Method for treating 5-HT1A receptor related conditions
Field of the Invention
This invention relates to a method for treating 5-Hydroxytryptamine 1A (5-HT1A) receptor related conditions using arylpiperazines and aryloxyethylamine derivatives. Also provided herein are pharmaceutical compositions comprising one or more arylpiperazines and aryloxyethylamine derivatives together with one or more pharmaceutically acceptable carriers, excipients, diluents or mixture thereof, for treatment or prevention of 5-HTiA receptor related conditions.
Background of invention
Serotonin (5-Hydroxytryptamine (5-HT)) is a neurotransmitter in the peripheral and central nervous system well known for its implication in mood regulation, anxiety, depression and insomnia. The discovery of several classes of receptors for serotonin and the search for their implications in the mechanisms of mood and anxiety has been widely studied. 5-HT receptors belonging to both the G protein-coupled and ligand-gated ion channel super families have been identified. These have been divided into seven distinct families, or classes, according to structural diversity and the preferred effector mechanism. Some of these classes comprise multiple receptors, which share similar structural and effector properties, but display very different operational profiles
One of these receptor subtypes, such as 5-HTIA, is found in high concentration in the limbic system in which it is thought to play a role in emotional processes. The activation of 5-HTIA receptor leads to a number of physiological changes. Several structurally different compounds possess high affinity and selectivity for 5-HT 1A receptor. Among these compounds like buspirone, gepirone exhibit selective agonist or partial agonist activity for 5-HTIA receptor and have proved to be effective for the treatment of anxiety states or depression. Therefore, despite during recent years serotoninergic ligands have been suggested to be useful as therapies for anxiety, depression, psychosis, sleep disturbances/disorders, feeding behaviour/eating disorders, sexual dysfunction, hypertension, cognitive disorders, gastric motility disorders, brain trauma, memory loss, obesity, substance abuse, obsessive-compulsive disease, panic disorder and migraine, there still remains need of, 5-HTiA ligands with a remarkable affinity for the serotoninergic 5-HTiA receptors.
WO 2006/069993 describes arylpiperazine derivatives and use thereof. US 6982332 disclose hybrid 2-aminotetralin and aryl-substituted piperazine compounds and their use in altering CNS activity. US 7247633 describes pyrimidine compounds and their use for the preparation of a
medicament which particularly acts on the central nervous system. US 6670400 disclose phenoxyethylamine derivatives having high affinity for the 5-HT1A receptor, preparation thereof, use thereof as drugs and pharmaceutical compositions containing said derivatives. US5998666 and US 6150417 disclose phenoxyethylamine derivatives, method of preparation, application as medicine and pharamaceutical compositions containing the same. EP 0771563 describes use of 5-HT1A receptor ligands for the treatment of glaucoma.
US 6699864 relates to substituted phenyl-piperazine derivaties, their preparation and use. WO 97/08159 discloses 1 -(Hetero)aryl-4-(condensed thiazol-2-ylalkyl)-piperazine derivatives, their preparation and use in the treatment of 5-HT1A-receptor mediated disorders. US 6063784 describes heteroaryloxyethylamines, method of preparation, application as medicine and pharmaceutical compositions containing them. US 5229412 discloses method for relieving anxiety using 5-Hydroxytryptamine-lA-receptor binding compounds
EP 0633260 describes 2,3-dihydro-l,4-benzodioxin-5-yl-piperazine derivatives having 5-HT1A-antagonistic activity. EP 0512755 describes piperazine derivatives that are 5-HT1A binding agents, particularly 5-HT1A antagonists and may be used as anxiolytics.
5-HT1A ligands , particularly arylpiperazines can also bind at other population of receptors such as 5-HT2, dopamine, adrenergic, sigma, therefore attempts are made to use combination of these. US 6312717 relates to method for treatment of anxiety and depression comprising the concurrent administration of effective doses of certain azapirones, such as buspirone, given in a manner that suppresses formation of 1 -(2-pyrimidinyl)piperazine metabolite; and a 5-HT1A autosomal receptor antagonist, such as pindolol. WO 0244142 describes piperazine derivatives, their preparation and their use for treating central nervous disorders.US 5106849 describes use of aryl- and heteroaryl piperazinyl carboxamides in the treatment of various central nervous system disorders.
PCT applications WO 2005/037282, WO 2005/037281, WO 2005/118537, WO 2006/051374 and WO 2007/039809 disclose adrenergic receptor antagonists.
Summary of the Invention
This invention relates to a method for treating a mammal suffering from or susceptible to a condition related with 5-HTiA receptor using arylpiperazines and aryloxyethylamine derivatives. Also provided herein is a pharmaceutical composition comprising one or more arylpiperazines and aryloxyethylamine derivatives together with one or more pharmaceutically acceptable carriers, excipients, diluents or mixture(s) thereof, for treatment or prevention of 5-HT1A receptor related conditions.

This invention relates to arylpiperazines and aryloxyethylamine derivatives which by virtue of their high binding affinity to the 5-HT1A receptor are useful for the treatment of central nervous system (CNS) disorders for example depression, anxiety, panic disorder, obsessive-compulsive disorder(OCD), psychosis, sleep disturbances/disorders, feeding behaviour/eating disorders, sexual dysfunction, hypertension, cognitive disorders, gastric motility disorders, brain trauma, memory loss, obesity, substance abuse, and migraine.
Detailed Description of the Invention
In one embodiment, the invention relates to a method for treating a mammal suffering from or susceptible to a condition related with 5-HT1A receptor comprising administering to a mammal in need thereof a therapeutically effective amount of a compound selected from the group of compounds of the Formula I and II
(Formula Removed)
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs thereof, wherein:
(Figure Removed)
X is -(CH2)n, -NHCH2-, CH(OH), -(C=O)NHCH2-, wherein n is integer from 1 to 3
R' and R" can be independently hydroxyl, methyl
R1 and R2can be independently hydrogen, hydroxyl, halogen, C1-6, alkyl or C1-6 alkoxy
A is
(Figure Removed)
— represents no bond or a single bond; R3 and R4 are independently selected from
hydrogen, halogen, hydroxyl, acetoxy, optionally substituted alkyl (C1-C6)[ wherein the substituents are selected from the group consisting of halogen (F, Cl, Br or I), cycloalkyl(C3-C7), cycloalkenyl (C3-C7)], alkenyl, alkynyl (C2-C7), cycloalkyl (C3-C7) group optionally substituted with halogen (F, Cl, Br or I) atoms, halogen, hydroxyl, acetoxy, -(CH2)t- N(R10)R11 [wherein t is integer 0 to 1, R1O is hydrogen or alkyl, R11 is selected from alkyl or cycloalkyl], R3 and R4 can together form a group selected from cycloalkyl, cycloalkenyl, bicyclic alkyl,
bicyclic alkenyl, aryl , heterocycle, or ° ( wherein Z is CFk or CO),
R5 and R7 are independently hydrogen, alkyl, allyl, or phenyl, R6 is hydrogen, alkyl, phenyl,
hydroxyl or alkoxy.
R8 and R9 are each independently hydrogen, hydroxyl, alkoxy, acetyl or acetyloxy.

R is 13 wherein R12 is selected from alkyl or cycloalkyl, and wherein R^ is selected
from hydrogen, halogen or alkyl.
