric acid and stirred for 30 minutes, filtered and dried to obtain compound of formula D. (55%, 172-174° C) (v)P reparation of a Compound of Formula (E), wherein n=0, R=H: Compound (D) (5 gm, 19.763 mmoles) was dissolved in Dimethyl formamide. Temperature of the reaction mixture was brought down to 0-5cC by placing the RB flask in ice bath. Dicyclohexylcarbodimide was added to the mixture, followed by 10 moles of hydrazine hydrate (9.88gm, 197.63mmoles). Reaction mixture was brought to room temperature and stirred for 4 hours. The mixture was filtered off to remove dicyclohexyl urea. The filtrate was extracted with ethyl acetate and concentrated in vacuo to obtain compound of formula E. (53%, 158-160° C) (vi)Pre pa ration of Compounds of Formula 1(a): Compound (E) was reacted with equimoiar amounts of the corresponding aldehyde or ketone, by refluxing for 4 hours followed by precipitation in cold water to yield the respective acid hydrazones of formula 1(a). Example 2 Specific preparation related with compound of formula 1(a) Synthesis of 4-(7, 9-dioxo-8-azaspiro (4.5] dec-8-yl)-A"-[(lZ)-l-(4-nitrophenyl) ethylidine butanoic acid hydrazide: 4-(7,9-dioxo-8-azaspiro[4.5]decan-8-yl)butanoic acid hydrazide (0.5 gm, 1.87 mmol) (obtained by taking cyclopentanone as starting material and following the same methods described for preparing compound (E)) was taken in a 100 ml one neck round bottom flask. To this 10 ml of glacial acetic acid and 10 ml of absolute alcohol were added, followed by the addition of 4-Nitroacetophenone (0.339 gm, 2.24mmol). The reaction mixture was refluxed on an oil bath for 4 hours. After the completion of reaction, the reaction mixture was distilled and then cold water was added to the reaction mass. The obtained precipitate was filtered, washed and dried to afford the title compound. (407mg, 51.19%), (M.P. 189-191°C), FT-IR (cm"1 KBr): 3400, 3050, 2900, 1675, 1575 1550, 1525, 1375 and 1300. MS: (M+l) + 415.19. 'H-NMR (DMSO): 8 ppm 0.99 (4H, m), 1.18 23 (2H, t) l.34(2H, m), 1.93(2R m), 2.29(4H. m), 2.32(3H. s), 2.39(2Ht), 3.1(2H, t), 5.31( s, IH, N//), 8.04 (d, 2H, aromatic ), 8.09(d, 2H, aromatic). Elemental Analysis Calcd for C2,H36N405 C: 60.86, H: 6.32, N: 13.52, O: 19.30; Found: C: 60.66, H: 6.47, N: 13.62,0: 19.26. Synthesis of 4-(7, 9-dioxo-8-azaspiro [4.5] dec-8-yI)-An-l-(4-methylphenyl)ethylidinc butane hydrazide: 4-(7,9-dioxo-8-azaspiro[4.5]decan-8-yl) butanoic acid hydrazide (0.5gm, 1.87 mmol) (obtained by taking cyclopentanone as starting material and following the same methods described for preparing compound (E)) was taken in a 100 ml one neck round bottom * flask. To this 10 ml of glacial acetic acid and 10 ml of absolute alcohol were added, followed by the addition of4-methyl acetophenone (0.280 gm, 2.05mmol). The reaction mixture was refluxed on an oil bath for 4 hours. After completion of the reaction, the reaction mixture was distilled and then coid water was added to the reaction mass. The obtained precipitate was filtered, washed and dried to afford the title compound. (400mg, 60.77%), (M.P. 205-207°C) FT-IR (cm*1 KBr): 3400, 3050, 2900, 1675, 1575, 1550, 1375, and 1300. MS: (M-H) + 384.22. 'H-NMR (DMSO): 5 ppm 0.99 (4H, m), 1.18 (2H, t) 1.34(2H, m), 1.93(2H. m), 2.29(4K m), 2.32(3R s), 2.39(2Ht), 3.01(3Hs), 3.1(2H, t), 5.3I( s, IH, Ntf), 8.04 (d, 2H, aromatic ), 8.09(d, 2H, aromatic). Elemental Analysis Calcd for C22H29N3O3C: 68.90, H: 7.62, N: 10.96, O: 12.52; Found: C: 68.70, H: 7.51, N: 10.85,0:12.43. Example 2 General Procedure for preparation of Compounds of Formula 1(b) (i)Prcparation of a Compound of Formula (A), wherein n=l, R=H: Cyclohexanone (30 gm, 306.12 mmoles) and ethyl cyanoacetate (72.7 gm, 642 mmoles) were treated at 0°C with an excess of ammonia in ethanol and the mixture was stored at 0-5°C in a stopper bottle for a period of 1 week. The precipitated ammonium salt was filtered off, pressed and washed several times with alcohol. After the filter cake had stopped dripping, the solid ammonium salt was dissolved in large amount of boiling 24 water; the solution was filtered while hot and acidified with HC1. The free imide was filtered, washed with water and dried to obtain compound A. (75%, 2I0-2I2°C) (ii)Preparation of a Compound (1,1-cyclohexane diacetic acid) of Formula (B), wherein n=l,R=H: Compound (A) (30 gm, 129.87 mmoles) was soaked in sulphuric acid (four times the weight of imide). After standing for 8 hours, water (three times the weight of imide) was added with frequent shaking. The mixture was heated under reflux for 15 hours with intermittent shaking, until frothing had ceased. After the mixture