Field of the Invention
This invention relates to isoindoledione derivatives, which can be used to treat a disease or disorder mediated through α1a and/or α1d adrenergic receptors. Compounds disclosed herein can be used to treat benign prostatic hyperplasia (BPH) and the related symptoms thereof, lower urinary tract symptoms (LUTS) associated with or without BPH. Processes for the preparation of described compounds, pharmaceutical compositions thereof, and methods of treating BPH and related symptoms thereof, LUTS associated with or without BPH are also provided.
Background of the Invention
Benign prostatic hyperplasia (BPH) is a condition, which develops in elderly males and refers to the benign overgrowth of the stromal and epithelial elements of the prostate with aging. The symptoms of BPH vary, but the most common ones involve changes or problems with urination, such as hesitant or interrupted urination, weak stream, urgency, leaking or dribbling or more frequent urination, especially at night. Consequences of BPH can involve hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection.
There are two components of BPH, static and a dynamic component. The static component is due to enlargement of the prostate gland, which may result in compression of the urethra and obstruction to the flow of the urine from the bladder. The dynamic component is due to increased smooth muscle tone of the bladder neck and prostate itself and is regulated by α1 adrenergic receptor.
Currently, the most effective treatment for BPH is the surgical procedure of transurethral resection of the prostate (TURP), since it removes the obstructing tissue (C. Chappie, Br. Med. Journal, 304: 1198-1199 (1992). It is a treatment, which is directed to the static and dynamic components of the BPH. However this surgical treatment is associated with rates of mortality (1%) and adverse event (incontinence 2-4%) infection 5-10 %, and impotence 5-10%. A noninvasive alternative treatment is therefore highly desirable. There are some drug therapies, which address the static component of this condition. Administration of finasteride is one such therapy, which is indicated for the treatment of symptomatic BPH. This drug is a competitive inhibitor of the enzyme 5a- reductase that is responsible for the conversion of testosterone to dihydrotestosterone in the prostate gland.
Dihydrotestosterone appears to be the major mitogen for prostate growth, and agents, which inhibit 5 a- reductase reduce the size of the prostate and improve urine flow through the prostatic urethra. Although finasteride is a potent 5 a- reductase inhibitor and causes a marked decrease in serum and tissue concentrations of dihydrotestosterone, it is moderately effective in the treatment of symptomatic BPH. The effects of finasteride take 6-12 months to become evident and for many men the clinical development is minimal.
The dynamic component of BPH has been addressed by the use of adrenergic receptor blocking agents, which act by decreasing the smooth muscle tone within the prostate gland. A variety of α1 AR antagonists, for example, terazosin, doxazosin, prazosin, alfuzosin and tamulosin have been investigated for the treatment of symptomatic bladder outlet obstruction due to BPH. However, these drugs are associated with vascular side effects (e.g. postural hypertention, syncope, dizziness, headache etc) due to lack of selectivity of action between prostatic and vascular α1 adrenoceptor. There are several lines of evidence to suggest that selectivity for α1a adrenoceptor over α1b adrenoceptor will result in relative lack of vascular side effects, thus lead to a better tolerability. Mice deficient in N adrenoreceptors show diminished blood pressure response to phenylephrine injection compared to homozygous controls (Decreased blood pressure response in mice deficient of α1b adrenergic receptor. (Proc. Nat'l Acad Sci USA, 94: 11589-11594 (1997)). In-vivo studies in healthy subjects comparison of α1a / α1d selective antagonists (for example, tamsulosin) or α1a selective antagonists (for example, urapidil) with non selective antagonists (for example,doxazosin, prazosin, or terazosin) under a variety of experimental conditions (e.g. involving the administration of exogenous agonist or release of endogenous agonist by cold stimulation) in several vascular beds including the skin circulation in finger tips, the dorsal hand vein, or with total peripheral resistance have been reported. (Eu.r J. Clin. Pharmacol., 49: 371-375 (1996); Naunyn Schmiedeberg's Arch. Pharmacol, 354: 557-561 (1996); Jpn. J. Pharmacol. 80: 209-215 (1999); Br. J. Clin. Pharmacol. 47: 67-74 (1999). These studies have reported that an antagonist with high affinity for α1a or α1a/α1d can cause some degree of vasodilation but that it is much smaller than with non-subtype-selective α1 adrenoceptor antagonist. Further, there is increased vascular N adrenoceptor expression in elderly patients and thus α1a/α1d selective agents with selectivity over N adrenoceptor subtype would be of particular importance in benign prostatic hyperplasia, which is generally a disease of old age. Antagonism of both α1a adrenoceptor and N adrenoceptor is important to relieve lower urinary tract symptoms especially associated (suggestive of) with BPH. Targeting α1a
adrenoceptor with antagonists is important in relaxing prostate smooth muscle and relieving bladder outlet obstruction whereas α1d adrenoceptor antagonism is important to target irritative symptoms.
Over the past decade, there has been an intensive search for selective α1a adrenoceptor antagonists for benign prostatic hyperplasia, which would avoid the cardiovascular side effects, associated with currently used drugs. Many selective antagonists have been described in the literature.
The compounds described in U.S. Patent Nos. 6,083,950, 6,090,809, 6,410,735, 6,420,559 and 6,420,366, U.S. Patent Application No. 2002/0156085, PCT Publication Nos. WO 02/44151, WO 00/05206, WO 03/084928, WO 03/084541 and WO 00/05205 exhibited α1 -adrenergic blocking activity and selectivity. The disclosures of these publications are incorporated herein by reference in their entireties. PCT Publication No. WO 2005/037282 discloses l-alkylpiperazinyl-pyrrolidin-2,5-dione as adrenergic receptor antagonists. U.S. Patent No. 6,914,064 discloses 1,4-disubstituted piperazine derivatives useful as uro-selective α1/-adrenoceptor blockers.
Summary of the Invention
Generally provided herein are isoindoledione derivatives, which can be used to treat a disease or disorder mediated through α1Aa and/or α1d adrenergic receptors. Processes for the synthesis of these compounds, pharmaceutical compositions thereof, are also provided. Encompassed pharmaceutical compositions may also contain one or more pharmaceutically acceptable carriers or diluents. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, conjugates, or prodrugs of such compounds having the same type of activity are also provided, which can be useful to treat a disease or disorder mediated through α1a and/or α1d adrenergic receptors. Pharmaceutical compositions comprising the compounds described herein, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, conjugates or prodrugs in combination with one or more pharmaceutically acceptable carriers, and optionally included excipients, are also included, which can be useful to treat a disease or disorder mediated through α1a and/or N adrenergic receptors.
In one aspect, provided herein are compounds having the structure of Formula I,
(FORMULA REMOVED)

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof, wherein:
A and B can be independently hydrogen, halogen, hydroxy, alkyl, alkoxy, cyano, nitro, amino, alkylamino or thio, further A and B together can form a ring of the form
(FORMULA REMOVED)

L can be (CH2)3, (CH2)5, CH2CONHCH2CH2 or CH2COOCH2CH2;
Y and Y' can be independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl, further Y and Y' together can form a bridging group (C0-3);
X can be N, C, CH or C(OH);
Z can be alkyl, cycloalkyl, aryl, NHCORi, CH(COORi)R! or NHCONHRi, wherein R1 can be alkyl, aryl or heterocyclyl, further X and Z together with Y (or Y') can form a 5-7 membered ring, which may be partially saturated, saturated or unsaturated;
— can be an optional bond ;
with the provisos that when L is -(CH2)3- i) Y and Y' together form a bridging group (C0.3) ii) X is -COH in) CH(COORi)Ri iv) X and Z together with Y (or T) form phenyl ring v) Z is 2-(2,3-dihydro-lH-inden-2-yloxy)-5-fluorophenyl or vi) A and B together can form a ring of the form