Bis
(Figure Removed)
m is 2; q is 0 -3
In another embodiment, the invention encompasses compounds of Formula I and Formula II, which are contemplated for use in condition, related with 5-HT]A receptor, may include, but not limited to the following, for example
2-(2,4-dioxo-l,3-thiazolidin-3-yl)-N-(2-{4-[2-(l-methylethoxy)phenyl]piperazin-l-yl}ethyl)acetamide hydrochloride salt (Compound No. 1),
N-[2-(2-ethoxyphenoxy)ethyl]-7-methoxy-l,2,3,4-tetrahydronaphthalen-2-amine hydrochloride salt (Compound No. 2),
1 - [(2- {4- [2-( 1 -methylethoxy)phenyl]piperazin-1 -yl} ethyl)amino] -2-phenylpropan-2-ol hydrochloride salt (Compound No. 3),
2-(5-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}pentyl)-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 4),
l-(2-hydroxy-3-{4-[2-(2,2,3,3-tetrafluoropropoxy)phenyl]piperazin-l-yl}propyl)piperidine-2,6-dione hydrochloride salt (Compound No. 5),
5,6-difluoro-2-(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propyl)hexahydro-lH-isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 6),
2-(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propyl)-l,3-dioxooctahydro-lH-isoindole-5,6-diyl diacetate hydrochloride salt (Compound No. 7),
2-(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propyl)-4,5,6,7-tetrahydro-lH-isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 8),
3-(cyclopropylamino)-l-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}pyrrolidine-2,5-dione hydrochloride salt (Compound No. 9),
1 -(3 - {4- [2-(cyclopentyloxy)phenyl]piperazin-1 -yl} propy l)-3 -(cyclopropylamino)pyrrolidine-2,5-dione hydrochloride salt (Compound No. 10),
1 - {3-[4-(2-methoxyphenyl)piperazin-1 -yl]propyl} -3-prop-2-en-1 -ylpiperidine-2,6-dione hydrochloride salt (Compound No. 11),
1 -(3-{[2-(2-ethoxyphenoxy)ethyl]amino}propyl)piperidine-2,6-dione hydrochloride salt (Compound No. 12),
1 -(3-{[2-(2-methoxyphenoxy)ethyl]amino}propyl)piperidine-2,6-dione hydrochloride salt (Compound No. 13),
1 -(3 - {4- [2-(cyclopentyloxy)phenyl]piperazin-1 -yl} propyl)-3 -(cyclopropylamino)-4-methylpyrrolidine-2,5-dione hydrochloride salt (Compound No. 14),
l-(3-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}propyl)-3,4-dimethylpyrrolidine-2,5-dione hydrochloride salt (Compound No. 15),
l-(3-{4-[2-(cyclopropylmethoxy)phenyl]piperazin-l-yl}propyl)-3,4-dimethylpyrrolidine-2,5-dione hydrochloride salt (Compound No. 16),
l-{3-[4-(5-fluoro-2-propoxyphenyl)piperazin-l-yl]propyl}-3-methylpyrrolidine-2,5-dione hydrochloride salt (Compound No. 17),
3,4-dimethyl-l-(3-{4-[2-(2,2,3,3-tetrafluoropropoxy)phenyl]piperazin-l-yl}propyl)pyrrolidine-2,5-dione hydrochloride salt (Compound No. 18),
3-(cyclopropylamino)-4-methyl-l-(3-{4-[2-(2,2,3,3-tetrafluoropropoxy)phenyl]piperazin-l-yl}propyl)pyrrolidine-2,5-dione hydrochloride salt (Compound No. 19), 3 -[(cyclopropylamino)methyl] -1 -(3 - {4- [2-(2,2,3,3 -tetrafluoropropoxy)phenyl]piperazin-1 -yl}propyl)pyrrolidine-2,5-dione hydrochloride salt (Compound No. 20), 3-(cyclobutylamino)-4-methyl-l-(3-{4-[2-(2,2,3,3-tetrafluoropropoxy)phenyl]piperazin-l-yl}propyl)pyrrolidine-2,5-dione hydrochloride salt (Compound No. 21), 3-[(cyclobutylamino)methyl]-l-(3-{4-[2-(2,2,3,3-tetrafluoropropoxy)phenyl]piperazin-l-yl}propyl)pyrrolidine-2,5-dione hydrochloride salt (Compound No. 22),
2-[(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propyl)carbamoyl]-4,5-dihydroxycyclohexanecarboxylic acid hydrochloride salt (Compound No. 23), 4,7-dihydroxy-2- {3 - [4-(2-methoxyphenyl)piperazin-1 -yljpropyl} -3a,4,7,7a-tetrahydro-1H-isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 24),
2-(3-{4-[2-(2,2,3,3-tetrafluoropropoxy)phenyl]piperazin-l-yl}propyl)hexahydro-lH-isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 25),
2-(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propyl)-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 26),
2-(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propyl)-5,6-dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 27),
2-(3-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl}propyl)-4,7-dihydroxy-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 28),
6-(3 - {4- [5 -fluoro-2-( 1 -methyl ethoxy)phenyl]piperazin-1 -yl} propyl)tetrahydro-3 aH-[l,3]dioxolo[4,5-f]isoindole-5,7(4H,6H)-dione hydrochloride salt (Compound No. 29), or
6-(3 - {4- [5 -fluoro-2-( 1 -methylethoxy)phenyl]piperazin-1 -yl} propyl)tetrahydro-3 aH-[l,3]dioxolo[4,5-f]isoindole-2,5,7(4H,6H)-trione hydrochloride salt (Compound No. 30).
and their hydrochloride salts.
In another embodiment, the invention encompasses pharmaceutical compositions of compounds of Formula I and Formula II, together with one or more pharmaceutically acceptable carriers, excipients, diluents or mixture thereof for treatment or prevention of 5-HT1A receptor related conditions. The 5-HTiA receptor related conditions are for example depression, anxiety, panic disorder, obsessive-compulsive disorder(OCD), psychosis, sleep disturbances/disorders, feeding behaviour/eating disorders, sexual dysfunction, hypertension, cognitive disorders, gastric motility disorders, brain trauma, memory loss, obesity, substance abuse, hypertension and migraine.
In another embodiment, the invention encompasses compounds which may include, for example
2-(2,4-dioxo-l,3-thiazolidin-3-yl)-N-(2-{4-[2-(l-methylethoxy)phenyl]piperazin-l-yl}ethyl)acetamide hydrochloride salt (Compound No. 1),
N-[2-(2-ethoxyphenoxy)ethyl]-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine hydrochloride salt (Compound No. 2),
l-[(2-{4-[2-(l-methylethoxy)phenyl]piperazin-l-yl}ethyl)amino]-2-phenylpropan-2-ol hydrochloride salt (Compound No. 3),
2-(5 - {4- [5 -fluoro-2-( 1 -methylethoxy)phenyl]piperazin-1 -yl} pentyl)-3 a,4,7,7a-tetrahydro-1H-
isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 4),
l-(2-hydroxy-3-{4-[2-(2,2,3,3-tetrafluoropropoxy)phenyl]piperazin-l-yl}propyl)piperidine-2,6-
dione hydrochloride salt (Compound No. 5),
5,6-difluoro-2-(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propyl)hexahydro-lH-
isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 6),
2-(3 - {4-[5 -fluoro-2-( 1 -methylethoxy)phenyl]piperazin-1 -yl} propyl)-1,3-dioxooctahydro-1H-
isoindole-5,6-diyl diacetate hydrochloride salt (Compound No. 7),
2-(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propyl)-4,5,6,7-tetrahydro-lH-
isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 8),
3-(cyclopropylamino)-l-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}pyrrolidine-2,5-dione
hydrochloride salt (Compound No. 9),
l-(3-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}propyl)-3-(cyclopropylamino)pyrrolidine-
2,5-dione hydrochloride salt (Compound No. 10),
l-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-3-prop-2-en-l-ylpiperidine-2,6-dione
hydrochloride salt (Compound No. 11),
1 -(3- {[2-(2-ethoxyphenoxy)ethy 1]amino}propyl)piperidine-2,6-dione hydrochloride salt
(Compound No. 12),
1 -(3-{[2-(2-methoxyphenoxy)ethyl]amino}propyl)piperidine-2,6-dione hydrochloride salt
(Compound No. 13),
and their hydrochloride salts, pharmaceutically acceptable solvates, polymorphs, prodrugs,
stereoisomers, tautomeric forms, N-oxides and metabolites thereof.
In yet another embodiment, the invention encompasses a method of preparing compounds(compound nos 1-13) and their pharmaceutical compositions together with one or more pharmaceutically acceptable carriers, excipients, diluents or mixture(s) thereof.
Other objects will be set forth in accompanying detailed description, which follows and in the part will be apparent from the description or may be learnt by the practice of the invention. However, It should be understood that the following detailed description are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art and are intended to be encompassed within the scope of this invention.
Definition
The term "alkyl," unless otherwise specified, refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like. Alkyl groups may be substituted further with one or more substituents selected from alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, aryl, heterocyclyl, heteroaryl, arylthio, thiol, alkylthio, aryloxy, nitro, aminosulfonyl, aminocarbonylamino, -NHC(=O)Rf, -NRfRq, -C(=O)NRfRq,-NHC(=O)NRfRq,, -C(=O)heteroaryl, C(=O)heterocyclyl, -O-C(=0)NRfRq {wherein Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl}, nitro, or -SO2Rb (wherein Rb is alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, alkyl substituents may be further substituted by 1-3 substituents selected from alkyl, carboxy, -NRfRq, -C(=O)NRfRq,-OC(=O)NRfRq, -NHC(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), hydroxy, alkoxy, halogen, CFa, cyano, and -SO2Rb, (wherein Rb is same as defined earlier); or an alkyl group also may be interrupted by 1-5 atoms of groups independently selected from oxygen, sulfur or -NRa- {wherein Ra is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl,-C(=O)ORf (wherein Rf is the same as defined earlier), SO2R4 (where R4 is as defined earlier), or -C(=O)NRfRq (wherein Rf and Rq are as defined earlier)}. Unless otherwise constrained by the definition, all substituents may be substituted further by 1-3 substituents selected from alkyl, carboxy, -NRfRq, -C (=O)NRfRq, -O-C(=O)NRfRq, NHCOORb (wherein Rf ,Rq and Rb are the same as defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, and -SO2Rb(where Rb is same as defined earlier); or an alkyl group as defined above that has both substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above.
The term "alkenyl or alkynyl" stands for unsaturated hydrocarbon having two to six carbon atoms. One or more hydrogen of said alkenyl or alkynyl can be replaced by halogen, NHCORb, NHCOORb, CORb, OCORb (wherein, Rb is the same as defined earlier). Examples of alkenyl and alkynyl include, but are not limited to, ethylene, propylene, ethynyl, propynyl, and the like.
The term "alkoxy" stands for a radical represented by Formula O-alkyl and wherein alkyl is the same as defined above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and the like.
The term "cycloalkenyl" refer to unsaturated carboxylic ring having three to seven carbon atoms. Example of cycloalkenyl include, but are not limited to, include cyclopropenyl, and cyclobutenyl and the like,
The term "cycloalkyl" refers to saturated carbocyclic ring having three to seven carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl and cyclopentyl, and the like.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "aryl," unless otherwise specified, refers to carbocyclic aromatic groups, for example, phenyl, biphenyl or napthyl ring and the like, optionally substituted with 1 to 3 substituents selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CF3, cyano, nitro, COORe (wherein Re is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl), NHC(=O)Rf, -NRfRq, -C(=O)NRfRq, -NHC(=O)NRfRq, -O-C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), -SO2Rb (wherein Rb is same as defined earlier), carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or amino carbonyl amino. The aryl group optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S.
The term "heteroaryl," unless otherwise specified, refers to an aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having from 8 to 10 ring atoms, with one or more heteroatom(s) independently selected from N, O or S optionally substituted with 1 to 4 substituent(s) selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, aryl, alkoxy, aralkyl, cyano, nitro, heterocyclyl, heteroaryl, -NRfRq, CH=NOH, -(CH2)wC(=O)Rg {wherein w is an integer from 0-4 and Rg is hydrogen, hydroxy, ORf, NRfRq, -NHORZ or -NHOH}, -C(=O)NRfRq and -NHC(=O)NRfRq , -SO2Rb, -O-C(=O)NRfRq, -O-C(=O)Rf, -O-C(=O)ORf (wherein Rb, Rf and Rq are as defined earlier, and Rz is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, the substituents are attached to a ring atom, i.e., carbon or heteroatom in the ring. Examples of heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, or benzoxazolyl, and the like.
