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Title:
METABOLITES OF 2- {3-[4-(5-FLUORO-2-ISOPROPOXY-PHENYL)-PIPERAZIN-1-YL]-PROPYL} -5,6-DIHYDROXY-HEXAHYDRO-ISOINDOLE-1,3-DIONE
Document Type and Number:
WIPO Patent Application WO/2007/039809
Kind Code:
A1
Abstract:
The present invention relates to metabolites of 2-{3-[4-(5-fiuoro-2-isopropoxy- phenyl)-piperazin-1-yl]-propyl}-5,6-dihydroxyhexahydro-lH-isoindole-1 ,3(2H;-dione of Formula (I). The compounds described herein can function as α1a-adrenoceptor antagonists and thus can be used to treat benign prostatic hyperplasia (BPH) and related symptoms thereof. Processes for preparing such metabolites, pharmaceutical compositions thereof, and methods of treating BPH and related symptoms thereof are also provided.

Inventors:
SARMA, Pakala, Kumara, Savithru (1091, 17B IFFCO Colon, Gurgaon Haryana 1, 12200, IN)
GUPTA, Praful (119 Mahaveer Colony, Jain Bag Saharanpur, Uttar Pradesh 1, 24700, IN)
PALLE, Vekata, P. (G901, Sylvan Heights Sanewadi Aund, Pune Maharashtra 7, 41100, IN)
RAO, Mukkavilli, Subba (House No. 34, 2nd Floor 6 Main, Sreekanteshwara Naga, Mahalakshmi Layout Bangalore 6, 56008, IN)
KOMBU, Rajan, S. (2235 Overlook Road, Abtzio Cleveland Heights, Ohio, 44106, IN)
RAUTHAN, Kamal (House No. 216, 2nd Floor Block-A, Todays Blossom-I, May Fields Garden, Sector 4, Gurgaon Haryana 1, 12200, IN)
RAMANATHAN, Vikram, Krishna (34B Sobha Emerald, Phase I Near Jakkur Airfield, Bangalore 4, 56006, IN)
Application Number:
IB2006/002758
Publication Date:
April 12, 2007
Filing Date:
October 04, 2006
Export Citation:
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Assignee:
RANBAXY LABORATORIES LIMITED (Plot No. 90, Sector - 32 Gurgaon, Haryana 1, 122 00, IN)
SARMA, Pakala, Kumara, Savithru (1091, 17B IFFCO Colon, Gurgaon Haryana 1, 12200, IN)
GUPTA, Praful (119 Mahaveer Colony, Jain Bag Saharanpur, Uttar Pradesh 1, 24700, IN)
PALLE, Vekata, P. (G901, Sylvan Heights Sanewadi Aund, Pune Maharashtra 7, 41100, IN)
RAO, Mukkavilli, Subba (House No. 34, 2nd Floor 6 Main, Sreekanteshwara Naga, Mahalakshmi Layout Bangalore 6, 56008, IN)
KOMBU, Rajan, S. (2235 Overlook Road, Abtzio Cleveland Heights, Ohio, 44106, IN)
RAUTHAN, Kamal (House No. 216, 2nd Floor Block-A, Todays Blossom-I, May Fields Garden, Sector 4, Gurgaon Haryana 1, 12200, IN)
RAMANATHAN, Vikram, Krishna (34B Sobha Emerald, Phase I Near Jakkur Airfield, Bangalore 4, 56006, IN)
International Classes:
C07D209/48; A61K31/496; A61P13/08; C07D295/08
Domestic Patent References:
WO2003084928A12003-10-16
WO2002044151A12002-06-06
WO2005018643A12005-03-03
WO2005037282A12005-04-28
WO2005118537A22005-12-15
Attorney, Agent or Firm:
RANBAXY LABORATORIES LIMITED (JAY R. 600 College Road East, Suite 210, Princeton NJ, 08540, US)
Download PDF:
Claims:

We Claim

1 1. A metabolite of 2- {3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]propyl}-5,6-

2 dihydroxy-hexahydro-isoindole-l,3-dione of Formula I,

7 pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymorphs, conjugates or prodrugs thereof.

1 2. A metabolite according to claim 1 wherein the metabolite of the compound of

2 Formula I is a desisopropylated, hydroxylated or N-oxide derivative having the

3 structure of Formula II,

7 pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymorphs, conjugates or prodrug thereof,

10 wherein R 1 , R 2 and R 4 can be independently hydrogen or hydroxy; R 3 can be I l hydrogen or isopropyl; and n can be an integer 0 or 1.

1 3. A metabolite according to claim 1 wherein the metabolite of the compound of

2 Formula I is a ring-opened isoindole-l,3-dione derivative having the structure of 3 Formula III,

their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers or polymorphs wherein R 1 , R 2 and R 4 are independently selected from hydrogen, or hydroxy, R 3 represents hydrogen, or isopropoxy, and R 5 represents hydrogen,or methyl. A metabolite selected from the group consisting of: 2-{3-[4-(5-fluoro-2-hydroxyphenyl)piperazin-l-yl]propyl}-5,6-dihydroxyhexahydro- l/i-isoindole-l,3(2H)-dione (Compound No. 2),

2-[( {3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin- 1 -yljpropyl} amino)carbonyl]-4,5- dihydroxycyclohexanecarboxylic acid (Compound No. 3),

2-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}-4,5,6- trihydroxyhexahydro- lH-isoindole- 1 ,3 (2H)-dione (Compound No . 4),

2-{3-[4-(5-fluoro-4-hydroxy-2-isopropoxyphenyl)piperazin-l-yl]propyl}-5,6- dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione (Compound No. 5),

2-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2-hydroxypropyl}-5,6- dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione (Compound No. 6),

2-[({3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2- hydroxypropyl}amino)carbonyl]-4,5-dihydroxycyclohexanecarboxylic acid (Compound No. 7),

2-[({3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]proρyl}amino)carbonyl]- 3,4,5-trihydroxycyclohexanecarboxylic acid (Compound No. 8),

2-{3-[4-(5-fluoro-2-hydroxyphenyl)piperazin-l-yl]-2-hydroxypropyl}-5,6- dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione (Compound No. 9),

2-{3-[4-(5-fluoro-2,4-dihydroxyphenyl)piperazin-l-yl]-2-hydroxypropyl}-5,6- dihydroxyhexahydro- lH-isoindole- 1 ,3 (2H)-dione (Compound No . 10),

l-[3-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)propyl]-4-(5-fluoro-2- isopropoxyphenyl)-l-oxypiperazin-l-ium (Compound No. 11),

4-(5-fluoro-2-isopropoxyphenyl)-l-oxy-l-[3-(4,5,6-trihydroxy-l,3-dioxooctahydro- 2H-isoindol-2-yl)propyl]piperazm-l-ium (Compound No. 12),

2-[({3-[4-(5-fluoro-4-hydroxy-2-isopropoxyphenyl)piperazin-l-yl]-2- hydroxypropyl} amino)carbonyl]-4,5-dihydroxycyclohexanecarboxylic acid (Compound No. 13), and their pharmaceutically acceptable salts. 5. A prodrug having the structure of Formula IV,

Formula IV pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, or polymorph thereof, wherein W is -SO 2 , -CO-, -CONR 6 , wherein R 6 is (C 1 -C 4 )- alkyl or aryl; R is (Q-C^-alkyl, aryl or aralkyl; the circle is a compound of Formula II or III. 6. A prodrug selected from the group consisting of , 2-(5,6-dihydroxy- 1 ,3-dioxooctahydro-2//-isoindol-2-yl)- 1 - {[4-(5-fluoro-2- isopropoxyphenyl)piperazin-l-yl]methyl} ethyl methanesulfonate (Compound No. 14),

2-(5 ,6-dihydroxy- 1 ,3 -dioxooctahydro-2H-isoindol-2-yl)- 1 - { [4-(5-fluoro-2- isopropoxyphenyl)piperazin-l-yl]methyl} ethyl benzenesulfonate (Compound No. 15),

2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-l-{[4-(5-fluoro-2- isopropoxyphenyl)piperazin-l-yl]methyl} ethyl phenylacetate (Compound No. 16),

4- {4-[3-(5,6-dihydroxy- 1 ,3-dioxooctahydro-2H-isoindol-2-yl)propyl]piperazm- 1 -yl} - 2-fluoro-5-isopropoxyphenyl methanesulfonate (Compound No. 17),

4- {4-[3 -(5, 6-dihydroxy- 1 ,3-dioxooctahydro-2H-isoindol-2-yl)propyl]piperazin- 1 -yl} - 2-fluoro-5-isopropoxyphenyl benzenesulfonate (Compound No. 18),

