RELATED APPLICATIONS

This application claims the benefit of Indian Patent Application No. 2647/MUM/201 1 filed on September 19, 201 1 which is hereby incorporated by reference.

FIELD OF INVENTION

The present invention relates to novel hydrazide group containing carbamate prodrugs of formula I, and process for the preparation thereof.

formula (I)

BACKGROUND OF THE INVENTION

Several important classes of drugs contain phenolic group(s); these include opioids, NSAIDs, estrogens, neurotransmitters, anticancer agents, antibacterial agents etc. Certain drawbacks are usually associated with these drugs such as limited solubility, poor and variable absorption by oral route and metabolic instability. Phenolic drugs are often subjected to strong first pass metabolism and produce water soluble metabolites that are excreted out in the urine or bile. These drugs are rapidly inactivated in the gut and/ or liver through glucuronidation, sulfation or methylation, thus rendering low bioavailability upon administration. Further, by virtue of being acidic, they can cause gastric irritation when administered by the oral route. Prodrugs are a special class of drug derivatives which are usually inactive or less active than the parent drug, and undergo initial in-vivo biotransformation to the therapeutically active drug. Prodrugs are generally used to improve pharmacological effects (pharmacokinetic/ pharmacodynamic), physicochemical characteristics and patient compliance.

It is the object of the present invention to overcome the limitations mentioned vide supra of phenolic drugs by converting them to prodrugs through appropriate derivatization of the phenolic functionality. Esters, carbonates and carbamates of phenolic hydroxyl group have generally been the preferred prodrug strategy in the art for this purpose. Herein we disclose a novel prodrug strategy which is generally applicable for phenolic drugs, and having the potential to advantageously alter the characteristics of the parent drug.

We prepared prodrugs by attaching to the phenolic hydroxyl group of a phenolic drug an innocuous moiety to form novel hydrazide group containing carbamates of formula (I), wherein the linking functionality is labile under physiological conditions.

formula (I)

The compounds of the present invention convert predictively under physiological conditions to the parent phenolic drug and the innocuous moiety. Using this prodrug strategy described in the present invention it is possible to achieve one or more of the following desirable attributes: enhancement of intestinal or lymphatic transport ^■ delivery to central nervous system (CNS)

^■ improved systemic delivery through mucosal routes such as nasal, buccal, pulmonary etc

^■ delivery of a phenolic drug having low solubility in the form of a more soluble prodrug for example, oral delivery to provide fast dissolving prodrug for absorption or soluble prodrug in the form of a aqueous solution suitable for intravenous administration

^■ sustained/ controlled delivery of the phenolic drug from a prodrug exhibiting slow conversion to the phenolic drug

^■ minimization of systemic toxicity due to the parent drug especially in cytotoxic drugs

^■ reduction in gastro-intestinal (GI) related side effects such as GI motility (as . in case of opioids), GI irritation (as in NSAIDs), diarrhea etc.

Prodrugs of the present invention may be prepared from any phenolic drug. Examples of phenolic drugs suited for modification into prodrugs of the present invention include, but are not limited to the following:

• Opioids agonists such as morphine, oxymorphone, hydromorphone, meptazinol, oripavine; opioid mixed agonist-antagonists such as nalbuphine, buprenorphine etc; opioid antagonists for e.g. naloxone, naltrexone, nalorphine etc. - to enhance oral bioavailability, reduce opioid related side effects and improve suitability for transdermal administration, (cf. patents US 2010/0035826, US 2009/0186832, US 2009/0192095, WO2010/1 12942, US 7,230, US 6,225,321 , W096/28451 , US 7,51 1 ,054).

• Anticancer drugs including natural cytotoxic drugs for e.g. combretastatins;

DNA topoisomerase inhibitors such as camptothecin, 7-ethyl-10- hydroxycamptothecin (SN-38), topotecan, etoposide; synthetic retinoids for e.g. fenretinide etc - to enhance solubility, reduce toxicity and side effects. (US Pat. 4,604,463).

• Estrogens viz. estrone, estradiol and estriol; estrogen receptor modulators such as tamoxifen - to enhance oral bioavailability and reduce hepatotropic estrogenic effect. (Elger et al; J. Steroid Biochem Biol 1995; 55: 395-403).

• NSAIDs such as piroxicam, meloxicam etc.- to improve solubility, oral bioavailability and reduce GI irritation (US Pat. 4,551,452).

• Antiparkinsonian drugs such as L-DOPA, decarboxylase inhibitors for e.g. carbidopa, methyldopa, benserazide; COMT inhibitors for e.g. entacpone, tolcapone etc, - to improve oral bioavailability and stability (Leppanen JM. et al; Bioorg Med Chem Lett 2000; 10: 1967-9)

• Bronchodilators such as ^-adrenergic receptor agonists for e.g. terbutaline - to enhance oral bioavailability/ stability/ solubility.

• Anesthetic agents such as propofol - to improve aqueous solubility (US Pat.

7,645,792)

• Antibiotics such as pleuromutilin - to improve aqueous solubility and oral bioavailability (Fu L et al; Bioorg Med Chem Lett 2009; 19:5407-10).

SUMMARY OF THE INVENTION

The present invention relates to novel hydrazide group containing carbamate prodrugs of phenolic drugs of formula (I),

formula (I) or pharmaceutically acceptable salt thereof, wherein,

X represents the moiety of the phenolic drug XOH,

Ri is selected from the group consisting of hydrogen and (Ci _-6 )-alkyl;

R ₂ and R ₃ ; R' ₂ and R' ₃ may be same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted (Q^-alkyl, aryl, arylalkyl and heterocyclyl; or Ri and R ₂ together can form (C ₃ -Ci3)-heterocyclic ring system together with the nitrogen atom bearing Rj;

R ₄ and R ₅ may be same or different and are independently selected from hydrogen, substituted or unsubstituted alkenyl, alkylnyl, aryl or heterocylyl group; or R4 and R ₅ together can form a (C ₃ -C ₁₃ )-heterocyclic ring system along with the nitrogen atom to which they are attached and optionally may contain one or more heteroatom selected from O, S and N in the heterocyclic ring system,

'n and 'η ₂ ' are independently selected from integers 0, 1, 2 or 3, and

Ύ' is a bond or absent or a linker selected from the group consisting of an alkylene, a cycloalkylene, an arylene or a heterocyclylene moiety.

One aspect of the present invention relates to compounds of formula (la),

formula (la) or pharmaceutically acceptable salt thereof, wherein, X represents the moiety of the phenolic drug XOH,

R ₃ is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci.

₆ )-alkyl, aryl, arylalkyl, or heterocyclyl; R4 and R ₅ may be same or different and are independently selected from hydrogen, substituted or unsubstituted (Ci _-6 )-alkyl, alkenyl, alkylnyl, aryl or heterocylyl group; or R4 and R ₅ together can form a (C ₃ -Ci ₃ )-heterocyclic ring system along with the nitrogen atom to which they are attached and optionally may contain one or more heteroatom selected from O, S and N in the heterocyclic ring system, and 'm' is an integer selected from 1, 2, 3, 4, 5 or 6.

Another aspect of the present invention relates to compounds of formula (lb),

formula (lb) or pharmaceutically acceptable salt thereof, wherein, Ri is selected from the group consisting of hydrogen and (C _1-6 )-alkyl;

R ₂ and R ₃ ; R' ₂ and R' ₃ may be same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted (C _1-6 )-alkyl, aryl, arylalkyl and heterocyclyl; or Ri and R ₂ together can form (C ₃ -C ^-heterocyclic ring system together with the nitrogen atom bearing R ;

R4 and R ₅ may be same or different and are independently selected from hydrogen, substituted or unsubstituted alkenyl, alkylnyl, aryl or heterocylyl group; or R4 and R ₅ together can form a (C ₃ -Ci ₃ )-heterocyclic ring system along with the nitrogen atom to which they are attached and optionally may contain one or more heteroatom selected from O, S and N in the heterocyclic ring system,

'η and 'η ₂ ' are independently selected from integers 0, 1, 2 or 3;

Ύ is a bond or absent or a linker selected from the group consisting of an alkylene, a cycloalkylene, an arylene or a heterocyclylene moiety;

R ₆ and R ₇ are independently selected from hydrogen, hydroxy, methoxy or acetyl; or R ₆ and R ₇ together represent =0 or =CH ₂ ;

selected from hydrogen or a group of the formula

selected from methyl or t-butyl;

R ₉ when present is in ^-conformation and is selected from group consisting hydrogen and hydroxy; RJO is selected from C _3- 8 alkyl, alkenyl, alkynyl, cycloalkylalkyl, arylalkyl and alkoxyalkyl; the dotted lines ( ), indicate an optional single bond, and

T is ethano (-CH2CH2-) or etheno (-CH=CH-); with a proviso that when T is present, R ₆ and R ₉ are absent.

Another aspect of the present invention relates to compounds of formula (Ic),

formula (Ic) or pharmaceutically acceptable salt thereof, wherein, R] is selected from the group consisting of hydrogen and (C _1-6 )-alkyl;

R ₂ and R ₃ ; R' ₂ and R' ₃ may be same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted (C _1-6 )-alkyl, aryl, arylalkyl and heterocyclyl; or R] and R ₂ together can form (C ₃ -C ₁₃ )-heterocyclic ring system together with the nitrogen atom bearing Rj; R4 and R ₅ may be same or different and are independently selected from hydrogen, substituted or unsubstituted (C _1-6 )-alkyl, alkenyl, alkylnyl, aryl or heterocylyl group; or R4 and R ₅ together can form a (C3-Ci3)-heterocyclic ring system along with the nitrogen atom to which they are attached and optionally may contain one or more heteroatom selected from O, S and N in the heterocyclic ring system,

'ni' and 'η ₂ ' are independently selected from integers 0, 1, 2 or 3;

Ύ is a bond or absent or a linker selected from the group consisting of an alkylene, a cycloalkylene, an arylene or a heterocyclylene moiety, and

Ri ₂ represents hydrogen, halogen or (Ci. ₆ )-alkyl.

Another aspect of the present invention relates to compounds of formula (Id),

formula (Id) or pharmaceutically acceptable salt thereof, wherein,

R _\ is selected from the group consisting of hydrogen and (Ci _-6 )-alkyl; R ₂ and R3; R' ₂ and R' ₃ may be same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted (C _1-6 )-alkyl, aryl, arylalkyl and heterocyclyl; or Ri and R ₂ together can form (C3-Ci ₃ )-heterocyclic ring system together with the nitrogen atom bearing R j and R ₅ may be same or different and are independently selected from hydrogen, substituted or unsubstituted (Ci _-6 )-alkyl, alkenyl, alkylnyl, aryl or heterocylyl group; or R ₄ and R ₅ together can form a (C ₃ -C ₁ 3)-heterocyclic ring system along with the nitrogen atom to which they are attached and optionally may contain one or more heteroatom selected from O, S and N in the heterocyclic ring system,

'ni' and 'η ₂ ' are independently selected from integers 0, 1, 2 or 3;

Ύ' is a bond or absent or a linker selected from the group consisting of an alkylene, a cycloalkylene, an arylene or a heterocyclylene moiety;

Ri ₃ and Ri ₄ may be same or different and are independently selected from substituted or unsubstituted (C^ ^' -alkyl, or (C _{3- 1} 3)-cycloalkyl group, and

Ri5 and R ₁ may be same or different and are independently selected from hydrogen, halogen, -OR', -NH ₂ , -N0 ₂ , and -COOR', where R' is a hydrocarbon group contain 1 to about 20 carbon atoms.

Another aspect of the present invention relates to compounds of formula (Ie),

formula (Ie) or pharmaceutically acceptable salt thereof, wherein,

Ri is selected from the group consisting of hydrogen and (Ci _-6 )-alkyl;

R ₂ and R ₃ ; R' ₂ and R' ₃ may be same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted (C _1-6 )-alkyl, aryl, arylalkyl and heterocyclyl; or R _\ and R ₂ together can form (C ₃ -Ci ₃ )-heterocyclic ring system together with the nitrogen atom bearing Ri;

R and R ₅ may be same or different and are independently selected from hydrogen, substituted or unsubstituted (Ci _-6 )-alkyl, alkenyl, alkylnyl, aryl or heterocylyl group; or } and R ₅ together can form a (C ₃ -Ci ₃ )-heterocyclic ring system along with the nitrogen atom to which they are attached and optionally may contain one or more heteroatom selected from O, S and N in the heterocyclic ring system,

'ni' and 'η ₂ ' are independently selected from integers 0, 1, 2 or 3;

'Y' is a bond or absent or a linker selected from the group consisting of an alkylene, a cycloalkylene, an arylene or a heterocyclylene moiety; represents a single or double bond;

ΛΛΛΛΛ/

represents a or /^-configuration, and

Ri ₇ represent oxygen or -OH group and Ri ₈ represent hydrogen or -OH group, when R ₁₇ and R ₁₈ represents -OH group, it may be either in a or ^-configuration. The invention also provides the use of compound of formula (I), (la), (lb), (Ic), (Id) or (Ie) or salt thereof for the preparation of pharmaceutical composition comprising compound of formula (I), (la), (lb), (Ic), (Id) or (Ie) thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. These novel prodrugs of formula (I) give the corresponding active parent drug upon administration to mammals.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel hydrazide group containing carbamate prodrugs of phenolic drugs of formula (I), and process for the preparation thereof,

formula (I) or pharmaceutically acceptable salt thereof, wherein,

X represents the moiety of the phenolic drug XOH,

Ri is selected from the group consisting of hydrogen and (C _1- )-alkyl; R ₂ and R ₃ ; R' ₂ and R' ₃ may be same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted (C _1-6 )-alkyl, aryl, arylalkyl and heterocyclyl; or Ri and R ₂ together can form (C ₃ -C ^-heterocyclic ring system together with the nitrogen atom bearing Ri; R ₄ and R ₅ may be same or different and are independently selected from hydrogen, substituted or unsubstituted (C _1-6 )-alkyl, alkenyl, alkylnyl, aryl or heterocylyl group; or R ₄ and R5 together can form a (C ₃ -Ci ₃ )-heterocyclic ring system along with the nitrogen atom to which they are attached and optionally may contain one or more heteroatom selected from O, S and N in the heterocyclic ring system,

'ni ' and 'η ₂ ' are independently selected from integers 0, 1, 2 or 3, and

Ύ' is a bond or absent or a linker selected from the group consisting of an alkylene, a cycloalkylene, an arylene or a heterocyclylene moiety.

In one of the preferred embodiment provided are compounds of formula (I) wherein Ri and R ₂ are independently selected from hydrogen and substituted or unsubstituted C _1-6 -alkyl.

In yet another embodiment provided are compounds of formula (I) wherein R _\ and R ₂ together can form C ₃ -Ci ₃ -heterocyclic ring system along with the nitrogen atom to which they are attached, preferably a 5-membered heterocyclic ring system. In yet another preferred embodiment provided are compounds of formula (I) wherein R ₃ is selected from hydrogen or substituted or unsubstituted Ci _-6 -alkyl.