In another aspect, provided herein are specific compounds selected from:
2-{3-[8-hydroxy-8-(2-methoxyphenyl)-3-azabicyclo[3.2.1]oct-3-yl]propyl}-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione and its hydrochloride salt,
2-{3-[4-hydroxy-4-(2-methoxyphenyl)piperidin-l-yl]propyl}-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione and its hydrochloride salt,
2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-N-{2-[4-(2-methoxyphenyl) piperazin- 1-yl] ethyl }acetamide and its hydrochloride salt,
iV-{3-[3-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)propyl]-3-azabicyclo[3.1.0]hex-6-yl}acetamide and its hydrochloride salt,
Methyl {4-[3-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yI)propyl]piperazin-l-yl}(phenyl)acetate and its hydrochloride salt,
Methyl {4-[3-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)propyl]piperazin-l-yl}(phenyl)acetate and its hydrochloride salt,
2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-N-{2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt,
2-(5,6-dihydroxy-1,3-dioxooctahydro-2H-isoindol-2-yl)-.N- {2-[4-(2-ethoxyphenyl) piperazin-l-yl]ethyl}acetamide and its hydrochloride salt,
2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-N-{2-[4-(2-isopropoxyphenyl) piperazin-l-yl]ethyl}acetamide and its hydrochloride salt,
2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-iV-{2-[4-(2-isopropoxyphenyl) piperazin-l-yl]ethyl}acetamide and its hydrochloride salt,
N-(2-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}ethyl)-2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)acetamide and its hydrochloride salt,
N-(2-{ 4- [2-(cyclopenty loxy)pheny l]piperazin-1 -y 1} ethy l)-2-(5,6-dihydroxy-1,3-dioxooctahydro-2H-isoindol-2-yl)acetamide and its hydrochloride salt,
2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-N-{2-[4-(2-methoxyphenyl) piperazin-1-yl] ethyl}acetamide and its hydrochloride salt,
N{3-[3-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)propyl]-3-azabicyclo[3.1.0]hex-6-yl}tetrahydrofuran-2-carboxamide and its hydrochloride salt,
2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-N-{2-[4-(2-isopropoxyphenyl) piperazin-l-yl]ethyl}acetamide and its hydrochloride salt,
N-(2-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}ethyl)-2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)acetamido and its hydrochloride salt,
2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-N2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt,
2-(5,6-dihydroxy-1,3-dioxooctahydro-2H-isoindol-2-yl)-H-{2-[4-(2-ethoxyphenyl) piperazin-l-yl]ethyl}acetamide and its hydrochloride salt,
2-(5,6-dihydroxy4,3-dioxooctahydro-2H-isoindol-2-yl)-N-{2-[4-(2-isopropoxyphenyl) piperazin-l-yl]ethyl}acetamide (Compound No.37) and its hydrochloride salt (Compound No.38),
N-(2-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}ethyl)-2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)acetamide and its hydrochloride salt,
2-(l ,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-N- {2-[4-(2-methoxyphenyl)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt,
2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-N-{2-[4-(2-methoxyphenyl)piperazin-l-yl] ethyl }acetamide and its hydrochloride salt,
2-[4-(2-methoxyphenyl)piperazin-l-yl]ethyl (l,3-dioxooctahydro-2H-isoindol-2-yl) acetate and its hydrochloride salt,
7-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}tetrahydro-4aH-[l,4]dioxino[2,3-fisoindole-2,3,6,8(5H,7H)-tetrone and its hydrochloride salt,
2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)acetate and its hydrochloride salt,
2-[5-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(lH)-yl)pentyl]-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione and its hydrochloride salt,
2-[5-(3,4-dihydroisoquinolin-2(lH)-yl)pentyl]-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione and its hydrochloride salt,
2-{5-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]pentyl}-5,6-dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione and its hydrochloride salt,
2-[3-(3,4-dihydroisoquinolin-2(lH)-yl)propyl]-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione and its hydrochloride salt,
2-(3-{4-[2-(2,3-dihydro-lH-inden-2-yloxy)-5-fluorophenyl]piperazin-l-yl}propyl)-5,6-dihydroxyhexahydro-li/-isoindole-l,3(2H)-dione and its hydrochloride salt,
2-[5-(3,4-dihydroisoquinolin-2(lH)-yl)pentyl]-5,6-dihydroxyhexahydro-lH-isoindole-1,3(2H)-dione and its hydrochloride salt,
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof.
In another aspect, provided herein are methods to treat a patient suffering from a disease or disorder mediated through α1a and/or α1d adrenergic receptor, comprising administering to a patient therapeutically effective amount of one or more compounds or compositions described herein.
In another aspect, provided herein are methods to treat a patient suffering from benign prostatic hyperplasia (BPH) and related symptoms, lower urinary tract symptoms (LUTS) with or without BPH comprising administering to a patient therapeutically effective amount of one or more compounds or compositions described herein. LUTS may include, for example, irritative symptoms such as frequent urination, urgent urination, nocturia and unstable bladder contractions, obstructive symptoms such as hesitancy, poor stream, prolong urination, and feelings of incomplete emptying.
In another aspect, provided herein are processes for preparing compounds described herein.
In yet another aspect, provided herein are methods to treat a patient suffering from BPH or LUTS with or without BPH, comprising administering to a patient therapeutically effective amount of one or more compounds or compositions described herein in combination with one or more other therapeutic agents selected from muscarinic receptor antagonists (e.g. derifenacin, solifenacin), bladder selective muscarinic receptor antagonists (e.g., RBx-9841 or RBx-10416), testosterone 5 alpha-reductase inhibitor (e.g. finasteride or dutasteride), HMG-CoA reductase inhibitors (e.g. atorvastatin, pravastatin, simvastatin, RBx-10558 or RBx-11901), endothelin antagonists (e.g. tracleer, atracentan), nitric oxide donor, cGMP elevators, 5-HT antagonists (e.g. palonosetron) or combination thereof.
The compounds of this invention are potent adrenergic receptor antagonists. Compounds described herein exhibit affinity towards α1a adrenergic receptor subtypes and good selectivity for α1a over ecu,. α1a adrenergic receptors are involved in relieving the obstructive symptoms whereas α1d adrenoreceptor antagonism is associated with alleviation of irritative symptoms. The relatively low affinity at the α1b adrenergic receptor limits the cardiovascular side effects, for example, orthostatic hypotension. The present invention therefore provides pharmaceutical compositions for treatment of a disease or disorder mediated through α1a and/ or α1d adrenoceptors. Compounds and compositions described herein can be administered orally, parenterally, subcutaneously, transdermally or topically.
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, -0-C(=O)NRfRq {wherein Rf and Rq are independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl}, nitro, or -SO2R4 (wherein R4 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, CF3, cyano, and -SO2R4, (wherein R4 are the 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, -0-C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, and -SO2R4 (where R4 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. 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 "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, CI, 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 , -0-C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), -SO2R4 (wherein R4 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, CI, 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, -SO2R4, -0-C(=O)NRfRq, -O-C(=O)Rf, -O-C(=O)ORf (wherein R4, 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 1Heterocyclyl," 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, CI, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, alkoxy, alkaryl, cyano, nitro, oxo, carboxy, heterocyclyl, heteroaryl, -0-C(=O)Rf, -0-C(=O)ORf, -C(=O)NRfRq, SO2R6, -0-C(=O)NRfRq, -NHC(=O)NRfRq, -NRfRq (wherein R6, 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 olefinic 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(0)aRb, OCOORb, OCORb, SO2NHRb, NHSO2Rb, NHCORb, NHCSRb, (CH)0.2C(=O)NRcRd or NRcRd (wherein Rb, Rc, and Ra are and a are the same as defined earlier). 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 ofany 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 (i.e hydrates, hemihydrate or sesquihydrate) or pharmaceutically acceptable solvents, for example solvates with common organic solvents as ethanol and the like. Such solvates are also encompassed within the scope of the disclosure.
The present invention also includes, within its scope," prodrugs" of these agents. In general, such prodrugs will be functional derivatives of these compounds, which are readily convertible in vivo into the required compound. They may be carrier-linked or bioprecursors. The carrier-linked prodrugs may be bipartite, tripartite or mutual prodrugs. Prodrugs are intended to improve drug efficacy by improving solubility and consequently absorption and distribution as desired. Conventional procedure for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H Bundgaard and, Elsevier, 1985. Enantiomers and Diastereomers, are as defined by the IUPAC 1974 Recommendations for Section E.
Other aspect and properties of this matter will be set forth in description which follows, and will be apparent from the description or may be learnt by the practice thereof.
Detailed Description of the Invention
The compounds described herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist. In addition, the compounds described herein may be prepared by the following reaction sequences as depicted in Schemes I, II, III, IV and V.
(FORMULA REMOVED)

Compounds of Formula 7 can be prepared according to Scheme I. Thus, compound of Formula 2 can be reacted with compounds of Formula 3 (wherein, d and G2 are leaving groups selected from CI, Br, I and the like) to form compounds of Formula 4. Compounds of 4 can be treated with compounds of Formula 5 to form compounds of Formula 6. Compounds of Formula 6 can be oxidized to form compounds of Formula 7.
The reaction of a compound of Formula 2 can be carried out in aprotic polar solvent, for example, acetonitrile, acetone, dimethylsulfoxide, dimethylformamide or mixture thereof. The reaction can also be carried out in the presence of one or more bases, for example, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate or triethylamine.
The reaction of a compound of Formula 4 can be carried out in one or more solvents, for example, polar solvent, for example, ethyl methyl ketone, methanol, ethanol, isopropyl alcohol, acetone, 1,4-dioxane, ethyl acetate or mixture thereof. The reaction can also be carried out in the presence of one or more bases, for example, potassium carbonate, sodium, carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate or triethylamine and in presence of potassium iodide.
The oxidation of a compound of Formula 6 can be carried out in presence of oxidizing agent, for example, potassium permanganate, osmium tetraoxide, periodic acid or mixture thereof, in polar protic solvent, for example, methanol, ethanol, n-propyl alcohol, isopropyl alcohol,

Compounds of Formula 8 can be prepared according to Scheme II. Thus, compounds of Formula 7 can be reacted with oxalyl dichloride to form compounds of Formula 8.
The reaction of compounds of Formula 7 can be carried out in ether solvent, for example, tetrahydrofuran, dioxane or mixture thereof.
(SCHEME REMOVED)