4- {4-[3-(5,6-dihydroxy- 1 ,3-dioxooctahydro-2H-isoindol-2~yl)propyl]piperazin- 1 -yl} - 2-fluoro-5-isopropoxyphenyl dimethylcarbamate (Compound No. 19),

2-(5,6-dihydroxy- 1 ,3 -dioxooctahydro-2H-isoindol-2-yl)- 1 - {[4-(5 -fluoro-2- hydroxyphenyl)piperazin- 1 -yl]methyl} ethyl benzenesulfonate (Compound No. 20),

2-(5,6-dihydroxy- 1 ,3-dioxooctahydro-2H-isoindol-2-yl)- 1 -[(4- {5-fluoro-2-hydroxy-4- [(methylsulfonyl)oxy]phenyl}piperazin-l-yl)methyl]ethyl benzenesulfonate (Compound No. 21 ),

2-[({3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2- [(phenylacetyl)oxy]propyl}amino)carbonyl]-4,5-dihydroxycyclohexanecarboxylic acid (Compound No. 22)

2-[({2-(benzoyloxy)-3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l- yl]propyl}amino)carbonyl]-4,5-dihydroxycyclohexanecarboxylic acid (Compound No. 23),

2-({[3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2- ({[methyl(phenyl)amino]carbonyl}oxy)propyl]amino}carbonyl)-4,5- dihydroxycyclohexanecarboxylic acid (Compound No. 24), and

2-[({3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2- [(methylsulfonyl)oxy]propyl}amino)carbonyl]-4,5-dihydroxycyclohexanecarboxylic acid (Compound No. 25). 7. A pharmaceutical composition comprising a therapeutically effective amount of a metabolite of claim 1 , optionally together with one or more pharmaceutically acceptable carriers, diluents or excipients. 8. A method for treatment of a subject suffering from a disease or disorder mediated through α la -adrenceptor, comprising administering to said subject a therapeutically effective amount of a metabolite according to claim 1. 9. A method for treatment of a subject suffering from a disease or disorder selected from high intraocular pressure, disorder associated with high cholesterol, cardiac arrhythmia, impotency, sympathetically mediated pain and migraine comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1. 10. A method for treating benign prostatic hyperplasia comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1. 11. A process for preparing compounds of Formula VIII

wherein R 2 and R 4 are hydrogen or hydroxy; and R 3 is hydrogen or isopropyl; which method comprises the steps of: a) reacting a compound of Formula V with a compound of Formula VI

Formula V

to give a compound of Formula VII; and

Formula VlI

reacting the compound of Formula VII with a peroxy acid to give a compound of Formula VIII. 12. A process for preparing compounds of Formula XI

Formula Xl wherein

R 2 is hydrogen or hydroxy; and

R 3 is hydrogen or isopropyl; which method comprises the steps of: a) reacting a compound of Formula IX with a compound of Formula VI

Formula Vl

to give a compound of Formula X; and

Formula X

reacting the compound of Formula X with a peroxy acid to give a compound of Formula XI.

13. A process for preparing compounds of Formula XVI and Formula XIV

Formula XIV (Formula III wherein R 5 =H;n=1 )

Formula XVI (Formula III wherein R 5 =CH 3 ;n=1 )

wherein

R 1 , R 2 and R 4 is hydrogen or hydroxy; and

R 3 is hydrogen or isopropyl; which method comprises the steps of:

a) reacting of a compound of Formula XII

Formula XII (Formula Il wherein n=0)

to give a compound of Formula XIII; and

Formula XIII (Formula III wherein R 5 =H;n=1)

reaction of a compound of Formula XIII with a peroxy acid to give a compound of Formula XIV, or, reaction of compound of Formula XIII with methanol and hydrochloric acid to give a compound of Formula XV; and

Formula XV (Formula 111 wherein R 5 =CH 3 ;n=1)

reaction of a compound of Formula XV with a peroxy acid to give a compound of Formula XVI.

1 14. A process for preparing prodrug of Formula IV

Formula IV

(Prodrugs)

3 wherein

4 W is -SO 2 -, -CO-, -CONR 6 , wherein R 6 is CrQalkyl or aryl (e.g., phenyl or

5 naphthyl); and

6 R is C 1 -C 4 alkyl, aryl (e.g. , phenyl or naphthyl) or aralkyl (e.g. , benzyl);

7 and the circle represents main structure of any compound described herein, for

8 example, the main structure of Formulae II or III,

9 which method comprises the steps of:-

10 a) reaction of a compound of Formula XVII

Formula XVII j j (Hydroxy I ated metabolites)

12 with a compound of Formula Cl-W-R to give a compound of Formula IV.

Description:

METABOLITES OF 2-(3-[4-(5-FLUORO-I-ISOPROPOXY-PHENYL)- PIPERAZIN-I-YL]-PROPYL)-S 5 O-DIHYDROXY-HEXAHYDRO-ISOINDOLE-I 5 S-

DIONE

Field of the Invention The present invention relates to metabolites of 2- {3-[4-(5-fiuoro-2-isopropoxy- phenyl)-piperazin- 1 -yl] -propyl} -5 ,6-dihydroxyhexahydro- lH-isoindole- 1 ,3 (2H)-dione of Formula I.

The compounds described herein can function as α la -adrenoceptor antagonists and thus can be used to treat benign prostatic hyperplasia (BPH) and related symptoms thereof. Processes for preparing such metabolites, pharmaceutical compositions thereof, and methods of treating BPH and related symptoms thereof are also provided.

Background of the Invention

The αα-adrenoceptor antagonists are in clinical use for symptomatic treatment of benign prostatic hyperplasia (BPH) (Oesterling, Drug Therapy, 332(2) :99-l 10, 1995; Chappie, Br. J. Urology, 1:47-55, 1995). It is disclosed that the effects of Oc 1 -adrenoceptor antagonists result from antagonism of noradrenaline induced contraction of prostatic smooth muscle that occurs via Ot 1 adrenoceptors (Hieble et al, European Journal of Pharmacology, 107:111-117, 1985). However, as Ct 1 -adrenoceptors are widely distributed, poor organ selectivity limits therapeutic usefulness for this class of drugs. In recent years, the existence of at least three distinct subtypes of ^-adrenoceptors designated as α la , a^ and α 1( i has been established. Several studies have indicated that α la -adrenoceptor mediate the contraction of human and dog prostatic smooth muscle (Marshall et al, Br. J. Pharmacol, H2:59p, 1992; Forray et al, Molecular Pharmacology, 45:703-708, 1994). It has been suggested that selective α la -antagonists would be more efficacious and better-tolerated agents for symptomatic BPH.

2-{3-[4-(5-Fluoro-2-isopropoxyphenyi)-piperazin-l-yl]propyl} -5,6- dihydroxyhexahydro-lH " -isoindole-l,3(2H)-dione is disclosed in WO05118537 as a α la - adrenoceptor antagonist for the treatment of benign prostatic hypertrophy, also known as BPη. BPη is highly prevalent in men beyond the age of 50 and increases in severity and incidence with increase in age. The incidence is 70 % at 70 years of age and becomes nearly universal with advancing age, reaching about 90 % incidence at 80 years of age. BPη is characterized by a nodular enlargement of prostatic tissue resulting in obstruction of the urethra, resulting in increased frequency of urination, nocturia, a poor urine stream and hesitancy or delay in starting the urine flow. Chronic consequences of BPη can include hypertrophy of bladder smooth muscle, a decompensated bladder and increased incidence of urinary tract infection. The method of choice for treating BPη reportedly is surgery (Lepor, et al, The Journal of Urology, 143:553-537, 1990). Limitations of surgical treatments of BPη include high morbidity rates of an operative procedure in elderly men, persistence or recurrence of obstructive and irritative symptoms, as well as high costs of surgery.

Accordingly, there is a need for a medicinal alternative to surgery in treating BPη and in particular, a drug-based therapy in treating BPη.

Summary of the Invention

Generally provided herein are metabolites of 2-{3-[4-(5-ffuoro-2-isopropoxy- phenyl)-piperazin- 1 -yl]propyl} -5 ,6-dihydroxyhexahydro- 1/i-isoindole- 1 ,3 (2H)-dione.

Such metabolites can be used in safe and effective treatments of BPη or related symptoms thereof. Processes for the synthesis of these metabolites, as well as 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 metabolites having the same type of activity are also provided, which can be useful for safe and effective treatment of BPη or related symptoms thereof.

