WO2008036967A2

WO2008036967A2 - Novel heterocyclic compounds as lasy activators

Info

Publication number: WO2008036967A2
Application number: PCT/US2007/079286
Authority: WO
Inventors: Dumbala Srinivas Reddy; Indira Padmalayam; Debnath Bhuniya; Sivaram Pillarisetti; Ranjan Chakrabarti
Original assignee: Reddy US Therapeutics Inc
Current assignee: Reddy US Therapeutics Inc
Priority date: 2006-09-22
Filing date: 2007-09-24
Publication date: 2008-03-27
Anticipated expiration: 2009-03-22
Also published as: WO2008036967A3

Abstract

This invention provides a compound of formula (I), which is a free species and/or a pharmaceutically-acceptable salt or a stereoisomer of the compound of formula (I). Another aspect of the present invention provides the compound of the formula (I) as a Lipoic acid synthase (LASY) inducer

Description

NOVEL HETEROCYCLIC COMPOUNDS AS LASY ACTIVATORS

CROSS REFERENCE TO RELATED PATENT APPLICATIONS

The present application is a Patent Cooperation Treaty application and claims the benefit of U.S. Provisional Application No. 60/846,499, filed September 22, 2006, which is relied on herein and incorporated herein by reference in its entirety.

The present application is related to co-pending and commonly owned Patent Cooperation Treaty application having the title: Methods and Compositions for the Treatment of Inflammation, Obesity, and Related Metabolic Disorders, and having attorney docket number RUS 3.4-026, which was filed on the same date as the present application, and is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

In accordance with one aspect, the invention provides a compound of formula (I), which is a free species and/or a pharmaceutically-acceptable salt or a stereoisomer of the compound of formula (I). Another aspect of the present invention provides the compound of the formula (I) as a Lipoic acid synthase (LASY) inducer.

BACKGROUND OF THE INVENTION

Lipoic acid synthase (LASY) is an enzyme that is involved in the endogeneous synthesis of lipoic acid - a crucial antioxidant, and an essential co-factor of dehydrogenase enzymes. Administration of lipoic acid has been found clinically beneficial for diseases related to the metabolic syndrome and induction of LASY could have therapeutic benefits.

BREIF SUMMARY OF THE INVENTION

In accordance with one aspect, the invention provides a compound of formula (I), which is a free species and/or a pharmaceutically-acceptable salt or a stereoisomer of the compound of formula (I)

wherein:

R¹ and R² which may be same or different, are independently selected from hydrogen, halogen, hydroxy, cyano, nitro; or optionally substituted groups selected from alkyl, haloalkyl, alkoxy, haloalkoxy, carboxylic acid or its esters or its amides;

X represents NH or N-R⁷, wherein R⁷ is selected from optionally substituted group selected from (C₁-C₅) alkyl or aralkyl or -SO₂-R' wherein R' represents optionally substituted alkyl or optionally substituted aryl;

wherein R⁶ represents hydrogen, optionally substituted groups selected from alkyl, haloalkyl, alkoxy, haloalkoxy; m is an integer from 1 to 2 inclusive; n is an integer from O to 4 inclusive; p is an integer from O to 1 inclusive

A represents

or — CR^aR^bR^c wherein R^a and R is hydrogen or optionally substituted groups selected from alkyl, alkenyl and R^c represents carboxylic acid or its esters or its amides;

— is a bond or no bond;

B represents -CH₂-, -NH-, Or -NH-CH₂-;

R³ represents hydrogen, halogen, hydroxy, cyano, nitro or optionally substituted groups selected from alkyl, haloalkyl, alkoxy, haloalkoxy, carboxylic acid or its esters or its amides.

R⁴ and R⁵ represents hydrogen atom, or R⁴ and R⁵ together form aryl, cycloalkyl which is optionally substituted by one or more same or different groups selected from halogen, hydroxy, cyano, nitro; or optionally substituted groups selected from alkyl, haloalkyl, alkoxy, haloalkoxy, carboxylic acid or its esters or its amides. DETAILED DESCRIPTION OF THE INVENTION

To describe the invention, certain terms are defined herein as follows. The term "compound" is used to denote a molecule of unique, identifiable chemical structure. A compound may exist as a free species. Also, the free species form of the compound may form various salts, usually with external acids or bases.