The term 'heterocyclyl," unless otherwise specified, refers to a non-aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1 to 4 carbon atoms in a ring are replaced by heteroatoms selected from O, S or N, and optionally are benzofused or fused
heteroaryl having 5-6 ring members and/or optionally are substituted, wherein the substituents are selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, alkoxy, alkaryl, cyano, nitro, oxo, carboxy, heterocyclyl, heteroaryl, -O-C(=O)Rf, -0-C(=O)ORf, -C(=O)NRfRq, SO2Rb, -O-C(=O)NRfRq, -NHC(=O)NRfRq, -NRfRq (wherein Rb, Rf and Rq are as defined earlier) or guanidine. Heterocyclyl can optionally include rings having one or more double bonds. Unless otherwise constrained by the definition, the substituents are attached to the ring atom, i.e., carbon or heteroatom in the ring. Also, unless otherwise constrained by the definition, the heterocyclyl ring optionally may contain one or more olefmic bond(s). Examples of heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl or piperazinyl.
The groups " alkyl, aryl, heteroaryl and heterocyclyl" can optionally be substituted with substituent(s) selected from alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, heterocyclyl, heteroaryl, aralkyl, heteroarylalkyl, heterocycloalkyl, halogen, hydroxy, alkoxy, cyano, nitro, aryloxy, haloalkoxy, CORb, CSRb, COORb, S(O)aRb, OCOORb, OCORb, SO2NHRb, NHSO2Rb, NHCORb, NHCSRb, (CH)aC(=O)NRcRd or NRcRd (wherein, Rc and Rd are independently selected from hydrogen, alkyl, aryl, heteroaryl, heterocyclyl, Rb is the same as defined earlier and a is an integer of from 0-2). Unless otherwise constrained, all substituents may optionally be further substituted by substituent(s) defined earlier.
The term "polymorphs" includes all crystalline form as well as amorphous form for compounds described herein and as such are encompassed in the present invention.
The term "pharmaceutically acceptable carriers" is intended to include non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
The term "pharmaceutically acceptable salts" refer to a salt prepared from pharmaceutically acceptable organic or inorganic acids; such salts include hydrochlorides, sulfates, phosphates, tartarates, fumarates, citrates and the like. The free base forms of compounds of the present invention may be prepared from the salt forms, if desired, by contacting the salt with dilute aqueous solution of a base. The acid addition salts may differ from the free base forms of the compounds of this invention in such physical characteristics as solubility and melting point.
The salt forms differ from the compound described herein in certain physical properties such as solubility, but the salts are otherwise equivalent for purposes of this invention.
The term "pharmaceutically acceptable" means approved by regulatory agency of the federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
The term "pharmaceutically acceptable solvates" refers to solvates with water or pharmaceutically acceptable solvents.
The compounds described herein may be prepared by techniqes well known to one of ordinary skill in the art. In addition, method of making some pyrrolidine dione derivatives and their metabolites are described in our PCT application Nos. WO 2005/037282, WO 2005/037281, WO 2005/118537, WO 2006/051374, WO 2007/039809 and the compounds not specifically disclosed elsewhere are prepared as shown in Schemes I, II, III, IV, V and VI below.
(Figure Removed)
Compounds of Formulae IV and VI can be prepared according to scheme I. Thus, treatment of compound of Formula III
a) with a fluorinating agent gives a compound of Formula IV (wherein X and R are same as
defined earlier).
b) with a compound of Formula V (wherein RH is alkyl, aryl and U is leaving group for
example, halide, acyloxy or aryloxy) forms a compound of Formula VI.
The compounds of Formula IV and VI can be further converted to any pharmaceutically acceptable salt known to one ordinary skilled in art.
The reaction of compound of Formula III to give a compound of Formula IV can be carried out in presence of fluorinating agent, for example, DAST (diethyl amino sulfur trifluoride) or tris(dimethylamino)sulfur(trimethylsilyl)difluoride in a solvent for example, dichloromethane, tetrahydrofuran, dichloroethane, xylene, benzene , or toluene.
The compound of Formula III can be reacted with a compound of Formula V to form a compound of Formula VI in the presence of a base, for example, triethylamine, N-ethyl diisopropylamine, N-methylmorpholine, 4-dimethylaminopyridine, 1-methylimidazole, 1,2,4-triazole using relatively polar including dipolar aprotic solvent for example dimethylformamide, dichloromethane, tetrahydrofuran, dioxane, dimethylsulphoxide, N,N-dimethyl acetamide, trifluoroethanol, l-methyl-2-pyrrolidinone, l,l,l,3,3,3,-hexafluoro-2-propanol or mixture thereof.
(Figure Removed)
Compounds of Formulae X and XI can be prepared according to scheme II. Thus, reacting Compound of Formula VII
a) with maleic anhydride gives a compound of Formula VIII (wherein X and R are same as
defined earlier) which on reaction with a compound of Formula IX (wherein RIO and RH
are same as defined earlier) gives a compound of Formula X.
b) with 4,5,6,7-tetrahydro-2-benzofuran-l,3-dione gives a compound of Formula XL
The compounds of Formula X and XI can be further converted to any pharmaceutically
acceptable salt known to one ordinary skilled in art.
The reaction of a compound of Formula VII with maleic anhydride to form a compound of
Formula VIII can be carried out in a solvent for example, acetonitrile, toluene, xylene, benzene,
dichloromethane, or chloroform. The reaction of a compound of Formula VIII with a compound
of Formula IX to give a compound of Formula X can be carried out in a solvent, for example,
methanol, ethanol, tetrahydrofuran, chloroform, acetonitrile, dimethylsulfoxide,
dimethylformamide, cyclohexane, dichloromethane, methanol or mixtures thereof.
The reaction of a compound of Formula VII with 4,5,6,7-tetrahydro-2-benzofuran-l,3-dione to
give a compound of Formula XI can be carried out under similar conditions as that of
conversion of a compound of Formula VII to form a compound of Formula VIII.
(Formula Removed)
Compounds of Formula XIV can be prepared according to scheme III. Thus, reacting a compound of Formula XII with a compound of Formula XIII (wherein hal is Cl or Br) gives a compound of Formula XIV.
The reaction of a compound of Formula XII with a compound of Formula XIII can be carried out in presence of a reducing agent, for example, lithium diisopropylamide or n-butyl lithium in a solvent, for example, diethyl ether, tetrahydrofuran, hexane or cyclohexane at a suitable temperature ranging from about -78 to about -20°C.

(Figure Removed)
Compounds of Formulae XX and XXII can be prepared according to scheme IV. Thus, compounds of Formula XV (wherein m is 2 and hal is Cl or Br) is reacted with compound of Formula XVI (wherein R is defined same as earlier) to form a compound of Formula XVII which can be further deprotected to form a compound of Formula XVIII. Reacting a compound of Formula XVIII
a) with a compound of Formula XIX (wherein R1 and R2 are defined same as earlier) gives a compound of Formula XX
b) with a compound of Formula XXI (wherein X and Hal are defined same as earlier) gives a compound of Formula XXII.
Compounds of Formula XV can be reacted with a compound of Formula XVI in the presence of one or more inorganic bases, for example, potassium carbonate, sodium carbonate, sodium hydride, barium carbonate, calcium carbonate or mixture thereof, in one or more solvents, for example, aprotic polar solvents (e.g. dimethylformamide, dimethylsulfoxide or dimethylacetamide), nitriles (acetonitrile or propionitrile), polar protic solvents (methanol, ethanol, isopropanol or water) or mixture thereof.
Compound of Formula XVII can be deprotected to form a compound of Formula XVIII in the presence of bases, for example, hydrazine hydrate or sodium hydroxide under reflux conditions or under microwave conditions in one or more solvents, for example, polar protic solvents(for example methanol, ethanol isopropanol or water) or mixture thereof.
Compound of formula XVIII can be reacted with compounds of Formula XIX in the presence of one or more reducing agents, catalytic reducing agents (for example hydrogen platinum, hydrogen/raney nickel or hydrogen/palladium-carbon), boron reagents (for example, sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride), metal ammonia reduction (ammonia, hydrogen/nickel) or mixtures thereof in one or more solvents, for example, chlorinated solvents (for example, dichloromethane, dichloroethane or chloroform), polar protic solvents (for example methanol, ethanol, isopropanol or water) or mixtures thereof. Compound of Formula XVIII can be reacted with a compound of Formula XXI to form a compound of Formula XXII under similar conditions as that of conversion of a compound of Formula XV to form a compound of Formula XVII.
(Formula Removed)
Compounds of Formula XXVIII can be prepared according to scheme V. Thus, compounds of Formula XV is reacted with compound of Formula XXIII (wherein R is defined same as earlier) to form a compound of Formula XXIV which can be further deprotected to form a compound of Formula XXV. The compound of Formula XXV is then coupled with a compound of Formula XXVI (wherein RI, R2, R' and R" are same as defined earlier) to form compound of Formula XXVII, which is then reduced to give a compound of Formula XXVIII.
Compounds of Formula XV can be reacted with a compound of Formula XXIII to form a compound of Formula XXIV under similar conditions as that of conversion of a compound of Formula XV to form a compound of Formula XVII.
Compounds of Formula XXIV can be deprotected to form a compound of Formula XXV under similar conditions as that of deprotection of a compound of Formula XVII to form a compound of Formula XVIII.