Pharmaceutical compositions comprising the metabolites of the present invention, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, conjugates, or prodrugs in combination with one or more pharmaceutically acceptable

carxiers, and optionally included excipients, are also included, which can be useful for safe and effective treatment of BPH or related symptoms thereof.

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.

In one aspect, provided herein are metabolites of 2-{3-[4-(5-fluoro-2-isopropoxy- phenyl)-piperazin-l-yl]propyl}-5,6-dihydroxyhexahydro-lH ' -isomdole-l,3(2H^-dione of Formula I,

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymorphs, conjugates or prodrugs thereof, wherein the metabolite can be desisopropylated, hydroxylated, or N-oxide derivative or conjugate or prodrug thereof. hi another aspect, provided herein are compounds having the structure of Formula

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymorphs, conjugates or prodrug thereof, wherein R 1 , R 2 and R 4 can be independently hydrogen or hydroxy; R 3 can be hydrogen or isopropyl; and n can be an integer 0 or 1.

Embodiments of the compounds of Formula II may include one or more of the following. For example, compounds of Formula II can be desisopropylated, hydroxylated, or N-oxide metabolites of 2-{3-[4-(5-fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]propyl }- 5,6-dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione of Formula I.

- A -

Conjugates can be sulfate, phosphate or glucuronide derivatives. Prodrugs can be carbamoyl, (CrC^-alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, (CrC^-alkylsulfonyl or arylsulphonyl derivatives.

Compounds of Formula II can include desisopropylated metabolite 2-{3-[4-(5- fluoro-2-hydroxyphenyl)piperazin-l-yl]propyl}-5,6-dihydroxyh exahydro-lH-isoindole- l,3(2H)-dione. The metabolite can have a molecular ion peak of m/z 422.2 and its retention time can be 9.3 or 12.6 minutes. The fragmentation pattern of the metabolite can be 422.2, 226.1, 208.1, 198.1, 180.2 m/z.

Compounds of Formula II can include hydroxylated metabolite 2-{3-[4-(5-fluoro- 2-isopropoxyphenyl)piperazin- 1 -yljpropyl} -4,5,6-trihydroxyhexahydro- lH-isoindole- l,3(2H)-dione. The metabolite can have a molecular ion peak of m/z 480.1 and its retention time can be 16.4 or 17.2. The fragmentation pattern of the metabolite can be 480.3, 438.2, 285.2, 271.2, 242.2, 224.2, 214.2, 196.1, 178.1 m/z.

Compounds of Formula II can include hydroxylated metabolite 2-{3-[4-(5-fluoro- 2-isopropoxyphenyl)piperazin-l-yl]-2-hydroxypropyl}-5,6-dihy droxyhexahydro-lH- isoindole-l,3(2H)-dione. The metabolite can have a molecular ion peak of m/z 480.1 and its retention time can be 14.7. The fragmentation pattern of the metabolite can be 480.3,

438.2, 242.2, 226.2, 224.2, 214.2, 196.1 m/z.

Compounds of Formula II can include hydroxylated metabolite 2-{3-[4-(5-fiuoro- 4-hydroxy-2-isopropoxyphenyl)piperazin- 1 -yl]propyl} -5,6-dihydroxyhexahydro- IH- isoindole-l,3(2H)-dione. The metabolite can have a molecular ion peak of m/z 480.1 and its retention time can be 13.0 minutes. The fragmentation pattern of the metabolite can be

480.3, 438.2, 255.2, 226.1, 208.1, 198.1 and 180.1 m/z.

Compounds of Formula II can include desisopropylated hydroxylated metabolite 2- {3-[4-(5-fluoro-2-hydroxyphenyl)piperazm-l-yl]-2-hydroxyprop yl}-5,6-dihydroxy- hexahydro- lH-isoindole- 1 ,3 (2H)-dione.

Compounds of Formula II can include desisopropylated hydroxylated metabolite 2- {3-[4-(5-fluoro-2,4-dihydroxyphenyl)piperazin-l-yl]-2-hydrox ypropyl}-5,6- dihydroxyhexahydro- lH-isoindole- 1 ,3 (2H)-dione. Compounds of Formula II can include N-oxide metabolite l-[3-(5,6-dihydroxy- l,3-dioxooctahydro-2H-isoindol-2-yl)propyl]-4-(5-fluoro-2-is opropoxyphenyl)-l- oxypiperazin-1-ium. Compounds of Formula II can include hydroxylated N-oxide

metabolite 4-(5-fluoro-2-isopropoxyphenyl)-l-oxy-l-[3-(4,5,6-trihydroxy -l,3- dioxooctahydro-2H-isoindol-2-yl)propyl]piperazin- 1 -ium.

In another aspect, provided herein are the metabolites having the structure of Formula III,

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymorphs, conjugates or prodrug thereof, wherein R 1 , R 2 and R 4 can be independently hydrogen or hydroxy; R 3 can be hydrogen or isopropyl; R 5 can be hydrogen or methyl; and n can be an integer 0 or 1.

Embodiments of the compounds of Formula III may include one or more of the following. For example, compounds of Formula III can include ring opened or ring opened hydroxylated metabolites of 2-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l- yljpropyl} -5,6-dihydroxy-hexahydro- lH-isoindole- 1 ,3(2H)-dione of Formula I.

Compounds of Formula III can include ring opened metabolite 2-[({3-[4-(5-fluoro-2- isopropoxyphenyl)piperazin- 1 -yl]propyl} amino)carbonyl] -4,5 - • dihydroxycyclohexanecarboxylic acid. The metabolite can have molecular ion peak m/z 482.2 and its retention time can be 13.4 minutes. A glucuronide conjugate of the metabolite can have molecular ion peak m/z 658.1 and its retention time can be 11.7 or 12.2 minute. The fragmentation pattern of the metabolite can be 482.2, 296.2, 279.2, 251.3, 244.1, 226.1, 208.2, 198.2 and 180.1 m/z. The fragmentation pattern of glucuronide conjugate of metabolite can be 658.2, 482.2, 420.1, 296.3, 279.4, 244.1, 226.1, 208. land 198.1 m/z.

Compounds of Formula III can include ring opened hydroxylated metabolite 2-[({3-[4-(5- fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}amino)carbon yl]-3,4,5- trihydroxycyclohexanecarboxylic acid. The metabolite can have molecular ion peak m/z 498.2 and its retention time can be 13.5 minutes. The fragmentation pattern of the

metabolite can be 498.4, 296.3, 279.3, 260.2, 251.3, 242.2, 224.2, 209.2, 196.1 and 180.2 m/z.

Compounds of Formula III can include ring opened hydroxylated metabolite 2-[({3-[4-(5- fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2-liydroxypropyl}a mino)carbonyl]-4,5- dihydroxycyclohexanecarboxylic acid. The metabolite can have molecular ion peak m/z 498.2 and its retention time can be 13.5 minutes. The fragmentation pattern of the metabolite can be 498.4, 296.3, 279.3, 260.2, 251.3, 242.2, 224.2, 209.2, 196.1 and 180.2 m/z.

Compounds of Formula III can include ring opened hydroxylated metabolite 2- [({3-[4-(5-fluoro-4-hydroxy-2-isopropoxyphenyl)piperazin-l-y l]-2- hydroxypropyl}amino)carbonyl]-4,5-dihydroxycyclohexanecarbox ylic acid.

In another aspect, provided herein are pharmaceutical compositions comprising therapeutically effective amounts of one or more compounds of Formula II and/or III,

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymorphs, conjugates or prodrugs thereof, and a pharmaceutically acceptable carrier, wherein R 1 , R 2 and R 4 can be independently hydrogen or hydroxy; R 3 can be hydrogen or isopropyl; R 5 can be hydrogen or methyl; and n can be an integer 0 or 1.

Embodiments of the pharmaceutical compositions can encompass one or more of the following. The pharmaceutical compositions can contain conjugates that include, for

example, a sulfate, phosphate or glucuronide derivatives. The pharmaceutical compositions can also contain prodrugs that include, for example, carbamoyl, (C 1 -C 4 )- alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, (Q-C^-alkylsulfonyl or arylsulphonyl derivatives. In one aspect, provided herein are methods for treating a disease or disorder mediated through α la adrenoceptor comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound disclosed herein.

In another aspect, provided herein are methods for treating a disease or disorder selected from high intraocular pressure, disorder associated with high cholesterol, cardiac arrhythmia, impotency, sympathetically mediated pain and migraine, comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound disclosed herein.