In describing the compounds, certain nomenclature and terminology is used throughout to refer to various groups and substituents. The description "C_x-Cy" refers to a chain of carbon atoms or a carbocyclic skeleton containing from x to y atoms, inclusive. The designated range of carbon atoms may refer independently to the number of carbon atoms in the chain or the cyclic skeleton, or to the portion of a larger substituent in which the chain or the skeleton is included. For example, the recitation "(C₁-C₅) alkyl" refers to an alkyl group having a carbon chain of 1 to 5 carbon atoms, inclusive of 1 and 5. The chains of carbon atoms of the groups and substituents described and claimed herein may be saturated or unsaturated, straight chain or branched, substituted or unsubstituted.

The term "Halogen or Halo" represents fluorine, chlorine, bromine or iodine.

The term "alkyl," whether used alone or as a part of another group is a group or a substituent that includes a chain of carbon atoms. The chains of carbon atoms of the alkyl groups described and claimed herein may be saturated or unsaturated, straight chain or branched, substituted or unsubstituted. In a non-limiting example, "C₁-C₅ alkyl" denotes an alkyl group having carbon chain with from 1 to 5 carbon atoms, inclusive, which carbon may be saturated or unsaturated, straight chain or branched, substituted or unsubstituted.

"Haloalkyl" is a group containing at least one halogen and an alkyl portion as define above. Exemplary haloalkyl groups include fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, trilfiuoromethyl and the like. Unless otherwise specified, a haloalkyl group typically has from 1 to about 10 carbon atoms.

'Aralkyl' is an alkyl group with an aryl substituent, where alkyl and aryl groups are as defined above. Exemplary of the aralkyl includes benzyl, phenethyl (e.g., 2- phenethyl), phenylpropyl (e.g., 3-phenylpropyl), naphthylmethyl (e.g., 1 -naphthylmethyl and 2-naphthylmethyl) and the like.

The term "alkoxy" refers to an oxygen ether radical. An "alkoxy" group contains a chain of carbon atoms connected to the rest of the molecule through the oxygen atom. The chains of carbon atoms of the alkoxy groups described and claimed herein may be saturated or unsaturated, straight chain or branched, substituted or unsubstituted.

"Haloalkoxy" is an alkoxy group with a halo substituent, where alkoxy and halo groups are as defined above. Exemplary haloalkoxy groups include chloromethoxy, trifluoromethoxy, trifluoroethoxy, perfluoroethoxy (-OCF2CF3), trifluoro-t-butoxy, hexafluoro-t-butoxy, perfluoro-t-butoxy (-OC(CF3)3), and the like. Unless otherwise specified, an haloalkoxy group typically has from 1 to about 10 carbon atoms.

"Carboxylic acid or its esters or its amides": Exemplary carboxylic acid groups include CONH₂, CONHMe, CONMe₂, CONHEt, CONEt₂, CONHPh, CON(OMe)Me, COOH, COOR" wherein R" represents optionally substituted alkyl or optionally substituted cycloalkyl.

The term "aryl", whether used alone or as part of a substituent group, denotes a carbocyclic aromatic radical derived from an aromatic hydrocarbon. Non-limiting examples of the "aryl" radicals include phenyl, naphthyl, diphenyl, fluorophenyl, methoxyethylphenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, tolyl, xylyl, and dimethylcarbamylphenyl. The "aryl" groups of the compounds described herein may be substituted by independent replacement of 1 to 3 of the hydrogen atoms on the carbocyclic aromatic skeleton with substituents including, but not limited to, halogen, -OH, -CN, mercapto, nitro, amino, substituted amino, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylamino, halogenated C₁-C₆ alkyl, formyl, C₁-C₆ acyl, C₁-C₆ alkoxyacyl, and C₁-C₆ acylamido.