In one of the preferred embodiment provided are compounds of formula (I) wherein R' ₂ and R'3 are independently selected from hydrogen and substituted or unsubstituted Ci _-6 -alkyl. In yet another preferred embodiment provided are compounds of formula (I) wherein Rt and R ₅ may be same or different and are independently selected from hydrogen and substituted or unsubstituted Ci _-6 -alkyl. In yet another preferred embodiment provided are compounds of formula (I) wherein R and R ₅ together form a (C3-Ci ₃ )-heterocyclic ring system along with the nitrogen to which they are attached and optionally may contain one or more heteroatom selected from O, S and N in the heterocyclic ring system. In yet another preferred embodiment provided are compounds of formula (I) wherein 'ni ' is 1 and 'η ₂ ' is 0.

In yet another preferred embodiment provided are compounds of formula (I) wherein

In yet another preferred embodiment provided are compounds of formula ((I) wherein 'ni' is 1 and 'η ₂ ' is 1.

In yet another preferred embodiment provided are compounds of formula (I) wherein 'ni' is 1 and 'η ₂ ' is 2.

In yet another preferred embodiment provided are compounds of formula (I) wherein 'ni ' is 2 and 'η ₂ ' is 1. In yet another preferred embodiment provided are compounds of formula (I) wherein 'ni' is 2 and 'η ₂ ' is 2.

In yet another preferred embodiment provided are compounds of formula (I) wherein 'ni' is 0 and 'η ₂ ' is 0.

In yet another preferred embodiment provided are compounds of formula (I) wherein Ύ' is absent. In yet another preferred embodiment provided are compounds of formula (I) wherein Ύ' is a cycloalkylene group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.

In yet another preferred embodiment provided are compounds of formula (I) wherein Ύ' is linker selected from the group consisting of an alkylene, an arylene or a heterocyclylene moiety.

In yet another preferred embodiment provided are compounds of formula (I) wherein X represents the moiety of the phenolic drug (X-OH) selected from NSAIDs such as piroxocam, meloxicam, sex hormones such as estrone, estradiol, anesthetic drug asuch as propofol, oncolytic drug such as 7-ethyl-lO-hydroxycamptothecin, tamoxifen, fenertidine, antiparkinson drug such as levodopa, carbidopa, entacapone, bronchodilator drug such as terbutaline, and opioids like morphine, oxymorphone, naltrexone, naloxone, buprenorphine, 6-acetylmorphine, hydromorphone, nalbuphine, meptazinol, tapentadol, and desmethyltramadol. In yet another embodiment provided is compound of formula (la),

formula (la) or pharmaceutically acceptable salt thereof, wherein,

X represents the moiety of the phenolic drug XOH, R ₃ is selected from the group consisting of hydrogen, substituted or unsubstituted (Cj. ₆ )-alkyl, aryl, arylalkyl or heterocyclyl;

R ₄ and R ₅ may be same or different and are independently selected from hydrogen, substituted or unsubstituted (Ci _-6 )-alkyl, alkenyl, alkylnyl, aryl or heterocylyl group; or R_, and R ₅ together can form a (C ₃ -Ci ₃ )-heterocyclic ring system along with the adjacent nitrogen and optionally may contain one or more heteroatom selected from O, S and N in the heterocyclic ring system, and^

'm' is an integer selected from 1, 2, 3, 4, 5 or 6.

In one of the preferred embodiment provided are compounds of formula (la) wherein R ₃ is selected from hydrogen or substituted or unsubstituted Ci _-6 -alkyl.

In another preferred embodiment provided are compounds of formula (la) wherein R4 and R ₅ may be same or different and are independently selected from hydrogen and substituted or unsubstituted C _1-6 -alkyl.

In yet another preferred embodiment provided are compounds of formula (la) wherein R4 and R ₅ together form a (C ₃ -C ₁₃ )-heterocyclic ring system along with the nitrogen to which they are attached and optionally may contain one or more heteroatom selected from O, S and N in the heterocyclic ring system.

In yet another preferred embodiment provided are compounds of formula (la) wherein 'm' is 3. In yet another preferred embodiment provided are compounds of formula (la) wherein X represents the moiety of the phenolic drug (X-OH) selected from NSAIDs such as piroxocam, meloxicam, sex hormones such as estrone, estradiol, anesthetic drug asuch as propofol, oncolytic drug such as 7-ethyl-lO-hydroxycamptothecin (SN- 38), tamoxifen, fenertidine, antiparkinson drug such as levodopa, carbidopa, entacapone, bronchodilator drug such as terbutaline, and opioids like morphine, oxymorphone, naltrexone, naloxone, buprenorphine, 6-acetylmorphine, hydromo hone, nalbuphine, meptazinol, tapentadol and desmethyltramadol. In yet another embodiment provided is compound of formula (lb),

formula (lb) or pharmaceutically acceptable salt thereof, wherein,

Ri is selected from the group consisting of hydrogen and (Cj _-6 )-alkyl;

R ₂ and R ₃ ; R' ₂ and R' ₃ may be same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted (Ci _-6 )-alkyl, aryl, arylalkyl and heterocyclyl; or R _\ and R ₂ together can form (C ₃ -C ₁₃ )-heterocyclic ring system together with the nitrogen atom bearing Ri;

R4 and R ₅ may be same or different and are independently selected from hydrogen, substituted or unsubstituted alkenyl, alkylnyl, aryl or heterocylyl group; or R4 and R ₅ together can form a (C ₃ -C ₁ 3)-heterocyclic ring system along with the nitrogen atom to which they are attached and optionally may contain one or more heteroatom selected from O, S and N in the heterocyclic ring system,

'n and are independently selected from integers 0, 1 , 2 or 3; Ύ' is absent or a bond or a linker selected from the group consisting of an alkylene, a cycloalkylene, an arylene or a heterocyclylene moiety;

R ₆ and R are independently selected from hydrogen, hydroxy, methoxy or acetyl; or R ₆ and R ₇ together represent =0 or =CH ₂ ;

R ₈ is selected from hydrogen or a group of the formula wherein Ri 1 is selected from methyl or t-butyl;

R ₉ when present is in beta conformation and is selected from group consisting of hydrogen and hydroxy;

R ₁₀ is selected from C _3-8 alkyl, alkenyl, alkynyl, cycloalkylalkyl, arylalkyl and alkoxyalkyl; the dotted lines ( ), indicate an optional single bond, and

T is ethano (-CH ₂ CH ₂ -) or etheno (-CH=CH-); with a proviso that when T is present, R ₆ and R9 are absent.

In one of the preferred embodiment provided are compounds of formula (lb) wherein

Rj and R ₂ are independently selected from hydrogen and substituted or unsubstituted C _1-6 -alkyl. In yet another embodiment provided are compounds of formula (lb) wherein R _\ and R ₂ together can form C3-C] ₃ -heterocyclic ring system along with the adjacent nitrogen, preferably a 5-membered heterocyclic ring system.

In yet another preferred embodiment provided are compounds of formula (lb) wherein R ₃ is selected from hydrogen or substituted or unsubstituted C _1-6 -alkyl.

In one of the preferred embodiment provided are compounds of formula (lb) wherein R' ₂ and R' ₃ are independently selected from hydrogen and substituted or unsubstituted C _1-6 -alkyl.

In yet another preferred embodiment provided are compounds of formula (lb) wherein R ₄ and R ₅ may be same or different and are independently selected from hydrogen and substituted or unsubstituted Ci _-6 -alkyl.

In yet another preferred embodiment provided are compounds of formula (lb) wherein R and R ₅ together form a (C ₃ -C ₁₃ )-heterocyclic ring system along with the nitrogen to which they are attached and optionally may contain one or more heteroatom selected from O, S and N in the heterocyclic ring system.

In yet another preferred embodiment provided are compounds of formula (lb) wherein 'n is 1 and 'η ₂ ' is 1.

In yet another preferred embodiment provided are compounds of formula (lb) wherein 'n is 1 and 'η ₂ ' is 2. In yet another preferred embodiment provided are compounds of formula (lb) wherein 'nf is 2 and 'η ₂ ' is 1.

In yet another preferred embodiment provided are compounds of formula (lb) wherein 'n is 2 and 'η ₂ ' is 2. In yet another preferred embodiment provided are compounds of formula (lb) wherein 'ni' is 0 and ' ^η ₂ ' is 0.

In yet another preferred embodiment provided are compounds of formula (lb) wherein 'Υ' is absent. In yet another preferred embodiment provided are compounds of formula (lb) wherein Ύ' is a cycloalkylene group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.

In yet another preferred embodiment provided are compounds of formula (lb) wherein Ύ is linker selected from the group consisting of an alkylene, an arylene or a heterocyclylene moiety.

In yet another preferred embodiment provided are compounds of formula (lb) wherein R ₆ and R ₇ are independently selected from hydrogen, hydroxyl, methoxy or acetyl.

In yet another preferred embodiment provided are compounds of formula (lb) wherein R ₆ and R ₇ together represent =0 or =CH ₂ .

In yet another preferred embodiment provided are compounds of formula (lb) wherein R ₈ is selected from hydrogen or a group of the n is selected from methyl or t-butyl.

In yet another preferred embodiment provided are compounds of formula (lb) wherein R ₉ when present is in beta conformation and is selected from group consisting of hydrogen and hydroxy. In yet another preferred embodiment provided are compounds of formula (lb) wherein R ₁₀ is selected from C _3-8 alkyl, alkenyl, alkynyl, cycloalkylalkyl, arylalkyl and alkoxyalkyl.

In yet another preferred embodiment provided are compounds of formula (lb) wherein the dotted lines ( ) indicate a single bond.

In yet another preferred embodiment provided are compounds of formula (lb) wherein the dotted lines ( ) is absent.

In yet another preferred embodiment provided are compounds of formula (lb) wherein T is ethano (-CH ₂ CH ₂ -) or etheno (-CH=CH-) such that when T is present, ¾ and R-9 are absent.

In yet another embodiment provided is compound of formula (Ic),

formula (Ic) or pharmaceutically acceptable salt thereof, wherein, Rj is selected from the group consisting of hydrogen and (C _1- )-alkyl; R ₂ and R ₃ ; R' ₂ and R' ₃ may be same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted (C _1- 6)-alkyl, aryl, arylalkyl and heterocyclyl; or Ri and R ₂ together can form (C ₃ -Ci ₃ )-heterocyclic ring system together with the nitrogen atom bearing Ri;

R4 and R ₅ may be same or different and are independently selected from hydrogen, substituted or unsubstituted (Ci _-6 )-alkyl, alkenyl, alkylnyl, aryl or heterocylyl group; or R4 and R ₅ together can form a (C ₃ -C ₁₃ )-heterocyclic ring system along with the nitrogen atom to which they are attached and optionally may contain one or more heteroatom selected from O, S and N in the heterocyclic ring system,

'ni' and 'η ₂ ' are independently selected from integers 0, 1, 2 or 3;

'Y' is a bond or absent or a linker selected from the group consisting of an alkylene, a cycloalkylene, an arylene or a heterocyclylene moiety, and

Ri ₂ represents hydrogen, halogen or (C _1-6 )-alkyl. In one of the preferred embodiment provided are compounds of formula (Ic) wherein and R ₂ are independently selected from hydrogen and substituted or unsubstituted C _1-6 -alkyl.

In yet another embodiment provided are compounds of formula (Ic) wherein R _\ and R ₂ together can form C ₃ -C ₁₃ -heterocyclic ring system along with the nitrogen atom to which they are attached, preferably a 5-membered heterocyclic ring system.

In yet another preferred embodiment provided are compounds of formula (Ic) wherein R3 is selected from hydrogen or substituted or unsubstituted C _1-6 -alkyl. In one of the preferred embodiment provided are compounds of formula (Ic) wherein R' ₂ and R' ₃ are independently selected from hydrogen and substituted or unsubstituted Ci _-6 -alkyl.

In yet another preferred embodiment provided are compounds of formula (Ic) wherein R4 and R ₅ may be same or different and are independently selected from hydrogen and substituted or unsubstituted Ci _-6 -alkyl.

In yet another preferred embodiment provided are compounds of formula (Ic) wherein R and R ₅ together form a (C3-C ₁₃ )-heterocyclic ring system along with the nitrogen to which they are attached and optionally may contain one or more heteroatom selected from O, S and N in the heterocyclic ring system.

In yet another preferred embodiment provided are compounds of formula (Ic) wherein 'nf is 1 and 'η ₂ ' is 1.

In yet another preferred embodiment provided are compounds of formula (Ic) wherein 'm ' is 1 and is 2. In yet another preferred embodiment provided are compounds of formula (Ic) wherein 'm' is 2 and 'η ₂ ' is 1.

In yet another preferred embodiment provided are compounds of formula (Ic) wherein 'n is 2 and 'η ₂ ' is 2.

In yet another preferred embodiment provided are compounds of formula (Ic) wherein is 0 and 'η ₂ ' is 0.

In yet another preferred embodiment provided are compounds of formula (Ic) wherein 'Y' is absent. In yet another preferred embodiment provided are compounds of formula (Ic) wherein Ύ' is a cycloalkylene group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.

In yet another preferred embodiment provided are compounds of formula (Ic) wherein Ύ' is linker selected from the group consisting of an alkylene, an arylene or a heterocyclylene moiety.

In yet another preferred embodiment provided are compounds of formula (Ic) wherein Ri ₂ is hydrogen.

In yet another preferred embodiment provided are compounds of formula (Ic) wherein R ₁₂ is halogen.

In yet another preferred embodiment provided are compounds of formula (Ic) wherein R ₁₂ is (Ci _-6 )-alkyl.

In yet another embodiment provided is compound of formula (Id),

formula (Id) or pharmaceutically acceptable salt thereof, wherein,

Ri is selected from the group consisting of hydrogen and (C _1- )-alkyl; R ₂ and R ₃ ; R' ₂ and R' ₃ may be same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted (C _1-6 )-alkyl, aryl, arylalkyl and heterocyclyl; or Ri and R ₂ together can form (C ₃ -Ci ₃ )-heterocyclic ring system together with the nitrogen atom bearing R<;

R-t and R ₅ may be same or different and are independently selected from hydrogen, substituted or unsubstituted (C _1-6 )-alkyl, alkenyl, alkylnyl, aryl or heterocylyl group; or R4 and R ₅ together can form a (C ₃ -C ₁₃ )-heterocyclic ring system along with the nitrogen atom to which they are attached and optionally may contain one or more heteroatom selected from O, S and N in the heterocyclic ring system,

'ni ' and 'η ₂ ' are independently selected from integers 0, 1, 2 or 3;

Ύ' is a bond or absent or a linker selected from the group consisting of an alkylene, a cycloalkylene, an arylene or a heterocyclylene moiety;

Ri3 and Rj ₄ may be same or different and are independently selected from substituted or unsubstituted (C _1-6 )-alkyl, or (C _3- i ₃ )-cycloalkyl group, and

Ri ₅ and Ri ₆ may be same or different and are independently selected from hydrogen, halogen, -OR', -NH ₂ , -N0 ₂ , and -COOR', where R' is a hydrocarbon group contain 1 to about 20 carbon atoms.

In one of the preferred embodiment provided are compounds of formula (Id) wherein Ri and R ₂ are independently selected from hydrogen and substituted or unsubstituted Ci-6-alkyl. In yet another embodiment provided are compounds of formula (Id) wherein Ri and R ₂ together can form C ₃ -C ₁₃ -heterocyclic ring system along with the adjacent nitrogen, preferably a 5-membered heterocyclic ring system.