In another aspect, provided herein are methods for treating benign prostatic hyperplasia comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound disclosed herein. Embodiments of this method can include one or more of the following. For example, compound does not cause a fall in blood pressure. The compound can also relax the lower urinary tract tissue, for example, the prostate smooth muscle.

In another aspect, provided herein are methods for treating a disease or disorder mediated through α la adrenoceptor comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed herein.

In another aspect, provided herein are methods for treating a disease or disorder selected from high intraocular pressure, disorder associated with high cholesterol, cardiac arrhythmia, impotency, sympathetically mediated pain and migraine comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed herein. In yet another aspect, provided herein are methods for treating benign prostatic hyperplasia comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed herein.

In another aspect, provided herein are processes for preparing compounds disclosed herein, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, conjugates and prodrugs thereof.

In another aspect, provided herein are prodrugs having the structure of Formula IV,

Formula IV

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, or polymorphs thereof, wherein W can be -SO 2 , -CO-, -CONR 6 , wherein R 6 can be (C 1 -C 4 )- alkyl or aryl; R can be (Q-C^-alkyl, aryl or aralkyl; the circle can be the structure of any compound of Formula II or III.

Embodiments of the prodrugs can include one or more of the following. For example, the aryl can be phenyl or naphthyl. The aralkyl can be benzyl. W and R can respectively be, SO 2 and (Ci-C 4 )-alkyl; SO 2 and methyl; SO 2 and aryl; SO 2 and phenyl; CO and (C 1 -C 4 )-alkyl; CO and methyl; CO and ethyl; CO and aralkyl; CO and benzyl; CONR 6 and (CrC^-alkyl, wherein R 6 can be (Q-C^-alkyl; CONR 6 and methyl, wherein R 6 methyl; CONR 6 and aryl, wherein R 6 can be (CrC^-alkyl; CONR 6 and phenyl, wherein R 6 can be methyl; CONR 6 and aryl, wherein R 6 can be aryl; or CONR 6 and phenyl, wherein R 6 can be phenyl.

Particular illustrative examples of prodrugs can include, but are not limited to:

2-(5,6-dihydroxy- 1 ,3 -dioxooctahydro-2H-isoindol-2-yl)- 1 - { [4-(5 -fluoro-2- isopropoxyphenyl)piperazin- 1 -yljmethyl} ethyl methanesulfonate,

2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-l-{ [4-(5-fluoro-2- isopropoxyphenyl)piperazin- 1 -yljmethyl} ethyl benzenesulfonate,

2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-l-{ [4-(5-fluoro-2- isopropoxyphenyl)piperazin- 1 -yl]methyl} ethyl phenylacetate,

4-{4-[3-(5,6-dih.ydroxy-l,3-dioxooctahydro-2H " -isoindol-2-yl)propyl]piperazin-l-yl}-2- fluoro-5-isopropoxyphenyl methaiiesulfonate,

4-{4-[3-(5,6-dihydroxy-l,3-dioxooctaliydro-2H-isoindol-2- yl)propyl]piperazin-l-yl}-2- fluoro-5-isopropoxyphenyl benzenesulfonate,

4- {4-[3 -(5 ,6-dihydroxy- 1 ,3 -dioxooctahydro-2H-isoindol-2-yl)propyl]piperazin- 1 -yl} -2- fluoro-5 -isopropoxyphenyl dimethylcarbamate,

2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-l-{ [4-(5-fluoro-2- hydroxyphenyl)piperazin- 1 -yljmethyl} ethyl benzenesulfonate,

2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-l-[ (4-{5-fluoro-2-liydroxy-4- [(methylsulfonyl)oxy]phenyl}piperazin- 1 -yl)methyl] ethyl benzenesulfonate,

2-[({3-[4-(5 -fluoro-2-isopropoxyphenyl)piperazin- 1 -yl] -2- [(phenylacetyl)oxy]propyl}amino)carbonyl]-4,5-dihydroxycyclo hexanecarboxylic acid

2-[({2-(benzoyloxy)-3-[4-(5-fluoro-2-isopropoxyphenyl)pip erazin-l- yl]propyl} amino)carbonyl]-4,5-dihydroxycyclohexanecarboxylic acid,

2-({[3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2- ({[methyl(phenyl)amino]carbonyl}oxy)propyl]amino}carbonyl)-4 ,5- dihydroxycyclohexanecarboxylic acid, and

2-[({3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2- [(methylsulfonyl)oxy]propyl}amino)carbonyl]-4,5-dihydroxycyc lohexanecarboxylic acid.

In another aspect, provided herein are processes for preparing prodrugs disclosed herein.

Detailed Description of the Invention

The invention provides metabolites of 2-{3-[4-(5-fluoro-2-isopropoxyphenyl)- piperazin-l-yl]propyl}-5,6-dihydroxyhexahydro-lH-isoindole-l ,3(2H)-dione (Compound No. 1) of Formula I,

wherein the metabolites can comprise desisopropylated, hydroxylated or N-oxide derivatives of Formula I.

Desisopropylated, hydroxylated or N-oxide derivatives of compound of Formula I can be represented by the general Formula II,

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymorphs, conjugates or prodrugs thereof, wherein R 1 , R 2 and R 4 can be independently hydrogen or hydroxy; R 3 can be hydrogen or isopropyl; and n can be an integer 0 or 1.

Further, this invention provides metabolites of 2-{3-[4-(5-Fluoro-2-isopropoxy- phenyl)-piperazin- 1 -yl] -propyl} -5 ,6-dihydroxyhexahydro-isoindole- 1 ,3-dione having the structure of Formula III,

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymorphs, conjugates or prodrugs thereof, wherein R 1 , R 2 and R 4 can be independently hydrogen or hydroxy; R 3 can be hydrogen or isopropyl; R 5 can be hydrogen or methyl; and n can be an integer 0 or 1. Examples of metabolites encompassed herein include, but are not limited to,

2- {3-[4-(5-fluoro-2-hydroxyphenyl)piperazin- 1 -yljpropyl} -5,6-dihydroxyhexahydro-lH " - isoindole-l,3(2ϋf)-dione (Compound No. 2),

2-[({3-[4-(5-fluoro-2-isopropoxyphenyl)piperazm-l-yl]prop yl}amino)carbonyl]-4,5- dihydroxycyclohexanecarboxylic acid (Compound No. 3),

2- {3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin- 1 -yl]propyl} -4,5,6-trihydroxyhexahydro- lH-isomdole-l,3(2/7)-dione (Compound No. 4),

2-{3-[4-(5-fluoro-4-hydroxy-2-isopropoxyphenyl)piperazin- l-yl]propyl}-5,6- dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione (Compound No. 5),

2- {3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin- 1 -yl]-2-hydroxypropyl} -5,6- dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione (Compound No. 6),

2-[({3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2- hydroxypropyl}amino)carbonyl]-4,5-dihydroxycyclohexanecarbox ylic acid (Compound No. 7),

2-[( {3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin- 1 -yl]propyl} amino)carbonyl]-3,4,5- trihydroxycyclohexanecarboxylic acid (Compound No. 8),

2- {3-[4-(5-fluoro-2-hydroxyphenyl)piperazin-l -yl]-2-hydroxypropyl} -5,6- dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione (Compound No. 9),

2- {3-[4-(5-fluoro-2,4-dihydroxyphenyl)piperazin-l -yl]-2-hydroxypropyl} -5,6- dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione (Compound No. 10),

l-[3-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)p ropyl]-4-(5-fluoro-2- isopropoxyphenyl)-l-oxypiρerazin-l-ium (Compound No. 11),

4-(5-fluoro-2-isopropoxyphenyl)-l-oxy-l-[3-(4,5,6-trihydr oxy-l,3-dioxooctahydro-2H- isoindol-2-yl)propyl]piperazin-l-ium (Compound No. 12),

2-[({3-[4-(5-fluoro-4-hydroxy-2-isopropoxyphenyl)piperazi n-l-yl]-2- hydroxypropyl} amino)carbonyl]-4,5-dihydroxycyclohexanecarboxylic acid (Compound No. 13), and their hydrochloride salts.

The term "pharmaceutically acceptable salts," unless otherwise specified, refer to a salt prepared from one or more pharmaceutically acceptable non-toxic inorganic or organic acids. Examples of such inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitrous, nitric, carbonic, sulfuric, phosphoric acid, and the like. Appropriate organic acids include, but are not limited to, aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, for example, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, panthenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid and the like.

The salt forms can differ from the metabolites described herein in certain physical properties, for example, solubility. Pharmaceutically acceptable salts can be prepared following procedures well known to the skilled artisan.