Compounds of Formula 14 can be prepared according to the Scheme III. Thus, compound of Formula 2 can be reacted with a compound of Formula 9 to give a compound of Formula 10. Compound of Formula 10 can be treated with an acid to give a compound of Formula 11. Compound of Formula 11 can be reacted with compounds of Formula 12 to give compounds of Formula 13. Compounds of Formula 13 can be oxidized to give compounds of Formula 14.
The reaction of a compound of Formula 2 can be carried out in presence of a base, for example, potassium hydroxide, sodium hydroxide, sodium hydride, potassium carbonate or sodium carbonate or mixture thereof, in aprotic polar solvent, for example, dimethylsulfoxide, dimethylformamide, acetonitrile, N-methylpyrrolidone or mixture thereof.
The deprotection of a compound of Formula 10 can be carried out in the presence of an acid, for example, acetic acid, trifluoroacetic acid or trichloro acetic acid in chlorinated solvent, for example, dichloromethane, dichloroethane, chloroform or mixture thereof.
The coupling of a compound of Formula 11 can be carried out in presence of activating agents, for example, 1-hydroxybenzotriazole hydrate, hydroxypyridine, nitrophenol, N-hydroxyphthalimide or mixture thereof, coupling agents, for example, l-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, l-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide methiodide, N, N'Diisopropylcarbodiimide, N,N'-Dicyclohexylcarbodiimide or mixture thereof in aprotic polar solvents, for example, acetonitrile, acetone, dimethylsulfoxide, dimethylformamide, N-methylmorpholine or mixture thereof.
The oxidation of compounds of Formula 13 can be carried out in presence of oxidizing agents, for example, potassium permanganate, osmium tetraoxide, periodic acid or mixture thereof in one or more solvents, for example, polar protic solvents (e.g. methanol, ethanol, n-propanol, isopropanol, n-butanol or f-butanol), aprotic polar solvents (e.g. acetonitrile, acetone, dimethylsulfoxide or dimethylformamide) or mixture thereof. .
(SCHEME REMOVED)

Compounds of Formula 16 can be prepared according to Scheme IV. Thus, compound of Formula 11 can be reacted with a compound of Formula 15 and thionyl chloride to form compounds of Formula 16.
The reaction of a compound of Formula 11 can be carried out in one or more solvents, for example, ether solvents (e.g. tetrahydrofuran, dioxane or diethylether), halogenated solvents (e.g. chloroform, dichloromethane or dichloroethane) or mixture thereof. The reaction can also be carried out in presence of acylation catalyst, for example, 4-dimethylaminopyridine, 1,2,4-Triazole, 1-Methylimidazole or 4(l-Pyrrolidino)pyridine.
(SCHEME REMOVED)