In yet another preferred embodiment provided are compounds of formula (Id) wherein R ₃ is selected from hydrogen or substituted or unsubstituted C _1-6 -alkyl.

In one of the preferred embodiment provided are compounds of formula (Id) wherein R' ₂ and R' ₃ are independently selected from hydrogen and substituted or unsubstituted Ci _-6 -alkyl.

In yet another preferred embodiment provided are compounds of formula (Id) wherein t and R ₅ may be same or different and are independently selected from hydrogen and substituted or unsubstituted C]. ₆ -alkyl.

In yet another preferred embodiment provided are compounds of formula (Id) wherein R4 and R ₅ together form a (C ₃ -C ₁₃ )-heterocyclic ring system along with the nitrogen to which they are attached and optionally may contain one or more heteroatom selected from O, S and N in the heterocyclic ring system.

In yet another preferred embodiment provided are compounds of formula (Id) wherein 'n is 1 and 'η ₂ ' is 1.

In yet another preferred embodiment provided are compounds of formula (Id) wherein 'ηι' is 1 and 'η ₂ ' is 2. In yet another preferred embodiment provided are compounds of formula (Id) wherein 'nf is 2 and 'η ₂ ' is 1.

In yet another preferred embodiment provided are compounds of formula (Id) wherein is 2 and 'η ₂ ' is 2. In yet another preferred embodiment provided are compounds of formula (Id) wherein 'n is 0 and 'η ₂ ' is 0.

In yet another preferred embodiment provided are compounds of formula (Id) wherein 'Y' is absent. In yet another preferred embodiment provided are compounds of formula (Id) wherein Ύ' is a cycloalkylene group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.

In yet another preferred embodiment provided are compounds of formula (Id) wherein Ύ' is linker selected from the group consisting of an alkylene, an arylene or a heterocyclylene moiety.

In yet another preferred embodiment provided are compounds of formula (Id) wherein Ri ₃ and Rj ₄ may be same or different and are independently selected from substituted or unsubstituted (Ci _-6 )-alkyl.

In yet another preferred embodiment provided are compounds of formula (Id) wherein Rn and Ri ₄ may be same or different and are independently selected from substituted or unsubstituted (C _{3- 1} 3)-cycloalkyl group.

In yet another preferred embodiment provided are compounds of formula (Id) wherein R ₁₅ and R ₁₆ may be same or different and are independently selected from hydrogen, halogen, -OR', -NH ₂ , -N0 ₂ , and -COOR', where R' is a hydrocarbon group containing 1 to about 20 carbon atoms.

In yet another embodiment provided is compound of formula (le),

formula (Ie) or pharmaceutically acceptable salt thereof, wherein,

Ri is selected from the group consisting of hydrogen and (Ci- )-alkyl; R ₂ and R ₃ ; R' ₂ and R' ₃ may be same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted (Ci _-6 )-alkyl, aryl, arylalkyl and heterocyclyl; or Ri and R ₂ together can form (Ca-Co^heterocyclic ring system together with the nitrogen atom bearing Ri; R4 and R ₅ may be same or different and are independently selected from hydrogen, substituted or unsubstituted (Q^-alkyl, alkenyl, alkylnyl, aryl or heterocylyl group; or R4 and R ₅ together can form a (C ₃ -C ₁₃ )-heterocyclic ring system along with the nitrogen atom to which they are attached and optionally may contain one or more heteroatom selected from O, S and N in the heterocyclic ring system, ' ' and 'η ₂ ' are independently selected from integers 0, 1 , 2 or 3;

Ύ' is a bond or absent or a linker selected from the group consisting of an alkylene, a cycloalkylene, an arylene or a heterocyclylene moiety; represents a single or double bond; wwv

represents a or -coniiguration, and

Ri ₇ represent oxygen or -OH group and R[ ₈ represent hydrogen or -OH group, when Rn and Rj ₈ represents -OH group, it may be either in a or ^-configuration. In one of the preferred embodiment provided are compounds of formula (le) wherein Ri and R ₂ are independently selected from hydrogen and substituted or unsubstituted C _1-6 -alkyl.

In yet another embodiment provided are compounds of formula (le) wherein R and R ₂ together can form C Co-heterocyclic ring system along with the adjacent nitrogen, preferably a 5-membered heterocyclic ring system.

In yet another preferred embodiment provided are compounds of formula (le) wherein R ₃ is selected from hydrogen or substituted or unsubstituted Ci _-6 -alkyl.

In one of the preferred embodiment provided are compounds of formula (le) wherein R' ₂ and R' ₃ are independently selected from hydrogen and substituted or unsubstituted C] _-6 -alkyl.

In yet another preferred embodiment provided are compounds of formula (le) wherein R ₄ and R ₅ may be same or different and are independently selected from hydrogen and substituted or unsubstituted Ci _-6 -alkyl.

In yet another preferred embodiment provided are compounds of formula (le) wherein R4 and R ₅ together form a (C ₃ -Ci ₃ )-heterocyclic ring system along with the nitrogen to which they are attached and optionally may contain one or more heteroatom selected from O, S and N in the heterocyclic ring system. In yet another preferred embodiment provided are compounds of formula (le) wherein 'η is 1 and 'η ₂ ' is 1.

In yet another preferred embodiment provided are compounds of formula (le) wherein 'm' is 1 ^' and 'η ₂ ' is 2. In yet another preferred embodiment provided are compounds of formula (le) wherein 'm' is 2 and 'η ₂ ' is 1.

In yet another preferred embodiment provided are compounds of formula (le) wherein 'm' is 2 and 'η ₂ ' is 2.

In yet another preferred embodiment provided are compounds of formula (le) wherein 'm' is 0 and is 0.

In yet another preferred embodiment provided are compounds of formula (le) wherein Ύ' is absent.

In yet another preferred embodiment provided are compounds of formula (I) wherein 'Y' is a cycloalkylene group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.

In yet another preferred embodiment provided are compounds of formula (le) wherein 'Υ' is linker selected from the group consisting of an alkylene, an arylene or a heterocyclylene moiety.

In yet another preferred embodiment provided are compounds of formula (le) wherein represents a single bond.

In yet another preferred embodiment provided are compounds of formula (le) wherein represents a double bond. In yet another preferred embodiment provided are compounds of formula (Ie) wherein represents oc-configuration.

In yet another preferred embodiment provided are compounds of formula (Ie)

, . wvw

wherein represents -contiguration. In yet another preferred embodiment provided are compounds of formula (Ie) wherein R] ₇ represent oxygen or -OH group.

In yet another preferred embodiment provided are compounds of formula (Ie) wherein R ₁₈ represent hydrogen or -OH group.

In addition to the above text, and in the entire disclosure, the terms described have the following meanings unless otherwise indicated.

The following are definitions of the terms used in this specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated. As used herein 'alkyl' can be straight-chain, branched or cyclic aliphatic group containing 1 to 12 carbon atoms, and/or can have one or more hetero atom incorporated therein and optionally, in each case have one or more hydrogen atoms replaced by halogen, -OH, -OCO-(C _t -C ₃ )-alkyl, (C ₃ -C ₁₃ )-cycloalkyl, -NH ₂ , - NH(alkyl), -N(alkyl) ₂ , -NH(alkyl)-OC(0)-alkyl, -OC(0)-alkyl, -SH, substituted or unsubstituted aryl or heterocyclic radical.

The term 'alkenyl' refers to an unsaturated straight chain, branched or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom form a single carbon atom of parent alkene. The group may be in either the (E) or (2) confirmation about the double bond(s). Exemplary alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl(allyl), prop-2-en-2-yl; cycloprop-l-en-l-yl; butenyls such as (E)-but-2-en-l -yl, but-l-en-2-yl, 2-methyl-prop-l-en-l -yl, but-2-en-l-yl, but- (Z)-2-en-2-yl, buta-l ,3-dien-l-yl, buta-l ,3-dien-2-yl, cyclobut-l-en-l-yl, cyclobut-1- en-3-yl, cyclobuta-l ,3-dien-l-yl, etc.; and the like.

The term 'alkynyl' refers to an unsaturated straight chain, branched or cyclic alkyl radical having at least one carbon-carbon triple bond derived by the removal of hydrogen atoms each from two adjacent carbons of parent alkane. Exemplary alkynyl groups include, but are not limited to ethynyl, 2-propynyl, but-l -yne-2-yl, and the like.

The term 'alkylene' refers to a divalent alkyl group containing 1 to 15 carbon atoms obtained by removal of two hydrogen atoms from a single carbon atom (geminal). Exemplary alkylene groups include, but are not limited to, -CH ₂ -, -C(CH ₃ ) ₂ )-, - CH(CH ₂ CH(CH ₃ ) ₂ )-, -CH(CH ₂ C ₆ H ₅ )-, -CH(C ₆ H _S )CH ₂ -, -C(CH ₃ )(C ₆ H ₅ )-, - C(CH ₃ )(CH ₃ CH ₂ )- etc.

The term ' alkenyl ene' refers to a divalent alkene having 2 to 15 carbon atoms obtained by removal of two hydrogen atoms from either the adjacent (vicinal) carbons or single carbon (geminal) bearing the double bond; the double bonds being in either (E) or (Z) configuration Exemplary alkenylene groups include, but are not limited to, -CH=CH-, C ₆ H ₅ CH=C<, -CH=C(CH ₃ )-, (Z) -C(CH ₃ )=C(CH ₃ )-, etc.; and the like.

The term "cycloalkyl" denotes a non-aromatic mono-, or multicyclic ring system of 3 to about 12 carbon atoms. Monocyclic rings include, but are not limited to, cylcopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of simple multicyclic cycloalkyl groups include perhydronapththyl, perhydroindenyl etc; bridged multicyclic groups include adamantyl and norbornyl etc, and spriromulticyclic groups for e.g., spiro(4,4)non-2-yl. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted and can optionally contain one or more unsaturations The term "cycloalkylene", refers to a divalent cycloalkyl radical of 3 to 12 carbon atoms wherein a hydrogen atom each is removed from two carbons of the carbocycle. Examples of cycloalkyl enes are cyclopropan-l ,l-diyl, , c/s-cyclopentan-l,2-diyl„ cyclohexan-l,l-diyl, cyclohexen-l,2-diyl, exo-bicyclo[3.3.1]hepane-2,3-diyl and the like. The term "cycloalkylalkyl," as used herein, refers to any cycloalkyl group attached to an alkylene group such as, but are not limited to, cyclopropylmethyl, 2- cyclopropylethyl, cyclobutylmethyl, and 1-cyclopentylethyl. The cycloalkylalkyl groups of this invention can be optionally substituted. The term "alkoxyalkyl" as used herein refers to an alkyl substituent, as defined herein, wherein one or more hydrogens of the alkyl are replaced with an -O-alkyl substituent.

As used herein 'halogen' or 'halo group' refers to -F, -CI, -Br, or -I.

The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems such as phenyl, naphthyl, tetrahydronapthyl, indanyl and biphenyl. Unless set forth or recited to the contrary, all aryl groups described or claimed herein may be substituted or unsubstituted.

The term 'arylene' refers to an aryl-diyl group, optionally having one or more hydrogen atoms replaced by other substitutions. The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH ₂ C H ₅ and -C ₂ H ₄ C ₆ H5. Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted. As mentioned above the term "heterocyclyl" or "heterocyclic ring" unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. The heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; also, unless otherwise constrained by the definition the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s). This definition furthermore includes ring systems in which the heterocyclyl rings are aromatic, i.e. 'heteroaryl'. Examples of such heterocyclyl radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted. The term "heterocyclylene", refers to a divalent heterocyclyl radical of 3 to 15 carbon atoms wherein a hydrogen atom each is removed from two carbons of the heterocycle. Examples of heterocyclylenes are pyridin-3,5-diyl, imidazol-2,4-diyl, thiazol-2,5-diyl, benzimidazol-l,6-diyl, pyrimidin-2,4-diyl, etc.; and the like. Unless otherwise specified, the term "substituted" as used herein refers to a group or moiety having one or more of the substituents attached to the structural skeleton of the group or moiety, including, but not limited to such substituents as hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), alkyl, haloalkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, amino, alkylamino, dialkylamino, heteroaryl, heterocyclylalkyl ring, heteroarylalkyl, heterocyclic ring, guanidine, alkylguanidine, -COOR _x , -C(0)R _x , -C(S)R _X , -C(0)NRxRy, - (O)ONRxRy, -NRxCONRyRz, -N(Rx)SORy, -N(Rx)S0 ₂ Ry, -(=N-N(Rx)Ry), - NRxC(0)ORy, -NRxRy, -NRxC(0)Ry, -NRxC(S)Ry, -NRxC(S)NRyRz, - SONRxRy, -S0 ₂ NRxRy, -OR _x , -ORxC(0)NRyRz, -ORxC(0)ORy, -OC(0)RX, - OC(0)NRxRy, -RxNRyC(0)Rz, -RxORy, -RxC(0)ORy, -RxC(0)NRyRz, - RxC(0)Ry, -RxOC(0)Ry, -SR _X , -SOR _x , -S0 ₂ R _x , and -ON0 ₂ , wherein Rx, Ry and Rz are independently selected from hydrogen, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, amino, alkylamino, dialkylamino, aryl, heteroaryl, heterocyclylalkyl ring, heteroarylalkyl, or substituted or unsubstituted heterocyclic ring.

The term 'prodrug' refers to a derivative of an active agent that requires a transformation within the active agent. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the active agent.

The "phenolic drugs" may be understood as drugs that bear a phenolic function, i.e. one of the aryl carbon atom of the drug bears a hydroxyl group. With the groups of preferred compounds of formula (I) and N-oxides thereof mentioned hereinafter, definitions of substituents from the general definitions mentioned hereinbefore may reasonably be used, e.g. to replace more general definitions with more specific definitions or especially with definitions characterized as being preferred..

Any asymmetric carbon atom may be present in the (R)-, (S)- or (i?,5)-configuration. The compounds may thus be present as mixtures of isomers or as pure isomers.

The invention relates also to possible tautomers of the compounds of formula (I).

Where the plural form is used for compounds, salts and the like, this is taken to mean also a single compound, salt, or the like.

Salts are especially the pharmaceutically acceptable salts of compounds of formula (I). Such salts are formed, e.g. as acid addition salts, preferably with organic or inorganic acids or from compounds of formula (I) with a basic nitrogen atom, especially the pharmaceutically acceptable salts. Suitable inorganic acids are, e.g. halogen acids, such as hydrochloric acid, sulfuric acid or phosphoric acid. Suitable organic acids are, e.g. carboxylic, phosphonic, sulfonic or sulfamic acids, e.g. acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartartic acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, mandelic acid, cinnamic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1 ,5-naphthalene-disulfonic acid, 2- , 3- or 4-methylbenzenesulfonic acid, or other organic protonic acids, such as ascorbic acid. In the presence of negatively charged radicals, such as carboxy or sulfo, salts may also be formed with bases, e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, e.g. sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, e.g. erbumine or tris(2-hydroxyethyl)amine, or heterocyclic bases, e.g. vV-ethylpiperidine orN,A^-dimethylpiperazine. Whe an acid group is present in the same molecule, the compound of formula (I) may also form internal salts.

For isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, e.g. picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds are employed and these are therefore preferred.

In view of the close relationship between the novel compounds in free form and those in the form of their salts, including those salts that can be used as intermediates, e.g. in the purification or identification of the novel compounds, any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate and expedient.