The term "pharmaceutically acceptable solvates," unless otherwise specified, refers to solvates with water (i.e., hydrates) or pharmaceutically acceptable organic solvents. Such solvates are also encompassed herein. Furthermore, some crystalline forms of the compounds described herein can exist as polymorphs and as such are intended to be encompassed herein. Where metabolites encompassed by the invention have ( at least one chiral center, they may accordingly exist as enantiomers. It is to be understood that all such optically active isomers and racemic mixture therefore are encompassed herein.

The conjugates disclosed herein include sulfate or glucuronide derivatives of particular hydroxylated compounds. Prodrugs of particular hydroxylated compounds are also encompassed herein. Prodrugs include, but are not limited to, derivatives of compounds having one or more carbamoyl, (CrC^-alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkylsulfonyl, or arylsulfonyl groups and the like.

Examples of prodrugs as disclosed herein include, but are not limited to:

2-(5,6-dihydroxy-l,3-dioxooctahydro-2H ' -isomdol-2-yl)-l-{[4-(5-fluoro-2- isopropoxyphenyl)piperazin-l-yl]methyl} ethyl methanesulfonate (Compound No. 14),

2-(5,6-dihydroxy-l,3-dioxooctahydro-2/f-isoindol-2-yl)-l- {[4-(5-fluoro-2- isopropoxyphenyl)piperazin-l-yl]methyl} ethyl benzenesulfonate (Compound No. 15),

2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-l-{ [4-(5-fluoro-2- isopropoxyphenyl)piperazin-l-yl]methyl} ethyl phenylacetate (Compound No. 16),

4-{4-[3-(5,6-dihydroxy-l,3-dioxooctahydro-2H r -isoindol-2-yl)propyl]piperazin-l-yl}-2- fluoro-5-isopropoxyphenyl methanesulfonate (Compound No. 17),

4-{4-[3-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-y l)propyl]piperazin-l-yl}-2- fluoro-5-isopropoxyphenyl benzenesulfonate (Compound No. 18),

4- {4-[3 -(5 ,6-dihydroxy- 1 ,3-dioxooctahydro-2H-isoindol-2-yl)propyl]piperazin- 1 -yl} -2- fluoro-5-isopropoxyphenyl dimethylcarbamate (Compound No. 19),

2-(5,6-dihydroxy-l,3-dioxooctahydro-2i7-isoindol-2-yl)-l- {[4-(5-fluoro-2- hydroxyphenyl)piperazin-l-yl]methyl} ethyl benzenesulfonate (Compound No. 20),

2-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)-l-[ (4-{5-fluoro-2-hydroxy-4- [(methylsulfonyl)oxy]phenyl}piperazin-l-yl)methyl]ethyl benzenesulfonate (Compound No. 21),

2-[({3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2-

[(phenylacetyl)oxy]propyl}amino)carbonyl]-4,5-dihydroxycy clohexanecarboxylic acid (Compound No. 22)

2-[({2-(benzoyloxy)-3-[4-(5-fluoro-2-isopropoxyphenyl)pip erazin-l- yl]propyl}amino)carbonyl]-4,5-dihydroxycyclohexanecarboxylic acid (Compound No. 23),

2-({[3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2- ({[metliyl(phenyl)amino]carbonyl}oxy)propyl]amino}carbonyl)- 4,5- dihydroxycyclohexanecarboxylic acid (Compound No. 24), and

2-[( {3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin- 1 -yl]-2-

[(methylsulfonyl)oxy]propyl}amino)carbonyl]-4,5-dihydroxy cyclohexanecarboxylic acid (Compound No. 25).

Also included herein are pharmaceutical compositions comprising metabolites of 2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]propyl} -5,6-dihydroxy-hexahydro- isoindole-l,3-dione (Formula I), their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymorphs, conjugates or prodrugs and one or more pharmaceutically acceptable carriers or excipients.

The compositions disclosed herein contain one or more metabolites in compositions that are suitable for oral, parenteral, topical, transdermal, colonic, buccal, sublingual or intravaginal administration. The compositions may be formulated to provide immediate or sustained-release of the therapeutic agents. The agents described herein can be administered alone, but will generally be administered as an admixture with one or more suitable pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier(s)," unless specified otherwise, refers to non-toxic, inert solid, semisolid or liquid filter, diluent, encapsulating material or formulation auxiliary of any type.

Solid form preparations for oral administration include capsules, tablets, pills, powder, granules or suppositories. In solid form preparations, one or more active metabolites can be mixed with one or more inert, pharmaceutically acceptable excipients or carriers (e.g., sodium citrate, dicalcium phosphate, filter or mixtures thereof), one or

more extenders (e.g., starch, lactose, sucrose, glucose, mannitol, silicic acid or mixtures thereof), one or more binders (e.g., carboxymethyl cellulose, alginates, gelatins, polyvinylpyrrolidinone, sucrose, acacia or mixtures thereof), one or more disintegrating agents (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate or mixtures thereof); one or more absorption accelerators (e.g., quaternary ammonium compounds); one or more wetting agents (e.g., cetyl alcohol, glycerol, monostearate or mixtures thereof); one or more adsorbents (e.g., kaolin); one or more lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium lauryl sulphate or mixtures thereof); or mixtures thereof. Capsules, tablets or pills can also comprise one or more buffering agents. The solid preparation of tablets, capsules, pills, granules can be prepared using one or more coatings and/or shells (e.g., enteric coating and other coatings well known in the pharmaceutical formulating art).

Liquid form preparations for oral administration include one or more pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs or mixtures thereof, hi liquid form preparations, one or more metabolites can be mixed with water or one or more other solvents, solubilizing agents and/or emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, one or more oils (for example, cottonseed, groundnut, corn, germ, olive, castor or sesame oil), glycerol, fatty acid ester of sorbitan or mixture thereof.

Besides inert diluents, the oral composition can also include one or more adjuvants, for example, a wetting agent, an emulsifying agent, a suspending agent, a sweetening agent, a flavoring agent, a perfuming agent or mixtures thereof. Injectable preparations (e.g., sterile injections, aqueous or oleaginous suspensions) can be formulated according to the art using one or more suitable dispersing or wetting suspending agents. Among the acceptable vehicles and solvents that may be employed include water, Ringers solution, isotonic sodium chloride or mixtures thereof.

Dosage forms for topical or transdermal administration include ointments, pastes, creams, lotions, gel, powders, solutions, spray, inhalants or patches. Typically, one or

more metabolites are admixed under sterile condition with one or more pharmaceutically acceptable carriers and any preservatives or buffers as may be desirable.

The pharmaceutical preparations are desirably in unit dosage form. In such forms, the preparations are subdivided into unit doses containing therapeutic quantities of one or more active metabolites.

The formulations described herein may be formulated so as to provide quick- released or delayed-release of the active ingredient(s) after administration to the patient by utilizing procedures well known to the skilled artisan.

The term "patient," as used herein, refers to an animal, a mammal, or a human, who is the subject of treatment, observation or experiment.

The compositions may be administered as depot formulations that permit sustained release, limit access to general circulation, and increase the prostate- and/or bladder- specific localization of the compositions. Such formulations may be provided as slow release implants, be microencapsulated, or attached to biodegradable polymers or one or more prostate-specific immunoglobulins. Sustained release formulations are preparations that release active metabolites over extended periods of time. Sustained release formulations are prepared by applying one or more biodegradable, bioerodible or bioabsorbable polymeric formulations that are compatible on the surface of active metabolites. Effective release of metabolites is regulated by slow erosion of biodegradable, bioerodible or bioabsorbable polymeric formulations. One or more polymers form the polymer matrix, wherein such one or more polymers are recognized by an artisan skilled in the art of pharmaceutical compounding for release-retarding properties. Metabolites are entrapped within this polymeric matrix. The rate of release of metabolite for such a system is primarily dependent on rate of water imbibitions, resultant rate of swelling of matrix, drug dissolution and diffusion from the matrix. In addition to the rate controlling polymers, compositions may additionally contain 6 to 50 % w/w of other pharmaceutically acceptable excipients, for example, gas generating component, swelling agent, lubricant and filler. Examples of pharmaceutically acceptable rate- controlling polymers used in accordance with the present invention include, but are not limited to, hydroxypropylmethylcellulose (HPMC), hydrogenated vegetable oil (HVO), ethylcellulose, polyvinylpyrrolidione, pyran copolymer, polyhydroxypropylmethacryl -

amidephenol, polyhydroxy - ethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues, polyacetic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyano acrylates. Compositions according to the invention may be formulated as capsules or tablets. Tablet formulations can be prepared by wet granulation, dry granulation, direct compression or by any other techniques known in the pharmaceutical art. Tablets can be coated with a layer of rapidly dissolving water-soluble polymer or pharmaceutical excipient(s).