was allowed to cool to room temperature, water was added to dilute the reaction mixture. The crude acid together with charred material was filtered off and washed well with water. The crude reaction product was then suspended in hot water and sufficient potassium bicarbonate was added to dissolve all the acid. After boiling with charcoal, the solution was filtered, acidified with concentrated hydrochloric acid. The precipitate was filtered off, washed with water and dried. (45%, 180-183°C) (iii) Preparation of a Compound of Formula (C), wherein n=l, R=H: Compound (B) (20 gm, 100 mmoles) was mixed with 3 times its weight of acetyl chloride and refluxed for 3 to 4 hours (as per drawings). The reaction mixture was cooled to room temperature and crushed ice was added to the reaction mixture. The precipitated solid was filtered off and washed several times with water and dried to obtain Compound C. (55%, 65-66° C) (iv)Preparation of a Compound of Formula (D), wherein n=l, R=H: Compound (C) (10 gm, 54.94 mmoles) and of GABA (6.22gm, 60.38 mmoles) was refluxed in toluene in the presence of triethylamine for 3 or 4 hours in Dean-stark apparatus. The organic solvents were removed in vacuo, water was added to the reaction mixture and acidified with concentrated hydrochloric acid and stirred for 30 minutes, filtered and dried to obtain compound D. (57%, 163-166° C) (v)Preparation of a Compound of Formula (E), wherein n=l,R=H: Compound (D) (5 gm, 18.72 mmoles) was dissolved in Dimethyl formamide. The temperature of the reaction mixture was brought down to 0-5°C by placing the RB flask 25 in ice bath. Dicyclohexylcarbodimide was added to the mixture, followed by 10 moles of hydrazine hydrate. The reaction mixture was brought to room temperature and stirred for 4 hours. The mixture was filtered off to remove dicyclohexyl urea. The filtrate was extracted with ethyl acetate and concentrated in vacuo to obtain compound of formula E. (65%, 120-124° C) (vi)Preparation of Compounds of Formula (1(b)): Compound (E) was reacted with equimolar amounts of the corresponding aldehyde or ketone, by refluxing for 4 hours followed by precipitation in cold water to yield the respective acid hydrazones of formula 1(b). Specific preparation related with compound of formula Kb): Synthesis of 4-(2,4-dioxo-3-azaspiro [5.5] dec-3-yl)-/V-[(lZ)-l-(4-nitrophenyl) ethylidine butanoic acid hydrazide: 4-(2,4-Dioxo-3-azaspiro[5.5]undecan-3-yl)butanoic acid hydrazide (compound E) (0.5 gm, 1.77 mmol) was taken in a 100ml one neck round bottom flask. To this 10ml of glacial acetic acid and 10 ml of absolute alcohol were added followed by the addition of 4-nitroacetophenone (0.323gm, 1.95mmol). The reaction mixture was refluxed on an oil bath for 4 hours. After completion of the reaction, the reaction mixture was distilled and then cold water was added to the reaction mass. The obtained precipitate was filtered, washed and dried to afford the title compound. (325mg, 47.10%) (M.P 190-195°C). FT-IR (cm'1 KBr): 3400,3050,2900, 1675, 1575 1550, 1525, 1375, and 1300. MS: (M+l) + 429.21. 'H-NMR (DMSO): 5 ppm 0.99 (4H, m), 1.0t(2H, m), 1.18 (2H, t) 1.34(2H, m), 1.90 (2H, m), 2.29(4H, m), 2.32(3H, s), 2.39(2Ht), 3.1(2H, t), 5.31( s, 1H, NH), 8.04 (d, 2H, aromatic ), 8.09(d, 2H, aromatic). Elemental Analysis Calcd for C22H28N4O5 C: 61.67, H: 6.59, N: 13.08, O: 18.67; Found: C: 60.97, H: 6.53, N: 13.32, O: 19.17. Synthesis of 4-(2,4-dioxo-3-azaspiro |5.5] dec-3-yl)-A^-l-(biphenyl)methylene butanoic acid hydrazide: 4-(2,4-Dioxo-3-azaspiro[5.5]undecan-3-yl)butanoic acid hydrazide (compound £) (0.5 gm, 1.77 mmol) was taken in a 100ml one neck round bottom flask. To this 10ml of glacial acetic acid and 10 ml of absolute alcohol were added followed by the addition of 26 benzophenone (0.356gm, 1.95mmol). The reaction mixture was refluxed on an oil bath for 4hours' After completion of the reaction, the reaction mixture was distilled and then cold water was added to the reaction mass. The obtained precipitate was filtered, washed and dried to afford the title compound. (270mg, 37.70), (M.P 185-190°C) FT-IR (cm"1 KBr): 3400, 3050, 2900, 1675, 1575 1550, 1525, 1350 and 1300. MS: (M+l) + 446.24. 