The compounds of formula (I) in the present invention are novel prodrugs of phenolic drugs, where phenolic drugs include, but are not limited to opioids like morphine, oxymorphone, naltrexone, naloxone, buprenorphine, 6-acetylmorphine, hydromorphone, nalbuphine, meptazinol, tapentadol, desmethyltramadol etc; NSAIDS such as piroxocam, meloxicam etc; sex hormones such as estrone, estradiol and estriol; anesthetic drugs asuch as propofol; oncolytic drugs such as 7-ethyl-10- hydroxycamptothecin, tamoxifen, fenertidine etc; antiparkinsonian drugs such as levodopa, carbidopa, entacapone; bronchodilator drugs such as terbutaline. Preferably the phenolic drug is a phenolic opioid.

The term Opioid' refers to a chemical substance that exerts its pharmacological action by interaction at opioid receptors. "Phenolic opioid" refers to a subset of the opioids that contains a phenol group. Examples of phenolic opioids include morphine, hydromorphone, oxymorphone, buprenorphine, O-desmethyltramadol, naltrexone, naloxone, N-methylnaloxone, 6-acetylmorphine, nalbuphine, meptazinol, tapentadol, etorphine, dihydroetorphine, diprenorphine, levorphanol, nalmefene, oripavine; and the like.

The novel prodrugs of phenolic drugs in the present invention can in general be described as hydrazide containing carbamate derivatives of phenolic function represented by the general formula (I) or salts thereof.

These novel prodrugs of formula (I) give the corresponding active parent drugs upon administration to mammals. The novel prodrug strategy of phenolic drugs in the present invention provides improved physicochemical characteristics such as solubility, advantageous pharmacokinetic profile upon administration in terms of enhanced bioavailability, onset, duration of action etc. Besides these prodrugs show better efficacy to side effect profile i.e. better therapeutic index, when compared to their corresponding parent phenolic drugs.

The compounds of the present invention can be exemplified by the following non- limiting examples:

N-Methyl-N-(piperidin-l-ylcarbamoylmethyl) carbamic acid [(5α,6α)-7,8- Didehydro-4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester (Compound No. l);

(S)-2-(Piperidin- 1 -ylcarbamoyl)pyrrolidine- 1 -carboxylic acid [(5 ,6 or)-7,8- didehydro-4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester (Compound No.2); [2-(Piperidin-l-ylcarbamoyl)ethyl]carbamic acid [(5«,6a)-7,8-didehydro-4,5-epoxy- 17-methylmorphinan-6-ol-3-yloxycarbonylamino] ester (Compound No.3);

N-Methyl-N-[2-(piperidin- 1 -ylcarbamoyl)ethyl]carbamic acid [(5 α,6α)-7,8- didehydro-4,5-epoxy-17-methylmorphinan-6-ol-3-yloxycarbonyl- amino] ester (Compound No.4);

[(5)- 1 -(Piperidin- l-ylcarbamoyl)ethyl]carbamic acid [(5«,6a)-7,8-didehydro-4,5- epoxy-17-methylmo hinan-6-ol-3-yl]propionate (Compound No.5);

(Piperidin- 1 -ylcarbamoylmethyl)carbamic acid [(5 ,6 a)-7,8-didehydro-4,5-epoxy- 17-methylmorphinan-6-ol-3-yl] ester (Compound No.6); [(S)-2-Methyl-l -(piperidin- l-ylcarbamoyl)propyl]carbamic acid [(5οτ,6α)-7,8- didehydro-4,5-epoxy- 17-methylmorphinan-6-ol-3-yloxycarbonylamino] ester (Compound No.7);

[(5)-3 -Methyl- 1 -(piperidin- 1 -ylcarbamoyl)butyl]carbamic acid [(5 α,6α)-7,8- didehydro-4,5-epoxy- 17-methylmorphinan-6-ol-3-yloxycarbonylamino] ester (Compound No.8);

[(5)-2-Phenyl-l -(piperidin- l-ylcarbamoyl)ethyl]carbamic acid [(5a,6«)-7,8- didehydro-4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester (Compound No.9);

(S)-2-(4-Methylpiperazin- 1 -ylcarbamoyl)pyrrolidine- 1 -carboxylic acid [(5 a,6 cc)-7,8- didehydro-4,5-epoxy-l 7-methylmo hinan-6-ol-3-yl] ester trihydrochloride (Compound No.10); (S -2-(N'-tert-Butylhydrazinocarbonyl)pyrrolidine- 1 -carboxylic acid [(5 α,6α)-7,8- didehydro-4,5-epoxy- 17-methylmorphinan-6-ol-3-yl] ester trihydrochloride (Compound No .1 1 ) ;

(S)-2-(Morpholin-4-ylcarbamoyl)pyrrolidine- 1 -carboxylic acid [(5 a,6 a)-7,8- didehydro-4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.12);

(iS)-2-(N-Methyl-hydrazinocarbonyl)pyrrolidine-l -carboxylic acid [(5 α,6α-7,8- didehydro-4,5-epoxy- 17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.13); N-Methyl-(morpholin-4-ylcarbamoylmethyl)carbamic acid [(5 a,6a)-7,8-didehydro- 4,5-epoxy-17-methylmo hinan-6-ol-3-yl] ester dihydrochloride (Compound No.14);

(S)-2-(N,N-Dimethyl-hydrazinocarbonyl)-pyrrolidine- 1 -carboxylic acid [(5 a,6 )-7,S- didehydro-4,5-epoxy-17-methylmo hinan-6-ol-3-yl] ester dihydrochloride (Compound No.15); Methyl-(N'-methylhydrazinocarbonylmethyl)carbamic acid [(5 a,6a)-7,8-didehydro- 4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.16);

Methyl-(N, N-dimethylhydrazinocarbonylmethyl)carbamic acid [(5 a,6 a)-7, 8- didehydro-4,5-epoxy-l 7-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.17);

(N-tert-Butyl-hydrazinocarbonylmethyl)methylcarbamic acid [(5α,6α)-7,8- didehydro-4,5-epoxy- 17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.18); (Azepan- 1 -ylcarbamoylmethyl)methylcarbamic acid [(5 a,6 a)-7,8-didehydro-4,5- epoxy-17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.19);

(S)-2-(Azepan- 1 -ylcarbamoyl)-pyrrolidine- 1 -carboxylic acid [(5 a,6 a)-7, 8-didehydro- 4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.20); (5 -2-Hydrazinocarbonyl-pyrrolidine-l -carboxylic acid [(5<ar,6<z)-7,8-didehydro-4,5- epoxy-17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.21);

(Hydrazinocarbonylmethyl)-methylcarbamic acid [(5or,6«)-7,8-didehydro-4,5-epoxy- ^ 17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.22);

(5)-2-(N'-Isopropyl-hydrazinocarbonyl)-pyrrolidine-l -carboxylic acid [(5a,6a)-7,8- didehydro-4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.23);

Methyl-[2-(morpholin-4-ylcarbamoyl)ethyl]carbamic acid [(5a,6a)-7,8-didehydro- 4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.24);

[(5)-l-(N'-tert-Butylhydrazinocarbonyl)-2-methyl-propyl]c arbamic acid [(5a,6a)- 7,8-didehydro-4,5-epoxy- 17-methylmorphinan-6-ol-3-yl] ester (Compound No.25);

[(5)- 1 -(Azepan- l-ylcarbamoyl)-2-methyl-propyl]carbamic acid . [(5α,6α)-7,8- didehydro-4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester (Compound No.26);

(Azepan- 1 -ylcarbamoylmethyl)carbamic acid [(5 ,6 a;)-7,8-didehydro-4,5-epoxy- 17- methylmo hinan-6-ol-3-yl] ester dihydrochloride (Compound No.27); [(5)-l-(Azepan-l-ylcarbamoyl)-3-methyl-butyl]carbamic acid [(5α,6α)-7,8- didehydro-4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester (Compound No.28); [(5)-3-Methyl-l-(N'-tert-Butyl-hydrazinocarbonyl)butyl]carba mic acid [(5α,6α)-7,8- didehydro-4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester (Compound No.29);

[2-(JV'-tert-Butyl-hydrazinocarbonyl)ethyl]carbamic acid [(5 a,6a)-7,8-didehydro-4,5- epoxy-17-methylnlO hinan-6-ol-3-yl] ester dihydochloride (Compound No.30); [(S)-3-Methyl-l-(N'-methyl-hydrazinocarbonyl)butyl]carbamic acid [(5α,6α)-7,8- didehydro-4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.31);

[2-(Azepan- 1 -ylcarbamoyl)ethyl]carbamic acid [(5 a,6 a)-7,8-didehydro-4,5-epoxy- 17-methylmorphinan-6-ol-3-yl] ester (Compound No.32); [1 -(Azepan- l-ylcarbamoyl)ethyl]carbamic acid [(5a,6a)-7,8-didehydro-4,5-epoxy- 17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.33);

[(5)-4-Methyl-2-(piperidin- 1 -ylcarbamoylmethyl)pentyl]carbamic acid [(5 a,6 a)-7,8- didehydro-4,5-epoxy- 17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.34); [(S)-l-(N',N'-Dimethyl-hydrazinocarbonyl)-3-methyl-butyl]car bamic acid [(5a,6«)- 7,8-didehydro-4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester (Compound No.35);

[3-(Piperidin-l-ylcarbamoyl)propyl]carbamic acid [(5a,6a)-7,8-didehydro-4,5- epoxy-17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.36);

[(5 -2-(N'-tert-Butyl-hydrazinocarbonylmethyl)-4-methyl-pentyl]c arbamic

[(5 a, 6 a)-7, 8 -didehydro-4, 5 -epoxy- 17-methylmorphinan-6-ol-3 -yl]

dihydrochloride (Compound No.37); [3-(N -tert-Butyl-hydrazinocarbonyl)propyl]carbamic acid [(5 ar,6a)-7,8-didehydro- 4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.38);

[(5)- 1 -(N'-tert-Butyl-hydrazinocarbonyl)ethyl]carbamic acid [(5 ,6 a)-7,8-didehydro- 4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.39); (Pyrr0lidin-l-ylcarbamoylmethyl)carbamic acid [(5a,6a:)-7,8-didehydro-4,5-epoxy- 17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.40);

[(S)- 1 -(N'-tert-Butyl-hydrazinocarbonyl)-2-phenyl-ethyl]carbamic acid [(5 a,6 a)-7,8- didehydro-4,5-epoxy- 17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.41); [(5)-l-(Azepan-l-ylcarbamoyl)-2-phenyl-ethyl]carbamic acid [(5α,6«)-7,8- didehydro-4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.42);

[(15,25)- 1 -(Azepan- 1 -ylcarbamoyl)-2-methyl-butyl]carbamic acid [(5 a,6 a)-7,8- didehydro-4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.43);

(Azepan- 1 -ylcarbamoylmethyl)carbamic acid [(5 a,6 a)- 17-allyl-4,5-epoxy- 14- hydroxy-morphinan-6-one-3-yl] ester dihydrochloride (Compound No.44);

(Azepan- 1 -ylcarbamoylmethyl)carbamic acid [5 a,l a(S)]-l 7-cyclopropylmethyl-a- (1,1 -dimethylethyl)-4,5-epoxy- 18,19-dihydro-6-methoxy-a-methyl-6, 14- ethanomorphinan-6-one-7-methanol-3-yl] ester dihydrochloride (Compound No.45); [(S)-2-(Azepan-l -ylcarbamoylmethyl)-4-methyl-pentyl]carbamic acid [(5 a,6a)-T,8- didehydro-4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.46);

(Azepan- 1 -ylcarbamoylmethyl)carbamic acid [ 17-(cyclopropylmethyl)-(5 a,6 a)-4,5- epoxy- 14-hydroxy-morphinan-6-one-3 -yl] ester dihydrochloride (Compound No .47) ;

[3-(Azepan-l-ylcarbamoyl)propyl]carbamic acid [(5a,6a:)-7,8-didehydro-4,5-epoxy- 17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.48);

(Azepan- 1 -ylcarbamoylmethyl)carbamic acid [(5 a,6 a:)-6-acetyl-7,8-didehydro-4,5- epoxy-17-methylmorphinan-3-yl] ester dihydrochloride (Compound No.49); (Piperidin-l-ylcarbamoylmethyl) carbamic acid [(5a)-4,5-epoxy-14-hydroxy-17- methylmo hinan-6-one-3-yl] ester dihydrochloride (Compound No.50);

(Azepan- 1 -ylcarbamoylmethyl)methylcarbamic acid [7-ethyl-camptothecin- 10-yl] ester dihydrochloride (Compound No.51);

(Azepan- 1 -ylcarbamoylmethyl)carbamic acid 2,6-diisopropylphenyl ester hydrochloride (Compound No.52);

[(^-l-^-tert-Butyl-hydrazinocarbony^ethylJcarbamic acid [(5a)-4,5-epoxy-14- hydroxy-17-methylmorphinan-6-one-3-yl] ester dihydrochloride (Compound No.53)

(Azepan- l-ylcarbamoylmethyl)carbamic acid [estra-l,3,5(10)-trien-17-one-3-yl] ester (Compound No.54). (Azepan- 1 -ylcarbamoylmethyl)carbamic acid [(5a)-4,5-epoxy-14-hydroxy-17- methylmorphinan-6-one-3-yl] ester dihydrochloride (Compound No.55). [(£)- 1 -(Piperidin- 1 -ylcarbamoyl)ethyl]carbamic acid [(5 or)-4,5-epoxy- 14-hydroxy- 17-methylmorphinan-6-one-3-yl] ester dihydrochloride (Compound No.56).

[(S)-2-Phenyl- 1 -(piperidin- 1 -ylcarb ^' amoyl)ethyl]carbamic acid [(5 a)-4,5-epoxy- 14- hydroxy-17-methylmorphinan-6-one-3-yl] ester dihydrochloride (Compound No.57). (Piperidin- 1 -ylcarbamoylmethyl)methylcarbamic acid [7-ethylcamptothecin- 10-yl] ester dihydrochloride. (Compound No.58).

(N-tert-Butylhydrazinocarbonylmethyl)methylcarbamic acid [7-ethylcamptothecin- 10-yl] ester dihydrochloride (Compound No.59).

[(/?)- 1 -(N'-tert-Butylhydrazinocarbonyl)ethyl]carbamic acid [(5 a,6 a)-7,8-didehydro- 4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.60).

[2-Methyl-2-(piperidin-l -ylcarbamoyl)propyl]carbamic acid [(5 a,6a)-7,8-didehydro- 4,5-epoxy-17-methylmorphinan-6-ol-3-yl] ester hydrochloride (Compound No.61).

[1,1 -Dimethyl-2-(piperidin- 1 -ylcarbamoyl)ethyl]carbamic acid [(5 ,6 «)-7,8- didehydro-4,5-epoxy- 17-methylmorphinan-6-ol-3-yl] ester dihydrochloride (Compound No.62).

[(5)-2-Methyl- 1 -(piperidin- 1 -ylcarbamoyl)propyl]carbamic acid [(5 #)-4,5-epoxy- 14- hydroxy-17-methylmorphinan-6-one-3-yl] ester dihydrochloride (Compound No.63).