The term "biodegradable" refers to the degradation of polymeric formulations over time by action of enzymes, by hydrolytic action and/or by other similar mechanisms in the human body. The term "bioerodible" refers to a polymeric formulation erodes or degrades over time due, at least in part, to contact with substances found in the surrounding tissue fluids or cellular action. The term "bioabsorbable" refers to polymeric formulations that are broken down and absorbed within the human body, for example, by a cell or tissue. The term "biocompatible" refers to polymeric formulations that do not cause substantial tissue irritation or necrosis.

Metabolites described herein can also be administered in the form of liposome delivery systems, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, for example, cholesterol, stearylamine or phosphatidylcholines.

Aqueous parenteral compositions containing therapeutically effective amounts of one or more metabolites are disclosed herein. Methods of delivery such that direct intraprostatic injection of therapeutically effective amounts of compositions encompasses herein result in the relief of the obstructive symptoms associated with benign prostatic hyperplasia. Intraprostatic injection can be accomplished by, for example, utilizing a long, fine needle inserted into the prostate under digital rectal control and/or ultrasonic guidance while the patient is under local anesthesia. Injection solutions may be diluted with, for example, lidocaine. During injections, needles may be frequently relocated in order to obtain the best possible distribution of the composition. Several routes of administration are available for introducing the compositions herein into the prostate. Preferred routes of administration include by transurethral intraprostatic (intralesional) injection. Alternatively, transperineal or transrectal routes of prostatic injection can be used.

Metabolites disclosed herein can be prepared by techniques known to one of ordinary skill in the art. In addition, metabolites described herein can be prepared by following reaction sequences, for example, as depicted in Schemes I, II and III.

Scheme I

Formula VIII

Compounds of Formula VIII can be prepared, for example, according to Scheme I. The preparation can comprise reacting a compound of Formula V with a compound of Formula VI to give a compound of Formula VII (wherein R 2 and R 4 can be hydrogen or hydroxy, R 3 can be hydrogen or isopropyl), which on reaction with one or more peroxyacids can give a compound of Formula VIII. Suitable peroxyacids include, for example, m-chloroperbenzoic acid, monoperoxyphthalate, potassium peroxymonosulfate or mixture thereof.

The reaction of a compound of Formula V with a compound of Formula VI can be carried out in presence of alkali metal halides (e.g., sodium iodide, potassium iodide or sodium chloride), one or more inorganic base (e.g., potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, calcium carbonate, barium carbonate or sodium hydride) in one or more solvents, for example, acetonitrile, acetone,

tetrahydrofuran, cyclohexane, toluene, dimethylformamide, dimethylsulfoxide or mixtures thereof.

The reaction of a compound of Formula VII can be carried out in one or more solvents, for example, chloroform, dichloromethane, tetrahydrofuran, acetonitrile or mixtures thereof.

Scheme Il

Formula Xl

Compounds of Formula XI can be prepared, for example, according to Scheme II. The methods can comprise reacting a compound of Formula IX with a compound of Formula VI to give a compound of Formula X (wherein R 2 can be hydrogen or hydroxy, R 3 can be hydrogen or isopropyl), which on reaction with one or more peroxyacids can give a compound of Formula XI. Suitable peroxyacids include, for example, m- chloroperbenzoic acid, monoperoxyphthalate, potassium peroxymonosulfate or mixtures thereof.

The reaction of a compound of Formula IX with a compound of Formula VI can be carried out in one or more alcoholic solvents, for example, methanol, ethanol, isopropanol, n-butanol or mixtures thereof.

The reaction of the compound of Formula X to give a compound of Formula XI can be carried out in one or more solvents, for example, chloroform, dichloromethane, tetrahydrofuran, acetonitrile or mixtures thereof.

Scheme II!

Formula XVI (Formula III wherein R 5 =CH 3 ;n=1)

Compounds of Formula XIV and XVI can be prepared, for example, according to methods in Scheme III. The methods can comprise reacting a compound of Formula XII with an inorganic base, for example, sodium hydroxide or potassium hydroxide to give a ' compound of Formula XIII (wherein R 2 can be hydrogen or hydroxy, R 3 can be hydrogen ) or isopropyl), which on (a) reaction with one or more peroxyacids can give a compound of Formula XIV, (b) reaction with methanol and hydrochloric acid can give a compound of Formula XV, which on reaction with one or more peroxyacids can give a compound of Formula XVI. Suitable peroxyacids include, for example, m-chloroperbenzoic acid, monoperoxyphthalate, potassium peroxymonosulfate or mixture thereof. The reaction of a compound of Formula XIII to give a compound of Formula XIV and the reaction of a compound of

Formula XV to give a compound of Formula XVI can be carried out in one or more solvents, for example, chloroform, dichloromethane, tetrahydrofuran, acetonitrile or mixture thereof.

Scheme IV

Formula XVII Formula IV (Hydroxylated metabolites) (Prodrugs)

Compounds of Formula IV, which are prodrugs of the hydroxylated compounds, can be prepared, for example, according to methods in Scheme IV. The methods comprise reacting hydroxylated metabolites of Formula XVII with a compound of Formula ClWR or BrWR to give a compound (prodrug) of Formula IV, wherein:

W can be -SO 2 -, -CO-, -CONR 6 , wherein R 6 can be C 1 -C 4 alkyl or aryl (e.g., phenyl or naphthyl); R can be C 1 -C 4 alkyl, aryl (e.g., phenyl or naphthyl) or aralkyl (e.g., benzyl), and the circle represents any compound described herein including, for example, compounds of Formulae II or III. Compounds of Formula X-W-R may also be used in place of Cl-W-R in this reaction, wherein X can be a halogen atom, e.g., Br or I.

The reaction of the hydroxylated metabolites of Formula XVII with a compound of Formula X-W-R to form a compound of Formula IV can be carried out in one or more solvents, for example, chloroform, dichloromethane, tetrahydrofuran, dimethylformamide or mixtures thereof. This reaction can also be carried out in the presence of an organic base like triethylamine or one or more inorganic bases (e.g., sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride or mixtures thereof). Prodrugs encompassed herein include compounds of Formula XVII, wherein W and R are respectively, SO 2 and (Ci-GO-alkyl; SO 2 and methyl; SO 2 and aryl; SO 2 and phenyl; CO and (Q-C^-alkyl; CO and methyl; CO and ethyl; CO and aralkyl; CO and benzyl; CONR 6 and (Ci-C 4 )-alkyl, wherein R 6 is (C 1 -C 4 ) alkyl; CONR 6 and methyl, wherein R 6 is methyl; CONR 6 and aryl, wherein R 6 is (CrC 4 )-alkyl; CONR 6 and phenyl, wherein R 6 is methyl; CONR 6 and aryl, wherein R 6 is aryl; or CONR 6 and phenyl, wherein R 6 is phenyl.

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 mentioned below demonstrate some illustrative synthetic procedures for preparing metabolites described herein. The examples are provided to illustrate particular aspect of the disclosure and do not limit the scope of the present invention as defined by the claims.

Examples

Example 1 : Preparation of a compound of Formula VII A mixture of a compound of Formula V (50 equiv.), a compound of Formula VI

(40 equiv.), anhydrous potassium carbonate (100 equiv.) and potassium iodide (1 equiv.) in dimethylformamide (10-15 mL) is heated at about 75-80°C for about 6 to 8 hours. Reaction is quenched by adding water (30-40 mL) to it, extracting with ethyl acetate, drying over anhydrous sodium sulphate and concentrating with rotary evaporation. The resulting crude product is purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent.

Example 2: Preparation of a compound of Formula X

A mixture of a compound of Formula IX (1.1 equiv.), a compound of Formula VI (1 equiv.) and triethylamine (1.1 equiv.) in ethanol (10-15 mL) is refluxed for about 4 to 5 hours. After completion of the reaction, it is concentrated, purified on a silica gel (60-120 mesh) column using dichloromethane and methanol as eluent.

Example 3 : Preparation of a compound of Formula XIII

A compound of Formula XII (1 equiv.) was taken in round bottom flask (100 mL) and dissolved in sodium hydroxide solution (0.1N, 10%) at room temperature. After the completion of the reaction, the reaction mixture was neutralized (pH 7) with hydrochloric acid at about 5-10 0 C. The organic compound was extracted in ethyl acetate. Organic layer was washed with water and dried over anhydrous sodium sulfate. Reaction mixture was filtered and filtrate was evaporated on a Bochi rotary evaporator.

