WO2018150347A1

WO2018150347A1 - Compounds with beta-adrenergic agonist and antimuscarinic activity

Info

Publication number: WO2018150347A1
Application number: PCT/IB2018/050922
Authority: WO
Inventors: Sanjay Srivastava; Pundlik SHINDE; Appaji Mandhare; Ramesh Chandra Gupta; Anita Chaudhary; Ram Gupta; Shailesh Deshpande; Kiran Chaudhari; Jaya Abraham; Deepa Joshi; Chaitanya Dutt
Original assignee: Torrent Pharmaceuticals Limited
Priority date: 2017-02-17
Filing date: 2018-02-15
Publication date: 2018-08-23
Also published as: AR110936A1; TW201835041A

Abstract

The present invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, and isomers, stereoisomers, atropisomers, conformers, tautomers, atropisomers, polymorphs, hydrates, solvates, N-oxide or S-oxide thereof. The present invention also relates to pharmaceutically acceptable compositions and process for preparing said compounds. The invention further relates to the use of the above-mentioned compounds for the preparation of medicament for use as pharmaceuticals.

Description

C OM POU NDS WIT H BE TA-A DR E N E R G IC AG O NIST A ND

A NTIM USCA RINIC ACTIVITY

FIE L D O F T H E INV E NTION:

The present invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, and isomers, stereoisomers, atropisomers, conformers, tautomers, atropisomers, polymorphs, hydrates, solvates, N-oxide or S-oxide thereof. The present invention also encompasses pharmaceutically acceptable compositions and process for preparing said compounds. The i nvention further relates to the use of the above- mentioned compounds for the preparation of medicament for use as pharmaceuticals.

BAC K G R OU ND OF T H E INV E NT ION:

The prevalence of ai rway diseases has increased in recent decades despite therapeutic advances. A mong the ai rway di seases are obstructive I ung di sorders whi ch i ncl ude A sthma, Bronchiectasis, Cystic Fibrosis and Chronic Obstructive Pulmonary Disease (COPD). C 0 P D i s a term whi ch refers to a I arge group of I ung di seases character! zed by obstruct! on of air flow that interferes with normal breathing. E mphysema and chronic bronchitis are the most important conditions that compose COPD. (Australian lung foundation, 2006). Further, Asthma exacerbations and chronic obstructive pulmonary disease (COPD) are major causes of hospitalization. Chronic obstructive pulmonary disease (COPD) is a major global health problem that is becoming prevalent particularly in developing countries. It is one of the most common di seases i n the worl d, wi th a I i f eti me ri sk esti mated to be as hi gh as 25%, and now equally affects both men and women (Nature Reviews. 2013; 12: 543- 559) Current forms of therapy for COPD includes Bronchodilators, Phosphodiesterase-4 inhi bitors, Corticosteroids, and other medicines like methyl xanthines, however; Bronchodi lators conti nue to remain one of the important approaches used for the symptomatic pharmacological management for patients with pulmonary disorders such as asthma and chronic obstructive pulmonary disease (J Allergy Clin Immunol. 2007 Nov; 120(5): S94-138; Curr Opin Pharmacol. 2008J un;8(3):300-7). Two classes of bronchodilators, b2-adrenoceptor agonists and muscarinic receptor antagonists, are currently available and used widely in clinical settings. These compounds are generally administered as inhalation. Short acting b2-adrenoceptor agonists, such as salbutamol and terbutaline, are used to relieve episodes of dyspnea, whereas long acting b2-adrenoceptor agonists, such as formoterol and salmeterol, are used to control more persistent symptoms. Inhaled muscarinic antagonists which are currently used include the short-acti ng i pratropi um or oxitropi um and the I ong-acti ng ti otropi um.

Results from several preclinical and cli nical studies have clearly demonstrated that indeed, the combination of bronchodilators from these two classes, that is b2-adrenoceptor agonists and muscarinic receptor antagonist yields greater efficacy in asthma and COPD patients than either mechanism alone (J Pharmacol Exp Ther. 2014 Feb; 348(2): 303-10; Ther Clin Risk Manag. 2015 Mar 25; 11:481-7; Pulm Pharmacol Ther. 2011 Feb;24(1): 147-52). T hi s has I ed to cl i ni cal use of these bronchodi I ators where they have been co-admi ni stered either through separate inhalers or as their fix dose combination delivered through si ngle inhaler. The use of b2-adrenoceptor agonists and muscarinic receptor antagonists in combination has also been disclosed in patent applicationsW 00238154 and WO03000241.