[(5 -2,2-Dimethyl- 1 -(piperidin- 1 -yl-carbamoyl)propyl]carbamic acid [(5 a,6 a)-7,8- didehydro-4,5-epoxy- 17-methylmorphinan-i ester dihydrochloride (Compound No.64). The present invention provides process for the preparation of the compounds of formula (I), which comprises reacting the compound of formula (II) with a compound of formula (III) (Schemes 1 to 8).

The compounds of formula (III) (promoieties) described herein, may be prepared and attached to the phenolic group of the phenolic drugs by procedures known to the those in the art e.g., Green et al., "Protective groups in organic chemistry" (Wiley, 2 ^nd ed. 1991); Feiser et al., "Reagents for Organic synthesis", Volume l-17(Wiley Interscience); Trost et al., "Comprehensive Organic Synthesis", (Pergamon Press, 1991); March, "Advanced Organic Chemistry", (Wiley Interscience, 1991), Larock "Comprehensive organic transformations", (VCH publishers, 1989); Paquette, "Encyclopedia of reagents for organic synthesis", (John Wiley & Sons, 1995), Bodanzsky, "Principles of Peptide Synthesis", (Springer Verlag, 1984); Bodanzsky, "Practice of peptide synthesis" (Springer Verlag, 1984). Further, the starting materials for formula (III) may be obtained from commercial sources, or prepared via well established synthetic procedures.

Compound of formula (I), wherein Rj, R ₂ , R ₃ , R' ₂ , R' ₃ R4, R ₅ , m, n ₂ , X and Y are as defined above, can be synthesized by condensation of compound of formula Ila, wherein L is leaving group, with compound of formula (III) in the presence of a base, optionally in conjunction with a suitable catalyst (such as 4-(N,N- dimethylamino)pyridine, 1 -hydroxybenzotrazole) in an aprotic solvent, Scheme 1.

Scheme 1 Alternatively, the compounds of formula (I), wherein, R _l5 R ₂ , R ₃ , R _l5 R ₂ , R ₃ , R' ₂ , R' ₃ R4, Rs, n _ls - n ₂ , X and Y are as defined above, can be synthesized by condensation of compound of formula (Ilia), wherein L is leaving group, with compound of formula (II) in presence of a base, optionally in conjunction with a suitable catalyst in an aprotic solvent, Scheme 2.

The compounds of formula (I) can also be synthesized by condensation of compound of formula (IV) (wherein L is leaving group and compound is in activated form) with compound of formula (V) in presence of a base, optionally in conjunction with a suitable catalyst in an aprotic solvent, Scheme 3.

Scheme 3

Compound of formula (V) can be obtained from commercial sources or prepared from the corresponding amines using processes generally known in the art for the preparation of hydrazines.

Compound of formula Ila, wherein X is as defined above and L is leaving group, can be synthesized from the phenolic drug (X-OH) or its suitably protected form by using any carbonylating reagent commonly known for such purpose, Scheme 4. X— OH

X— O

II Ila

Scheme 4

The general methods for this purpose are well known to those skilled in the art. Some of the commonly used methods include treatment of the phenolic drug (X-OH), or its suitably protected form, with the following reagents:

• Phosgene, diphosgenes, or triphosgenes to obtain formula Ila wherein L=C1.

An aryl chloroformate such as phenyl chloroformate, 4-nitrophenyl chloroformate etc. to obtain formula Ila wherein L=aryloxy.

• An haloalkyl chloroformate such as trifluoroethyl chloroformate, chloroethyl chloroformate etc., L=haloalkyloxy.

• A carbonyl diheterocyclyl compound such as carbonyldiimidazole, L=l- imidazolyl.

• A JV-hydroxyheterocyclyl choroformate such as N-hydroxysuccinimidyl chloroformate, L= N-hydroxyheterocyclyl The carbonylation reaction is preferably performed in presence of a base, optionally in conjunction with a suitable catalyst in an aprotic solvent.

The carbonylation reaction is preferably performed in presence of an aprotic solvent such as methylene dichloride, toluene and tetrahydrofuran.

Alternatively, the compounds of formula Ila can be generated in situ from the compound of formula (II) using carbonylating reagent in presence of a base, and optionally a suitable catalyst, in an aprotic solvent and then condensed with the compound of formula (III) to yield the compound of formula (I), Scheme 5.

Scheme 5

Compounds of formula (III), wherein R _1; R ₂ , R ₃ , R' ₂ , R' ₃ , R4, R ₅ , n _l5 n ₂ and Y are as defined above and P is protecting group, may be prepared by a process known in the art, for example, by coupling the corresponding protected amino acid of formula (IIIc), wherein P is protecting group, with a suitable hydrazine derivative of formula (Illb) to provide compounds of formula (Hid) which then may be deprotected to yield compound of formula (III), Scheme 6. The amino protecting group P maybe selected from groups which are well known to those skilled in the art such as t- butyloxycarbony, benzyloxycarbonyl and the like.

Deprotection

Illb

Illc Hid

Scheme 6

The coupling reaction can be carried out in a manner known per se, the reaction conditions being dependent especially on how the acid group of formula (IIIc) has been activated, usually in the presence of a suitable solvent or diluent or of a mixture thereof and, if necessary, in the presence of a condensation agent. Customary condensation agents are, for example, carbodiimides such as N,N '-diethyl-, Ν,Ν'- diisopropyl, N,N'-dicyclohexyl- or N-ethyl-N'-(3-diethylaminopropyl)-carbodiimide; suitable carbonyl compounds, for example carbonyldiimidazole, or 1 ,2-oxazolium compounds, for example 2- ⁱ ethyl-5-phenyl-l,2-oxazolium 3 '-sulfonate and 2-tert- butyl-5-methyl-isoxazolium perchlorate, or a suitable acylamino compound, for example, 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline. The bases normally used for aiding the condensation are either inorganic bases such as sodium or potassium carbonate, or organic bases, such as pyridine, triethylamine, N,N- diisopropylethylamine or 4-(dimethylamino)pyridine.

Alternately, wherein Ri, R ₂ , R ₃ R' ₂ , R' ₃ , R4, R ₅ , n _l5 n ₂ and Y are as defined above and P is protecting group, compound of formula (III) can be synthesized from the corresponding protected amino acid hydrazides of formula (VI) by alkylation with an appropriate alkyl halides (or alkylidene dihalide) to provide compounds of formula (Hid), which then may be deprotected to yield compound of formula (III), Scheme 7. Compound of formula (VI) may be prepared, from the corresponding protected amino acid by methods known to those skilled in the art.

Ill

Scheme 7 Compound of formula (Ilia), wherein Ri, R ₂ , R ₃ , R' ₂ , R' ₃ R4, R ₅ , , n ₂ and Y are as defined above and L is leaving group, can be synthesized from compound of formula (III), or its suitably protected form, by using any carbonylating reagent commonly known for such purpose, Optionally the compound of formula (Ilia) may be prepared in situ without prior isolation and reacted with the phenolic drug X-OH. When R _\ represents "H" in the compound of formula (III) the product is an isocynate of formula (Ilia') which is not isolated, and is in situ reacted with the phenolic drug X- OH of formula (II), Scheme 8.

The general methods for the purpose of conversion of formula (III) to formula (Ilia or rtla') are well known to those skilled in the art. Some of the commonly used methods include but are not limited to treatment of the compound of formula (III), or its suitably protected form, with the following reagents: · Phosgene, diphosgenes, or triphosgenes to obtain formula (Ilia) (wherein

L=C1) or an isocynate {if Rt is hydrogen in compound of formula (III)} • An aryl chloroformate such as phenyl chloroformate, 4-nitrophenyl chloroformate etc. to obtain formula (Ilia) wherein L=aryloxy.

• An haloalkyl chloroformate such as trifluoroethyl chloroformate, chloroethyl chloroformate etc., L=haloalkyloxy.

· A carbonyl diheterocyclyl compound such as carbonyldiimidazole, L=l- imidazolyl.

• A iV-hydroxyheterocyclyl choroformate such as N-hydroxysuccinimidyl chloroformate, L= N-hydroxyheterocyclyl

The above reaction is preferably performed in the presence of a base, optionally in conjuction with a suitable catalyst (such as 4-(N,N-dimethylamino)pyridine, 1- hydroxybenzotrazole), in an aprotic solvent, preferably the aprotic solvents are methylene dichloride, toluene and tetrahydrofuran.

The compounds of formula (I), including their salts, are also obtainable in the form of hydrates. The following examples serve to illustrate the invention without limiting the invention in its scope.

EXPERIMENTAL

Exam le 1: Preparation of 2-amino-N-azepan-l-yl-acetamide

l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC HC1) (6.87 g, 35.8 mniol) was added to a stirred solution containing iV-carbobenzyloxyglycine (1.2 g, 1.32 mmol), 4-dimethylaminopyridine (0.58 g, 4.7mmol) and 1- aminohomopiperidine (2.59 g, 22.7 mmol) in anhydrous methylene chloride (50 ml). The mixture was stirred under a blanket of nitrogen at 25 to 30°C for 4 hrs and then poured into water. The organic layer was separated, washed with water, dried, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (10% acetone in chloroform) and resulting product was hydrogenated using Pd-C as catalyst to yield the title compound as yellowish thick liquid. Ή NMR (500MHz in D ₂ 0), δ. 1.48-1.54(m, 4H), 2.80-2.82(m, 4H), 3.1 l(s, 2H)

Example 2: Preparation of 2-amino-N-azepan-l-yl-acetamide

A mixture of N-carbobenzyloxyglycine hydrazide (1 10 g, 0.492 mole), 1,6- dibromohexane (132.5 g, 0.541 mole), triethanolamine (184 g, 1.232 mole) in dry N,N-dimethylamirioformamide (550 ml) was stirred at 90-95 °C for 4 hrs. The mixture was cooled to 25-30°C and quenched with water. The product was extracted into ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel (4% methanol in dichloromethane) and the resulting product was hydrogenated to yield the title compound as yellowish thick liquid. Exam le 3: Preparation of 2-amino-N-piperidin-l-yl-acetamide

Oxalyl chloride (5.76 g, 45.4 mmol) was added to a stirred solution containing N- carbobenzyloxyglycine (10 g, 47.8 mmol) and N,N-dimethylformamide (1 ml) in anhydrous methylene chloride (100ml). The mixture was stirred at 25 to 30°C for 0.5 hr. 1-Aminopiperidine (4.31 g, 43 mmol) and triethylamine (14.5 g, 143 mmol) in dichloromethane (40 ml) were charged and stirring was continued for 1 hr. The mixture was poured into water, organic layer was separated, washed with water, dried and concentrated in vacuo. Purification by leaching with diethyl ether and hydrogenation over Pd-C catalyst yielded the title compound as an off-white solid. 1H NMR (500MHz in D ₂ 0), δ. 1.50-1.51(m, 2H), 1.75-1.80(m, 4H), 3.34(m, 2H), 3.78(s, 2H).

Example 4: Preparation of (5)-2-(morpholin-4-ylcarbamoyl)-pyrrolidine-l- carboxylic acid [(5 ,6α)-7,8-didehydro-4,5-epoxy-17-methylmo hinan-6-ol-3-yl] ester dihydrochloride [Compound No 12].

4-Nitrpphenyl chloroformate (0.5 g, 2.5 mmol) was added to a stirred mixture of morphine (0.6 g, 2.1 mmol) and triethylamine (0.87 ml, 6.3 mmol) in anhydrous methylene chloride (60 ml) and stirred at 25-30°C for 0.5 hrs.

To the above stirred reaction mixture, (5)-pyrrolidine-2-carboxylic acid morpholin-4- ylamide (0.68 g, 3.1 mmol) in 5.0 ml N.N-dimethylformarnide was added at 25-30°C and stirred for 2 hrs at 25-30°C. The mixture was washed once with water, dried and concentrated in vacuo. The residue was purified by column chromatography (10% methanol in chloroform). Treatment with a methanolic hydrogen chloride at 0-5°C, concentration under vacuo and trituration with ether provided a white solid. 1H NMR

(500 MHz in D ₂ 0), δ. 2.11-2.17(m, 4H), 2.22-2.37(m, 1H), 2.45-2.5 l(m, 2H), 2.95(s, 3H), 3.02-3.14(m, 5H), 3.21-3.55(m, 2H), 3.67-3.73(m, 1H), 3.88-3.96(m, 4H), 4.34-4.39(m, 1H), 4.58-4.68(m, 1H), 5.25(d, J=5.80Hz, 1H), 5.56(d, J=9.90Hz, 1H), 5.92(d, J=9.86Hz, 1H), 6.93-7.12(m, 2H). Mass(ES+): 511.30.

Compounds 2, 10, 1 1, 15, 20, 21 & 23 were synthesized in a manner analogous to compound 12.

Example 5: Preparation of methyl-(N'-methyl-hydrazinocarbonylmethyl)carbamic acid [(5or,6«)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-6-ol-3 -yl] ester dihydrochloride [Compound No.16] .

4-Nitrophenyl chloroformate (0.50 g, 2.5 mmol) was added to a stirred mixture of morphine (0,6 g, 2.1 mmol) and triethylamine (0.86 ml, 6.3 mmol) in anhydrous methylene chloride (40 ml) at 25-30°C and stirred at 25-30°C for 0.5 hrs.

To the above stirred reaction mixture, 2-methylaminoacetic acid N -methylhydrazide (0.68 g, 3.15 mmol) was added and stirring continued for further 4 hrs. The mixture was washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography (10% methanol in chloroform). Treatment with hydrogen chloride solution in ethyl acetate at 0-5°C, concentration under vacuo and trituration with ether provided a white solid. Ή NMR (500 MHz in D ₂ 0), δ. 2.33(d, J=14.40Hz, 1H), 2.47(dt, J _/ =13.23Hz, J ₂ =4.32Hz, 1H), 3.13(s, 3H), 3.05-3.39(m, 7H), 3.47- 3.60(m, 2H), 4.30-4.52(m, 3H), 5.25(d, J=5.50Hz, 1H), 5.55(d, J=10.10Hz, 1H), 5.90(d, J=9.85Hz, 1H), 6.96-7.13(m, 2H). Mass(ES+): 429.28.

Compound 13 was synthesized in a manner analogous to compound 16.

Example 6; Preparation of methyl-(N,N-dimethylhydrazinocarbonylmethyl)carbamic acid [(5a,6a)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-6-ol-3-y l] ester dihydrochloride [Compound No.17]

4-Nitrophenyl chloroformate (0.34 g, 1.72 mmol) was added to a stirred mixture of morphine (0.41 g, 1.43 mmol) and triethylamine (0.60 ml, 4.3 mmol) in anhydrous methylene chloride (30 ml) at 25-30°C and stirred at 25-30°C for 0.5 hrs. A solution of 2-methylaminoacetic acid-N'N'-dimethylhydrazide (0.22 g, 1.66 mmol) in N,N- dimethylformamide (2 ml) was added stirred for further 2 hrs. The mixture was washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography (10% methanol in chloroform) and treated with hydrochloric acid in ethyl acetate (5.0 ml) at 0-5°C. Concentration under vacuo and trituration of with n-hexane, filteration and drying yielded the title compound as a white solid. Ή NMR (500 MHz in D ₂ 0), δ. 2.37(m, 1H), 2.48(t, J=12.00Hz, 1H), 3.06(s, 3H), 3.12(s, 3H), 3.14(s, 3H), 3.14-3.40(m, 7H), 3.48-3.82(m, 2H), 4.25-4.52(m, 3H), 5.26(d, 1H), 5.57(d, J=9.75Hz, 1H), 5.92(d, J=9.66Hz, 1H), 6.96-7.15(m, 2H). Mass(ES+): 443.26. Compounds 1, 4, 14, 18, 18 & 24 were synthesized in a manner analogous to compound 17.