'H-NMR (DMSO): 5 ppm 0.99 (4H, m), 1.18 (2H, t) 1.34(4H, m), I.93(2H, m), 2.29(4H, m), 2.39(2Ht), 3.4(2K t), 5.31(s, 1H, N//), 7.79(d, 2H, aromatic), 7.84(m, 4H, aromatic), 8.04 (m, 4H, aromatic ). Elemental Analysis Calcd for C27H3iN303 C: 72.78, H: 7.01, N: 9.43, O: 10.77; Found: C: 72.81, H: 7.13, N: 9.39, O: 10.67. Example 3 General Procedure for preparation of Compounds of Formula Ifc): (i)Preparation of a Compound of Formula (A), wherein n=l,R=-CH3: Substituted cyclohexanone (30 gm, 267 mmoles) and ethyl cyanoacetate (63.56 gm, 562.47 mmoles) were treated at 0°C with an excess of ammonia in ethanol and the mixture was stored at 0-5°C in a stopper bottle for a period of 1 week. The precipitated ammonium salt was filtered off, pressed and washed several times with alcohol. After the filter cake had stopped dripping, the solid ammonium salt was dissolved in large amount of boiling water; the solution was filtered while hot and acidified with HCl. The free imide was filtered, washed with water and dried to obtain compound A. (77%, 201-202°C) (ii)Prepa ration of a Compound of Formula (B), wherein n=l, R—CH3: Compound (A) (30 gm, 122.44 mmoles) was soaked in sulphuric acid (four times the weight of imide). After standing for 8 hours, water (three times the weight of imide) was added with frequent shaking. The mixture was heated under reflux for 15 hours with intermittent shaking, until frothing had ceased. After the mixture was allowed to cool to room temperature, water was added to dilute the reaction mixture. The crude acid together with charred material was filtered off and washed well with water. The crude reaction product was then suspended in hot water and sufficient potassium bicarbonate was added to dissolve all the acid. After boiling with charcoal, the solution was filtered, 27 acidified with concentrated hydrochloric acid. The precipitate was filtered off, washed with water and dried to obtain comound of formula B. (48%, 170-172°C) (iii) Preparation of a Compound of Formula (C), wherein n=I, R—CH3: Compound (B) (20 gm, 93.45 mmoles) was mixed with 3 times its weight of acetyl chloride and refluxed for 3 to 4 hours. The reaction mixture was cooled to room temperature and crushed ice was added to the reaction mixture. The precipitated solid was filtered off and washed several times with water and dried to obtain Compound C. (58%, 55-57° C) (iv)Prepa ration of a Compound of Formula (D), wherein n=l, R=-CH3: 10 gm, 51.02 mmoles of Compound (C) and of GAB A (5.78 gm, 56.11 mmoles) was refluxed in toluene in the presence of triethylamine for 3 or 4 hours in Dean-stark apparatus. The organic solvents were removed in vacuo, water was added to the reaction mixture and acidified with concentrated hydrochloric acid and stirred for 30 minutes, filtered and dried to obtain compound D. (56%, 133-134° C) (v)Prepa ration of a Compound of Formula (E), wherein n=l, R—CH3: Compound (D) (5 gm, 17.79 mmoles) was dissolved in Dimethylformamide. The temperature of the reaction mixture was brought down to 0-5°C by placing the RB flask in ice bath. Dicyclohexylcarbodimide was added to the mixture, followed by 10 moles of hydrazine hydrate (8.89 gm, 177.93 mmoles). Reaction mixture was brought to room temperature and stirred for 4 hours. The mixture was filtered off to remove dicyclohexyl urea. The filtrate was extracted with ethyl acetate and concentrated in vacuo to obtain compound of formula E. (54%, 165-168° C) (vi)Prepa ration of Compounds of Formula 1(c): Compound (E) was reacted with equimolar amounts of the corresponding aldehyde or ketone, by refluxing for 4 hours followed by precipitation in cold water to yield the respective acid hydrazones of formula 1(c). Specific preparation related with compound of formula 1(c): 28 Synthesis of 4-(9-methyl-2, 4-dioxo-3-azaspiro (5.5] dec-3-yl)-A"-[(lZ)-l-(3-nitro phenyl)ethylidine butanoic acid hydrazide: 4-(9-Methyl-2,4-dioxo-3-azaspiro[5.5]undecan-3-yl)butanoic acid hydrazide (0.5 gm, 1.69 mmol) (obtained by taking methylcyclohexanone as starting material and following the same methods described for preparing compound E) was taken in a 100ml one neck round bottom flask. To this 10ml of glacial acetic acid and 10 ml of absolute alcohol were added followed by the addition of 3-Nitrobenzaldehyde (0.28Igm, 1.86mmol).The reaction mixture was refluxed on an oil bath for 4 hours. After completion of the reaction, the reaction mixture was distilled and then cold water was added to the reaction mass. The obtained precipitate was filtered, washed and dried to afford the title compound. (321 mg, 48.71%), (M.P 181-184°C). FT-IR (cm-1 KBr): 3400, 3050, 2900, 1675, 1575. 1550, 1525, 1375, 1350, 1325 and 1300. MS: (M+l) + 429.21. 