"Alkenyl" is an unsaturated aliphatic group containing a C=C double bond. Exemplary alkenyl groups include ethenyl, propenyl, prop-1-enyl, isopropenyl, butenyl, but-1-enyl, isobutenyl, pentenyl, pent-1-enyl, hexenyl, pent-2-enyl, 2-methyl-but-2-ene, 2-methyl-pent-2-enyl and the like. Unless otherwise specified, an alkenyl group typically has from 2 to about 10 carbon atoms. "Cycloalkyl" group refers to a cyclic alkyl group which may be mono or polycyclic. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Unless otherwise specified, a cycloalkyl group typically has from 3 to about 10 carbon atoms.

Unless specified otherwise, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.

A group may be referred to generally or more specifically, as desired. For example, a group containing a carbon chain with one carbon-carbon double bond may be described as alkyl or alkenyl, as desired. In another non-limiting example, a group containing a carbon chain with a chloro substituent may be described as alkyl or halogenated alkyl, as desired.

A "composition" may contain one compound or a mixture of compounds. A "pharmaceutical composition" is any composition useful or potentially useful in producing physiological response in a subject to which such pharmaceutical composition is administered. The term "pharmaceutically acceptable" with respect to an excipients is used to define non-toxic substances generally suitable for use in human or animal pharmaceutical products.

One embodiment of the present invention provides a compound of formula (I), which is a free species and/or a pharmaceutically-acceptable salt or a stereoisomer of the compound of formula (I)

(I) wherein: R¹ and R² which may be same or different, are independently selected from hydrogen, halogen, hydroxy, cyano, nitro; or optionally substituted groups selected from alkyl, haloalkyl, alkoxy, haloalkoxy, carboxylic acid or its esters or its amides;

X represents NH or N-R⁷, wherein R⁷ is selected from optionally substituted group selected from (C₁-C5) alkyl or aralkyl or -SO₂-R¹ wherein R' represents optionally substituted alkyl or optionally substituted aryl;

—

( ₂)_n ( _{2 p} ( ₂)_n wherein R⁶ represents hydrogen, optionally substituted groups selected from alkyl, haloalkyl, alkoxy, haloalkoxy; m is an integer from 1 to 2 inclusive; n is an integer from O to 4 inclusive; p is an integer from O to 1 inclusive

A represent

or — CR^aR^bR^c wherein R^a and R^b is hydrogen or optionally substituted groups selected from alkyl, alkenyl and R^c represents carboxylic acid or its esters or its amides;

— is a bond or no bond;

B represents -CH₂-, -NH-, Or -NH-CH₂-;

R³ represents hydrogen, halogen, hydroxy, cyano, nitro or optionally substituted groups selected from alkyl, haloalkyl, alkoxy, haloalkoxy, carboxylic acid or its esters or its amides

R⁴ and R⁵ represents hydrogen atom, or R⁴ and R⁵ together form aryl, cycloalkyl which is optionally substituted by one or more same or different groups selected from halogen, hydroxy, cyano, nitro; or optionally substituted groups selected from alkyl, haloalkyl, alkoxy, haloalkoxy, carboxylic acid or its esters or its amides.

Another embodiment of the present invention provides compounds of formula (II)

(II) wherein:

wherein R⁶ represents hydrogen, optionally substituted groups selected from alkyl, haloalkyl, alkoxy, haloalkoxy; m is an integer from 1 to 2 inclusive; n is an integer from 0 to 4 inclusive; p is an integer from 0 to 1 inclusive

— is a bond or no bond;

B represents -CH₂-, -NH-, or -NH-CH₂-;

R⁴ and R⁵ represents hydrogen atom, or R⁴ and R⁵ together form aryl, cycloalkyl which is optionally substituted by one or more identical or different groups selected from halogen, hydroxy, cyano, nitro; or optionally substituted groups selected from alkyl, haloalkyl, alkoxy, haloalkoxy, carboxylic acid or its esters or its amides.