Example 4: Preparation of a compound of Formula XV

To a solution of a compound of Formula XIII (1.0 gm, 0.0027 mole) in methanol (5-10 mL) is added methanol-hydrochloride solution at 0-5°C and reaction mixture stirred for about 6-10 hours at this temperature. After completion of the reaction, it is neutralized with chloroform-ammonia (pH-7) and concentrated with rotary evaporation. The crude product is purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent.

Example 5: Preparation of a compound of Formula VIIL XI, XIV or XVI

To a solution of a compound of Formula VII, X, XIII or XV (1.2 equiv.) in dichloromethane (15-20 mL) is added meta chloroperbenzoic acid (1 equiv.) at 0-5 0 C. The reaction mixture is stirred for about 5 hours at this temperature. After completion of the reaction, the mixture is concentrated and purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent.

Example 6: Preparation of hydrochloride salt of a compound of Formula VIL VIIL LX, X, XL XIIL XLV, XV or XVI

To a solution of a compound of Formula VII, VIII, IX, X, XI, XIII, XV or XVI in isopropyl alcohol is added isopropyl alcohol/hydrochloric acid at about 10-15 0 C and the reaction mixture is stirred for about 1 hour. A solid precipitate was filtered, dried and weighed to yield hydrochloride salt of a compound of Formula VII, VIII, IX, X, XI, XIII, XLV, XV or XVI.

The following compounds can be prepared following the procedure described above:

2-{3-[4-(5-fluoro-2-hydroxyphenyl)piperazin-l-yl]propyl}- 5,6-dihydroxyhexahydro-l/J- isoindole-l,3(2H)-dione (Compound No. 2) and its hydrochloride salt,

2-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propy l}-4,5,6-trihydroxyhexahydro- lH-isoindole-l,3(2H)-dione (Compound No. 4) and its hydrochloride salt,

2-{3-[4-(5-fluoro-4-hydroxy-2-isopropoxyphenyl)piperazin- l-yl]propyl}-5,6- dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione (Compound No. 5) and its hydrochloride salt,

2-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2-hy droxypropyl}-5,6- dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione (Compound No. 6) and its hydrochloride salt,

2-[({3-[4-(5 -fluoro-2-isopropoxyphenyl)piperazin- 1 -yl] -2- hydroxypropyl}amino)carbonyl]-4,5-dihydroxycyclohexanecarbox ylic acid (Compound No. 7) and its hydrochloride salt,

2- [( {3 - [4-(5-fluoro-2-isopropoxyphenyl)piperazin- 1 -yl]propyl } amino)carbonyl] -3,4,5- trihydroxycyclohexanecarboxylic acid (Compound No. 8) and its hydrochloride salt,

2-{3-[4-(5-fluoro-2-hydroxyphenyl)piperazm-l-yl]-2-hydrox ypropyl}-5,6- dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione (Compound No. 9) and its hydrochloride salt,

2-{3-[4-(5-fluoro-2,4-dihydroxyphenyl)piperazin-l-yl]-2-h ydroxypropyl}-5,6- dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione (Compound No. 10) and its hydrochloride salt,

l-[3-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)p ropyl]-4-(5-fluoro-2- isopropoxyphenyl)-l-oxypiperazin-l-ium (Compound No. 11) and its hydrochloride salt,

4-(5-fluoro-2-isopropoxyphenyl)-l-oxy-l-[3-(4,5,6-trihydr oxy-l,3-dioxooctahydro-2H- isoindol-2-yl)propyl]piperazin-l-mm (Compound No. 12) and its hydrochloride salt,

2- [( { 3 - [4-(5 -fluoro-4-hydroxy-2-isopropoxyphenyl)piperazin- 1 -yl] -2- hydroxypropyl} amino)carbonyl]-4,5-dihydroxycyclohexanecarboxylic acid (Compound No. 13) and its hydrochloride salt.

Example 7: Preparation 2-[( " {3-[4-(5-fluoro-2-isopropoxyphenvDpiperazin-l- yl1propyUamino)carbonyll-4,5-dilivdroxycvcloliexanecarboxyli c acid f Compound No. 3) i

To a solution of 2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]propyl} -

5,6-dihydroxy-hexahydro-isoindole-l,3-dione (1.0 gm, 0.0027 mole) in methanol (5-10 mL) was added methanol-hydrochloride solution at 0-5°C and reaction mixture stirred for about 6-10 hours at this temperature. After completion of the reaction, it was neutralized with chloroform-ammonia (pH-7) and concentrated with rotary evaporation. The crude product was purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent. Example 8: Preparation 2-[({3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l- yl " ]propyl|amino)carbonyl1-4,5-dihvdroxycvclohexanecarboxylic acid hydrochloride salt

To a solution of 2-[({3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l- yl]propyl}amino)carbonyl]-4,5-dihydroxycyclohexanecarboxylic acid in isopropyl alcohol was added isopropyl alcohol/hydrochloric acid at about 10-15 0 C and the reaction mixture is stirred for about 1 hour. A solid precipitate was filtered, dried and weighed 2-[({3-[4- (5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}amino)car bonyl]-4,5- dihydroxycyclohexanecarboxylic acid hydrochloride salt.

1 R NMR (300 MHz, CDCl 3 ): δ 1.36-1.37 (d, 6H), 2.12-2.23 (m, 3H), 2.27-2.41 (d, 2H), 2.50 (s, IH), 2.98-3.00 (d, 4H), 3.07-3.08 (d, 4H), 3.20-3.26 (m, 6H), 3.55-3.58 (m, IH), 4.58-4.61 (m, IH), 5.73 (s, 2H), 6.87-6.91 (m 5 3H), 7.01-7.09 (m, 2H); Mass: m/z 483 (M + +l); IR (KBr): 1711.0 cm "1 .

Example 9: Metabolite identification and quantification

(1) Identification of metabolites of2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)- piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l, 3-dione in rat and human liver microsomes.

Samples

Incubated in- vitro metabolism samples of rat and human liver microsomes at 0 min, 60 min and 120 min were taken for analysis.

Method

Preparation of buffer: About 1.54 gm of ammonium acetate was dissolved in about one liter water. The pH of the solution was adjusted to 4.5 with acetic acid.

Chromatographic conditions

Column : Inertsil Cl 8 (250 x 4.6 mm, 5 μm) Flow rate : 1000 μL/mm

Injection volume : 50 μL

Column temperature : Ambient

Mobile phase : Gradient as below

Time (min) % Buffer % Acetonitride 0 85 15

15 30 70

20 10 90

22 10 90

25 85 15

35 85 15

ESI positive mode

Curtain gas CUR 20

Collision gas CAD MEDIUM

Ion spray voltage IS 5500

Temperature TEM 400

Ion source gas 1 GSl 25

Ion source gas 2 GS2 50

Declustering potential DP 55

Entrance potential EP 10

Collision energy CE 5

Sample preparation: The incubated in-vitro metabolism samples were vortexed and centrifuged at 12000 rpm for about 10 min. Supernatant was injected on to LC-MS/MS for analysis. Enhanced MS (EMS) scan followed by enhanced product ion (EPI) scans were performed to identify the metabolites.

Result: The parent compound (compound No. 1) and its glucuronide conjugate have been identified in rat and human microsomes. The retention time, mass values and fragmentation pattern are shown in Table 1.

Table 1

(2) Identification of metabolites of2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)- piperazin-l-yl]-propyl}-5, 6-dihydroxy-hexahydro-isoindole-l,3-dione in rat and human hepatocyte.

Samples

Incubated in-vitro metabolism samples of rat and human hepatocytes at 0 min, 15 min, 30 min, 45 min, 60 min, 90 min, and 120 min were taken for analysis. Method

Preparation of buffer: About 630 mg of ammonium formate was dissolved in about one liter water.