Compounds of Formula 21 can be prepared according to the Scheme V. Thus, compounds of Formula 17 can be reacted with compounds of Formula 18 (wherein, G1 and
G2 are same as defined earlier) to form compounds of Formula 19. Compounds of Formula 19 can be reacted with compounds of Formula 4 to form compounds of Formula 20. Compounds of Formula 20 can be finally oxidized to form compounds of Formula 21.
The reaction of compounds of Formula 17 can be carried out in one or more solvents, for example, protic polar solvents (e.g. methanol, ethanol, n-propanol, isopropanol or n-butanol), aprotic polar solvents, (e.g. acetonitrile, dimethylformamide, dimethylsulfoxide) or mixture thereof.
The reaction of compounds of Formula 19 can be carried out in aprotic polar solvents, for example, acetonitrile, dimethylformamide, dimethylsulfoxide or mixture thereof.
The oxidation of compounds of Formula 20 can be carried out in the presence of oxidizing agents, for example, potassium permanganate, osmium tetraoxide, periodic acid or mixture thereof, in protic polar solvents, for example, methanol, ethanol, n-propyl alcohol, isopropanol, n-butanol or mixture thereof.
Compounds of the present invention useful for such purpose are listed below:
2-{3-[8-hydroxy-8-(2-methoxyphenyl)-3-azabicyclo[3.2.1]oct-3-yl]propyl}-3a,4,7,7a-tefrahydro-lH-isoindole-l,3(2H)-dione (Compound No.l) and its hydrochloride salt (Compound No. 2),
2- {3 -[4-hydroxy-4-(2-methoxypheny l)piperidin-1 -yl]propy 1} -3 a,4,7,7a-tetrahy dro-1H-isoindole-l,3(2H)-dione (Compound No.3) and its hydrochloride salt (Compound No. 4),
2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-7/-{2-[4-(2-methoxyphenyl) piperazin-1-yl]ethyl}acetamide (Compound No.5) and its hydrochloride salt (Compound No. 6),
N-{3-[3-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)propyl]-3-azabicyclo[3.1.0]hex-6-yl}acetamide (Compound No.7) and its hydrochloride salt (Compound No. 8),
Methyl {4-[3-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)propyl]piperazin-l-yl}(phenyl)acetate (Compound No.9) and its hydrochloride salt (Compound No. 10),
Methyl {4-[3-(5,6-dihydroxy-1,3 -dioxooctahydro-2H-isoindol-2-yl)propyl]piperazin-1 -yl}(phenyl)acetate (Compound No.l 1) and its hydrochloride salt (Compound No. 12),
2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-A'-{2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl}acetamide (Compound No. 13) and its hydrochloride salt (Compound No. 14),
2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-N-{2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl}acetamide (Compound No. 15) and its hydrochloride salt (Compound No. 16),
2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-N-{2-[4-(2-isopropoxyphenyl) piperazin-l-yl]ethyl}acetamide (Compound No. 17) and its hydrochloride salt (Compound No. 18),
2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yI)-Af-{2-[4-(2-isopropoxyphenyl) piperazin-l-yl]ethyl}acetamide (Compound No. 19) and its hydrochloride salt (Compound No.20),
N-(2-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}ethyl)-2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)acetamide (Compound No.21) and its hydrochloride salt (Compound No.22),
N-(2-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}ethyl)-2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)acetamide (Compound No.23) and its hydrochloride salt (Compound No.24),
2-(5,6-dihydroxy-1,3 -dioxooctahydro-2H-isoindol-2-y l)-N- {2- [4-(2-methoxypheny 1) piperazin-l-yl]ethyl}acetamide (Compound No.25) and its hydrochloride salt (Compound No.26),
N-{3-[3-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)propyl]-3-azabicyclo[3.1.0]hex-6-yl}tetrahydrofuran-2-carboxamide (Compound No.27) and its hydrochloride salt (Compound No.28),
2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-N-{2-[4-(2-isopropoxyphenyl) piperazin-1-yl]ethyl}acetamide (Compound No.29) and its hydrochloride salt (Compound No.30),
N-(2-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}ethyl)-2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)acetamide (Compound No.31) and its hydrochloride salt (Compound No.32),
2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2N-isoindol-2-yl)-N-{2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl}acetamide (Compound No.33) and its hydrochloride salt (Compound No.34),
2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-N-{2-[4-(2-ethoxyphenyl)piperazin-1-yl]ethyl}acetamide (Compound No.35) and its hydrochloride salt (Compound No.36),
2-(5,6-dihydroxy-1,3 -dioxooctahydro-2H-isoindol-2-y l)-N- {2- [4-(2-isopropoxypheny 1) piperazin-1-yl]ethyl}acetamide (Compound No.37) and its hydrochloride salt (Compound No.38),
N-(2- {4- [2-(cyclopenty loxy)pheny l]piperazin-1 -y 1} ethy l)-2-(5,6-dihydroxy-1,3-dioxooctahydro-2H-isoindol-2-yl)acetamide (Compound No.39) and its hydrochloride salt (Compound No.40),
2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-N-{2-[4-(2-
methoxyphenyl)piperazin-l-yl]ethyl}acetamide (Compound No.41) and its hydrochloride salt (Compound No.42),
2-(5,6-dihydroxy-1,3-dioxooctahydro-2H-isoindol-2-yl)-N- {2-[4-(2-
methoxyphenyl)piperazin-l-yl]ethyl}acetamide (Compound No.43) and its hydrochloride salt (Compound No.44),
2-[4-(2-methoxyphenyl)piperazin-l-yl]ethyl(l,3-dioxooctahydro-2^/-isoindol-2-yl) acetate (Compound No.45) and its hydrochloride salt (Compound No.46),
7-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}tetrahydro-4aH-[l,4]dioxino[2,3-/|isoindole-2,3,6,8(5iy,7H)-tetrone (Compound No.47) and its hydrochloride salt (Compound No.48),
2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)acetate (Compound No.49) and its hydrochloride salt (Compound No.50),
2-[5-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(lH)-yl)pentyl]-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione (Compound No.51) and its hydrochloride salt (Compound No.52),
2-[5-(3,4-dihydroisoquinolin-2(lif)-yl)pentyl]-3a,4,7,7a-tetrahydro-li7-isoindole-l,3(2H)-dione (Compound No.53) and its hydrochloride salt (Compound No.54),
2- {5-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-1 -yl]pentyl} -5,6-dihydroxyhexahydro-1H-isoindole-l,3(2H)-dione (Compound No.55) and its hydrochloride salt (Compound No.56),
2-[3-(3,4-dihydroisoquinolin-2(l/0-yl)propyl]-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione (Compound No.57) and its hydrochloride salt (Compound No.58),
2-(3- {4-[2-(2,3-dihydro- lH-inden-2-yloxy)-5-fluorophenyl]piperazin-1 -yl}propyl)-5,6-dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione (Compound No.59) and its hydrochloride salt (Compound No.60),
2-[5-(3,4-dihydroisoquinolin-2(lH)-yl)pentyl]-5,6-dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione (Compound No.61) and its hydrochloride salt (Compound No.62),
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof.
Compounds described herein can be administered to a patient (e.g., human or animal) orally, parenterally, topically, rectally, intranasally, subcutaneously or trandermally
In another aspect, there is provided pharmaceutical composition, which may comprise of an effective amount of a compound or admixture of compounds with apposite pharmaceutically acceptable carriers, if required, for oral, sublingual, parenteral, topical, nasal, rectal or transdermal administration.
The solid compositions include tablets, capsules, microcapsules, powders, granules, pills, wafers, dragees, catchets, caplets, suppositories and pastilles.
Tablets, capsules, pills are generally administered as a unit dose and may contain suitable excipients such as dispersing agents, binding agents, fillers, diluents, lubricants, disintegrants, colorants, flavouring agents, sweetners or preservatives.
Tablets, pills and granules may be sugar coated, enteric coated or film coated by standard techniques well known in the art. Immediate release tablets and tablets having sustained action may also be prepared by methods well known in the art. Capsules may be hard capsules or soft capsules of suitable size wherein the compound is mixed with inert solid diluent, for example, sodium carbonate, calcium carbonate, lactose, starch, calcium phosphate or sodium phosphate; disintegrants, for example, sodium starch glycolate or croscarmelose sodium.
Dispersible powders and granules suitable for reconstitution to form a stable suspension by addition of water are provided with the active ingredient with a dispersing and a suspending agent. Additional excipients, for example, coloring agents, flavoring agents and sweetening agents may also be added.
Suppositories for rectal administration may include carbondioxide releasing laxative suppositories, dosage form for topical or transdermal administration of a compound of the present invention includes ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, spot-on or patches. The active compound is admixed under sterile condition with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
Liquid form preparation for oral administration includes pharmaceutically acceptable emulsions, microemulsions, solutions, aqueous or oily suspensions, syrups, sprays and elixirs. For liquid form preparation, the active compound is mixed with water or other solvent, solubilizing agents, cosolvents, buffers, emulsifiers, for example, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils, for example, cottonseed, groundnut, corn, germ, olive, castor and sesame oil), glycerol, and fatty acid esters of sorbitan and mixture thereof; suspending agents, for example, sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose or carboxymethylcellolose and preservatives, for example, methyl or propyl p-hydroxybenzoate and sorbic acid. The spray composition contains suitable propellants.
Injectable preparations, for example, sterile aqueous or non-aqueous injections, injectable depot forms, aqueous suspensions or emulsions may be formulated according to
the art using parenterally dispersing or wetting and suspending agent. Among the acceptable vehicles and solvents that may be employed are water for injection, Ringer's solution and isotonic sodium chloride. Ophthalmic formulations, eardrops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