'H-NMR (DMSO): 5 ppm 0.90(1H, d), 1.34(4H, m), 1.53(4H, t), 1.57 (4H, m), 1.93(2H. m), 2.29(2H. t), 2.51(3H, s), 3.32(2H. t), 5.1(1H, s), 5.31( s, IH, N//>, 8.04 (d, 2H, aromatic ), 8.09(d, 2H, aromatic). Elemental Analysis Calcd for C22H28N4O5 C: 61.67, H: 6.59, N: 13.08, O: 18.67; Found: C: 61.70, H: 6.57, N: 13.11, O: 18.61. Synthesis of 4-(9-methyl-2,4-dioxo-3-azaspiro [5.5]dec-3-yl)-7V-[(lZ)-l-phenyl ethylidine butanoic acid hydrazide: 4-(9-MethyI-2,4-dioxo-3-azaspiro[5.5]undecan-3-yI)butanoic acid hydrazide (0.5 gm, 1.69 mmol) (obtained by taking methylcyclohexanone as starting material and following the same methods described for preparing compound E), was taken in a 100ml one neck round bottom flask. To this 10ml of glacial acetic acid and 10 ml of absolute alcohol were added followed by the addition of acetophenone (0.223gm, 1.86mmol).The reaction mixture was refluxed on an oil bath for 4hours.After completion of the reaction, the reaction mixture was distilled and then cold water was added to the reaction mass. The obtained precipitate was filtered, washed and dried to afford the title compound. (294mg, 44.61%) (M.P 192-193°C) FT-IR (cm"1 KBr): 3400, 3050, 2900, 1675, 1575 1550, 1525, 1375, and 1300. MS: (M+l) +398.24. lH-NMR (DMSO): 5 ppm 0.90(1H, d), 1.34(4H, m), 1.53(4H, t), 1.57 (4H, m), 1.93(2H, m), 2.29(2H, t), 2.83(3H, s), 3.31(2H. t), 5.31(s, IH, N#), 8.13 (d, 2H, aromatic ), S.15(d, 3H, aromatic). Elemental Analysis Calcd for C23H31N3O3 C: 69.49, H: 7.86, N: 10.57, O: 12.07; Found: C: 60.70, H: 6.27, N: 13.42, O: 19.21. 29 The compounds of formula I were tested at various doses, ranging from ] to 300 mg/kg through intraperitoneal route. Control rats received a solution of physiological saline, through the same route (Positive control). In neuropathic surgery models, ongoing spontaneous pain was quantified by measuring the duration of paw-withdrawal under unprovoked conditions. Tactile or Dynamic allodynia was measured by noting the latency to paw-withdrawal after an innocuous stimulus e.g. stroking with a cotton-bud. Cold-allodynia was measured using the acetone-drop test, by squirting acetone in few drops and noting the duration of paw-withdrawal. Finally, in the mechanical hyperalgesia test, hindpaw withdrawal duration was measured after a mild pin-prick to the plantar-surface of the ligated and normal hindpaws. Example 4 Preliminary anticonvulsant screens were undertaken to test compounds of formula I, whether or not they increase the seizure threshold and prevent seizure spread. Firstly, in the MES (Maximal Eiectroshock Seizure) test, maximal seizures were elicited by a 60Hz alternating current of 50mA intensity, delivered for 0.2s via corneal electrodes. Test solutions of all compounds were prepared in 0.5% methyl cellulose and the animals were dosed intra-peritoneally 30min prior to testing. Abolition of the hindlimb tonic extensor component of the seizure was defined as protection in the MES test. Secondly, in the subcutaneous Pentylenetetrazol (scPTZ) tests, pentylenetetrazole was administered subcutaneously at a dose of 85mg/kg to mice. Test solutions of all compounds were prepared in 0.5% methyl cellulose and the animals were dosed intra-peritoneally 30 min prior to testing. Absence of a single 5s episode of clonic spasm was taken as the end-point of this test. Thirdly, in the neurotoxicity screen, the mice were trained to stay on an accelerating rotarod, which rotates at 6 rpm. Trained animals were given i.p.(intra-peritoneal) injections of the test compounds. Neurotoxicity was indicated by the inability of the animal to maintain equilibrium on the rod for at least 1 minute in each of the three trials. 30 Compounds of the present invention showed protection in the MES and scPTZ model at a dose ranging from 100 to 300mg/kg. Example 5 Picrotoxin and strychnine-induced seizure tests (ipPIC tests and scSTY) were undertaken to understand the mechanisms of action of the prepared compounds. Briefly, picrotoxin, a GABAA antagonist was injected intra-peritoneally at a dose level of 4mg/kg to a group of swiss albino mice. The control group mice received the vehicle (30% PEG 400), while the test group mice were pre-treated with compounds of formula I, 30 minutes prior to picrotoxin administration. The animals were observed for a period of 90 minutes after picrotoxin injection, during which the number of seizures, the duration of seizures and the time of onset of seizures were noted down. Compounds of the present invention showed protection against picrotoxin-induced seizures till 4 hours, at a dose range of 10 to 300mg/kg. In the strychnine-induced seizure pattern test, strychnine, a glycine receptor antagonist was injected subcutaneously at a dose of 1.2mg/kg. The control group mice received the vehicle (30% PEG 400), while the test group mice were pre-treated with compounds of formula I, 30 minutes prior to strychnine administration. The animals were observed for a period of 90 minutes after