Example 7: Preparation of [(S)-2-phenyl-l-(piperidin-l-ylcarbamoyl)ethyl]carbamic acid [(5 a,6 or)-7,8-didehydro-4,5-epoxy- 17-methylmorphinan-6-ol-3-yl] ester [Compound No. 9]

4-Nitrophenyl chloroformate (0.34 g, 0.168 mmol) was added to a stirred mixture of morphine (0.4 g, 0.14 mmol) and triethylamine (0.58 ml, 0.42 mmol) in anhydrous methylene chloride (30 ml) and stirred at 25-30°C for 0.5 hrs. (5)-2-Amino-3-phenyl- N-piperidin-l-yl-propionamide trifluoroacetic acid salt (0.73 g, 0.21 mmol) was added at 25-30°C and stirring continued for further 2 hrs. The mixture was washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography (10% methanol in chloroform) to yield the title compound as a white solid. Ή NMR (500 MHz in CDC13), δ. 1.32-1.68(m, 6H), 1.88(d, J=12.30Hz, 1H), 2.06(dt, J _/ =12.39Hz, J ₂ =5.05Hz, 1H), 2.28(dd, J _/ =18.63Hz, J ₂ =5.88Hz, 1H), 2.37- 2.43(m, 2H), 2.43(s, 3H), 2.54-2.70(m, 3H), 2.99-3.13(m, 4H), 3.32(m, 1H), 3.68- 3,70(m, 1H), 4.12(br-s, 1H), 4.24(br-s, 1H), 4.87(d, J=6.95Hz, 1H), 5.23-5.27(m, 2H), 5.71 (s, 1H), 5.72(d, J=9.85Hz, 1H), 6.02(s, 1H), 6.52-6.55(m, 1H), 6.71(d, J=7.25Hz, lH), 7.21 -7.28(m, 5H). Mass(ES+): 559.26.

Compounds 3, 5, 6, 7, 8, 9, 25, 26, 27, 28, 29, 30, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 46, 48, 60, 61, 62 & 64 were synthesized in a manner analogous to compound 9. Example 8: Preparation of (azepan-l-ylcarbamoylmethyl)carbamic acid [(5a,6a)- 17-allyl-4,5-epoxy-14-hydroxy-morphinan-6-one-3-yl] ester dihydrochloride [Compound No.44].

4-Nitrophenyl chloroformate (0.37 g, 1.82 mmol) was added to a stirred mixture of naloxane (0.55 g, 1.52 mmol) and triethylamine (0.64 ml, 4.55 mmol) in anhydrous methylene chloride (30 ml) and the mixture was stirred at 25-30°C for 0.5 hrs. 2- Amino-jV-azepan-l-yl-acetamide (0.39 g, 2.275 mmol) was added and stirring was continued for further 3 hrs. The mixture was washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography (5% methanol in dichloromethane) and treated with a solution of hydrogen chloride in methanol to yield the title compound as a white solid. 1H NMR (500 MHz in D ₂ 0 at 45°C), & 1.84(m, 4H), 1.91(t, J=14.55Hz, 2H), 2.03(m, 4H), 2.18(d, J=14.60Hz, 1H), 2.47(d, J=15.10Hz, 1H), 2.85-2.97(m, 2H), 3.14(dt, Jy=14.87Hz, J ₂ =3.83Hz, 1H), 3.32(dd, J _/ =20.17Hz, J ₂ =5.52Hz, 1H), 3.46(d, J=12.66Hz, 1H), 3.63(d, J=20:40Hz, 1H), 3.70(m, 4H), 4.01-4.04(m, 3H), 4.16(s, 2H), 5.23(s, 1H), 5.77- 5.80(m, 2H), 6.03-6.11(m, 1H), 7.10(d, J=8.20Hz, 1H), 7.22(d, J=8.16Hz, 1H).

Mass(ES+): 525.23

C

Example 9 : Preparation of (azepan-l-ylcarbamoylmethyl)carbamic acid [5a,7a(S)]- 17-cyclopropylmethyl-a-( 1 , 1 -dimethylethyl)-4,5-epoxy- 18,19-dihydro-6-methoxy-a- methyl-6, 14-ethanomorphinan-6-one-7-methanol-3-yl] ester dihydrochloride [Compound No.45].

4-Nitrophenyl chloroformate (0.26 g, 1.28 mmol) was added to a stirred mixture of buprenorphine (0.5 g, 1.06 mmol) and triethylamine (0.40 ml, 3.20 mmol) in anhydrous methylene chloride (25 ml) and stirred at 25-30°C for 0.5 hrs. 2-Amino-N- azepan-l-yl-acetamide (0.223 g, 1.28 mmol) was added at 25-30°C and stirring was continued for further 4.0 hrs. The mixture was washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography (60% ethyl acetate in hexane) and treated with a solution of hydrogen chloride in methanol to yield the title compound as a white solid. 1H NMR (500 MHz in D ₂ 0 at 45°C), δ. 0.52-0.60(m, 2H), 0.85-0.99(m, 3H), 1.12(s, 9H), 1.20-1.23(m, 2H), 1.53(s, 3H), 1.56-1.62(m, 1H), 1.83(m, 4H), 1.90-1.94(m, 1H), 2.02-2.07(m, 4H), 2.21-2.24(d, J=13.21Hz, 1H), 2.40-2.50(m, 2H), 2.73(t, J=9.87Hz, 1H), 2.97-3.12(m, 1H), 3.12- 3.24(m, 3H), 3.35-3.48(m, 4H), 3.62(s, 3H), 3.67(m, 3H), 4.10(s, 2H), 4.24(d, J=6.60Hz, 1H), 4.89(s, 1H), 7.02(d, J=8.20Hz, 1H), 7.21(d, J=7.95Hz, 1H). Mass(ES+): 665.41. Example 10; Preparation of (azepan-l-ylcarbamoylmethyl)carbaniic acid [(5o)-17- (cyclopropylmethyl)-4,5-epoxy- 14-hydroxy-morphinan-6-one-3 -yl] ester dihydrochloride [Compound No.47].

4-Nitrophenyl chloroformate (0.32 g, 1.59 mmol) was added to a stirred mixture of naltrexone (0.5 g, 1.32 mmol) and triethylamine (0.56 ml, 3.96 mmol) in anhydrous methylene chloride (30 ml) and stirred at 25-30°C for 0.5 hrs. 2- Amino-N-azepan- 1 - yl-acetamide (0.275 g, 1.58 mmol) was added at 25-30°C and stirring was continued for further 3 hrs. The mixture was washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography (15% methanol in dichloromethane) and treated with a solution of hydrogen chloride in methanol to yield the title compound as a white solid. 1H NMR (500 MHz in D ₂ 0 at 45°C), & 0.60(m, 2H), 0.88-0.96(m, 2H), 1.24(m, 1H), 1.84(m, 4H), 1.90-1.95(m, 2H), 2.04(m, 4H), 2.16 (d, J=13.0Hz, 1H), 2.23(d, J=14.61Hz, 1H), 2.90(m, 2H), 3.16-3.20(m, 2H), 3.39-3.51(m, 4H), 3.61(d, J=20.21Hz, 1H), 3.72(m, 4H), 4.17(s, 2H), 4.32(d, J=5.60Hz, 1H), 5.23(s, 1H), 7.10(d, J=8.15Hz, 1H), 7.22(d, J=8.0Hz, 1H). Mass(ES+): 539.26 Example 11: Preparation of (piperidin-l-ylcarbamoylmethyl)carbamic acid [(5 «-17- methyl-4 ; 5 -epoxy- 14-hydroxy-morphinan-6-one-3 -yl] ester dihydrochloride [Compound No.50].

4-Nitrophenyl chloro formate (0.44 g, 2.1 mmol) was added to a stirred mixture of oxymorphone (0.55 g, 1.8 mmol) and triethylamine (0.76 ml, 5.4 mmol) in anhydrous methylene chloride (30 ml) and stirred at 25-30°C for 0.5 hrs. 2-Amino-N-piperidin- 1 -yl-acetamide (0.43 g, 2.7 mmol) was added at 25-30°C and stirring was continued further for 1.5 hrs, .The mixture was washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography (10% methanol in dichloromethane) and treated with a solution of hydrogen chloride in methanol to yield the title compound as a white solid. 1H NMR (500MHz in D ₂ 0 at 45°C), δ. 1.74(m, 2H), 1.87-1.92(m, 2H), 2.02(m, 4H), 2.21(d, J=12.45Hz, 1H), 2.47(d, J=15.05Hz, 1H), 2.86-2.96(m, 2H), 3.09(s, 3H), 3.04-3.17(m, 1H), 3.34-3.46(m, 3H), 3.54(m, 4H), 3.65(d, J=20.30Hz, 1H), 3.92(d, J=5.71Hz, 1H), 4.15(s, 4H), 5.22(s, lH), 7.10(d, J=8.20Hz, 1H), 7.21(d, J=8.25Hz, 1H). Mass(ES+): 485.23.

Compounds 53, 55, 56, 57 & 63 were synthesized in a manner analogous to compound 50.

Example 12: Preparation of (azepan-l-ylcarbamoylmethyl)methylcarbamic acid [7- ethylcamptothecin- 10-yl] ester dihydrochloride [Compound No .51 ] .

Triphosgene (0.38 g, 1.27 mmol) was added to a stirred mixture of N-azepan-l-yl-2- (methylamino)acetamide (0.71 g, 3.82 mmol) and diisopropylethylamine (1.18 ml, 6.37 mmol) in anhydrous methylene chloride (50 ml) at 25-30°C. The reaction mixture was stirred at 25-30°C for 3.0 hrs. 7-ethyl-lO^hydroxycamptothecin (0.5 g, 1.27 mmol) was added and stirring was continued for further 18 hrs. The mixture was washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography (5% methanol in dichloromethane) and treated with a solution of hydrogen chloride in methanol to yield the title compound as a yellowish solid. 1H NMR (500MHz in D ₂ 0 at 45°C), δ. 1.10(m, 3H), 1.34(m, 3H), 1.88(m, 4H), 2.04(m, 2H), 2.08(m, 4H), 3.01-3.04(m, 2H), 3.22-3.37(two-s, 3H), 3.79-3.81(m, 4H), 4.35-4.55(two-s, 2H), 4.73-4.85(m, 2H), 5.41-5.60(m, 2H), 7.29-7.47(m, 2H), 7.73-7.82(m, 2H). Mass(ES+): 604.23.

Compounds 58 & 59 were synthesized in a manner analogous to compound 51. Example 13: Preparation of (azepan-l-ylcarbamoylmethyl)carbamic acid 2,6- diisopropylphenylester hydrochloride [Compound No.52].

Triphosgene (0.584 g, 1.96 mmol) was added to a stirred mixture of propofol (1.0 g, 5.6 mmol) and diisopropylethylamine (3.1 ml, 16.8 mmol) in anhydrous methylene chloride (50 ml) at 25-30°C and stirred for 4 hrs. 2-Amino-N-azepan-l-yl-acetamide hydrochloride (1.73 g, 8.4 mmol) was added and stirring was continued for further 3 hrs. The mixture was washed with water, dried, and concentrated in vacuo. The residue was purified by column chromatography (3% methanol in dichloromethane) and treated with a solution of hydrogen chloride in methanol to yield the title compound as a white solid. 1H NMR (500MHz in D ₂ 0 at 45°C), δ. 1.31(d, J=6.65, 12H), 1.85(m, 4H), 2.02-2.07(m, 4H), 3.12-3.16(m, 2H), 3.48-3.77(m, 4H), 4.15(s, 2H), 7.41-7.46(m, 2H). Mass(ES+): 376.23.

Example 14; Preparation of (azepan-l-ylcarbamoylmethyl)carbamic acid [estra- l,3,5(10)-trien-17-one-3-yl] ester [Compound No. 54].

4-Nitrophenyl chloroformate (0.440 g, 2.2 mmol) was added to a stirred mixture of estrone (0.5 g, 1.84 mmol) and triethylamine (1 ml, 7.4 mmol) in anhydrous methylene chloride (50 ml) at 25-30°C and stirred for 0.5 hrs. 2-Amino-7V-azepan-l- yl-acetamide hydrochloride (0.89 g, 3.68 mmol) was added and stirring was continued for further 3 hrs. The mixture was washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography (5% methanol in dichloromethane) to yield the title compound as a white solid. Ή NMR (500MHz in CDC1 ₃ at 45°C), δ. 0.90(s, 3H), 1.40-1.69(m, 9H), 1.69(m, 5H), 1.94-

2.16(m, 4H), 2.27(dt, J _; =10.66Hz, J =3.50Hz, IH), 2.37-2.41(m, 1H), 2.49(dd, IH), 2.82-2.94(m, 3H), 3.03-3.05(m, 2H), 4.24(d, J=4.40Hz, 2H), 5.81(s, IH), 6.68(s, IH), 6.87(s, IH), 6.90(d, J=8.50Hz, IH), 7.23(s, IH). Mass: 468.28. The following are the ¹ H-NMR (δ ppm) and mass (ES+, m/z) of the compounds of the present invention, prepared by using analogous method disclosed above.