Coupling of a compound of Formula XXV with a compound of Formula XXVI to give a compound of Formula XXVII can be carried out in a solvent, for example, dimethyl formamide, tetrahydrofuran, dioxane or diethyl ether and a base, for example, triethylamine, N,N-dimethylaminopyridine, 2,6-lutidine, 1-methylpiperidine, N,N-diisopropylethylamine or N-methylmorpholine, in the presence of a additives for example hydroxybenzotriazole, 3-hydroxy-3,4-dihydro-4-oxo-l,2,3-benzotriazine, 2-hydroxypyridine, N-hydroxysuccinimide or 1-hydroxy-7-azabenzotriazole, with a suitable condensing agent for example, dicyclohexyl carbodimide, l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride, chlortripyrrolidino
phosphoniumhexafluorophosphate or (benzotriazol-1 -yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate.
Compounds of Formula XXVII can be reduced to give a compound of Formula XXVIII in the presence of one or more reducing agent, for example, lithium aluminium hydride, sodium aluminium hydride; catalytic reducing agents for example (hydrogen/platinum, hydrogen/palladium/hydrogen/nickel), hydrazine hydrate in presence of a base, metal/acid (zinc in hydrochloric acid) or mixtures thereof, in one or more solvents, for example, aprotic olar solvents ( tetrahydrofuran, diisopropyl ether, acetone, acetonitrile), polar protic solvents (ethanol, methanol, isopropyl alcohol or water) or mixtures thereof.
(Figure Removed)
Compounds of Formula XXXII can be prepared according to scheme VI. Thus, compounds of Formula XXIX (wherein R'" is methyl, ethyl, isobutyl) is reacted with thiazolidine 2,4-dione to give a compound of Formula XXX which is then hydrolyzed to give a compound of Formula XXXI. The compound of Formula XXXI is coupled with a compound of Formula XXV to give a compound of Formula XXXII.
The reaction of a compound of Formula XXIX with thiazolidine 2,4-dione can be carried out in one or more solvents , for example, polar protic solvent (dimethylformamide, dimethylsulfoxide, acetone, methyl ethyl ketone, diisopropyl ketone or acetonitrile), ethers (tetrahydrofuran, dioxane, or diethyl ether) or mixture thereof in presence of one or more inorganic bases for example, sodium hydride, barium carbonate, cesium carbonate, calcium carbonate, sodium carbonate, potassium carbonate or mixtures thereof.
Compound of Formula XXX (when R"' is ethyl) can be hydrolysed to form a compound of Formula XXXI in a solvent selected from for example methanol, ethanol, tetrahydrofuran, dioxane, water or mixture(s) thereof in the presence of a base for example lithium hydroxide, potassium hydroxide or sodium hydroxide. Alternatively hydrolysis the compound of Formula XXX to form the compound of Formula XXXI when ester is tert-butyl or trimethylsilyl can be carried out in the presence of acid, for example, trifluoroacetic acid or hydrochloric acid in a solvent for example dichloromethane, water and mixture(s) thereof.
Coupling of a compound of Formula XXXI with a compound of Formula XXV to form a compound of Formula XXXII can be carried out under similar conditions as that of conversion of a compound of Formula XXVI to give a compound of formula XXVII. The salts described herein may be prepared by the useful prior art techniques, such as suspending the compound in water and then adding one equivalent of an organic acid such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, adipic acid, ascorbic acid, camphoenic acid, nicotinic acid, butyric acid, lactic acid, glucuronic acid, or inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, boric acid and perchloric acid.
The neutral solution of the resulting salt is subjected to rotary evaporation under reduced pressure to the volume necessary to ensure precipitation of the salt upon cooling, which is then filtered and dried. The salts of the present invention may also be prepared under strictly non-aqueous conditions, For example, dissolving free bases in an organic solvent such as ethanol, methanol, isopropanol, dichloromethane or diethyl ether adding exactly one equivalent of the desired acid to the same solvent and stirring the solution at 0°C to 5°C, causes the precipitation of the acid addition salt, which is then filtered, washed free from the solvent, and dried. Alternatively, the solvent is stripped completely to obtain the desired salt. These salt are often preferred for use in formulating the therapeutic composition of the invention because they are crystalline and relatively more stable and water soluble.
When administered to an animal, the compounds or pharmaceutically acceptable salts of the compounds can be administered alone or as a component of a composition that comprises a physiologically acceptable carrier or vehicle. A composition of the invention can be prepared using a method comprising admixing the compound or a pharmaceutically acceptable salt of the compound and a physiologically acceptable carrier, excipient, or diluent. Admixing can be accomplished using methods well known for admixing a compound or a pharmaceutically acceptable salt of the compound and a physiologically acceptable carrier, exipient, or diluent.
The compositions comprising compounds or pharmaceutically acceptable salts of the compounds of the invention can be administered orally. The compounds or pharmaceutically acceptable salts of compounds of the invention can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral, rectal, vaginal, and intestinal mucosa, etc.) and can be administered together with another therapeutic agent. Administration can be systemic or local. Various known delivery systems, including encapsulation in liposomes, microparticles, microcapsules, and capsules, can be used.
Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical, particularly to the ears, nose, eyes, or skin. In some instances, administration will result of release of the compound or a pharmaceutically acceptable salt of the compound into the bloodstream. The mode of administration is left to the discretion of the practitioner.
In one embodiment, the compound or a pharmaceutically acceptable salt of the compound may be administered orally.
In another embodiment, the compound or a pharmaceutically acceptable salt of the compound may be administered intravenously.
In another embodiment, it may be desirable to administer the compound or a pharmaceutically acceptable salt of the compound locally. This can be achieved, for example, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository or edema, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
In certain embodiments, it can be desirable to introduce the compound or a pharmaceutically acceptable salt of the compound into the central nervous system, circulatory system or gastrointestinal tract by any suitable route, including intraventricular, intrathecal injection, paraspinal injection, epidural injection, enema, and by injection adjacent to the peripheral nerve. Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.
Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant. In certain embodiments, the compound or a pharmaceutically acceptable salt of the compound can be formulated as a suppository, with traditional binders and excipients such as triglycerides.
The pharmaceutical compositions of the present invention can optionally comprise a pharmaceutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable excipients.
Such physiologically acceptable excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The physiologically acceptable excipients can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment the physiologically acceptable excipients are sterile when administered to an animal. The physiologically acceptable excipient should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms. Water is a particularly useful excipient when the compound or a pharmaceutically acceptable salt of the compound is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions. Suitable physiologically acceptable excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
The pharmaceutical compositions of the present invention comprise a pharmaceutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. The "pharmaceutically acceptable carriers" includes non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups, and elixirs. The compound or pharmaceutically acceptable salt of the compound of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fat. The liquid carrier can
contain other suitable pharmaceutical additives including solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particular containing additives as above, e.g., cellulose derivatives, including sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols), for example, ethyl alcohol, isopropyl alcohol, benzyl alcohol, propylene glycol, 1,3-butylene glycol) and their derivatives,(for example, ethyl acetate, benzyl benzoate) and oils (e.g., fractionated coconut oil, cottonseed, groundnut, corn, germ, olive, castor, sesame and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
The pharmaceutical compositions of the present invention can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. In one embodiment, the composition is in the form of a capsule. In one embodiment, the compound or a pharmaceutically acceptable salt of the compound is formulated in accordance with routine procedures as a composition adapted for oral administration to humans. Compositions for oral delivery can be in the form of tablets, lozenges, buccal forms, troches, aqueous or oily suspensions or solutions, granules, powders, emulsions, capsules, syrups, or elixirs for example. Orally administered compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. In powders, the carrier can be a finely divided solid, which is an admixture with the finely divided compound or pharmaceutically acceptable salt of the compound. In tablets, the compound or pharmaceutically acceptable salt of the compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets can contain up to about 99% of the compound or pharmaceutically acceptable salt of the compound.
Capsules may contain mixtures of the compounds or pharmaceutically acceptable salts of the compounds with inert fillers and/or diluents such as pharmaceutically acceptable starches (e.g., corn, potato, or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (such
as crystalline and microcrystalline celluloses), flours, gelatins, gums, etc.
Tablet formulations can be made by conventional compression, wet granulation, or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents (including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrroldine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins. Surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine.
Moreover, when in a tablet or pill form, the compositions can be coated to delay disintegration
and absorption in the gastrointestinal tract, thereby providing a sustained action over an
extended period of time. Selectively permeable membranes surrounding an osmotically active
driving compound or a pharmaceutically acceptable salt of the compound are also suitable for
orally administered compositions. In these latter platforms, fluid from the environment
surrounding the capsule can be imbibed by the driving compound, which swells to displace the
agent or agent composition through an aperture. These delivery platforms can provide an
essentially zero order delivery profile as opposed to the spiked profiles of immediate release
formulations. A time-delay material such as glycerol monostearate or glycerol stearate can also
be used. Oral compositions can include standard excipients such as mannitol, lactose, starch,
magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment
the excipients are of pharmaceutical grade.
In another embodiment, the compound or a pharmaceutically acceptable salt of the compound can be formulated for intravenous administration. Typically, compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, the compositions can also include a solubilizing agent. Compositions for intravenous administration can optionally include a local anesthetic such as lignocaine to lessen pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example,
as a dry lyophilized powder or water-free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent. Where the compound or a pharmaceutically acceptable salt of the compound is to be administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the compound or a pharmaceutically acceptable salt of the compound is administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
In another embodiment, the compound or pharmaceutically acceptable salt of the compound can be administered transdermally through the use of a transdermal patch. Transdermal administrations include administrations across the surface of the body and the inner linings of the bodily passages including epithelial and mucosal tissues. Such administrations can be carried out using the present compounds or pharmaceutically acceptable salts of the compounds, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (e.g., rectal or vaginal).