Dosage form for tropical or transdermal administration of a compound of the present invention includes ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active compound is admixed under sterile condition with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
Aerosol for nasal administration can be prepared according to the techniques well known in the art. It may contain suitable preservatives, anti-oxidants, dispersing agents etc.
The pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be packaged preparation, the package containing discrete capsules, powders, in vials or ampoules, and ointments capsule, sachet, tablet, gel, cream itself or it can be the appropriate number of any of these packaged forms.
Compounds described herein, muscarinic receptor antagonists, bladder selective muscarinic receptor antagonists, 5a reductase inhibitors, HMG-CoA reductase inhibitors, endothelin antagonists, nitric oxide donor, cGMP elevators, 5-HT antagonists, can be formulated in combination to achieve desired therapeutic effects, i.e., combination therapies. As such, the dosage amounts of such active ingredients can be adjusted accordingly, without undue experimentation and well within the abilities of one of ordinary skill in the art. As one of ordinary skill in the art can appreciate, dosage amounts of compounds described herein,, bladder selective muscarinic receptor antagonists, 5a reductase inhibitors, HMG-CoA reductase inhibitors, endothelin antagonists, nitric oxide donor, cGMP elevators, 5-HT antagonists, may be independently optimized and combined to achieve a synergistic therapeutic result. In accordance with methods encompassed herein, individual components of any combination can be administered separately in any sequence at the same or different times during the course of therapy, or concurrently in divided or single combination forms. The pharmaceutical compositions as described herein can be administered together combined in a single dosage form or they can be administered separately, simultaneously or sequentially, each in its dosage form but as part of the same therapeutic treatment program or
regimen. Separate administration of each compound, at different times and by different routes, will sometimes be recommended.
The dosage forms disclosed herein can be prepared by conventional methods known to a person ordinary skilled in the art. The dosage of the pharmaceutical composition of the present invention may be appropriately determined with reference to the dosages recommended for the respective active components and can be selected according to the recipient, the age and body weight, current clinical status, administration time, dosage form, method of administration, and combination of the active components, among other factors. The pharmaceutical composition of the present invention can show a marked synergistic effect compared with administration of either active component alone. Furthermore, since the pharmaceutical composition of the present invention can develop sufficient efficacy with reduced doses as compared with the administration of any one of the active components alone, the side effects of the respective components can be reduced.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.
Experimental Details
Scheme I
Preparation of 2-( 5-Chloropentyl)-3a,4,7,7a-tetrahydro-isoindole-1,3-dione
A solution of tetrahydropthalimide (1 equiv.), l-Bromo-5-chloropentane (7 equiv.) and potassium carbonate (3 equiv.) in acetone (25 times) was stirred for about 60 hours at room temperature. The reaction mixture was then filtered washed with acetone. The filtrate was evaporated on under reduced pressure to get oily residue. Oily residue was then stirred in hexane and solid separated out was dried under vacuum to get the desired product. Yield: 92%
Preparation of 2-{5-(3,4-Dihvdro-1 H-isoquinoline-2-yl)-pentyl]-3a,4,7,7a-tetrahydro-isoindole-1,3-dione
A solution of 2-(5-Chloropentyl)-3a,4,7,7a-tetrahydro-isoindole-l,3-dione (1 equiv.), 1,2,3,4-tetrahydro-isoquinoine, potassium carbonate and potassium iodide in ethyl methyl ketone was refluxed for about 6-7 hours. The reaction mixture was then filtered through a
sintered funnel and washed with dichloromethane. The filtrate obtained was concentrated under reduced pressure. The solid obtained was then purified.
Preparation of 2-{5-(3,4-Dihydro-lH-isoquinoline-2-yl)-pentvl]-5,6-dihvdroxy-hexahydro-isoindole-1,3-dione
To a clear solution of 2-{5-(3,4-Dihydro-lH-isoquinoline-2-yl)-pentyl]-3a,4,7,7a-tetrahydro-isoindole-l,3-dione (1 equiv.) in ethanol (20 ml) was added potassium permanganate solution (1 equiv. in water 5 ml) drop wise at about 0-5°C. The reaction mixture was stirred at room temperature for about 6-8 hours. After completion of the reaction, it was filtered through celite pad, washed with ethanol. Filtrate thus obtained was concentrated to yield the crude product which was then purified by column chromatography.
Scheme II
Preparation of 2-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-1 -yl]-propyl}-hexahydro-5,8-dioxa-2-aza-cyclopenta[b]naphthalene-l,3,6,7-tetraone
Reference: Chem.Pharm.Bull. 50 (3), 2002, 346-363
Scheme III
Preparation of 3-[4-(2-Methoxyphenyl)-piperazine-l-yl-]-popylamine (Compound of Formula 12)
i) Triethylamine (1.3 equiv.) and acrylonitrile were added to a solution of a l-(2-Methoxyphenyl) piperazine (1.18 equiv.) in methanol at room temperature and the reaction mixture was stirred overnight. Solvent was then removed and residue was taken in water followed by extraction with dichloromethane. The organic extract was concentrated and then purified by column chromatography to obtain the desired product.
ii) To a solution of l-(2-Isocyano-ethyi)-4-(2-methoxyphenyl)-piperazine (1 equiv.) in methanol was added Raney Ni (135 mg) followed by addition of methanol-ammonia. The reaction mixture was hydrogenated in parr apparatus for about 2 hours. The reaction mixture was filtered through a bed of celite, the bed washed well with methanol. The filtrate was then concentrated to afford the desired product.
Preparation of (1,3-Dioxo-l J,3a,4,7,7a-hexahydro-isoindol-2-yl)-acetic acid tert-butyl ester Sodium hydride (1.2 equiv.) was added to dimethylformamide and stirred at about 0-5°C. 3a,4,7,7a-Tetrahydro-isoindole-l,3-dione of Formula 2 (1.0 equiv.) was added and the reaction mixture was stirred at an ambient temperature for about 1 hour. The reaction mixture was cooled to about 0-5°C and bromo-acetic acid tert-butyl ester (1.0 equiv.) was added drop wise. The reaction mixture was heated at about 50°C for about 15 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, washed with water, brine and purified by column chromatography to form (l,3-Dioxo-l,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-acetic acid tert-butyl ester of Formula 10.
Preparation of (1,3-Dioxo-1,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-acetic acid
(l,3-Dioxo-l,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-acetic acid tert-butyl ester of Formula 10 was dissolved in dichloromethane and trifluroacetic acid (5.0 equiv.) was added to it and then the reaction mixture was stirred at an ambient temperature for overnight. The solvent was evaporated, followed by addition of dichloromethane. The solvent was then evaporated under vacuum to form (l,3-Dioxo-l,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-acetic acid of Formula 11.
Preparation of Compound of Formula 13
To a solution of (l,3-Dioxo-l,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-acetic acid of Formula 11 (1 equiv.) in dimethylformamide was added a compound of Formula 12 (1 equiv.). The reaction mixture was cooled to about 0-5°C and stirred for about 10 minutes. N-methyl morpholine (2 equiv.), hydroxy benzotriazole (1 equiv.) were added to the reaction mixture at about 0-5°C and stirred for about 10 minutes. l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride was added at about 0-5 °C and stirred at an ambient temperature for overnight. The reaction was quenched with water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulphate and evaporated the solvent to form a compound of Formula 13.
Preparation of Compound of Formula 14
To a clear solution of a compound of Formula 13(1 equiv.) in ethanol (20 ml) was added potassium permanganate solution (1 equiv. in water 5 ml) drop wise at about 0-5°C. The reaction mixture was stirred at room temperature for about 6-8 hours. After completion
of the reaction, it was filtered through celite pad, washed with ethanol. Filtrate thus obtained was concentrated to yield the crude product which was then purified by column chromatography.
Scheme IV
Preparation of Compound of Formula 16
A solution of a compound of Formula 11 (1 equiv.) with thionyl chloride (5 equiv.) in dichloromethane was refluxed for about 2 hours. The reaction mixture was distilled under reduced pressure. Hexane was added and again distilled under reduced pressure. Reaction mixture was dissolved in dichloromethane and 4-Dimethylaminopyridine was added (1.2 equiv.) followed by compound of Formula 15. The reaction mixture was then stirred at room temperature for about 3 hours. Sodium bicarbonate washings were given to the reaction mixture followed by water. The solvent was then concentrated under reduced pressure. The solid thus obtained was then purified by column chromatography.
Scheme V
Preparation of Compound of Formula 19
A solution of a compound of Formula 17 (1 equiv.), compound of Formula 18 (2 equiv.) in n-butanol was refluxed for about 15 hours. The reaction mixture was then concentrated under reduced pressure. To the oily residue obtained was added a base, like sodium hydroxide and the product was then extracted with chloroform. The organic layer was concentrated and purified by column chromatography to obtain the desired product.
Preparation of Compound of Formula 20