Mass : 497.26

1.43(d, J=6.85Hz, IH), 1.67(m, 6H), 1.92(d, J=10.89Hz, IH), 2.07(dt, J _/ =l 1.61Hz, J ₂ =6.69Hz, IH), 2.27-2.33(m, 2H), 2.35-2.45(m, IH), 2.61- 2.70(m, 3H), 3.01-3.06(m, 3H), 3.36(q, IH), 3.99(br-s, IH), 4.16-4.20(m, IH), 4.85-4.89(m, IH), 4.93(d, J=6.59Hz, IH), 5.25(d, J=9.65Hz, IH), 5.76(d, J=9.96Hz, IH), 6.06(d, J=7.75Hz, IH), 6.16(s, lH)„6.59-6.60(m, IH), 6.75(d, J=8.10Hz, IH). Mass: 483.39

1.42-1.71(m, 6H), 1.91(d, J=l l . l lHz, IH), 2.06(dt, J,=12.42Hz, J ₂ =5.0Hz, IH), 2.29(dd, J _/ =18.78Hz, J ₂ =6.12Hz, IH), 2.39(dt, J _/ =12.29Hz,

J ₂ =3.53Hz, IH), 2.43(s, 3H), 2.59(m, 2H), 2.69-3.05(m, 5H), 3.33(q,

J=3.25Hz, IH), 3.84(m, IH), 4.19-4.25(m, 3H), 4.90(d, J=6.90Hz, IH), 5.24(d, J=9.90Hz, IH), 5.75(d, J=9.80Hz, IH), 5.92(s, IH), 6.24(s, IH), 6.57(d, J=8.10Hz, IH), 6.75(d, J=8.15Hz, IH). Mass: 469.36

0.96-1.02(m, 6H), 1.41-1.68(m, 6H), 1.88(dd, J=12.20Hz, IH), 2.06(dt, J _/ =12.39 Hz, J ₂ =4.83 Hz, IH), 2.28(dd, J ₇ =18.76Hz, J ₂ =6.10 Hz, IH), 2.39-2.43(m, IH), 2.43(s, 3H), 2.58(dd, J,=12.10Hz J ₂ =4.35Hz, IH), 2.70(s, IH), 2.77(br-s, 2H), 3.02(d, J=10.97Hz, IH), 3.32(q, J=3.17Hz, IH), 4.12(br-s, IH), 4.87(d, J=7.0Hz, IH), 5.22(d, J= 10.01 Hz, IH), 5.73(d, J=8.30Hz, IH), 6.09(s, IH), 6.54(d, J=8.15Hz, IH), 6.72(d, J=8.15Hz, IH). Mass: 511.59

0.99(d, J=6.75Hz, 3H), 1.08(d, J=6.41Hz, 3H), 1.25-1.90(m, 9H), 1.92(d, J=12.31Hz, IH), 2.07(dt, J;=12.31Hz, J ₂ =4.67Hz, IH), 2.26-2.31(m, 2H), 2.35-2.4 l(m, IH), 2.44(s, 3H), 2.60-2.63(m, IH), 2.70-2.76(m, 2H), 3.01- 3.06(m, 2H), 3.1 l(m, IH), 3.35-3.36(m, IH), 3.82-3.85(m, IH), 4.15(br-s, IH), 4.88-4.93(m, IH), 5.04(dt, J _/ =9.69Hz, J ₂ =3.43Hz, IH), 5.24(td,

J;=10.15Hz, J2=2.38Hz, IH), 5.73-5.79(m, IH), 6.18(s, IH), 6.56(d, J=8.05Hz, IH), 6.74(d, J=8.10Hz, IH). Mass: 525.63

1.32-1.68(m, 6H), 1.88(d, J=12.30Hz, IH), 2.06(dt, J ₇ =12.39Hz,

J2=5.05Hz, IH), 2.28(dd, J;=l 8.63Hz, J ₂ =5.88Hz, IH), 2.37-2.43(m, 2Η), 2.43(s, 3H), 2.54-2.70(m, 3H), 2.99-3.13(m, 4H), 3.32(m, IH), 3.68- 3.70(m, IH), 4.12(br-s, IH), 4.24(br-s, IH), 4.87(d, J=6.95Hz, IH), 5.23- 5.27(m, 2H), 5.71(s, IH), 5.72(d, J=9.85Hz, IH), 6.02(s, IH), 6.52- 6.55(m, IH), 6.71(d, J=7.25Hz, IH), 7.21-7.28(m, 5H). Mass: 559.26

2.08-2.19 (m, 4H), 2.34(s, 2H), 2.44-2.54(m, 2H), 3.04(d, 3H), 3.09- 3.14(m, 6H), 3.16-3.29(m, 2H), 3.31-3.58(m, 6H), 3.60-3.72(m, 3H), 3.83- 3.87(m, IH), 4.36-4.37(m, IH), 4.51(m, IH), 5.23(d, J=5.76Hz, IH), 5.54(td, J;=9.90Hz, J2=2.39Hz, IH), 5.89(d, J=10.01Hz, IH), 6.92-6.99(m, IH), 7.10(d, J=8.25Hz, IH). Mass: 524.33

1.05(s, 3H), 1.88-2.09 (m, 5H), 2.29(dd, J _/ =18.82Hz, J2=6.20Hz, 2H), 2.39(dt, J _/ =12.26Hz, J ₂ =3.45Hz, IH), 2.43(s, 3H), 2.58(dd, J _/ =12.12Hz, J2=4.27Hz, IH), 2.68(s, IH), 3.03(d, J=18.79Hz, IH), 3.33(q, J=3.26Hz, IH), 3.61-3.63(m, 3H), 4.14(m, IH), 4.41-4.55(m, 2H), 4.88(d, J=6.70Hz, IH), 5.24(d, J=9.94Hz, IH), 5.71(d, J=9.79Hz, IH), 6.57(d, J=8.16Hz, IH), 6.76(m, IH), 7.57-7.78(m, IH). Mass: 497.19

2.11-2.17(m, 4H), 2.22-2.37(m, IH), 2.45-2.51(m, 2H), 2.95(s, 3H), 3.02- 3.14(m, 5H), 3.21-3.55(m, 2H), 3.67-3.73(m, IH), 3.88-3.96(m, 4H), 4.34- 4.39(m, IH), 4.58-4.68(m, IH), 5.25(d, J=5.80Hz, IH), 5.56(d, J=9.90Hz, IH), 5.92(d, J=9.86Hz, IH), 6.93-7.12(m, 2H). Mass: 511.30

2.10-2.22(m, 4H), 2.22-2.33(m, IH), 2.41-2.67(m, 2H), 3.01-3.05(d, 3H), 3.07-3.10(m, 4H), 3.20-3.36(m, 2H), 3.44-3.56(m, 3H), 3.68-3.70(m, IH), 3.84-3.87(m, IH), 4.35(m, IH), 4.50(m, IH), 5.22(d, J=13.62Hz, IH), 5.53(d, J=9.46Hz, IH), 5.87(d, J=9.45Hz, IH), 6.91-7.09(m, 2H). Mass: 6.94-7.13(m, 2H). Mass: 497.61

1.79-2.04(m, 8H), 2.12-2.34(m, 4H), 2.45-2.57(m, 2H), 3.08-3.12(m, IH), 3.12(s, IH), 3.20-3.38(m, 2H), 3.47-3.73(m, 7H), 3.86-3.89(m, IH), 4.37(br-s, IH), 4.52(m, IH), 5.23(d, J=4.55Hz, IH), 5.55(d, J=10.00Hz, IH), 5.89(d, J=9.70Hz, IH), 6.91-7.1 l(m, 2H). Mass: 523.35

1.86-1.99(m, 4H), 2.07-2.09(m, IH), 2.18-2.31(m, 2H), 2.87(s, 3H), 2.83- 3.15(m, 3H), 3.21-3.28(m, 2H), 3.43-3.48(m, IH), 3.61-3.63(m, IH), 4.13(q, J=2.87Hz, IH), 4.25-4.32(m, IH), 4.98-5.00(m, IH), 5.29(td,

J7=6.23Hz, J ₂ =3.37Hz, IH), 5.63(d, J _/ =10.05Hz, J ₂ =1.15Hz, IH), 6.67- 6.85(m, 2H). Mass: 441.30

2.00(d, J=13.96Hz, IH), 2.09-2.21(m, IH), 2.77(m, 3H), 2.77-3.03(m, 6H), 3.05-3.19(m, 2H), 3.93-4.12(m, 3H), 4.25(d, J=2.72Hz, IH), 4.96- 4.98(m, IH), 5.29(td, J _/ =6.20Hz, J ₂ =3.39Hz, IH), 5.61(d, J=9.81Hz, IH), 6.65-6.84(m, 2H). Mass: 415.30

1.09-1.1 l(m, 6H), 1.80-2.00(m, 3H), 2.07(dt, J _/ =12.39Hz, J ₂ =5.03Hz, 2H), 2.29(dd, J,=18.77Hz, J ₂ =6.16Hz, IH), 2.39(dt, J _; =13.08Hz, J ₂ =4.64Hz, IH), 2.43(s, 3H), 2.59(dd, J _/ =11.85Hz, J ₂ =4.30Hz, IH), 2.70(s, IH), 3.02(d, J=l 8.78Hz, IH), 3.33(q, J=3.30Hz, IH), 3.60-3.62(m, IH), 3.70(m, lH), 4.05(m, IH), 4.14(m, IH), 4.31-4.46(m, IH), 4.89(d,

J=7.03Hz, IH), 5.25(d, J= 10.02Hz, IH), 5.73(d, J=9.95Hz, IH), 6.04- 6.20(m, IH), 6.58(d, J=8.19Hz, IH), 6.74(br-s, IH). Mass: 468.47

2.07(dd, J _/ =14.53Hz, J ₂ =3.07Hz, IH), 2.22(dt, J _; =13.77Hz, J ₂ =4.78Hz, IH), 2.33-2.44(m, 2H), 2.69(t, J=4.55Hz, 2H), 2.75(t, J=4.50Hz, 2H), 2.85(s, 3H), 2.87(s, 3H), 2.90-3.05(m, 3H), 3.21-3.52(m, 3H), 3.65-3.71(m, 5H), 4.13(q, J=3.07Hz, IH), 4.26-4.28(m, IH), 4.97-5.00(m, IH), 5.29- 5.32(m, IH), 5.64-5.71(m, IH), 6.80-6.85(m, 2H). Mass: 499.38

J=9.68Hz, IH), 7.02(d, J=8.32Hz, IH), 7.16(d, J=7.87Hz, IH). Mass: 497.23

1.08(m, 6H), 1.31-1.49(m, IH), 1.82-2.07(m, 7H), 2.38-2.50(m, 5H), 3.15- 3.20(m, 2H), 3.20(s, 3H), 3.26-3.45(m, 5H), 3.52-3.70(m, 5H), 4.43(br-s, IH), 5.30(d, J=5.76Hz, IH), 5.62(d, J=9.80Hz, IH), 5.97(d, J=9.50Hz, IH), 7.02(d, J=8.02Hz, IH), 7.15(d, J=8.04Hz, IH). Mass: 553.15 l .l l(d, J=6.11Hz, 3H), 1.14(d, J=6.23Hz, 3H), 1.77-1.91(m, 3H), 2..37(d, J=l 1.91Hz, IH), 2.52(dt, J;=l 3.70Hz, J ₂ =4.85Hz, IH), 3.13-3.20(m, 2H), 3.17(s, 3H), 3.22(s, 6H), 3.26-3.85(m, 4H), 4.38-4.66(m, 2H), 5.28(d,

J=6.29Hz, IH), 5.59(d, J=10.09Hz, IH), 5.94(d, J=9.91Hz, IH), 7.00(d, J=8.45Hz, IH), 7.14(d, J=8.18Hz, IH). Mass: 485.22

1.82(m, 2H), 2.06-2.09(m, 6H), 2.39(dd, J _/ =14.00Hz, J ₂ =2.91Hz, IH), 2.51- 2.57(m, IH), 2.59(t, J=7.07Hz, 2H), 3.14-3.21(m, IH), 3.19(s, 3H), 3.25- 3.39(m, 2H), 3.43(m, 2H), 3.52-3.53(m, IH), 3.57-3.59(m, 2H), 4.42- 4.43(m, IH), 5.30(d, J=6.25Hz, IH), 5.61(d, J=9.80Hz, IH), 5.96(d,

J=9.90Hz, IH), 7.01(d, J=8.40Hz, IH), 7.15(d, J=8.28Hz, IH). Mass:

497.20

1.08(d, J=6.02Hz, 6H), 1.32-1.37(m, IH), 1.50-1.55(m, IH), 1.51(s, 9H), 1.83-1.87(m, IH), 2.37-2.40(m, 2H), 2.55-2.65(m, 3H), 3.14-3.25(m, 2H), 3.18(s, 3H), 3.28-3.61(m, 6H), 4.64(br-s, IH), 5.29(d, J=5.66Hz, IH), 5.60(d, J-9.22Hz, IH), 5.96(d, J=9.42Hz, IH), 7.01(d, J=7.76Hz, IH), 7.13(d, J=8.14Hz, IH). Mass: 541.29

1.45(s, 9H), 2.01-2.00(m, 2H), 2.31(d, J=14.26Hz, IH), 2.461(dt, 2H), 3.08-3. l l(m, IH), 3.1 l(s, 3H), 3.18-3.32(m, 2H), 3.37(m, 2H), 3.45-3.55(m, 2H), 4.35- 4.36(m, IH), 4.49(br-s, IH), 5.22(d, J=6.11Hz, IH), 5.54(d, J=9.86Hz, IH), 5.88(d, J=9.90Hz, IH), 6.93(d, J=8.65Hz, IH), 7.07(d, J=8.16Hz, 1Ή). Mass: 485.22

1.44(s, 9H), 1.62(d, J=7.31Hz, 3H), 2.28-2.34(m, IH), 2.46(dt, J =13.76Hz, J2=4.33Hz, IH), 3.08-3.13(m, IH), 3.12(s, 3H), 3.18-3.37(m, 3H), 3.46- 3.55(m, 2H), 4.33-4.35(br-s, IH), 4.50(br-s, IH), 5.20(d, J=5.40Hz, IH), 5.54(d, J=9.96Hz, IH), 5.88(d, J=9.60Hz, IH), 6.94(d, J=8.50Hz, IH), 7.09(d, J=8.25Hz, IH). Mass: 471.17

2.25(br-s, 4H), 2.32(d, J=14.2Hz, IH), 2.46(dt, J,=13.73Hz, J ₂ =4.29Hz, IH), 3.06-3.15(m, 2H), 3.1 l(s, 3H), 3.18-3.37(m, 3H), 3.40-3.58(m, 3H), 3.72(br-s, 4H), 4.13(s, 2H), 4.35-4.36(m, IH), 4.49-4.50(m, IH), 5.23(d, J=6.21Hz, IH), 5.53(d, J=10.01Hz, IH), 5.88(d, J=9.90Hz, IH), 6.94(d, J=8.50Hz, IH), 7.10(d, J=8.25Hz, IH). Mass: 455.15

1.27-1.30(m, 9H), 2.26-2.31(m, IH), 2.44(t, J=13.78Hz, IH), 3.06-3.10(m, IH), 3.10(s, 3H), 3.19(t, J=13.32Hz, IH), 3.26-3.36(m, 4H), 3.44-3.52(m, 2H), 4.34(m, IH), 4.48(br-s, IH), 5.20(d, J=6.25Hz, IH), 5.52 (d,

J-9.86Hz, IH), 5.87(d, J=9.50Hz, IH), 6.91(d, J=8.26Hz, IH), 6.98- 7.02(m, IH), 7.45-7.55(m, 5H). Mass: 547.24

1.75(m, 4H), 1.86(m, 4H), 2.31(d, J=14.11Hz, IH), 2.46(t, J=l 3.15Hz, IH), 3.07-3.1 l(m, IH), 3.1 l(s, 3H), 3.15-3.53(m, 10H), 4.35(br-s, IH), 4.49(br-s, IH), 5.23(d, J=6.21Hz, IH), 5.53(d, J=9.86Hz, IH), 5.87(d, J=8.85Hz, IH), 6.93(d, J=8.15Hz, IH), 7.02-7.05(m, IH), 7.44-7.55(m, 5H). Mass: 573.18

1.02-1.07(m, 3H), 1.09-1.13(m, 3H), 1.32-1.44(m, IH), 1.60-1.68(m, IH), 1.81-2.1 l(m, 8H), 2.32(dd, J ₇ =15.91Hz, J ₂ =4.30Hz, IH), 2.47(dt,

J/=l 3.72Hz, J ₂ =4.63Hz, IH), 3.08-3.14(m, IH), 3.12(s, 3H), 3.19-3.42(m, 2H), 3.46-3.57(m, 4H 3.65-3.73(m, 4H), 4.35(br-s, IH), 4.67(br-s, IH), 5.21(d, J=6.20Hz, IH), 5.55(d, J=9.90Hz, IH), 5.89(d, J=9.85Hz, IH), 6.95(d, J=8.45Hz, IH), 7.08(d, J=8.25Hz, IH). Mass: 539.31