Transdermal administration can be accomplished through the use of a transdermal patch containing the compound or pharmaceutically acceptable salt of the compound and a carrier that is inert to the compound or pharmaceutically acceptable salt of the compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams or ointments, pastes, gels, or occlusive devices. The creams or ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the compound or pharmaceutically acceptable salt of the compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the compound or pharmaceutically acceptable salt of the compound with or without a carrier, or a matrix containing the active ingredient.
The compounds or pharmaceutically acceptable salts of the compounds of the invention may be administered rectally or vaginally in the form of a conventional suppository. Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used. In one embodiment, the pharmaceutical composition is in unit dosage form, e.g., as a tablet,
capsule, powder, solution, suspension, emulsion, granule, or suppository. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage form can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Such unit dosage form may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg. Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention. Such compositions may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
When administered for the treatment or inhibition of a particular disease state or disorder, it is
understood that the effective dosage may vary depending upon the particular compound utilized,
the mode of administration, the condition, and severity thereof, of the condition being treated, as
well as the various physical factors related to the individual being treated. In therapeutic
application, compounds of the present invention are provided to a patient already suffering from
a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the
disease and its complications. An amount adequate to accomplish this is defined as a
"therapeutically effective amount". The dosage to be used in the treatment of a specific case
must be subjectively determined by the attending physician. The variables involved include the
specific condition and the size, age and response pattern of the patient. Effective administration
of the compounds of this invention may be given at an oral dose of from about 0.1 mg/day to
about 1000 mg/day. Preferably, administration will be from about 10 mg/day to about 600
mg/day, more preferably, a starting dose is about 5 mg/day with gradual increase in the daily
dose to about 150 mg/day, to provide the desired dosage level in the human. Doses may be
administered in a single dose or in two or more divided doses. The projected daily dosages are
expected to vary with route of administration.
The compound or a pharmaceutically acceptable salt of the compound can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans. Animal model systems can be used to demonstrate safety and efficacy.
Accordingly, in one embodiment, the invention provides the use of a compound or pharmaceutically acceptable salt of the compound of Formula I or Formula II for the manufacture of a medicament for treating a condition related to or affected by 5-HTu receptor. Example set forth demonstrates the general synthetic procedure for the preparation of
representative compounds. The examples are provided to illustrate particular aspect of the disclosure and should not be constrained to limit the scope of the present invention
Experimental
Synthesis of 2-(5-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}pentyl)-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione
The title compound was prepared following Example-4 of WO 2005/037282
'H NMR (300 MHz, CDC13): δ 1.32-1.34 (d, 6H), 1.58-1.62 (m, 4H), 1.90 (bs, 2H), 2.24 (d,
2H), 2.59-2.60 (m, 2H), 2.8 (bs, 2H), 3.09-3.11 (m, 4H), 3.45-3.50 (m, 8H), 4.49-4.52 (m, 1H),
5.90 (t, 2H; J=3.0Hz), 6.62-6.80 (m, 3H)
Mass: m/z 458 (M++l)
Synthesis of l-(2-hydroxy-3-{4-[2-(2,2,3,3-tetrafluoropropoxy)phenyl]piperazin-l-yl}propyl)piperidine-2,6-dione
The title compound was prepared following Example-2 of WO 03/084928
'H NMR (300 MHz, CDC13): δ 1.88 (2H,t; J=12Hz), 2.61-2.65 (m, 4H), 3.01-3.17 (m, 4H),
3.62-3.66 (m, 6H), 3.77-3.81 (m, 2H), 4.16 (bs, 2H), 4.58(2H,t; J=12Hz ), 6.65 (lH,t; J=51Hz ),
7.61-7.68 (m,4H), 9.73 (s,lH)
Mass: m/z 461 (M++1)
Example-1
Synthesis of 5,6-difluoro-2-(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yI}propyl)hexahydro-lH-isoindoIe-l,3(2H)-dione hydrochloride salt
Step-1 Synthesis of 5,6-difluoro-2-(3-{4-[5-fluoro-2-(l-methylethoxv)phenvl]piperazin-l-yl}propyl) hexahydro-1 H- iso indole-1,3 (2H) -dione
2-(3 - {4- [5 -fluoro-2-( 1 -methylethoxy)phenyl]piperazin-1 -yl} propyl)-5,6-dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione [prepared following Example-5 of WO05118537 (compound No. 44)] (1 equiv) in dichloromethane was added diethylaminosulfurtrifluoride (1.2 equiv) dropwise under stirring at 0-5°C. The reaction mixture was allowed to come at room temperature and stirred for about 1 h. After completion of reaction, organic layer was washed with water, and dried over anhydrous sulphate and concentrated under reduced pressure to afford the title compound.
Step-2 Synthesis of 5,6-difluoro-2-(3-{4-[5-fluoro-2-(l-methvlethoxv)phenyl]piperazin-l-vl}projjyl)hexahvdro-lH-isoindole-1,3(2H)-dione hydrochloride salt
An equimolar quantity of isopropylalcohol-hydrochloric acid was added to 5,6-difluoro-2-(3-{4-
[5-fluoro-2-( 1 -methylethoxy)phenyl]piperazin-1 -yl }propyl)hexahydro-1 H-isoindole-1,3 (2H)-
dione and the resulting salt was solidified by adding ether to it.
'H NMR (300 MHz, CDC13): δ 1.39(6H,d; J=3.0Hz), 1.84 (bs, 4H), 2.02-2.17 (m, 5H), 2.13-
2.17(m, 1H), 2.36-2.39 (m, 1H), 2.95-3.03 (m, 2H), 3.04-3.37 (m, 2H), 3.56-3.66 (m, 4H), 4.15
(lH,d; J=3.0Hz), 4.56-4.59 (m, 1H), 4.57(s, 1H), 6.84-7.05 (m, 3H).
Mass: m/z 468 ( M++ 1)
Example-2
Synthesis of 2-(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propyl)-l,3-dioxooctahydro-lH-isoindole-5,6-diyl diacetate hydrochloride salt
Step-1 Synthesis of 2-(3-{4-[5-fluoro-2-(1 -methylethoxy)phenyljpiperazin-l-yl}propyl)-1,3-dioxooctahydro-1 H-isoindole-5,6-diyl diacetate
To a solution of 2-(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propyl)-5,6-dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione [prepared following Example-5 of WO05118537 (compound No. 44)] (1 equiv) in dichloromethane was added triethylamine (4 equiv) at 0-5°C, followed by addition of 4-Dimethylaminopyridine ( 1 equiv). Reaction was allowed to stir for 15 min followed by addition of acetyl chloride (2 equiv) dropwise. Reaction mixture was stirred at room temperature for 5h. Reaction mixture was washed with aqueous sodium bicarbonate and water. Dichloromethane layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford the title compound. Step-2 Synthesis of2-(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propyl)-l,3-dioxooctahydro-1 H-isoindole-5,6-diyl diacetate hydrochloride salt
An equimolar quantity of isopropylalcohol-hydrochloric acid was added to 2-(3-{4-[5-fluoro-2-(1 -methylethoxy)phenyl]piperazin-1 -yl} propyl)-1,3 -dioxooctahydro-1 H-isoindole-5,6-diyl diacetate and the resulting salt was solidified by adding ether to it. 'H NMR (300 MHz, CDC13): 1.33(6H,d; J= 6.0Hz), 1.60(4H,s), 1.96-2.02(6H,m), 2.21-
2.28(4H,m), 2.99 (4H,s), 3.24(2H,s), 3.47(4H,d J=6.0Hz), 3.6-3.64(2H,m), 4.48-4.52(lH,m), 5.00- (2H,d; J=3.0Hz), 6.60-6.81(3H,m)
Mass: m/z 548 ( M+ + 1)
Example -3
Synthesis of 2-(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propyl)-4,5,6,7-tetrahydro-lH-isoindole-l,3(2H)-dione hydrochloride
Step-1 Synthesis of 2-(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl~lpiperazin-l-yl}propyl)-4,5,6,7-tetrahydro-1 H-isoindole-1,3 (2H)-dione
A solution of 3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propan-l-amine
(obtained from Step-2, Example-1 of WO05037282) (1 equiv) and 4,5,6,7-tetrahydro-2-
benzofuran-l,3-dione (1.2 equiv) in toluene was refluxed for about 1 h. The reaction mixture
was concentrated to yield the crude product which was purified by column chromatography over
silica gel using 5% methanol in dichloromethane as eluant to afford the title compound.
Step-2 Synthesis of 2-(3-{4-[5-fluoro-2-(l-methylethoxy)phenvl]piperazin-l-yl}propvl)-4,5,6,7-
tetrahydro-lH-isoindole-l,3(2H)-dione hydrochloride
An equimolar quantity of isopropylalcohol-hydrochloric acid was added to 2-(3-{4-[5-fluoro-2-
(l-methylethoxy)phenyl]piperazin-l-yl}propyl)-4,5,6,7-tetrahydro-lH-isoindole-l,3(2H)-dione
and the resulting salt was solidified by adding ether to it.
The title compound was prepared following Example-1 of WO 2005/037282
'HNMR(300 MHz, CDC13) : δ 1.33 (6H,d; J=6.0Hz), 1.78-1.88 (6H,m), 2.41-2.60 (4H,m), 2.90
(2H, s), 3.09-3.11 (4H,m), 3.45-3.50 (4H,m), 3.66(2H,m), 4.49-4.52 (lH,m), 6.62-6.80 (3H,m)
Example -4
Synthesis of 3-(cyclopropylamino)-l-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}pyrrolidine-2,5-dione hydrochloride
Step-1 Synthesis of l-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-lH-pyrrole-2,5-dione
3-[4-(2-methoxyphenyl)piperazin-l-yl]propan-l-amine (obtained from Step-2, Example-1 of
WO 2005/037281) ( 1 equiv) and maleic anhydride (1.2 equiv) in toluene was refluxed for about
1 h. The reaction mixture was concentrated to yield the crude product which was purified by
column chromatography over silica gel using 5% methanol in dichloromethane as eluant to
afford the title compound.