Another embodiment of the present invention provides the compound of formula (III), which has the structure

wherein:

X represents NH or N-R⁷, wherein R⁷ is selected from optionally substituted group selected from (C₁-C₅) alkyl or aralkyl or -SO₂-R' wherein R' represents optionally substituted alkyl or optionally substituted phenyl;;

R⁶ represents hydrogen, optionally substituted groups selected from alkyl, haloalkyl, alkoxy, haloalkoxy; n is an integer from 0 to 4 inclusive; m is an integer from 1 to 2 inclusive; p is an integer from 0 to 1 inclusive — is a bond or no bond;

According to another embodiment of the present invention, a derivative, which is a free species and/or a pharmaceutically-acceptable salt of the compound of the formula (I) as a Lipoic acid synthase (LASY) inducer.

According to another embodiment the present invention provides a pharmaceutical composition comprising a derivative of formula (I) and one or more pharmaceutically-acceptable excipients.

An embodiment of the present invention provides preparation of the novel compounds of formula (I) according to the procedure of the following schemes, using appropriate materials. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. Moreover, by utilizing the procedures described in detail, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein. Scheme 1

wherein Gi and G₂ are independently selected from carboxylic acid or its esters or its amides, n varies from 0 to 4 and all other symbols are as defined earlier. 1) By peptide coupling procedure, reacting the compound of formula (1a) with the compound of formula (1b) in the presence of a reagent to form a compound of formula

(I)-

The term "pharmaceutically acceptable," with respect to an excipient, is used to define non-toxic substances generally suitable for use in human or animal pharmaceutical products. The pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavorants, sweeteners, etc., in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. Such compositions typically contain from 0.1 to 50%, preferably 1 to 20% by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents.

Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active ingredient will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the active ingredient can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavourants, sweeteners, excipients and the like. For parenteral administration, the active ingredient can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds. Aqueous solutions with the active ingredient dissolved in polyhydroxylated castor oil may also be used for injectable solutions. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneal^, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.

For nasal administration, the preparation may contain the active ingredient of the present invention dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, such as propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin or preservatives such as parabenes.

Tablets, dragees or capsules having talc and/or a carbohydrate carried binder or the like are particularly suitable for any oral application. Preferably, carriers for tablets, dragees or capsules include lactose, corn starch and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.

The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 500 mg/kg/day.

In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as 'carrier' materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. The present invention is further illustrated by the following examples, which are not to be construed in any way as imposing limitations upon the scope thereof, but rather are illustrative only. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest them to one of ordinary skill in the art without departing from the spirit of the present invention.

The following acronyms, abbreviations, terms and definitions have been used throughout the experimental section.

Acronyms or abbreviations: MeOH (methanol), EDC (dichloroethane), HOBt (N- hydroxybenzotriazole), Na₂SO₄ (sodium sulphate), DMF (N,N-dimethylformamide) HCI (hydrochloric acid), EDCHCI (dichloroethane hydrochloride), LiOH (lithium hydroxide), TLC (thin layer chromatography), g (grams), mmol (millimoles), mL (milliliters), mp or MP (melting point), rt (room temperature), aq (aqueous), min (minutes), h, hr, or hrs (hours), atm (atmosphere), cone, (concentrated), MS, Mass Spec or Mass (mass spectroscopy/spectrometry), NMR (nuclear magnetic resonance), Rf (TLC retention factor), and Rt (HPLC retention time), IR (infrared ), KBr (potassium bromide). NMR abbreviations: br (broad), apt (apparent), s (singlet), d (doublet), t (triplet), q (quartet), dq (doublet of quartets), dd (doublet of doublets), dt (doublet of triplets), m (multiplet), CDCI₃ (deuterated chloroform).