A suspension of 2-(3-Chloropropyl)-3a,4,7,7a-tetrahydro-isoindole-l,3-dione (55 equiv.), phenyl-piperazin-1-yl-acetic acid methyl ester (46.25 equiv.), anhydrous potassium carbonate (108.75 equiv.) and potassium iodide (1 equiv.) in dimethylformamide was heated at about 70-75°C for about 6-8 hours. The reaction was quenched by adding water to it. The solid obtained was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulphate and concentrated to get the crude product. It was then purified over silica gel column by using dichloromethane and methanol as eluent.
Preparation of Compound of Formula 21
To a clear solution a compound of Formula 20 (1 equiv.) in ethanol was added potassium permanganate solution (1 equiv. in water 5 ml) drop wise at 0-5°C. The reaction mixture was stirred at room temperature for about 6-8 hours. After completion of the reaction, it was filtered through celite pad, washed with ethanol .Filtrate thus obtained was concentrated to yield the crude product which was then purified by column chromatography.
Preparation of Hydrochloride Salt
An equimolar quantity of isopropyl alcohol and hydrochloric acid was added to the base of Formula 7, Formula 8, Formula 14, Formula 16 and Formula 21. The solid which precipitates, was then filtered to obtain the hydrochloride salt of the respective compound.
The following compounds were prepared by following the above procedures:
Compound No.l: 2-{3-[8-hydroxy-8-(2-methoxyphenyl)-3-azabicyclo[3.2.1]oct-3-yl]propyl}-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione and its hydrochloride salt (Compound No. 2)
1H NMR (300MHz, CDC13): 8 1.68 (bs, 4H), 1.98 (bs, 3H), 2.20-2.25 (m, 2H), 2.45-2.50 (m,
2H), 2.92-2.95 (m, 4H), 3.27-3.31 (m, 7H), 3.55-3.59 (m, 5H), 3.80 (s, 3H), 7.08-7.35 (m,
4H),
Mass (m/z): 425 (M++l),
Compound No.3: 2-{3-[4-hydroxy-4-(2-methoxyphenyl)piperidin-1 -yl]propyl}-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione and its hydrochloride salt (Compound No. 4)
1HNMR (300 MHz, HC1 salt DMSOd6): 8 1.63-1.67 (m, 2H), 2.01-2.02 (m, 2H), 2.18-2.28 (m, 2H), 2.44-2.49 (m, 2H), 3.04-3.06 (m, 2H), 3.23-3.32 (m, 4H), 3.46-3.51 (m, 2H), 3.88-3.93 (m, 3H), 3.97 (s, 3H), 5.95-5.96 (m, 2H), 6.99-7.06 (m, 2H), 7.29-7.60 (m, 1H), 7.60-7.63 (m, 1H) Mass (m/z): 399 (M++l),
CompoundNo.5: 2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-N-{2-[4-(2-methoxyphenyl)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt (Compound No. 6)
1HNMR (300 MHz, CDCI3): 8 2.22-2.26 (m, 2H), 2.55-2.60 (m, 2H), 3.21-3.23 (m, 4H), 3.43-3.44 (m, 2H), 3.53-3.54 (m, 4H), 3.61-3.73 (m, 4H), 3.87 (s, 3H), 4.22 (s, 2H), 5.89 (s, 2H), 6.88-6.99 (m, 3H), 7.06-7.12 (m, 1H), 8.57 (s, 1H) Mass (m/z): 427.21(M++1),
Compound No.7: N-{3-[3-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)propyi]-3-azabicyclo[3.1.0]hex-6-yl}acetamide and its hydrochloride salt (Compound No. 8)
1H NMR (300 MHz, CDCI3): 8 1.48-1.55 (m, 4H), 1.91 (s, 3H), 2.29-2.57 (m, 6H), 2.57-2.60 (m, 2H), 2.90 (m, 1H), 3.05-3.14 (m, 4H), 3.44-3.49 (m, 2H), 5.88-5.89 (bs, 2H) Mass (m/z): 332 (M++l),
Compound No.9: Methyl {4-[3-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)propyl]piperazin-l-yl}(phenyl)acetate and its hydrochloride salt (Compound No. 10)
1HNMR (300 MHz, CDC13): 5 2.18-2.24 (m, 4H), 2.59-2.64 (m, 2H), 2.77-3.13 (m, 10H), 3.34 (bs, 2H), 3.44 (m, 2H), 3.67 (s, 3H), 4.10 (s, IH), 5.91 (bs, 2H), 7.36 (bs, 4H) Mass (m/z): 426(M++1),
Compound No.l 1: Methyl {4-[3-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)propyl]piperazin-l-yl}(phenyl)acetate and its hydrochloride salt (Compound No. 12)
1HNMR (300 MHz, CDCb): 8 1.68-1.70 (m, 2H), 2.14 (bs, 4H), 2.86-2.93 (m, 12H), 3.56 (bs, 2H), 3.67 (s, 3H), 3.82 (bs, 3H), 4.11 (s, IH), 7.36 (bs, 5H) Mass (m/z): 460 (M++l),
Compound No. 13: 2-(l,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-soindol-2-yl)-N-{2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt (Compound No. 14)
1HNMR (300 MHz, CDC13): 8 1.43-1.48 (m, 3H), 2.22-2.26 (m, 2H), 2.55-2.60 (m, 2H), 3.11-3.22 (m, 4H), 3.44-3.49 (m, 2H), 3.54-3.56 (m, 4H), 3.67-3.73 (m, 4H), 4.04-4.11 (m, 2H), 4.22 (s, 2H), 5.88-5.90 (t, 2H), 6.86-6.93 (m, 3H), 7.02-7.08 (m, IH), 8.57 (s, IH) Mass (m/z): 441.34 (M++l),
Compound No. 15: 2-(5,6-dihydroxy-1,3-dioxooctahydro-2H-isoindol-2-yl)-N-{2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt (Compound No. 16)
1HNMR (300MHz, CDCI3): 8 1.24(s,3H), 1.34-1.39 (m, 4H), 1.73-1.77 (m, 2H), 1.90-1.92 (m, 2H), 3.04-3.06 (m, 6H), 3.22 (m, 6H), 4.02-4.07 (m, 6H), 6.89-6.99 (m, 4H), 8.56 (s, IH) Mass (m/z): 475 (M++l),
Compound No.l7:2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-N-{2-[4-(2-isopropoxyphenyl)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt (Compound No. 18)
1HNMR (300MHz, CDCI3): 8 1.39-1.44 (m, 6H), 2.22 (m, IH), 2.26 (m, IH), 2.54 (m, IH), 2.54 (m, IH), 2.59 (m, IH), 3.24 (m, 2H), 3.41 (m, 4H), 3.54-3.58 (m, 2H), 3.64-3.73 (m, 6H), 4.22 (s, 2H), 4.61-4.65 (m, IH) 5.89 (s, 2H), 6.90-6.95 (m, 2H), 7.08-7.13 (m, 2H), 8.51 (s, IH) Mass (m/z): 455.2 (M++l),
Compound No. 19: 2-(5,6-dihydroxy-1,3-dioxooctahydro-2H-isoindol-2-yl)-N-{2-[4-(2-isopropoxyphenyl)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt (Compound No.20)
1HNMR (300MHz, CDCI3): 8 1.14-1.25 (m, 2H), 1.67-1.92 (m, 13H), 2.09-2.13 (m, 3H), 2.59 (m, 2H), 3.19-3.31 (m, 8H), 4.18 (m, 2H), 4.83 (m, IH), 6.89-6.91 (m, 2H), 7.00-7.07 (m, 2H), 8.75 (s, IH) Mass (m/z): 489.2 (M++l),
Compound No.21: AT-(2-{4-[2-(cyclopentyloxy)phenyl]piperazin-1 -yl}ethyl)-2-(l ,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)acetamide and its hydrochloride salt (Compound
No.22)
1HNMR (300MHz, CDCI3): 8 1.68-1.84 (m, 4H), 1.91-1.98 (m, 4H), 2.27 (m, 2H), 2.55 (m, 2H), 3.22 (m, 2H), 3.42-3.44 (m, 2H), 3.55-3.74 (m, 10H), 4.22 (s, 2H), 4.82 (s, IH), 5.89 (s, 2H), 6.87-6.93 (m, 2H), 7.00-7.09 (m, 2H), 8.57 (s, IH) Mass (m/z): 481.22 (M++l),
Compound No.23: N-(2-{4-[2-(cyclopentyloxy)phenyl]piperazin-1 -yl}ethyl)-2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)acetamide and its hydrochloride salt (Compound No.24)
1HNMR(300MHz, CDCb): 8 1.18-1.25 (m, 3H), 1.37-1.43 (m, 5H), 2.01-2.17 (m, 8H), 3.29
(m, 5H), 3.44-3.82 (m, 9H), 4.23 (m, 2H), 4.61 (m, IH), 6.90 (m, 2H), 7.05 (m, 2H),
8.57 (s, IH)
Mass (m/z): 515.23 (M++l),
Compound No.25: 2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-N-{2-[4-(2-methoxyphenyl)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt (Compound No.26)
1HNMR (300MHz, CDC13): 8 1.77 (m, 2H), 1.92 (m, 2H), 2.94-2.97 (m, 6H), 3.49 (m, 8H), 3.80 (m, 6H), 4.02 (m, 3H), 6.93-7.00 (m, 4H), 8.49 (s, IH) Mass (m/z): 461.21 (M++l),
Compound No.27: 7V-{3-[3-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)propyl]-3-azabicyclo[3.1.0]hex-6-yl}tetrahydrofuran-2-carboxamide and its hydrochloride salt (Compound No.28)
1H NMR (300MHz, CDCI3): 8 1.79 (s, bs, 5H), 1.92 (bs, 2H), 2.35-2.40 (m, 4H), 2.45-2.50 (m, 2H), 2.98 (bs, 2H), 3.08-3.13 (4H), 3.39-3.72 (m, 5H), 4.15 (s, IH), 5.86 (bs, 2H) Mass (m/z): 388 (M++l),
Compound No.29:2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-N-{2-[4-(2-isopropoxyphenyl)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt (Compound No.30)
1H NMR (300MHz, CDCI3): 8 1.37-1.39 (m, 6H), 2.04 (m, 2H), 2.22-2.27 (m, 2H), 2.55-2.59 (m, 2H), 3.13 (m, 4H), 3.44 (m, 4H), 3.60-3.64 (m, 6H), 4.19 (s, 2H), 4.58-4.66 (m, IH), 5.89-5.90 (m, 2H), 6.88-6.93 (m, 2H), 7.04-7.09 (m, 2H), 8.20 (s, IH) Mass (m/z): 470.17 (M++l),
Compound No.31: N-(2-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}ethyl)-2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)acetamide and its hydrochloride salt (Compound
No.32)
1HNMR (300MHz, CDCI3): 8 1.68-1.97 (m, 8H), 2.14 (m, 2H), 2.22-2.27 (m, 2H), 2.55-2.60 (m, 2H), 3.10 (m, 4H), 3.45-3.64 (m, 10H), 4.19 (s, 2H), 4.80-4.83 (m, IH), 5.89-5.90 (m, 2H), 6.89-7.04 (m, 4H), 8.20 (s, IH) Mass (m/z): 496 (M++l),
Compound No.33: 2-(l,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-N-{2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt (Compound No.34)
1H NMR (300MHz, CDCI3): 8 1.45-1.48 (m, 3H), 2.14-2.16 (m, 2H), 2.26-2.27 (m, 2H), 2.55-2.56 (m, 2H), 3.09-3.12 (m, 4H), 3.44-3.45 (m, 4H), 3.54-3.65 (m, 6H), 4.06-4.10 (m, 2H), 4.19 (s, 2H), 5.89-5.90 (m, 2H), 6.87-6.96 (m, 3H), 7.06.(m, IH), 8.18-8.21 (m, IH)
Mass (m/z): 455 (M++l),
Compound No.35: 2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-N{2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt (Compound No.36)
1HNMR (300MHz, CDCb): 8 1.34-1.37 (m, 3H), 1.80-1.82 (m, 2H), 1.87-1.89 (m, 4H), 3.02-3.16 (m, 10H), 3.46-3.48 (m, 8H), 3.97 (s, 2H), 4.02-4.04 (m, 2H), 6.89-6.99 (m, 4H), 8.37-8.40 (m, 1H) Mass (m/z): 489 (M++l),
Compound No.37: 2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-N-{2-[4-(2-isopropoxyphenyl)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt (Compound No.38)
!HNMR (300MHz, CDCI3): 8 1.23-1.28 (m, 6H), 1.76-1.77 (m, 2H), 1.87-1.91 (m, 4H), 3.01-3.18 (m, 10H), 3.95-3.97 (m, 8H), 3.97 (s, 2H), 4.59-4.63 (m, 1H), 6.88-6.98 (m, 4H), 8.38-8.40 (m, 1H) Mass (m/z): 504 (M++l),
Compound No.39: N-(2-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}ethyl)-2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)acetamide and its hydrochloride salt (Compound No.40)
1H NMR (300MHz, DMSO): 8 1.23-1.28 (m,8H), 1.75-1.76 (m, 2H), 1.85-1.90 (m, 4H), 3.00-3.18 (m, 12H), 3.50-3.54 (m, 6H), 3.97 (s, 2H), 4.59-4.63 (m, 1H), 6.86-6.98 (m, 4H), 8.37-8.39 (m, 1H) Mass (m/z): 529 (M++l),
Compound No.41:2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-N-{2-[4-(2-methoxyphenyl)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt (Compound No.42)
1HNMR (300MHZ, CDCI3): 8 2.122-2.151 (m, 2H), 2.228-2.271 (m, 2H), 2.556-2.600 (m, 2H), 3.076-3.105 (m, 4H), 3.426-3.646 (m, 10H), 3.878 (s, 3H), 4.190 (s, 2H), 5.89-5.903 (m, 2H), 6.890-6.977 (m, 3H), 7.068-7.089 (m, 1H), 8.175-8.203 (m, 1H) Mass (m/z): 441 (M++l),
Compound No.43: 2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-N-{2-[4-(2-methoxyphenyl)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt (Compound No.44)
1HNMR(300MHz, DMSO): 1.75-1.76 (m, 2H), 1.88-1.91 (m, 4H), 3.04-3.16 (m, 10H), 3.47-3.53 (m, 6H), 3.80-3.81 (s, 3H), 3.98 (m, 4H), 6.89-7.05 (m, 4H), 8.38-8.40 (m, 1H) Mass (m/z): 475 (M++l),
Compound No.45: 2-[4-(2-methoxyphenyl)piperazin-l-yl]ethyl (l,3-dioxooctahydro-2H-isoindol-2-yl)acetate and its hydrochloride salt (Compound No.46)