Step-2 Synthesis of 3-(cyclopropvlamino)-l-{3-[4-(2-methoxvphenyl)piperazin-l-
yl]propyl}pyrrolidine-2,5-dione
To a solution of l-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-lH-pyrrole-2,5-dione (1
equiv) in cyclohexane: methanol (9:1) was added cyclopropyl amine (1.2 equiv) and the reaction
mixture was stirred for 5-6 h. Solvents were evaporated and the crude oil thus obtained was
purified by column chromatography using 5% methanol in dichloromethane as eluant to afford
the title compound.
Step-3 Synthesis of3-(cyclopropylamino)-l-{3-[4-(2-methoxyphenyl)piperazin-l-
yl]pyropyl}pyrrolidine-2,5-dione hydrochloride
An equimolar quantity of isopropylalcohol-hydrochloric acid was added to 3-
(cyclopropylamino)-l-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}pyrrolidine-2,5-dione and
the resulting salt was solidified by adding ether to it.
'H NMR (300 MHz, CDC13): δ 0.64 (s, 4H), 1.56 (s, 2H), 2.27 (s, 4H), 2.64-2.70 (m, 1H), 3.20-
3.27(m, 5H), 3.34 (s, 1H), 3.45(s, 5H), 3.68 (s, 2H), 3.83 (s, 3H), 6.84-7.04 (4H, m)
Mass: m/z 386 (M++ 1)
The following compound was prepared similarly
1 -(3- {4-[2-(cyclopentyloxy)phenyl]piperazin-1 -yl}propyl)-3-(cyclopropylamino)pyrrolidine-
2,5-dione hydrochloride
'H NMR (300 MHz, CDC13): δ 0.46-0.551 (d, 4H), 1.255 (s, 1H), 1.669-1.752 (m, 8H), 2.24-
2.33 (m, 4H), 2.998-3.086 (m, 4H), 3.45-3.66(8H,m). 3.96(lH,s)4.787-4.814 (m, 1H), 6.84-7.26
(m, 4H).
Mass: m/z 440 (M++l)
Example -5
Synthesis of l-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-3-prop-2-en-l-ylpiperidine-2,6-dione hydrochloride
Step a: Synthesis of l-{3-[4-(2-methoxvphenyl)piperazin-l-vl]propvl}-3-prop-2-en-l-ylpiperidine-2,6-dione
In a dried 3-neck round bottom flask was added dry tetrahydrofuran (150 mL) followed by addition of lithium diisopropylamide (10.64 mL,3eq) in nitrogen atmosphere at -20°C. l-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}piperidine-2,6-dione (obtained similarly as Compound No. 13, WO 00/05205) (7.6 g. leq) was added slowly maintaining the temperature -20°C. Reaction mixture was allowed to stir for Ih at same temperature. To the reaction mixture was then added allyl bromide (1.748 g. 1 eq) dropwise maintaining the temperature -20°C. After completion of reaction, the reaction was quenched with water (50 mL) and extracted with ethyl acetate. Organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The crude oil thus obtained was purified by column chromatography using 2% methanol in dichloromethane to afford the title compound 3.4 g. Step b: Synthesis of l-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-3-prop-2-en-l-ylpiperidine-2,6-dione hydrochloride
An equimolar quantity of isopropylalcohol-hydrochloric acid was added to l-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-3-prop-2-en-l-ylpiperidine-2,6-dione and the resulting salt was solidified by adding ether to it.
'H NMR (300 MHz, CDC13): δ 2.02 (2H,b), 2.17 (2H,b), 2.63-2.82 (5H,m), 3.13 (2H, s), 3.54
3.58 (4H,m), 3.92-4.00 (7H,m), 4.55 (2H,s), 5.133 (2H,d; J=6.0Hz}, 5.76 (lH,s), 7.00-7.78
(4H,m).
Mass: m/z 386 ( M+ + 1)
Example -6
Synthesis of N-[2-(2-ethoxyphenoxy)ethyl]-7-methoxy-l,2,3,4-tetrahydronaphthalen-2-amine hydrochloride salt
Step a: Synthesis of2-[2-(2-ethoxyphenoxy)ethyl]-lH-isoindole-l,3(2H)-dione
2-Ethoxyphenol (1.1 equiv) was added to dimethylformamide and dissolved completely. 2-(2-
Chloroethyl)-lH-isoindole-l,3(2H)-dione (1 equiv) and potassium carbonate (2 equiv) was
added to the reaction mixture and the reaction was stirred at 60-70°C for 8h. After the
compeletion of reaction mixture was cool up to room temperature. Reaction was quenched with
water followed by extraction of compound in ethyl acetate. Organic layer was washed with
water and organic layer was evaporated under reduced pressure. The crude residue thus obtained
was purified by column chromatography with the mobile phase 2% ethyl acetate in hexane to
afford the title compound.
Step b: Synthesis of 2-(2-ethoxyphenoxy)ethanamine
2-[2-(2-ethoxyphenoxy)ethyl]-lH-isoindole-l,3(2H)-dione (1 equiv.) was dissolved in ethanol
followed by dropwise addition of addition of Hydrazine hydrate (1.5 equiv.). Reaction mixture
was refluxed for 7-8 h. White solid separated out was filtered of and filtrate was evaporated
under reduced pressure to yield title compound as oily residue.
Step c: Synthesis of N-[2-(2-ethoxyphenoxy)ethyll-7-methoxy-l,2,3,4-tetrahydronaphthalen-2-
amine
7-methoxy-3,4-dihydronaphthalen-2(lH)-one (1 equiv.) was dissolved in dry dichloroethane
followed by addition of 2-(2-ethoxyphenoxy)ethanamine (1 equiv.). Reaction mixture was
stirred at room temperature for 15 min followed by addition of sodium triacetoxy borohydride (3
equiv.). Reaction mixture was allowed to stir at room temperature for 5 h. Reaction mixture
washed with 10% sodium bicarbonate and water, extracted with dichloromethane. Organic layer
was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford title
compound.
Step d: Synthesis of N-[2-(2-ethoxyphenoxy)ethyl]-7-methoxy-l<2,3,4-tetrahydronaphthalen-2-
amine hydrochloride salt
An equimolar quantity of isopropylalcohol-hydrochloric acid was added to N-[2-(2-
ethoxyphenoxy)ethyl]-7-methoxy-l,2,3,4-tetrahydronaphthalen-2-amine and the resulting salt
was solidified by adding ether to it.
'H NMR (300 MHz, CDC13): δ 1.45(3H,d; J=6.0Hz),l.64 (lH,d; J=3Hz), 2.19 (2H,d;
J=3.0Hz), 2.64(2R,d;J=3.0Hz), 3.026-3.15(m, 3H), 3.787 (s, 3H), 4.065-4.179(m, 4H), 6.637-
7.03 (m, 7H)
Mass: m/z 342 (M++ 1)
Example -7
Synthesis of l-(3-{[2-(2-ethoxyphenoxy)ethyl]amino}propyl)piperidine-2,6-dione hydrochloride salt
Step a: Synthesis of l-(3-{[2-(2-ethoxvphenoxy)ethvl]amino}propyl)piperidine-2,6-dione
l-(3-bromopropyl)-piperidine-2,6-dione (obtained from step-1 of Example-10 of WO
2005/118537) (1 equiv.) was dissolved in dry dimethylformamide followed by addition of
potassium carbonate (3 equiv) and 2-(2-ethoxyphenoxy)ethanamine (1 equiv.). Reaction mixture
was heated up to 60°C for 8-10 h. Reaction was quenched with water and extracted with ethyl
acetate. Organic layer was washed with water to remove excess of DMF. Organic layer was
dried over anhydrous sodium sulfate and evaporate under reduced pressure. Crude oil was
purified by column chromatography using mobile phase 10% ethyl acetate in hexane to afford
the title compound.
Step b: Synthesis of l-(3-{[2-(2-ethoxyphenoxy)ethyl]amino}propyl)piperidine-2,6-dione
hydrochloride salt
An equimolar quantity of isopropylalcohol-hydrochloric acid was added to l-(3-{[2-(2-
ethoxyphenoxy)ethyl]amino}propyl)piperidine-2,6-dione and the resulting salt was solidified by
adding ether to it.
'H NMR (300 MHz, CDC13): δ 1.61(3H,t; J=6.0Hz), 2.06(2H,t J=6.0Hz), 2.90 (2H,t J=6.0Hz),
3.47(2H,d J=6.0Hz), 3.62-3.66(m, 2H), 4.05(2H,d J=6.0Hz),4.19-4.4l(m, 6H), 4.85-4.92 (m,
2H), 7.01-7.45 (m,4H)
Mass: m/z 335 ( M++ 1)
Following compound was prepared similarly
1 -(3-{[2-(2-methoxyphenoxy)ethyl]amino}propyl)piperidine-2,6-dione hydrochloride salt,
]H NMR (300 MHz, CDC13): δ 1.98 (2H,t; J=60Hz),2.192-2.49( m, 2H), 2.679-2.722 (m, 4H),
3.017-3.07(m, 4H), 3.479-3.562(m, 4H), 3.863-3.9623 (m, 4H), 6.866-7.269(m, 4H),
Mass: m/z 321 (M++ 1)
Example -8
Synthesis of 1 -[(2-{4-[2-(l-methylethoxy)pheny 1]piperazin-1 -y 1}ethyl)amino]-2-phenylpropan-2-ol hydrochloride salt
Step-a: Synthesis of2-(2-{4-[2-(l-methylethoxy)phenyl]piperazin-l-yl}ethyl)-lH-isoindole-
l.3(2H)-dione
l-[2-(l-methylethoxy)phenyl]piperazine (1 equiv.) was dissolved in dimethylformamide
followed by addition of 2-Chloroethylpthalimide (1 equiv.) and potassium carbonate (2 equiv.).