General Synthetic Procedures

Room temperature is defined as an ambient temperature range, typically 20-35 °C. An ice bath (crushed ice/water) temperature is defined as a range, typically -5 to 0 °C. Temperature at reflux is defined as about ±15 °C of the boiling point of the primary reaction solvent. Overnight is defined as a time range of about 8-16 hours. Vacuum filtration (water aspirator) is defined as range of about 5-15 mm Hg. Dried under vacuum is defined as using a high vacuum pump as a range of about 0.1-5 mm Hg. Neutralization is defined as a typical acid-based neutralization method and measured to a pH range of about pH 6-8 using pH-indicating paper. Brine is defined as a saturated aqueous sodium chloride. Nitrogen atmosphere is defined as positive static pressure of nitrogen gas passed through a Drierite column with an oil bubbler system. Concentrated ammonium hydroxide is defined as an approximately 15 M solution.

All eluents for column or thin layer chromatography were prepared and reported as volume:volume (v:v) solutions. The quantities of solvents and reagents used for reaction work-up or product isolation are those typically used by one trained in the art of organic chemical synthesis, and the quantity of these solvents and reagents used is determined based upon synthetic experience and appropriateness to the specific reaction. For example: 1) crushed ice quantity typically ranged from about 10-1000 grams depending on reaction scale; 2) silica gel quantity used in column chromatography depended on material quantity, complexity of mixture, and size of chromatography column employed and typically ranged from about 5-1000 grams; 3) extraction solvent volume ranged from about 10-500 ml_ depending on reaction size; 4) washes employed in compound isolation ranged from about 10-100 ml_ of solvent or aqueous reagent depending on scale of reaction; and 5) drying reagent amounts (potassium carbonate, sodium carbonate, magnesium sulfate, and the like) typically ranged from about 5-100 grams depending on the amount of solvent to be dried and its water content.

Preparation 1

2-isocyanoindane-2-carboxylic acid, methyl ester

To a mixtute of or#7θ-xylyl-1 ,1 ^'-dibromide (74.7 gram, 283 mmol), methyl 2- isocyanoacetate (28 gram, 283 mmol) in dry acetonitrile solvent (1.41 L) were added tetrabutylammonium bisulfate (19.2 gram, 56.6 mmol) and dry potassium carbonate ( 117 gram, 0.85 mol). The reaction mixture was refluxed for 3-4 hours. Another portion of dry potassium carbonate (117 gram, 0.85 mol) was added and it was continued to reflux for another 3-4 hours. The reaction mixture was filtered through celite, filtrate was condensed on rotavapor and diluted with ethyl acetate. Ethyl acetate layer was washed with water, dried over sodium sulphate (Na₂SO₄), concentrated, and the crude material was purified on flash chromatography (silica gel, ethyl acetate/hexanes) to obtain the title compound in pure form.

Yield: 20 gram (35 %).

¹H NMR (200 MHz, CDCI₃): D 3.44 (d, J=6.5 Hz, 2H); 3.69 (d, J=6.5 Hz, 2H); 3.85 (s,

3H); 7.20-7.30 (aromatics, 4H).

MS (CI) (/77/z): 219 (M+18).

IR (cm^"1) (KBr): 2967, 2142, 1745.

Preparation 2

2-Aminoindane-2-carboxylic acid, methyl ester

To a solution of 2-isocyano indane-2-carboxyllicacid methyl ester (20 gram, 99.5 mmol) in methanol (200 ml), con. HCI (5 ml) was added at 0 ⁰C and stirred at room temperature for 1 hour. The reaction mixture concentrated on rotavapour and diluted with water and washed with ether then the aqueous layer was basified with ammonia solution to adjust p^H 10. The product extracted into ethyl acetate, dried over Na₂SO₄ and concentrated to get pure product.

Yield: 15.2 gram (80%).

¹H NMR (200 MHz, CDCI₃): D 2.47 (bs, 2H, NH); 2.89 (d, J=5.9 Hz, 2H); 3.56 (d, J=6.1

Hz, 2H); 3.77 (s, 3H); 7.15-7.30 (aromatics, 4H).

MS (Cl) (m/z): 192 (M+1).

IR (KBr): 3375, 2925, 1732 cm^"1.