strychnine injection during which the number of seizures, the duration of seizures and the time of onset of seizures were noted down. Also prevention of mortality was taken as an important effect of the compounds. Compounds of the present invention showed protection against strychnine-induced seizures till 4 hours, at a doses ranging from 10 to 300mg/kg. Example 6 Acetic acid and Formalin Assays: Acetic acid and Formalin tests were used as preliminary tests for antinociceptive evaluation of compounds of formula 1. In acetic acid test, writhing was induced by an intra-peritoneal injection of 0.1 ml of 3% v/v acetic acid in mice (n=6). The test 31 compounds were suspended in 30% v/v PEG 400 and administered intra-peritoneally half an hour prior to acetic acid administration. The control group mice received normal saline (0.01 ml/g). The numbers of writhings occurring for a 30 min time period immediately after acetic acid injection were recorded. The percentage inhibition of the writhing response was calculated. The compounds of the present invention produced a significant inhibition in writhing behavior at the dose of 100 mg/kg.. In formalin test, an injection of a small amount of formalin was injected into the subcutaneous tissue, typically the dorsal surface of the rodent paw that gives flinches of paw in the early phase (0-5 min) and the late phase (30-40 min). Total time of lifting, licking and biting paw was monitored. The results showed that intra-peritoneal administration of the compounds of formula I had a significant effect in reducing flinching behaviors in both the phases at the dose of lOOmg/kg. Example 7 Spontaneous Pain In-vivo Assay: This assay determines the effectiveness of compounds of formula I in relieving one of the symptoms in an in vivo model of neuropathic pain, produced by Infra Orbital Nerve (ION) ligation, namely spontaneous pain. Spontaneous pain was induced in rats using the procedures described by Imamura et al. Brain Research, 1997, 116, 97-103. Briefly, the rats were anesthetized with an intra¬peritoneal dose of pentobarbital sodium (65 mg/kg) with additional doses of anesthetic given, as needed. An incision approximately 1 cm long was made along the gingivobuccal margin. The incision would begin just proximal to the first molar. About 0.5 cm of the infra orbital nerve (ION) branch of the trigeminal nerve was freed of adhering tissue, and two ligatures (4-0 chromic gut) were tied loosely around it. The incision was sutured at three points using 4-0 silk; the animal was transferred to its home-cage and left for recovery. The sham operation was identical except that, the nerve was not ligated. 32 Spontaneous pain was assessed for a total time period of 7 minutes. The operated rat was placed inside an observation cage. An initial acclimatization period of 3 minutes was given to each of the rats. A total number of four rats (n=4) were assigned to this group. A positive spontaneous pain response consisted of spontaneous grooming of face for a finite period of time. The duration of spontaneous grooming was then noted down. The pre-dose screening values were used as the animal's baseline spontaneous pain scores. The results show that at i.p. administration the compounds of formula I had a palliating effect on the pain response in the dose 100 mg/kg. Overall the compounds of the present invention were found to be effective in reversing spontaneous pain-like symptoms, when tested by this method. Example 8 Dynamic Allodynia In-vivo Assay: This assay determines the effectiveness of compounds of formula I in relieving one of the symptoms of neuropathic pain produced by spinal nerve ligation (SNL), namely dynamic allodynia, in an in vivo model. Dynamic allodynia was induced in rats, using the procedures described by Kim and Chung, Pain, 1992, 50, 355-363. Briefly, the rats were anesthetized with an intra¬peritoneal dose of pentobarbital sodium (65 mg/kg) with additional doses of anesthetic given, as needed. A 3-cm incision was made on the lateral aspect of the left hindlimb (ipsilateral) at the mid-thigh level, with the right hindlimb serving as the control (contralateral). The L5 spinal nerve was then exposed at the level of the dorsal root ganglion, and ligated tightly with a 4-0 silk thread. Only one tight ligature was made in this model. After confirmation of hemostasis, the wound was then closed by suturing the muscle using catgut with a continuous suture pattern. Finally, the skin was sutured using silk thread with horizontal-mattress suture pattern. The animal was then transferred to its home-cage and left for recovery. 