Reaction mixture was stirred at 60-70°C for 8h. After the competition of reaction mixture was
cool up to room temperature. Reaction was quenched with water followed by extraction of
compound in ethyl acetate. Organic layer was washed with water and organic layer was
evaporated under reduced pressure. The crude residue thus obtained was purified by column
chromatography with the mobile phase 2% ethyl acetate in hexane to afford the title compound.
Step b: Synthesis of2-f4-[2-(l-methylethoxy)phenyl]piperazin-l-yt}ethanamine
2-(2-14-[2-( 1 -methylethoxy)phenyl]piperazin-1 -yl}ethyl)-1 H-isoindole-1,3(2H)-dione (1 equiv.)
was dissolved in ethanol followed by dropwise addition of addition of Hydrazine hydrate (1.5
equiv.). Reaction mixture was refluxed for 7-8 h. White solid separated out was filtered of and
filtrate was evaporated under reduced pressure to yield title compound as oily residue.
Step c: Synthesis of 2-hydroxy-N-(2-{4-[2-(l-methylethoxy)phenyllpiperazin-l-yttethyl)-2-
phenylpropanam ide
2-Hydroxy-2-phenylpropanoic acid (1 equiv.) was dissolved in dimethylfomamide followed by
addition of 2-{4-[2-(l-methylethoxy)phenyl]piperazin-l-yl}ethanamine and cool up to 0-5°C.
Reaction mixture was stirred at same temperature for 15 min. N-methyl morpholine (2 equiv.)
and hydroxy benzotriazole (lequiv.) was added to reaction mixture and stirred further for 15min
maintaining temperature 0-5°C. l-Ethyl-3-(3-dimethyl amino propyl) carbodimide
hydrochloride (lequiv.) was added to reaction mixture maintaining temperature 0-5°C. After
complete addition reaction mixture was stirred at room temperature for 6-7 h. Reaction was
quenched with water and compound was extracted in ethyl acetate. Organic layer was washed
with water to remove excess of N,N-dimethylformamide. Organic layer was dried over
anhydrous sodium sulfate and evaporate under reduced pressure. Crude oil thus obtained was
purified by column chromatography using mobile phase 10% ethyl acetate in hexane to afford
the title compound
Step d: Synthesis of l-[(2-{4-[2-(l-methylethoxy)phenyl]piperazin-l-yl}ethyl)amino]-2-
phenylpropan-2-ol
2-hydroxy-N-(2- {4- [2-( 1 -methylethoxy)phenyl]piperazin-1 -yl} ethyl)-2-phenylpropanamide (1
equiv.) was dissolved in tetrahydrofuran and was cool up to 0-5°C. lithium aluminium hydride
(1.2 equiv.) was added to the reaction mixture in small portion maintaining temperature 0-5°C.
Reaction mixture was stirred at room temperature for 6-7 h. After completion of reaction,
tetrahydrofuran was evaporated. The crude product thus obtained was extracted in ethyl acetate
.Combined organic layer was washed with water, dried over anhydrous sodium sulphate and
evaporated to afford the title compound.
Step e: Synthesis of l-[(2-{4-[2-(l-methylethoxy)phenvl]piperazin-l-vl}ethyl)amino]-2-
phenylpropan-2-ol hydrochloride salt
An equimolar quantity of isopropylalcohol-hydrochloric acid was added to l-[(2-{4-[2-(l-
methylethoxy)phenyl]piperazin-l-yl}ethyl)amino]-2-phenylpropan-2-ol and the resulting salt
was solidified by adding ether to it.
'H NMR (300 MHz, CDC13): δ 1.38(6H,d; J=6Hz),\.89 ( s, 3H), 3.11( s, 4H), 3.33-3.48 (m,
8H), 3.57-3.71( m, 2H), 3.78-3.84 (m, 1H), 4.0-4.13 (m, 1H), 4.58-4.62 (m, 1H), 6.87-7.64 (m,
9H)
Mass: m/z 399 ( M+ + 1), M.Pt: 172-175°C
Example -9
Synthesis of 2-(2,4-dioxo-l,3-thiazolidin-3-yl)-N-(2-{4-[2-(l-methylethoxy)phenyl]piperazin-l-yl}ethyl)acetamide hydrochloride salt
Step a: Synthesis of ethyl (2,4-dioxo-l,3-thiazolidin-3-yl)acetate
Sodium hydride (1.2g) was dissolved in dimethylformamide (20 mL) under nitrogen and cool up to 5°C. A solution of thiazolidine-2,4-dione (5 g) in N,N-dimethylformamide (25mL) was added to the reaction mixture maintaining temperature 5°C in small portions. Reaction mixture was stirred at room temperature for 1h followed by drop wise addition of ethyl bromoacetate (5.6 mL). Reaction mixture was heated up to 60-70°C for 8-10 h. After completion of reaction, reaction was quenched with water and extracted in ethyl acetate. Combined organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. Crude oil thus obtained was purified by column chromatography using mobile phase 2% methanol in dichloromethane to afford the title compound Step b: Synthesis of(2,4-dioxo-l,3-thiazolidin~3-yl)acetic acid
Ethyl (2,4-dioxo-l,3-thiazolidin-3-yl)acetate (1 equiv.) was dissolved in mixture of solvents tetrahydrofuran:methanol: water (3: 1: 1) respectively followed by addition of lithium hydroxide monohydrate (1 equiv). After completion of reaction solvents were evaporate under reduced pressure and neutralized with Sodium hydrogen sulphate. The aqueous layer was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound.
Step c: Synthesis of2-(2.4-dioxo-l,3-thiazolidin-3-yl)-N-(2-f4-[2-(l-methvlethoxy)phenvl]piperazin-l-vttethyl)acetamide
(2,4-dioxo-l,3-thiazolidin-3-yl)acetic acid (1 equiv.) was dissolved in dimethylformamide) followed by addition of 2-{4-[2-(l-methylethoxy)phenyl]piperazin-l-yl}ethanamine (1 equiv.) and was cool up to 0-5°C. Reaction mixture was stirred at same temperature for 15 min. N-methyl morpholine (2 equiv.) and hydroxybenzotriazole (1 equiv.) was added to reaction mixture and stirred further for 15min maintaining temperature 0-5°C. l-Ethyl-3-(3-dimethyl amino propyl) carbodimide hydrochloride (1 equiv.) was added to reaction mixture maintaining temperature 0-5°C. After complete addition reaction mixture was stirred at room temperature for 6-7 h, reaction was quenched with water and extracted with ethyl acetate. Organic layer was washed with water to remove excess of N,N-dimethylformamide. Organic layer was dried over anhydrous sodium sulfate and evaporate under reduced pressure. Crude oil was purified by column chromatography using mobile phase 10% ethyl acetate in hexane afford title compound. Step d: Synthesis of2-(2,4-dioxo-L3-thiazolidin-3-yl)-N-(2-{4-[2-(l-methylethoxv)phenyl]piper azin-1-yl} ethyl) acetamide hydrochloride salt An equimolar quantity of isopropylalcohol-hydrochloric acid was added to 2-(2,4-dioxo-l,3-thiazolidin-3-yl)-N-(2-{4-[2-(l-methylethoxy)phenyl]piperazin-l-yl}ethyl)acetamide_and the resulting salt was solidified by adding ether to it.
'H NMR (300 MHz, CDC13): δ1.35(6H,d;J=6.0//7), 1.68 (2H,s), 2.55-2.65 (4H,m), 2.87-2.96 (4H,m), 3.11 (2H,s), 3.40(2H,t; J=6.0Hz\ 4.03(2H,d; J=6.0Hz), 4.29(2H,s), 4.57-4.59(lH,m), 6.86-6.95 (4H,m), 8.02 (lH,s)Mass: m/z 421( M+ + 1), M.Pt 183-185°C
Pharmacological testing Receptor Binding Assay
Receptor binding assays were performed using 5HT1A receptor (Rat brain crude extract). The affinity of different compounds for 5HT1A receptor was evaluated by studying their ability to displace 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH DPAT).
25µl of InM radioligand (8-OH DPAT) was added in the assay plate, followed by addition of compounds (25µl). 25µl of assay buffer was added for calculating total binding (TB), 25µl of lOµM Serotonin for non-specific binding (NSB) and 25µl of diluent for vehicle control. Finally 200µl of protein (which has to be preincubated at 37°C for lOmins) was added to the assay plate with appropriate concentration. The plate was incubated at 37°C for 30mins in dark with shaking, and the plate was harvested using a cell-harvester, the filter mat was placed in the oven at 60°C for overnight. Punched the filter mat the following day in a 24 well plate. Scintillation cocktail was added and the plates sealed with transparent adhesive tape. The plate were shaken
for minimum of 3Omins. Take the counts using a Wallac counter. The IC50 and Kd were estimated by using the non-linear curve fitting program using G pad prism software. The value of affinity constant Ki was calculated from competitive binding studies by using Cheng and Prusoff equation (Cheng and Prusoff, Biochem.Pharmacol;, 1973, 22_:3099-3108, Ki = ICso/O+L/Kd) where L is the concentration of (8-OH DP AT) used in the particular experiment.