1H NMR (300MHZ, CDC13): 2.25-2.30 (m, 2H), 2.58-2.62 (m, 2H), 3.18-3.24 (m, 4H), 3.33 (m, 2H), 3.47-3.52 (m, 4H), 3.61-3.63 (m, 2H), 3.88 (s, 3H), 4.28 (s, 2H), 4.79 (m, 2H), 5.90-5.94 (m, 2H), 6.88-6.95 (m, 3H), 7.06-7.10 (m, 1H) Mass (m/z): 428 (M++l),
Compound No.47: 7-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl} tetrahydro-4aH-[l,4]dioxino[2,3-f]isoindole-2,3,6,8(5i/,7H)-tetrone and its hydrochloride salt (Compound No.48)
1HNMR (300 MHz, CDC13)8: 1.20-1.25 (d, 6H), 1.60 (s, 2H), 1.60-2.52 (m, 4H), 3.01-3.08 (m, 6H), 3.10-3.41 (m, 6H), 3.62-3.65 (m, 2H), 4.48-4.51 (m, 1H), 5.08 (s, 2H), 6.59-6.80 (m, 3H) Mass (m/z): 518 (M++l),
Compound No.49: 2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl (l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)acetate and its hydrochloride salt (Compound No.50)
1HNMR (300MHZ, CDC13): 1.46-1.49 (m, 3H), 2.25-2.30 (m, 2H), 2.62-2.63 (m, 2H), 3.16-3.22 (m, 4H), 3.34 (m, 2H), 3.54-3.61 (m, 6H), 4.06-4.11 (m, 2H), 4.28 (s, 2H), 4.79 (m, 2H), 5.93-5.94 (m, 2H), 6.86-6.94 (m, 3H), 7.03-7.05 (m, 1H) Mass (m/z): 442 (M++l),
Compound No.51: 2-[5-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(lH)-yl)pentyl]-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione and its hydrochloride salt (Compound No.52)
'HNMR(300MHz, CDCI3): 1.28-1.33 (m, 2H), 1.55-1.64 (m, 4H), 2.14-2.18 (m, 2H), 2.51-2.59 (m, 4H), 2.78-2.85 (m, 4H), 3.06-3.07 (m, 2H), 3.46-3.49 (m, 2H), 3.61 (s, 2H), 3.84 (s, 6H), 5.87-5.88 (m, 2H), 6.52 (s, 1H), 6.59 (s, 1H) Mass (m/z): 413 (M++l),
Compound No.53: 2-[5-(3,4-dihydroisoquinolin-2(lH)-yl)pentyl]-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione and its hydrochloride salt (Compound No.54)
1HNMR (300MHz, CDCI3): 1.25-1.30 (m, 2H), 1.55-1.63 (m, 4H), 2.16-2.20 (m, 2H), 2.50-2.59 (m, 4H), 2.77-2.78 (m, 2H), 2.91-2.92 (m, 2H), 3.05-3.06 (m, 2H), 3.45-3.49 (m, 2H), 3.66 (s, 2H), 5.84-5.88 (m, 2H), 7.01-7.15 (m, 4H) Mass (m/z): 353 (M++l),
Compound No.55: 2- {5-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-1 -y 1]penty 1} -5,6-
dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione and its hydrochloride salt (Compound
No.56)
'HNMR (300 MHz, CDC13)8: 1.32-1.34 (d, 6H), 1.38 (s, 2H), 1.62-1.64 (m, 2H), 2.01-2.05
(m, 4H), 2.50 (s, 2H), 3.02-3.08 (m, 8H), 3.45-3.56 (m, 6H), 3.59-3.81 (m, 4H), 4.48-4.50
(m, 1H), 6.64-6.79 (m, 3H)
Mass (m/z): 492 (M++l),
Compound No.57: 2-[3-(3,4-dihydroisoquinolin-2(lH)-yl)propyl]-3a,4,7,7a-tetrahydro-177-isoindole-l,3(2H)-dione and its hydrochloride salt (Compound No.58)
1H NMR (300MHz, CDCI3): 1.80-1.82 (m, 2H), 2.14-2.28 (m, 9H), 2.53-2.58 (m, 2H), 3.01-3.02 (m, 2H), 3.12-3.13 (m, 2H), 3.38-3.42 (m, 2H), 3.61-3.64 (m, 2H), 4.01-4.03 (m, 1H), 4.55-4.56 (m, 1H), 5.63-5.74 (m, 2H), 7.10-7.30 (m, 4H) Mass (m/z): 325 (M++l),
Compound No.59: 2-(3-{4-[2-(2,3-dihydro-lH-inden-2-yloxy)-5-fluorophenyl]piperazin-l-yl}propyl)-5,6-dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione and its hydrochloride salt (Compound No.60)
1HNMR (300MHZ, CDC13): 1.25-1.37 (m, 4H), 1.74-2.18 (m, 6H), 2.34-2.42 (m, 7H), 2.95-3.26 (m, 8H), 3.50-3.79 (m, 4H), 6.57-6.84 (m, 3H), 7.17-7.19 (m, 4H) Mass (m/z): 538.0 (M++l),
Compound No.61:2-[5-(3,4-dihydroisoquinolin-2(lH)-yl)pentyl]-5,6-dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione and its hydrochloride salt (Compound No.62)
'HNMR(300MHz, CDCb): 1.25-1.33 (m, 4H), 1.59-1.62 (m, 2H), 1.59-1.68 (m, 2H), 2.16-2.20 (m, 2H), 2.63-2.66 (m, 2H), 2.91-3.01 (m, 6H), 3.47-3.50 (m, 2H), 3.66-3.69 (m, 2H), 3.88 (s, 2H), 7.04-7.23 (m, 4H) Mass (m/z): 387 (M++l),
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof.
Pharmacological testing
A] Human Recombinant Assay
Receptor Binding Assay: Receptor binding assays were performed using recombinant cells expressing human alpha-la and alpha-lb adrenoceptors. The affinity of different compounds for α1a and aib adrenoceptor subtypes was evaluated by studying their ability to displace specific [3H] prazosin binding from the membranes of recombinant clones expressing alpha-la and alpha-lb adrenoceptors. The binding assays were performed according to U'Prichard et al, Eur J Pharmacol, 50:87-89 (1978) with minor modifications.
Human embryonic kidney (HEK) cells which had been stably transfected with human alpha-la and alpha-lb adrenoceptors were cultured in an atmosphere of 5 % CO2 at 37 °C in DMEM medium supplemented with 10%heat inactivated fetal calf serum, 1 mM glutamine, 100 U/mL penicillin and 0.1 mg/mL streptomycin. Selection pressure was maintained by regular addition of puromycin (3 µg/mL) to the culture medium.
The cells were homogenized in 5-10 volumes of buffer (Tris HCl 5 mM, EDTA 5 mM, pH 7.4) using a polytron homogenizer. The homogenate was centrifuged at 40,000 g for 20 min at 4 °C. The pellet thus obtained was resuspended in assay buffer (Tris HCl 5 mM, EDTA 5 mM, pH 7.4) and were stored at -70 °C until the time of assay.
Competition radioligand binding to the cloned subtypes of α1 -adrenoceptors was performed using [3H] prazosin as the radioligand. The membrane homogenates (5-10 µg protein) were incubated in 250 µL of assay buffer (Tris HCl 50 mM, EDTA 5 mM, pH 7.4) at 24-25 °C for 1 hour. Non-specific binding was determined in the presence of 10-uM terazosin. The incubation was terminated by vacuum filtration over GF/B fiber filters. The
filters were then washed with ice-cold 50 mM Tris HC1 buffer (pH 7.4). The filter mats were
dried and bounded radioactivity retained on filters was counted. The IC50 and Kd were
estimated by using the non-linear curve-fitting program using Graph pad prism software. The
value of inhibition constant Ki was calculated from competitive binding studies by using
Cheng and Prusoff equation (Cheng and Prusoff, Biochem Pharmacol, 22:3099-3108 (1973)),
Ki = IC50 /(1+L/Kd) where L is the concentration of [3H] prazosin used in the particular
experiment.
Reference: Michel, M. C, Grubbel, B., Taguchi, K. et al: Drugs for treatment of benign prostatic hyperplasia: affinity comparison at cloned α1 -adrenoceptor subtypes and in human prostate. JAuton Pharmacol, 16:21 (1996).
The results of the human recombinant assays of the compounds disclosed herein are as follows:
a) The compounds disclosed herein exhibited α1a Ki (nM) values of between about
1 nM to about greater than 1500 nM, between about 4 nM to about 280 nM,
between about 7.7 nM to about greater than 95 nM, and even between about 8.2
nM to about 64 nM
b) The compounds disclosed herein exhibited α1b Ki (nM) values of between about
4.8 nM to about greater than 1333 nM, between about 8.9 nM to about greater than 900 nM, between 23 nM to 478 nM, and even between about 29 nM to about 175 nM.
B] Receptor binding assays
Receptor binding assays are performed using native α-1 adrenoceptors. The affinity of different compounds for α1a and α1b adrenoceptor subtypes is evaluated by studying their ability to displace specific [3H] prazosin binding from the membranes of rat submaxillary and liver respectively (Michel et al, Br J Pharmacol, 98: 883-889 (1989)). The binding assays are performed according to U'Prichard et al, Eur J Pharmacol, 50:87-89 (1978) with minor modifications.
Submaxillary glands are isolated immediately after sacrifice. The liver is perfused with buffer (Tris hydrochloric acid 50 mM, sodium chloride 100 mM, 10 mM ethylene diamine tetra acetic acid pH 7.4). The tissues are homogenized in 10 volumes of buffer (Tris hydrochloric acid 50 mM, sodium chloride 100 mM, ethylene diamine tetra acetic acid 10 mM, pH 7.4). The homogenate is filtered through two layers of wet guaze and filtrate is
centrifuged at 500g for 10 min. The supernatant is subsequently centrifuged at 40, OOOg for 45 min. The pellet thus obtained is resuspended in the same volume of assay buffer (Tris HCl 50 mM, EDTA 5 mM, pH 7.4) and are stored at -70 °C until the time of assay.
The membrane homogenates (150-250 jig protein) are incubated in 250 )il of assay buffer (Tris HCl 50 mM, EDTA 5 mM, pH 7.4) at 24-25 °C for I hour. Non-specific binding is determined in the presence of 300 nM prazosin. The incubation is terminated by vacuum filtration over GF/B fibre filters. The filters are then washed with ice cold 50 mM Tris HCl buffer (pH 7.4). The filtermats are dried and bounded radioactivity retained on filters is counted. The IC50 and Kd are estimated by using the non-linear curve-fitting program using G pad prism software. The value of inhibition constant Ki is calculated from competitive binding studies by using Cheng and Prusoff equation (Cheng and Prusoff, Biochem Pharmacol, 1973, 22:3099-3108), Ki = IC50 /(1+L/Kd) where L is the concentration of [3H] prazosin used in the particular experiment.
In vitro functional studies (In vitro α1a Adrenoceptor selectivity)
In order to study selectivity of action of the present compounds towards different α1a adrenoreceptor subtypes, the ability of these compounds to antagonize α1a adrenoreceptor agonist induced contractile response of aorta (α1d), prostate (α1a) and spleen ( α1b) is studied. Aorta, prostate and spleen tissue are isolated from thipentane anaesthetized ( 300 mg/Kg) male wistar rats. Isolated tissues are mounted in organ bath containing Krebs Henseleit buffer of the following composition (mM): sodium chloride (NaCl) 118; potassium chloride (KC1) 4.7; calcium chloride (CaCl2) 2.5; magnesium sulphate hepta hydrate (MgS04. 7H2O) 1.2; sodium bicarbonate (NaHCOs) 25; potassium dihydrogen phosphate (KH2PO4) 1.2; glucose 11.1. Buffer is maintained at 37 °C and aerated with a mixture of 95% oxygen (O2) and 5% carbon dioxide (CO2). A resting tension of 2 g (aorta and spleen) or 1 g (prostate) is applied to tissues. Contractile response is monitored using a force displacement transducer and is recorded on chart recorders. Tissues are allowed to equilibrate for 1 and 1/2 hour. At the end of equilibration period, concentration response curves to norepinephrine (aorta) and phenylepinephrine (spleen and prostate) are obtained in the absence and presence of the tested compound (at concentration of 0.1, 1 and 10 )jM).