EXAMPLE 1

One illustrative LASY inducer isCompound A, which has the structure: 2-[2-(1H-lndol-3-yl)acetylamino]indan-2-carboxylic acid, methyl ester

To a solution of 2-(1H-indol-3-yl)acetic acid (4.4 gram, 25.1 mmol) and HOBt (4.6 gram, 30.1 mmol) in dry DMF (120 mL) at 0 ⁰C was added EDCHCI (5.8 gram, 30.1 mmol) in portions. After 15 mins, a DMF (5 ml) solution of and triethylamine (7 ml, 50.2 mmol) and 2-aminoindane-2-carboxylic acid, methyl ester (4.8 gram, 25.1 mmol), obtained in preparation 2, was added drop-wise at 0 ⁰C. The reaction mixture was stirred at 0 ⁰C to room temperature for 16 hours. The reaction mixture was diluted with 200 ml of ethyl acetate and was washed with aqueous citric acid, followed by sodium bicarbonate solution. The ethyl acetate layer was dried over sodium sulphate (Na₂SO₄), condensed, and the crude was purified on flash chromatography (silica gel, ethyl acetate/hexanes) to obtain the title compound in pure form. Yield: 6.8 g, (78 %).

EXAMPLE 2

Another illustrative LASY inducer is Compound B, which has the structure: 2-[2-(1 H-lndol-3-yl)acetylamino]indan-2-carboxylic acid

To a solution of 2-[2-(1H-indol-3-yl)acetylamino]indan-2-carboxylic acid, methyl ester (6.8 gram, 19.5 mmol), obtained in example 1 , in MeOH (100 mL), was added at room temperature an aqueous solution (20 ml) of LiOH. H₂O (2.5 g, 58.62 mmol). The reaction mixture was stirred at room temperature and the progress was monitored by TLC. After completion of hydrolysis (takes 3-4h) the reaction mixture was condensed on rotavapor, diluted with water, and was washed with diethylether. Aqueous layer was acidified using HCI to adjust the pH at 4. The precipitated solid was filtered, washed with water followed by cold ethanol. The solid was dried under high vaccum to obtain the desired compound in pure form (yield: 5.5 g, 85 %). The title compounds of EXAMPLES 2-57 were prepared by using procedures analogous to that of Example 1 from appropriate starting material.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (I), R²

^(Ri)m~O^^

wherein:

X represents NH or N-R⁷, wherein R⁷ is selected from optionally substituted group selected from (C-₁-C₅) alkyl or aralkyl or -SO₂-R' wherein R' represents optionally substituted alkyl or optionally substituted aryl;

A represent

— is a bond or no bond;

B represents -CH₂-, -NH-, Or -NH-CH₂-;

2. A compound of the formula (II)

wherein:

-

p ,

— is a bond or no bond;

B represents -CH₂-, -NH-, Or -NH-CH₂-;

3. A compound of formula (III)

(III) wherein:

X represents NH or N-R⁷, wherein R⁷ is selected from optionally substituted group selected from (C₁-C₅) alkyl or aralkyl or -SO₂-R" wherein R' represents optionally substituted alkyl or optionally substituted phenyl;;

R⁶ represents hydrogen, optionally substituted groups selected from alkyl, haloalkyl, alkoxy, haloalkoxy; n is an integer from 0 to 4 inclusive; m is an integer from 1 to 2 inclusive; p is an integer from 0 to 1 inclusive is a bond or no bond;

4. pharmaceutically-acceptable salt of the compound of the formula (I) as a Lipoic acid synthase (LASY) inducer.

5. A pharmaceutical composition comprising a derivative of formula (I) and one or more pharmaceutically-acceptable excipients.

6. A process for the preparation of the compound of formula (I) according to the procedure of the following scheme:

wherein Gi and G₂ are independently selected from carboxylic acid or its esters or its amides, n varies from 0 to 4 and all other symbols are as defined earlier, which process comprises reacting the compound of formula (1a) with the compound of formula (1b) in the presence of a reagent to form a compound of formula (I).