(Table Removed)

WE CLAIM:
1. A method for treating a mammal suffering from or susceptible to a condition related with 5-HT1A receptor comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or pharmaceutical composition according to Formula I and Formula II

(Formula Removed)
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs thereof, wherein:
(Formula Removed)
X is -(CH2)n, -NHCH2-, CH(OH), -(C=O)NHCH2-, wherein n is integer from 1 to 3 R' and R" can be independently hydroxyl, methyl
R1and R2 can be independently hydrogen, hydroxyl, halogen, C1-6 alkyl or C1-6 alkoxy A is
(Formula Removed)
— represents no bond or a single bond;
R3 and R4 are independently selected from
hydrogen, halogen, hydroxyl, acetoxy, optionally substituted alkyl (C1-C6)[ wherein the
substituents are selected from the group consisiting of halogen (F, Cl, Br or I), cycloalkyl,
cycloalkenyl (C3-C7)], alkenyl, alkynyl (C2-C7), cycloalkyl (C3-C7) group optionally substituted
with halogen (F, Cl, Br or I) atoms, halogen, hydroxyl, acetoxy, -(CH2)t- N(R1o)R11 [wherein t is
integer 0 to 1, R1O is hydrogen or alkyl, R11 is selected from alkyl or cycloalkyl],
R3 and R4 can together form a group selected from cycloalkyl, cycloalkenyl, bicyclic alkyl,

bicyclic alkenyl, aryl, heterocycle, or ( wherein Z is CF2 or CO),
RS and R? are independently hydrogen, alkyl, allyl, or phenyl, R6 is hydrogen, alkyl, phenyl,
hydroxyl or alkoxy.
R8 and R9 are each independently hydrogen, hydroxyl, alkoxy, acetyl or acetyloxy.

(Figure Removed)
R is 13 wherein R12 is selected from alkyl or cycloalkyl, and wherein R13 is selected
from hydrogen, halogen or alkyl. Bis O

m is 2; q is 0 -3
2. A method for treating a mammal suffering from or susceptible to a condition related with 5-
HT1A receptor comprising administering to a mammal in need thereof a therapeutically effective
amount of a compound or pharmaceutical composition according to Claim 1 wherein the
compound is selected from
2-(2,4-dioxo-l,3-thiazolidin-3-yl)-Ar-(2-{4-[2-(l-methylethoxy)phenyl]piperazin-l-
yl}ethyl)acetamide hydrochloride salt (Compound No. 1),
N-[2-(2-ethoxyphenoxy)ethyl]-7-methoxy-l,2,3,4-tetrahydronaphthalen-2-aminehydrochloride
salt (Compound No. 2),
1 - [(2- {4- [2-(1 -methylethoxy)phenyl]piperazin-1 -yl} ethyl)amino]-2-phenylpropan-2-ol
hydrochloride salt (Compound No. 3),
2-(5-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}pentyl)-3a,4,7,7a-tetrahydro-lH-
isoindole-l,3(2//)-dione hydrochloride salt (Compound No. 4),
l-(2-hydroxy-3-{4-[2-(2,2,3,3-tetrafluoropropoxy)phenyl]piperazin-l-yl}propyl)piperidine-2,6-
dione hydrochloride salt (Compound No. 5),
5,6-difluoro-2-(3 - {4- [5 -fluoro-2-( 1 -methylethoxy)phenyl]piperazin-1 -yl} propyl)hexahydro-1H-
isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 6),
2-(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propyl)-l,3-dioxooctahydro-lH-isoindole-5,6-diyl diacetate hydrochloride salt (Compound No. 7),
2-(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propyl)-4,5,6,7-tetrahydro-lH-isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 8),
3-(cyclopropylamino)-l - {3-[4-(2-methoxyphenyl)piperazin-1 -yl]propyl}pyrrolidine-2,5-dione hydrochloride salt (Compound No. 9),
1 -(3 - {4-[2-(cyclopentyloxy)phenyl]piperazin-1 -yl} propyl)-3 -(cyclopropylamino)pyrrolidine-2,5-dione hydrochloride salt (Compound No. 10),
1 - {3 - [4-(2 -methoxyphenyl)piperazin-1 -yljpropyl} -3 -prop-2-en-1 -ylpiperidine-2,6-dione hydrochloride salt (Compound No. 11),
1 -(3- {[2-(2-ethoxyphenoxy)ethyl]amino}propyl)piperidine-2,6-dione hydrochloride salt (Compound No. 12),
l-(3-{[2-(2-methoxyphenoxy)ethyl]amino}propyl)piperidine-2,6-dione hydrochloride salt (Compound No. 13),
1 -(3 - {4- [2 -(cyclopentyloxy)phenyl]piperazin-1 -yl} propyl)-3 -(cyclopropy lamino)-4-methylpyrrolidine-2,5-dione hydrochloride salt (Compound No. 14),
l-(3-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}propyl)-3,4-dimethylpyrrolidine-2,5-dione hydrochloride salt (Compound No. 15),
l-(3-{4-[2-(cyclopropylmethoxy)phenyl]piperazin-l-yl}propyl)-3,4-dimethylpyrrolidine-2,5-dione hydrochloride salt (Compound No. 16),
l-{3-[4-(5-fluoro-2-propoxyphenyl)piperazin-l-yl]propyl}-3-methylpyrrolidine-2,5-dione hydrochloride salt (Compound No. 17),
3,4-dimethyl-l-(3-{4-[2-(2,2,3,3-tetrafluoropropoxy)phenyl]piperazin-l-yl}propyl)pyrrolidine-2,5-dione hydrochloride salt (Compound No. 18),
3-(cyclopropylamino)-4-methyl-l-(3-{4-[2-(2,2,3,3-tetrafluoropropoxy)phenyl]piperazin-l-yl}propyl)pyrrolidine-2,5-dione hydrochloride salt (Compound No. 19), 3-[(cyclopropylamino)methyl]-l-(3-{4-[2-(2,2,3,3-tetrafluoropropoxy)phenyl]piperazin-l-yl}propyl)pyrrolidine-2,5-dione hydrochloride salt (Compound No. 20), 3-(cyclobutylamino)-4-methyl-l-(3-{4-[2-(2,2,3,3-tetrafluoropropoxy)phenyl]piperazin-l-yl}propyl)pyrrolidine-2,5-dione hydrochloride salt (Compound No. 21), 3 - [(cyclobutylamino)methyl] -1 -(3 - {4- [2-(2,2,3,3 -tetrafluoropropoxy)phenyl]piperazin-1 -yl}propyl)pyrrolidine-2,5-dione hydrochloride salt (Compound No. 22), 2-[(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propyl)carbamoyl]-4,5-dihydroxycyclohexanecarboxylic acid hydrochloride salt (Compound No. 23),
4,7-dihydroxy-2-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 24),
2-(3-{4-[2-(2,2,3,3-tetrafluoropropoxy)phenyl]piperazin-l-yl}propyl)hexahydro-lH-isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 25),
2-(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propyl)-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 26),
2-(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propyl)-5,6-dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 27),
2-(3-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl}propyl)-4,7-dihydroxy-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 28), 6-(3 - {4- [5 -fluoro-2-( 1 -methyl ethoxy)phenyl]piperazin-1 -yl} propyl)tetrahydro-3 aH-[l,3]dioxolo[4,5-f]isoindole-5,7(4H,6H)-dione hydrochloride salt (Compound No. 29), or 6-(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propyl)tetrahydro-3aH-[l,3]dioxolo[4,5-f|isoindole-2,5,7(4H,6H)-trione hydrochloride salt (Compound No. 30).
and their hydrochloride salts
3. A compound selected from
2-(2,4-dioxo-1,3-thiazolidin-3-yl)-N-(2- {4-[2-(l -methylethoxy)phenyl]piperazin-1 -
yl}ethyl)acetamide hydrochloride salt (Compound No. 1),
N-[2-(2-ethoxyphenoxy)ethyl]-7-methoxy-l,2,3,4-tetrahydronaphthalen-2-amine hydrochloride
salt (Compound No. 2),
1 - [(2- {4- [2-( 1 -methy lethoxy)pheny IJpiperazin-1 -yl} ethyl)amino] -2-pheny lpropan-2-ol
hydrochloride salt (Compound No. 3),
2-(5-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}pentyl)-3a,4,7,7a-tetrahydro-lH-
isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 4),
l-(2-hydroxy-3-{4-[2-(2,2,3,3-tetrafluoropropoxy)phenyl]piperazin-l-yl}propyl)piperidine-2,6-
dione hydrochloride salt (Compound No. 5),
5,6-difluoro-2-(3 - {4- [5-fluoro-2-( 1 -methyl ethoxy)phenyl]piperazin-1 -yl }propyl)hexahydro-1H-
isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 6),
2-(3- {4-[5-fluoro-2-( 1 -methylethoxy)phenyl]piperazin-1 -yl} propyl)-1,3 -dioxooctahydro-1H-
isoindole-5,6-diyl diacetate hydrochloride salt (Compound No. 7),
2-(3-{4-[5-fluoro-2-(l-methylethoxy)phenyl]piperazin-l-yl}propyl)-4,5,6,7-tetrahydro-lH-
isoindole-l,3(2H)-dione hydrochloride salt (Compound No. 8),
3 -(cyclopropylamino)-1 - {3 - [4-(2-methoxyphenyl)piperazin-1 -yljpropyl} pyrrolidine-2,5 -dione
hydrochloride salt (Compound No. 9),
1 -(3 - {4- [2-(cyclopentyloxy)phenyl]piperazin-1 -yl} propyl)-3 -(cyclopropylamino)pyrrolidine-
2,5-dione hydrochloride salt (Compound No. 10),
1 - {3 - [4-(2-methoxyphenyl)piperazin-1 -yl]propyl} -3 -prop-2-en-1 -ylpiperidine-2,6-dione
hydrochloride salt (Compound No. 11),
l-(3-{[2-(2-ethoxyphenoxy)ethyl]amino}propyl)piperidine-2,6-dione hydrochloride salt
(Compound No. 12),
1 -(3-{[2-(2-methoxyphenoxy)ethyl]amino}propyl)piperidine-2,6-dione hydrochloride salt
(Compound No. 13),
and their hydrochloride salts.