33 All of the operated rats were assessed for dynamic allodynic response. The operated rat was placed inside an observation cage that was kept 5 cm from the ground level. An initial acclimatization period of 3 minutes was given to each of the rats. A total number of four rats (n=4) were assigned to this group. A positive dynamic allodynic response consisted of lifting the affected paw for a finite period of time, in response to mild stroking on the plantar region using a cotton-bud. This stimulus is non-noxious to a normal-behaving rat. The latency to paw-withdrawal was then noted down. A cut-off time of 15s was taken for a normal paw response. The pre-dose screening values were used as the animal's baseline dynamic allodynia scores. The results show that at i.p. administration, the compounds of formula I had a palliating effect on the pain response in the dose range of 1 -100 mg/kg. Example 9 Cold Allodynia In-vivo Assay: This assay determines the effectiveness of compounds of formula I in relieving one of the symptoms of neuropathic pain, produced by the Chronic Constriction Injury (CCl) to the common sciatic nerve, namely cold allodynia, in an in vivo model. Unilateral mononeuropathy was produced in rats, using the Chronic Constriction Injury (CCl) model, performed essentially as described by Bennet and Xie, Pain, 1988, 33, 87-107. Briefly, the rats were anesthetized with an intra-peritoneal dose of pentobarbital sodium (65 mg/kg) with additional doses of anesthetic given, as needed. A 3-cm incision was made on the lateral aspect of the left hindlimb (ipsilateral) at the mid-thigh level with the right hindlimb serving as the control (contralateral). The left paraspinal muscles were then separated from the spinous processes and the left sciatic nerve was exposed just above the trifurcation point. Four loose ligatures were then made with a 4-0 silk thread along the sciatic nerve each with a 1-2 mm spacing in between. The wound was then closed by suturing the muscle using catgut with a continuous suture pattern. Finally, the skin was sutured using silk thread with horizontal-mattress suture pattern. The animal was then transferred to Us home-cage and left for recovery. 34 The rats demonstrating unilateral mononeuropathy were assessed for acute cold allodynia sensitivity. The operated rat was placed inside an observation cage that was kept 5 cm from the ground level. An initial acclimatization period of 3 minutes was given to each of the rats. A total number of four rats (n=4) were assigned to this group. The test used was the acetone-spray test. Few drops of freshly dispensed acetone were sprayed as a fine mist onto the plantar region of the affected paw. A cold allodynic response was assessed by noting down the duration of paw-withdrawal. The pre-dose screening values were used as the animal's baseline cold allodynia scores. When tested in the acute cold-allodynia assay the compounds of formula I generally demonstrated anti-allodynic effects in the dose range of 1 -100 mg/kg. Example 10 Mechanical Hyperalgesia In-vivo Assay: This assay determines the effectiveness of compounds of formula I in relieving one of the symptoms in an in vivo model of neuropathic pain produced by unilateral mononeuropathy, namely mechanical hyperalgesia. A chronic constriction injury was produced by loosely ligating the left common sciatic nerve as described by Bennet and Xie, Pain, 1988, 33, 87-107. The right common sciatic nerve was visualized, but not manipulated to produce sham conditions. The rats demonstrating unilateral mononeuropathy were assessed for mechanical hyperalgesia sensitivity. The operated rat was placed inside an observation cage that was kept 5 cm from the ground level. An initial acclimatization period of 3 minutes was given to each of the rats. A total number of four rats (n=4) were assigned to this group. Hindpaw withdrawal duration was measured after a mild pin prick to the plantar surface of the ligated (left) and sham (right) hindpaws. The compounds of the present invention produced a long-lasting (3 hours) reversal of mechanical hyperalgesia, elicited by a pin-prick stimulus in rats with a chronic constriction injury when tested by this method in a dose range of 1 to 100 mg/kg. 35' Example 11 Diabetic Neuropathy: Diabetes was induced by a single intra-peritoneal injection of Streptozocin (50 mg/kg) in rats {Field et ai, 1998, Pain, 80 1999, 391-398. Control animals received a similar administration of isotonic saline. Diabetes was confirmed one week later by measurement of tail vein blood glucose levels with a suitable glucometer. Nociceptive behavioral assessment was undertaken