WE CLAIM:
1. Compounds having the structure of Formula I,
(FORMULA REMOVED)

pharmaceuticallyacceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof, wherein:
A and B are independently hydrogen, halogen, hydroxy, alkyl, alkoxy, cyano, nitro, amino, alkylamino or thio, further A and B together form a ring of the form
(FORMULA REMOVED)

L is (CH2)3, (CH2)5, CH2CONHCH2CH2 or CH2COOCH2CH2;
Y and Y' are independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl, further Y and Y' together form a bridging group (C0-3);
X is N, C, CH or C(OH);
Z is alkyl, cycloalkyl, aryl, NHCOR1, CH(COOR1)R1 or NHCONHR,, wherein R1 is alkyl, aryl or heterocyclyl, further X and Z together with Y (or Y') form a 5-7 membered ring, which may be partially saturated, saturated or unsaturated;
is optional bond ;
with the provisos that when L is -(CH2)3- i) Y and T together form a bridging group (C0-3) ii) X is -COH Hi) CH(COOR1)R1 iv) X and Z together with Y (or Y') form phenyl ring
(FORMULA REMOVED)

v) Z is 2-(2,3-dihydro-lH-inden-2-yloxy)-5-fluorophenyl or vi) A andB together conform a
ring of the form
2. A compound namely:
2-{3-[8-hydroxy-8-(2-methoxyphenyl)-3-azabicyclo[3.2.1]oct-3-yl]propyl}-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione and it's hydrochloride salt,
2- {3-[4-hydroxy-4-(2-methoxyphenyl)piperidin-1 -yljpropyl} -3a,4,7,7a-tetrahydro- \H-isoindole-l,3(2H)-dione and its hydrochloride salt,
2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-iV-{2-[4-(2-methoxyphenyl) piperazin-l-yl]ethyl}acetamide and its hydrochloride salt,
N-{3-[3-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)propyl]-3-azabicyclo[3.1.0]hex-6-yl}acetamide and its hydrochloride salt, Methyl {4-[3-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)propyl]piperazin-l-yl}(phenyl)acetate and its hydrochloride salt,
Methyl {4-[3-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)propyl]piperazin-l-yl}(phenyl)acetate and its hydrochloride salt,
2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-N-{2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt,
2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-N-{2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt,
2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-N-{2-[4-(2-isopropoxyphenyl) piperazin-1-yl] ethyl }acetamide and its hydrochloride salt,
2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-N-{2-[4-(2-isopropoxyphenyl) piperazin-1-yl] ethyl }acetamide and its hydrochloride salt,
N-(2- {4- [2-(cyclopenty loxy)pheny 1] piperazin-1 -y 1} ethy l)-2-( 1,3 -dioxo-1,3,3 a,4,7,7a-hexahydro-2H-isoindol-2-yl)acetamide and its hydrochloride salt,
N-(2- {4-[2-(cyclopentyloxy)phenyl]piperazin-1 -yl} ethyl)-2-(5,6-dihydroxy-1,3-dioxooctahydro-2H-isoindol-2-yl)acetamide and its hydrochloride salt,
2-(5,6-dihydroxy-1,3-dioxooctahydro-2H-isoindol-2-yl)-.N- {2-[4-(2-methoxyphenyl) piperazin-l-yl]ethyl}acetamide and its hydrochloride salt,
N-{3-[3-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)propyl]-3-azabicyclo[3.1.0]hex-6-yl}tetrahydrofuran-2-carboxamide and its hydrochloride salt,
2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-iV-{2-[4-(2-isopropoxyphenyl) piperazin-l-yl]ethyl}acetamide and its hydrochloride salt,
N-(2-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}ethyl)-2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)acetamide and its hydrochloride salt,
2-( 1,3 -dioxo-1,3,3 a,4,7,7a-hexahydro-2H-isoindol-2-y l)-N- {2- [4-(2-ethoxypheny l)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt,
2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-A'-{2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt,
2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-Af-{2-[4-(2-isopropoxyphenyl) piperazin-l-yl]ethyl}acetamide and its hydrochloride salt,
N-(2- {4-[2-(cyclopentyloxy)phenyl]piperazin-1 -yl} ethyl)-2-(5,6-dihydroxy-1,3-dioxooctahydro-2H-isoindol-2-yl)acetamide and its hydrochloride salt,
2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-N-{2-[4-(2-methoxyphenyl)piperazin-l-yl] ethyl }acetamide and its hydrochloride salt, 2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-N-{2-[4-(2-methoxyphenyl)piperazin-l-yl]ethyl}acetamide and its hydrochloride salt,
2-[4-(2-methoxyphenyl)piperazin-1 -yl]ethyl (1,3-dioxooctahydro-2H-isoindol-2-yl) acetate and its hydrochloride salt,
7-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-1 -yl]propyl} tetrahydro-4aH-[l,4]dioxino[2,3-f]isoindole-2,3,6,8(5H,7,H)-tetrone and its hydrochloride salt,
2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)acetate and its hydrochloride salt,
2-[5-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(lH)-yl)pentyl]-3a,4,7,7a-tetrahydro-lH-isoindole-1,3(2H)-dione and its hydrochloride salt,
2-[5-(3,4-dihydroisoquinolin-2(lH)-yl)pentyl]-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione and its hydrochloride salt,
2-{5-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]pentyl}-5,6-dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione and its hydrochloride salt,
2-[3-(3,4-dihydroisoquinolin-2(lH)-yl)propyl]-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione and its hydrochloride salt,
2-(3- {4-[2-(2,3-dihydro- lH-inden-2-yloxy)-5-fluorophenyl]piperazin-1 -yl}propyl)-5,6-dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione and its hydrochloride salt,
2-[5-(3,4-dihydroisoquinolin-2(lH)-yl)pentyl]-5,6-dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione and its hydrochloride salt,
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof.
3. Use of a compound as defined in claim 1 for the manufacture of a medicament for treating a disease or disorder mediated through α1a and/or α1d adrenergic receptor.
4. The use according to claim 3, wherein the disease or disorder is benign prostatic hyperplasia.
The use according to claim 4, wherein compound causes minimal fall or no fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
Use of a compound as defined in claim 1 for the manufacture of a medicament for treating lower urinary tract symptoms associated with or without benign prostatic hyperplasia.

A pharmaceutical composition for treating a disease or disorder mediated through aia and/or a1d adrenergic receptor, which comprises a therapeutically effective amount of one or more compounds of claim 1 together with pharmaceutically acceptable carriers, excipients or diluents.
A method for preparing compounds of Formula 7,
(FORMULA REMOVED)

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof, wherein, L, X, Y, Y' and Z are the same as defined in claim 1, which method comprises:
(a) reacting the compound of Formula 2 with compounds of Formula 3
(FORMULA REMOVED)

to form compounds of Formula 4,
(FORMULA REMOVED)

(b) reacting the compound of Formula 4 with compounds of Formula 5 to form compound of Formula 6,
(FORMULA REMOVED)

c) oxidizing the compound of Formula 6 to form compounds of Formula 7. 9. A method for preparing compounds of Formula 8,
(FORMULA REMOVED)

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof, wherein, L, X, Y, Y' and Z are the same as defined in claim 1, which method comprises:
(a) reacting compounds of Formula 7 with oxalyl chloride
(FORMULA REMOVED)

to form compounds of Formula 8.
10. A method for the preparing compounds of Formula 14,
(FORMULA REMOVED)

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof, wherein, Z is the same as defined in claim 1, which method comprises:
(a) reacting the compound of Formula 2 with a compound of Formula 9
(FORMULA REMOVED)

to form a compound of Formula 10,
(FORMULA REMOVED)

(b) reacting the compound of Formula 10 with an acid to form a compound of Formula 11,
(FORMULA REMOVED)

(c) coupling a compound of Formula 11 with compounds of Formula 12 to form
compounds of Formula 13,
(FORMULA REMOVED)

(d) oxidizing the compounds of Formula 13 to form compounds of Formula 14.
11. A method for the preparing compounds of Formula 16,
(FORMULA REMOVED)

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof, wherein, Z is the same as defined in claim 1, which method comprises: (a) reacting a compound of Formula 11 with thionyl chloride and compound of Formula 15
(FORMULA REMOVED)

to form compounds of Formula 16.
12. A method for the preparing compounds of Formula 21,
(FORMULA REMOVED)

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof, wherein, L and Ri is the same as defined in claim 1, which method comprises:
(a) reacting compounds of Formula 17 with compounds of Formula 18
(FORMULA REMOVED)

to form compounds of Formula 19,
(FORMULA REMOVED)

(b) reacting compounds of Formula 19 with a compound of Formula 4 to form compounds
of Formula 20.
(FORMULA REMOVED)

(c) oxidizing compounds of Formula 20 to form compounds of Formula 21.