Chromatographic conditions

Column : Kromasil Cl 8 (150 x 4.6 mm, 5 μm)

Flow rate : 800 μL/mm

Injection volume : 50 μL Column temperature : 30 C Mobile phase : Gradient as below

Time (min) % Buffer % Acetonitride

0 90 10

2 90 10

15 50 50 25 10 90

28 10 90

30 90 10

40 90 10

ESI positive mode Curtain gas CUR 28

Collision gas CAD HIGH

Ion spray voltage IS 5500

Temperature TEM 400

Ion source gas 1 GSl 25 Ion source gas 2 GS2 50

Declustering potential DP 60

Entrance potential EP 10

Collision enersv CE 5

Sample preparation: The incubated in-vitro metabolism samples were vortexed and centrifuged at 12000 rpm for about 10 min. Supernatant was injected on to LC-MS/MS for analysis. Enhanced MS (EMS) scan followed by enhanced product ion (EPI) scans were performed to identify the metabolites. Further, neutral loss scan was performed to confirm the glucuronidation.

Results: The parent compound, compound No. 2 (or 9), 3, 5, 4 (and 6), 7 (and 8), glucuronide conjugate of compound No. 3 and parent compound have been identified in rat and human hepatocytes. The retention time, mass values and fragmentation pattern of metabolites identified in rat and human hepatocytes are listed in Table 2 and 3.

Table 2 (Rat hepatocytes)

Table 3 (Human hepatocytes)

(3) Estimation of parent compound and its metabolites by LC/MS/MS

Method (By solid phase extraction): To 950 μL of urine, 500 μL of potassium dihydrogen phosphate buffer (0.1 M, pH 4.7+0.1) and 50 μL of solution of Internal Standard is added and vortexed to ensure proper mixing. Drug test cartridges (130mg) are used for processing the samples. The cartridges are conditioned on vacuum manifold at constant pressure using 2 niL methanol and 2 niL potassium dihydrogen phosphate buffer (0.1 M, pH 4.7+0.1) followed by loading of 1.4 mL of urine sample. The cartridges are washed using 3 mL of 5.75% acetic acid and dried for 2 minutes under vacuum. Washed again with 3 mL of methanol and dried for 2 minutes under vacuum. Finally parent compound and its metabolites are eluted with 3 mL each of elution solution (2% ammoniated ethyl acetate). The eluate is dried at 50 0 C under 10 psi of nitrogen. The

residue is reconstituted in 200 μL of mobile phase 20 μL of this solution is injected on LC/MS/MS for analysis.

Example 10: Pharmacological activity - Radioligand bindύiR assay

The affinities of metabolites of 2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin- 1 -yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l ,3-dione for α la and Od b -adrenceptor subtype are evaluated by studying their ability to displace specific [ 3 H] prazosin binding from the membrane of rat submaxillary and liver respectively (Michel et al., 1989). These tissues are reported to have a homogeneous population of respective ocradrenceptor subtype (Forel et al., 1994). The binding assays are performed according to U' (Prichard et al., 1978) with minor modifications.

Submaxillary glands are isolated immediately after sacrifice. The liver is perfused with buffer (Tris HCl 50 mM, pH 7.4). the tissues are homogenized 10 volume of buffer (Tris HCL 50 mM, NaCl 100 mM, EDTA ImM, pH 7.4) with a polytron. The homogenate is filtered through two layers of wet guaze and filtrate is centrifuged at 3000g for lO min. The supernatant is subsequently centrifuged at 60,00Og for 45 min. The pellet thus obtained is resuspended in same volume of assay buffer (Tris HCl 50 mM, EDTA ImM, pH 7.4) and are stored at -70°C until the time of assay. The membrane homogenates (150-250 μg protein) are incubated in titre plates in 250 μl of assay buffer (Tris HCl 50 mM, EDTA 1 mM, pH 7.4) at 24-25 0 C for 1 hour. Non-specific binding is determined in the presence of 300 mM prazosin or 10 μM terazosin. The in cubation is terminated by vaccum filtration over 0.5% polyethylenimine pre-treated GF/B fibers using skatron cell harvester. The filters are then washed with ice coed 50 mM Tris HCl buffer (pH 7.4). the filtermates are dried and transferred to 24 well plates (PET A No cross talk). Radio activity retained on filters is counted in 600 μl of supermix in microbeta with a counting efficiency of 46%. IC 50 value is determined using the non-linear curve fiting program using G pad prism software. Saturation binding assays are used to determined Kd (apparent dissociation constant) for [ 3 H] prazosin. The value of inhibition constant Ki is calculated from competitive binding studies by using Cheng and prusoff equation (Cheng and Prusoff, 1973),

Ki = IC 50 L

(1+ ) wherein L is the concentration of [ 3 H] prazosin used in the particular experiment. Ka

Subtype selective by (α la Vs α^) is expressed as ratio of mean Ki at an, receptors to mean Ki at α la receptors.

Example 11 : Preparation of 2-(5 ,6-dihydroxy- 1 ,3 -dioxooctahvdro^H-isoindol-σ-yl)- 1 - {[4-(5-fluoro-2-isopropoxyphenyl ' )piperazm-l-yllmethvUethyl methanesulfonate (Compound No. 14),

To a solution of 2-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2- hydroxypropyl}-5,6-dihydroxyhexahydro-lH-isoindole-l,3(2H)-d ione (1 equiv) in dichloromethane (80-100 ml) is added triethylamine (1.5 equi) at 0-5°C and reaction mixture stirred for 15-30 minutes. To the reaction mixture is added methansulfonyl chloride (1.5 equi) at 0 0 C to 5 0 C for half to one hour. Reaction mixture is poured in 5% sodium bicarbonate solution. Organic layer is separated and washed with water, dried over anhydrous sodium sulphate and solvent is removed under reduced pressure to yield the desired product.

Example 12: Preparation of 2-(5.6-dihvdroxy-L3-dioxooctahvdro-2H-isoindol-2-yl)-l- ([4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]methyl>et hyl phenylacetate (Compound No. 16)

To a solution of 2-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2- hydroxypropyl}-5,6-dihydroxyhexahydro-lH-isoindole-l,3(2H)-d ione (1 equiv.) in dichloromethane (80-100 ml) is added triethylamine (1.5 equi) at 0-5°C and reaction mixture stirred for 15-30 minutes. To the reaction mixture is added benzoyl chloride (1.5 equi) at 0 0 C to 5 0 C for half to one hour. The reaction mixture is poured in 5% sodium bicarbonate solution. Organic layer is separated and washed with water, dried over anhydrous sodium sulphate and solvent is removed under reduced pressure to yield the desired product.

The following prodrugs can be prepared following the procedure described in Examples 11 and 12:

2-(5 ,6-dihydroxy- 1 ,3 -dioxooctahydro-2H-isoindol-2-yl)- 1 - {[4-(5 -fluoro-2- isopropoxyphenyl)piperazin-l-yl]methyl} ethyl benzenesulfonate (Compound No. 15),

4-{4-[3-(5,6-dihydroxy-l,3-dioxooctahydro-2H " -isoindol-2-yl)propyl]piperazin-l-yl}-2- fluoro-5-isopropoxyphenyl methanesulfonate (Compound No. 17), 4-{4-[3-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-yl)p ropyl]piperazin-l-yl}-2- fluoro-5-isopropoxyphenyl benzenesulfonate (Compound No. 18),

4-{4-[3-(5,6-dihydroxy-l,3-dioxooctahydro-2H-isoindol-2-y l)propyl]piperazin-l-yl}-2- fluoro-5-isopropoxyphenyl dimethylcarbamate (Compound No. 19),

2-(5 ,6-dihydroxy- 1 ,3 -dioxooctahydro^H-isoindol^-yl)- 1 - { [4-(5 -fluoro-2- hydroxyphenyl)piperazin-l-yl]methyl} ethyl benzenesulfonate (Compound No. 20),

2-(5,6-dihydroxy- 1 ,3-dioxooctahydro-2H-isoindol-2-yl)- 1 -[(4- {5-fluoro-2-hydroxy-4- [(methylsulfonyl)oxy]phenyl}piperazin- 1 -yl)methyl] ethyl benzenesulfonate (Compound No. 21),

2-[({3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2-

[(phenylacetyl)oxy]propyl}amino)carbonyl]-4,5-dihydroxycy clohexanecarboxylic acid (Compound No. 22)

2-[( {2-(benzoyloxy)-3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin- l - yl]propyl}amino)carbonyl]-4,5-dihydroxycyclohexanecarboxylic acid (Compound No. 23),

2-({[3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2 ({[methyl(phenyl)amino]carbonyl}oxy)propyl]amino}carbonyl)-4 ,5- dihydroxycyclohexanecarboxylic acid (Compound No. 24),

2-[({3-[4-(5-fluoro-2-isopropoxyphenyl)piρerazin-l-yl]-2 -

[(methylsulfonyl)oxy]propyl}amino)carbonyl]-4,5-dihydroxy cyclohexanecarboxylic acid (Compound No. 25).