from 9* day onwards. Tail flick (radiant heat) test which is a pain receptive assay was performed. The rat was placed within a restraining tube with its tail protruding. The tail was placed on a level surface, a radiant heat was applied to the tail and the latency of the rat to remove its tail from the heat was recorded. The results showed that intra-peritoneal administration of the compounds of formula I increased the flicking latency and had a palliating effect on the pain response at the dose of lOOmg/kg It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. We Claim, 1. Novel N-spiro substituted compounds, represented by Formula I, useful in the treatment of epilepsy and various neuropathic pain conditions Formula I wherein, n is 0,1, 2, 3; R is hydrogen, halo or straight or branched alkyl from 1 to 6 carbons; Ri is hydrogen or alkyl from 1 to 6 carbons, unsubstituted phenyl or halo, nitro, amino or alkyl substituted phenyl; R2 is hydrogen or alkyl from 1 to 6 carbons or unsubstituted phenyl or alo, nitro, amino or alkyl substituted phenyl; or R] and R2 may form together unsubstituted isatinyl or halo or alkyl substituted isatinyl or cycloalkyl from 3 to 8 carbons. 2. A process for preparing novel N-spiro substituted compounds of formula (I), wherein the process for preparing the said compounds comprising the steps of: a. reacting compound of formula (C) with y-aminobutyric acid (GABA) to obtain compound of formula (D); Formula (C) wherein n and R are as defined above b. dissolving compound of formula (D) in DMF; 37 wherein R1 and R2 are as defined in claim 1. 4. A compound according to claim 3, selected from the group consisting of: 4-(7,9-dioxo-8-azaspiro [4.5] dec-8-yl)- A" - [(12) -l-(4-nitrophenyl) ethylidene butanoic acid hydrazide; 4-(7,9-dioxo-8-azaspiro[4.5]dec-8-yl)-AM-(biphenyl)methylidene butanoic acid hydrazide; 4'(7,9-dioxo-8-azaspiro[4.5Jdec-8-yl)-AM-(4-methyIphenyI)ethylidenebutanoic acid hydrazide; 4-(7,9-dioxo-8-azaspiro[4.5]dec-8-yl)-A'-cyclopentylidene butanoic acid hydrazide; 4-(7,9-dioxo-8-azaspiro[4.5Jdec-8-yl)-A',-cyclohexylidene butanoic acid hydrazide; 4-f7,9-dioxo-8-azaspiro [4.5] dec-8-yl)-AH(12)-l-(3-nitrophenyl) methylidene butane hydrazide; 4-(7,9-dioxo-8-azaspiro[4.5]dec-8-yl)-A'-[(12)-l-phenylethylidenebutanoic acid hydrazide; 4-(7,9-dioxo-8-azaspiro [4.5] dec-Z-y\)-N,-[(3Z)-2-o\o-i,2-d\hydro-3H-mdo\-3-yliden] butanoic acid hydrazide; 4-(7,9-dioxo-8-azaspiro[4.5]dec-8-yl)-W-[(3Z)-5-chloro-2-oxo-l,2-dihydro-3H-indoI-3-ylidene]butanoic acid hydrazide; 4-(7,9-dioxo-8-azaspiro[4.5]dec-8-yl)-A^-[(3Z)-5-methyl-2-oxo-l,2-dihydro-3//-indol-3-ylidene]butanoic acid hydrazide; 4-(7,9-dioxo-8-azaspiro [4.5] dec-8-yl)-A^-[(3Z)-5-fluoro-2-oxo-1,2-dihydro-3tf-indol-3-ylidene] butanoic acid hydrazide; 4-(7,9-dioxo-8-azaspiro [4.5] dec-8-yl)-y-[(lZ)-l-(2-nitrophenyl) methylidene butanoic acid hydrazide; 4-(7,9-dioxo-8-azaspiro[4.5] dec-8-yl)-AM-(4-aminophenyl)ethylidine butanoic acid hydrazide. 5. The novel N-spiro substituted compounds as claimed in claim 1, wherein n is 1; R is hydrogen; are represented by Formula 1(b), 'herein Rl and R2 are as defined in claim 1. 6. A compound according to claim 5, selected from the group consisting of: 4-(2,4-dioxo-3-azaspiro [5.5] dec-3-yl)-A"-[(lZ)-l-(4-nitrophenyl) ethylidene butanoic acid hydrazide; 4-(2,4-dioxo-3-azaspiro [5.5]'dec-3-yI)-AM-(biphenyl) methylidene butanoic acid hydrazide; 4-(254-dioxo-3-azaspiro[5.5]dec-3-yl)-A'-l-(4-methylphenyl)ethylidenebutanoic acid hydrazide; 4-(2,4-dioxo-3-azaspiro [5.5] dec-3-yl)-iV-cyclopentylidene butanoic acid hydrazide;' 4-(2,4-dioxo- 3-azaspiro [5.5] dec-3-yl) - jV-cyclohexylidene butanoic acid hydrazide; 4-(2,4-dioxo-3-azaspiro [5.5] dec-3-yl)-iV-[(lZ)-I-(3-nitrophenyl) methylidene butanoic acid hydrazide; 4-(2,4-dioxo-3-azaspiro [5.5] dec-3-yl)-JV-[(lZ)-l-phenylethy]idenebutanoic acid hydrazide; 4-(2,4-dioxo-3-azaspiro[5.5]dec-3-yl)-N'-i;(3Z)-2-oxo-l,2-dihydro-3H-indol-3-ylidene] butanoic acid hydrazide; 4-(2, 4-dioxo-3-azaspiro [5.5] dec-3-yl)-A^-[(3Z)-5-chIoro-2-oxo-L2-dihydro-3//-indol-3-ylidene]butanoic acid hydrazide; 4-(2, 4-dioxo-3-azaspiro [5.5] dec^-yO-TV-^ZJ-S-methyl^-oxo-l^-dihydro-3H-indol-3-ylidene]butanoic acid hydrazide; 4-(2,4-dioxo-3-azaspiro [5.5]dec-3-yl)-A^-[(3Z)-5-fluoro-2-oxo-l,2-dihydro-3/7-indol-3-ylidene] butanoic acid hydrazide; 4-(2,4-dioxo-3-azaspiro[5.5]dec-3-yl)-A^-[(lZ)-1-(2-nitrophenyl) ethylidine methylidene butanoic acid hydrazide; 4-(2,4-dioxo-3-azaspiro [5.5] dec-3-yl)-AM-(4-aminophenyl)ethylidine methylidene butanoic acid hydrazide; 4-(9-methyI-2,4-dioxo-3-azaspiro [5.5] dec - 3-yl)- A^-[(lZ)-l-(4-nitrophenyl) ethylidene butanoic acid hydrazide. 