1.84(m, 4H), 1.91(t, J=14.55Hz, 2H), 2.03(m, 4H), 2.18(d, J=14.60Hz, IH), 2.47(d, J=15.10Hz, IH), 2.85-2.97(m, 2H), 3.14(dt, Jl=14.87Hz,

J2=3.83Hz, IH), 3.32(dd, Jl=20.17Hz, J2=5.52Hz, IH), 3.46(d, J=12.66Hz, IH), 3.63(d, J=20.40Hz, IH), 3.70(m, 4H), 4.01-4.04(m, 3H), 4.16(s, 2H), 5.23(s, IH), 5.77-5.80(m, 2H), 6.03-6.1 l(m, IH), 7.10(d, J=8.20Hz, IH), 7.22(d, J=8.16Hz, IH). Mass: 525.23

0.52-0.60(m, 2H), 0.85-0.99(m, 3H), 1.12(s, 9H), 1.20-1.23(m, 2H), 1.53(s, 3H), 1.56-1.62(m, IH), 1.83(m, 4H), 1.90-1.94(m, IH), 2.02-2.07(m, 4H), 2.21-2.24(d, JH3.21Hz, IH), 2.40-2.50(m, 2H), 2.73(t, J=9.87Hz, IH), ^r 2.97-3.12(m, IH), 3.12-3.24(m, 3H), 3.35-3.48(m, 4H), 3.62(s, 3H), 3.67(m, 3H), 4.10(s, 2H), 4.24(d, J=6.60Hz, IH), 4.89(s, IH), 7.02(d, J=8.20Hz, IH), 7.21(d, J=7.95Hz, IH). Mass: 665.41

0.98-1.00(m, 6H), 1.22-1.40(m, 2H), 1.73-1.76(m, IH), 1.82(m, 4H), 2.01(m, 4H), 2.22-2.32(s, 2H), 2.43-2.45(m, 3H), 3.03-3.07(m, IH), 3.1 l(s, 3H), 3.19-3.37(m, 5H), 3.45-3.53(m, 2H), 3.69(m 4H), 4.35(br-s, IH), 4.49(br-s, IH), 5.22(d, J=5.85Hz, IH), 5.54(d, J=9.36Hz, IH), 5.88(d,

J=9.20Hz, IH), 6.94(d, J=8.30Hz, IH), 7.15(d, J=8.15Hz, IH). Mass:

665.41

0.60(m, 2H), 0.88-0.96(m, 2H), 1.24(m, IH), 1.84(m, 4H), 1.90-1.95(m, 2H), 2.04(m, 4H), 2.16 (d, J=13.0Hz, IH), 2.23(d, J=14.61Hz, IH), 2.90(m, 2H), 3.16-3.20(m, 2H), 3.39-3.51(m, 4H), 3.61(d, J=20.21Hz, IH), 3.72(m, 4H), 4.17(s, 2H), 4.32(d, J=5.60Hz, IH), 5.23(s, IH), 7.10(d, J=8.15Hz, IH), 7.22(d, J=8.0Hz, IH). Mass: 539.26

1.83(m, 4H), 2.02(m, 6H), 2.32(d, J=14.15Hz, IH), 2.442.53(m, 2H), 3.08- 3.12(m, IH), 3.12(s, 3H), 3.20-3.333.36-3.59(m, 4H), 3.65-3.71(m, 4H), 4.36(br-s, IH), 4.50 (br-s, IH), 5.23(d, J=4.95Hz, IH), 5.55(d, J=9.75Hz, IH), 5.89(d, J=9.55Hz, IH), 6.95(d, J=8.15Hz, IH), 7.08(d, J=7.76Hz, IH). Mass: 51 1.24

1.85-2.03(m, 8H), 2.27-2.31(m, IH), 2.31(s, 3H), 2.45-2.50(m, IH), 3.15(s, 3H), 3.12-3.57(m, 5H), 3.63-3.65(m, 4H), 4.13(s, 2H), 4.40(s, IH), 5.44(s, 2H), 5.76(d, J=9.86Hz, IH), 5.91(d, J=9.76Hz, IH), 7.02(d, J=8.45Hz, IH), 7.16(d, J=8.20Hz, IH). Mass: 525.18.

1.74(m, 2H), 1.87-1.92(m, 2H), 2.p2(m, 4H), 2.21(d, J=12.45Hz, IH), 2.47(d, J=l 5.05Hz, IH), 2.86-2.96(m, 2H), 3.09(s, 3H), 3.04-3.17(m, IH), 3.34-3.46(m, 3H), 3.54(m, 4H), 3.65(d, J=20.30Hz, IH), 3.92(d, J=5.71Hz, IH), 4.15(s, 4H), 5.22(s, IH), 7.10(d, J=8.20Hz, IH), 7.21(d, J=8.25Hz, IH). Mass: 485.23.

1.10(m, 3H), 1.34(m, 3H), 1.88(m, 4H), 2.04(m, 2H), 2.08(m, 4H), 3.01- 3.04(m, 2H), 3.22-3.37(two-s, 3H), 3.79-3.81(m, 4H), 4.35-4.55(two-s, 2H), 4.73-4.85(m, 2H), 5.41-5.60(m, 2H), 7.29-7.47(m, 2H), 7.73-7.82(m, 2H). Mass : 604.23

1.31(d, J=6.65, 12H), 1.85(m, 4H), 2.02-2.07(m, 4H), 3.12-3.16(m, 2H), 3.48-3.77(m, 4H), 4.15(s, 2H), 7.41-7.46(m, 2H). Mass: 376.23

1.36-1.39(m, 2H), 1.44(s, 9H), 1.64(d, J=7.20Hz, IH), 1.87-1.94(m, 2H), 2.21-2.35(m, IH), 2.49(d, J=l 5.12Hz, IH), 2.84-2.94(m, 2H), 3.10(s, 3H), 3.08-3.18(m, IH), 3.35-3.47(m, 2H), 3.65(d, J=20.30Hz, IH), 3.93(d, J=5.70Hz, IH), 5.21(s, IH), 7.10(d, J=8.25Hz, IH), 7.20(d, J=8.10Hz, IH). Mass: 487.25

0.90(s, 3H), 1.40-1.69(m, 9H), 1.69(m, 5H), 1.94-2.16(m, 4H), 2.27(dt, J _/ = 10.66Hz, J ₂ =3.50Hz, IH), 2.37-2.41(m, IH), 2.49(dd, J _/ =18.95Hz, Jr=8.70Hz, IH), 2.82-2.94(m, 3H), 3.03-3.05(m, 2H), 4.24(d, J=4.40Hz, 2H), 5.81(s, IH), 6.68(s, IH), 6.87(s, IH), 6.90(d, J=8.50Hz, IH), 7.23(s, IH). Mass: 468.28

1.83(m, 4H), 1.91 1.93(m, 2H), 2.0 l(m, 4H), 2.21 (d, J=l 4.06Hz, IH),

2.47(d, J=l 5.15Hz, IH), 2.85-2.97(m, 2H), 3.09(s, 3H), 3.05-3.18(m, IH), 3.35-3.47(m, 2H), 3.56-3.77(m, 5H), 3.93(d, J=5.80Hz, IH), 4.14(s, 2H), 5.23(s, IH), 7.1 1(d, J=8.30Hz, IH), 7.22(d, J=8.41Hz, IH). Mass: 499.29

1.61(s, 3H), 1.71(m, 2H), 1.92-1.97(m, 4H), 2.23(d, J=14.46Hz, IH), 2.33- 2.36(m, IH), 2.51(d, J=15.40Hz, IH), 2.86-2.96(m, 2H), 3.12(s, 3H), 3.07- 3.20(m, IH), 3.37-3.50(m, 6H), 3.68(d, J=20.26Hz, IH), 3.95(s, IH), 5.24 (s, IH), 7.11-7.1 l(m, 2H). Mass: 499.12

1.62(m, 4H), 1.87(m, 6H), 2.20(d, J=14.15Hz, IH), 2.47(d, J=l 5.00Hz, IH), 2.83-2.94(m, 3H), 3.04-3.08(m, IH), 3.08(s, 3H), 3.14(m, 4H), 3.23- 3.46(m, 4H), 3.65(d, J=20.40Hz, IH), 3.92(d, J=3.81Hz, IH), 5.21(s, IH), 7.02-7.1 l(m, 2H), 7.47-7.49(m, 3H), 7.52-7.54(m, 2H). Mass: 575.21

1.10(br-s, 3H), 1.39(t, J=7.47, 3H), 1.75(br-s, 2H), 2.03(m, 4H), 2.09(br-s, 2H), 3.13(br-s, 2H), 3.22-3.38(two-s, 3H), 3.48-3.53(m, 4H), 4.32-4.50(two- s, 2H), 5.02(s, 2H), 5.47-5.65(two-m, 2H), 7.42(s, IH), 7.56(d, J=8.30, IH), 7.85(d, J=12.56, IH), 7.93(t, J=8.83, IH). ). Mass: 590.02

1.12(br-s, 3H), 1.37(br-s, 3H), 1.53(s, 9H), 2.10(br-s, 2H), 3.07(br-s, 2H), 3.27-3.42(two-s, 3H), 4.28-4.42(two-s, 2H), 4.92-4.95(m, 2H), 5.48- 5.64(two-m, 2H), 7.37(s, IH), 7.48-7.51(m, IH), 7.79-7.84(m, 2H). Mass: 578.16

1.47(s, 9H), 1.63(d, J=7.10Hz, 3H), 2.32-2.34(m, IH), 2.46(t, J=5.62Hz, IH), 3.13(s, 3H), 3.09-3.54(m, 6H), 4.36-4.37(m, IH), 4.51(br-s, IH), 5.24(d, J=5.7Hz, IH), 5.55(d, J=9.90Hz, IH), 5.89(d, J=9.60Hz, IH), 6.95 (d, J=9.45Hz, IH), 7.10(d, J=7.10Hz, IH). 61 1.38(s, 6H), 1.74(m, 2H), 2.03(m, 4H), 2.32(d, J=13.65Hz, 1H), 2.48(t, J=l 1.47Hz, 1H), 3.13(s, 3H), 3.13-3.39(m, 3H), 3.48-3.53(m, 7H), 4.37(s, 1H), 4.51(s, 1H), 5.23(d, J=4.85Hz, 1H), 5.56(d, J=9.1Hz, 1H), 5.90 (d, J=8.6Hz, 1H), 6.96(d, J=8.05Hz, 1H), 7.07(d, J=7.86Hz, 1H). Mass: 511.29

62 1.27(s, 6H), 1.49(m, 2H), 1.76(m, 4H), 2.04(d, J=13.2Hz, 1H), 2.19(t, J=11.3Hz, 1H), 2.52-2.58(m, 2H), 2.84 (s, 3H), 2.69-2.99(m, 4H), 3.18- 3:32(m, 5H), 4.09(br-s, lH), 4.23(br-s, 1H), 4.96(d, J=5.7Hz, 1H), 5.27(d, J=9.50Hz, lH), 5.60(d, J=8.95Hz, 1H), 6.66(d, J=8.05Hz, 1H), 6.77(d, J=7.76Hz, 1 H). Mass: 511.22

63 1.13(br-s, 6H), 1.64(m, 2H), 1.89(m, 6H), 2.20-2.22(m, 2H), 2.47(d,

J=15.0Hz, 1H), 2.85-2.93(m, 2H), 3.08 (s, 3H), 3.04-3.21(m, 5H), 3.34- 3.67(m, 3H), 3.91(br-s, 1H), 4.02(br-s, 1H), 5.20(s, 1H), 7.09(m, 1H), 7.17 (m, 1H). Mass: 527.32

64 1.16(s, 9H), 1.57-1.63(m, 2H), 1.81-1.89(m, 4H), 2.29-2.49(m, 2H), 2.99- 3.11(m, 4H), 3.23(s, 3H), 3.23-3.36 (m, 2H), 3.42-3.66(m, 3H), 3.99(s, 1H), 4.34(br-s, 1H), 4.47(br-s, 1H), 5.19(br-s, 1H), 5.53(d, J=8.96Hz, 1H), 5.86(br-s, 1H), 6.93(d, J=8.65Hz, 1H), 7.06(br-s, 1H). Mass: 525.44

In-vitro stability study in simulated gastric/ intestinal fluids:

The conversion of the test prodrug of the present invention to the parent phenolic drug was determined in phosphate buffer (pH7.2), NaHC0 ₃ buffer (pH 10), Milli-Q water (pH 5.3), simulated gastric fluid (pH 1.1) and simulated intestinal fluids (pH 6.8) samples. The test compound of 100μg per ml concentration was added to phosphate buffer, NaHC0 ₃ buffer, Milli-Q water, simulated gastric fluid and simulated intestinal fluids at ambient temperature and was kept in an incubator maintained at 37°C. Aliquots of this sample were taken at definite time intervals and subjected to HPLC analysis. The samples were analyzed for amount of unconverted test compound and the amount of phenolic drug formed in the test solution using HPLC.

- Inestimable (>24hrs)

In-vitro stability study in human, rat and dog plasma: The conversion of the test prodrugs of the present invention to the parent phenolic drug was determined in the human, rat and dog plasma sample. The test compound of 2000 ng per ml concentration was added to human, rat and dog plasma at ambient temperature and was kept in an incubator maintained at 37°C. Aliquots of this plasma sample were taken at definite time intervals and subjected to LC-MS/MS analysis. The samples were analyzed for amount of unconverted test compound and the amount of phenolic drug formed in the test solution using LC-MS/MS.

8 1.81 1.74 ~

9 0.79 0.5 ~

26 0.87 0.63 0.53

27 0.63 0.69 0.59

28 0.9 1.11 0.79

32 0.98 1.19 1.09

33 0.57 0.65 0.59

40 0.80 0.90* 0.80

42 0.60 1.20 1.00

53 0.60 0.80* 0.60

54 0 3.20 5.82

55 0.5 0.6* 0.6

56 1.0 1.0* 1.0

57 1.0 1.0* 1.0

60 1.87 1.52* 0.81

61 3.9 1.6* 1.8

63 1.1 1.2* ~

64 1.6 1.1* 0

* mice plasma

Pharmacokinetic (PK) study of SN-38 prodrug in Dog by i.v. route

Adult male beagle dogs were infused intravenously through the cephalic vein using syringe (infusion) pump. Separate animals were administered irinotecan hydrochloride and compound 51, the prodrug of SN-38 (7-ethyl-10- hydroxycamptothecin), 15 mg/kg each respectively, over a 10 min infusion time period at a rate of 0.4 ml/min. For both the treatments blood was withdrawn at the end of the infusion (time 0 hr), 0.083, 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hrs after infusion. The blood samples were collected in tubes containing sodium heparin as an anticoagulant (100 IU/ml), centrifuged immediately at 7000 x g for 10 min at 4°C. Plasma samples were stored at -70°C until analysis. Aliquots of this plasma samples were analyzed for the amount of SN-38.

†Duration of iv infusion 12-14 min. *Immediately after completion of iv infusion.

Cmax = maximal plasma concentration of SN38; AUC = area under the plasma concentration of SN38 versus time curve; T _max = time to attain maximum plasma concentration of SN38; T _1/2 = elimination half-life^ MRT = Mean residence time,