7. The novel N-spiro substituted compounds as claimed in claim 1, wherein n is 1, R is methyl; are represented by Formula 1(c) Formula 1(c) wherein Rl and R2 are as defined in claim 1. 8, A compound according to claim 7, selected from the group consisting of: 4-(9-methyl-2,4-dioxo-3-azaspiro [5.5] dec-3-yl)-AM-(biphenyl)methy]idene butanoic acid hydrazide. 4-(9-methyl-2,4-dioxo-3-azaspiro [5.5] dec-3-yl)-AM-(4-methylphenyI) ethylidene butanoic acid hydrazide. 4-(9-methyl-2,4-dioxo-3-azaspiro[5.5]dec-3-yl)-A'-cyclopentylidene butanoic acid hydrazide. 4-(9-methyl-2,4-dioxo-3-azaspiro [5.5] dec^-yl^A7"- cyclohexylidene butanoic acid hydrazide. 4-(9-methyl-2,4-dioxo-3-azaspiro [5.5] dec - 3-yl)- N1- [ (1Z)- I- (3-nitrophenyl) methylidene butanoic acid hydrazide. 4-(9-methyI-2,4 - dioxo - 3-azaspiro [5.5]dec-3-yl)-A^-[(lZ)-l-phenylethyIidene butanoic acid hydrazide. 4-(9-methyl-2,4-dioxo-3-azaspiro[5.5]dec-3-yl)-A^-[(3Z)-2-oxo-l,2-dihydro-3/f-indol-3-ylidene] butanoic acid hydrazide. 4-(9-methyl-2,4-dioxo-3-azaspiro [5.5] dec-3-yl)-JV-[(3Z)-5-chloro-2-oxo-l,2-dihydro-3//-indol-3-ylidene]butanoic acid hydrazide. 41 11. A pharmaceutical composition comprising an effective amount of an active ingredient of formula I according to claim 1, in association with a pharmaceutically acceptable carrier or adjuvant. 12. A pharmaceutical composition according to claim 11, wherein an effective amount of the active ingredient in the said composition is ranging from about 1 mg/kg to 300 mg/kg. 42 13. A non-neurotoxic anticonvulsant composition, highly effective in scPTZ, scSTY or ipPIC tests comprising an effective amount of the compound of formula I as the active ingredient along with one or more pharmaceutically acceptable excipients. 14. The use of compounds of formula I according to claim 1, in the manufacture of a medicament useful in the treatment of epilepsy and various neuropathic pain conditions such as acute and/or chronic convulsive disorders, neuropathic pain syndromes; for slowing or delaying the progression of neuropathic pain syndromes and convulsive disorders; and for the treatment of a disorder or condition selected from the group consisting of diseases and conditions in which pain predominates, including acute pain, chronic pain, neuropathic pain including soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, muscular- skeletal pain, particularly after trauma, spinal pain, dental pain, myofacial pain syndromes; deep and visceral pain such as heart pain, muscle pain, eye pain; orofacial pain, for example, odontalgia, abdominal pain; gynaecological pain, for example, dysmenorrhea, and labor pain; pain associated with nerve and root damage including pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, atypical facial pain, nerve root damage, and arachnoiditis; pain associated with carcinoma, often referred to as cancer pain; central nervous system pain, such as pain due to spinal cord or brain stem damage; low back pain such as sciatica; headache, including migraine, acute or chronic tension headache, cluster headache and maxillary sinus pain; ankylosing spondylitis, gout; post- operative pain; and scar pain; the chronic or debilitating conditions selected from the group consisting of painful diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, post-stroke pain, neuropathies-associated pain such as in idiopathic or post¬ traumatic neuropathy and mononeuritis, HIV/AIDS-associated neuropathic pain, cancer-associated neuropathic pain, spinal cord injury-associated pain, complex regional pain syndrome, fibromyalgia-associated neuropathic pain, lumbar and cervical pain, phantom limb syndrome and other chronic and debilitating condition-associated pain syndromes. 15. A method of treatment for epilepsy or naturopathic pain related conditions in mammals, which comprises administering to a mammal in need thereof a pharmaceutical composition according to claims 11 to 13. 43

Documents:

1138-CHE-2009 FORM-3 24-09-2014.pdf

1138-CHE-2009 FORM-3 29-09-2014.pdf

1138-CHE-2009 FORM-5 24-09-2014.pdf

1138-CHE-2009 AMENDED CLAIMS 24-09-2014.pdf

1138-CHE-2009 POWER OF ATTORNEY 24-09-2014.pdf

1138-CHE-2009 AMENDED PAGES OF SPECIFICATION 24-09-2014.pdf

1138-che-2009 correspondence others.pdf

1138-che-2009 description(complete).pdf

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1138-CHE-2009 EXAMINATION REPORT REPLY RECIEVED 24-09-2014.pdf

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1138-che-2009 correspondence others-26-06-2009.pdf

1138-che-2009 correspondence others.pdf

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