Y et another approach for b2-adrenoceptor agonists and muscarinic receptor antagonist being explored is for the development of single molecule having both b2-adrenoceptor agonists and muscarinic receptor antagonist activity. Such an approach would bear advantages as ease of f ormul ati on, si ngl e pharmacoki neti c prof i I e for both pharmacol ogi cal activities, thereby maximizing the potential synergy between the two mechanism which would otherwise be difficult to achieve with co-administration of two separate compounds with distinct pharmacokinetic-pharmacodynamic profiles, along with better prospects in achieving combination with other potential drugs being used cli nically in combination with bronchodi lators for example, inhaled corticosteroids or other inhaled anti- inflammatories (J Allergy Cli n Immunol. 2007 Nov; 120(5): S94-138; Am Fam Physician. 2013 Nov 15;88(10):655-63). However, none of the compounds disclosed in prior art are commercially avail able or have been approved for marketi ng. Hence, there exists a need of compounds having both b2- adrenoceptor agonist as well as muscarinic receptor antagonist activity which will yield greater efficacy in COPD and Asthma patients than either mechanism alone.

SU M MA RY OF T H E INV E NTIO N:

In one embodiment the present invention provides novel compounds of formula (I), its pharmaceutically acceptable salts and isomers, stereoisomers, atropisomers, conformers, tautomers, polymorphs, hydrates, solvates, N -ox ides or S- ox ides thereof;

I

Wherein,

R^nd R² are independently selected from (C3-C₇)cycloalkyl, aryl and heteroaryl, the said (C3-C₇)cycloalkyl, aryl, and heteroaryl are optionally substituted by one or more (Ci- Ce)alkyl, aryl, (C₃-C₇)cycloalkyl, halogen, O-R¹⁴, SH, C N, (C H₂)_p-aryl, (CH₂)_p-heteroaryl, C H₂OH, CH₂-halogen, CH₂0-(CrC₆)alkyl, CH₂0-aryl, COOR¹², CONR¹⁶R¹⁷ or NHCOR¹²;

R³ is selected from hydrogen, hydroxyl, (Ci-C₄) alkoxy, CH₂OH, and (Ci-C6)alkyl;

R⁴ is selected from hydrogen, (CrC6)alkyl, aryl, (C H₂) -aryl, (CH₂)_p-heteroaryl and (C₃- C₇)cycloalkyl; m is 1 or 2;

R⁵ and R⁶ are independently selected from hydrogen, (CrC6)alkyl, halogen, (C₃- C7)cycloalkyl, heterocycloalkyi, (C H₂)_p-aryl and (CH₂)_p-heteroaryl or R⁵ and R⁶ on same carbon form a 3-7 membered cycloalkyi or heterocycloalkyi ring in a spiro manner or is gem di methyl; n is selected from 0-4; R⁷ and R⁸ are independently selected from hydrogen, (Ci-Ce)alkyl and heterocycloalkyi or R⁷ and R⁸ on same carbon form a 3-7 membered cycloalkyi or heterocycloalkyi ring in a spi ro manner or is gem di methyl; p is 1 or 2;

R⁹ and R¹⁰ are independently selected from hydrogen, (Ci-Ce)alkyl, (C₃-C7)cycloalkyl, heterocycloalkyi and oxo or R⁹ and R¹⁰ on same carbon form a 3-7 membered cycloalkyi or heterocycloalkyi ring in a spiro manner or is gem dimethyl; R¹¹ is selected from hydrogen, (C i-Ce)alkyl, aryl, C H₂OH, CH₂-halogen, halogen, (C₃- C7)cycloalkyl, heteroaryl, heterocycloalkyi, O-R¹⁴, SH, C N, (CH₂)_p-aryl, (CH₂)_P- heteroaryl, CH₂0-(Ci-C₆)alkyl, CH₂0-aryl, COOR¹², CONR¹⁶R¹⁷and NHCOR¹²;

Q is N(A)R¹²or O-A;

R¹² is selected from hydrogen, (C i-Ce)alkyl, aryl, (C H₂) -aryl, (C H₂) - heteroaryl, (C₃- C7)cycloalkyl and heterocycloalkyi;

R¹³ is selected from hydrogen, O-R¹⁴ and

R¹⁴ is independently selected from hydrogen, (CrC6)alkyl, aryl, heteroaryl, (C H₂)p-aryl, (C H₂) -heteroaryl, (C3-C7)cycloalkyl, Si(Ci-C6)alkyl, and

R¹⁵ is selected from (Ci-Ce)alkyl, (C3-C7)cycloalkyl, aryl, heteroaryl, (CH₂)p-aryl and (C H₂)p-heteroaryl;

R¹⁶ and R ¹⁷ are independently selected from hydrogen, (Ci-Ce)alkyl, (C3-C7)cycloalkyl and heterocycloalkyl or R¹⁶ and R ¹⁷ together with nitrogen atom form a 3-10 membered heterocycloalkyl ring;

A is selected from

: denotes point of attachment. In another embodiment the present invention pertains to a compound as above, however only incl udi ng pharmaceutical ly acceptable salts thereof.

In another embodiment the present invention includes synthetic intermediates that are useful in preparing the compounds of formula (I) and process for preparing such intermediates.

In another embodiment the present invention includes metabolites of the compounds of formula (I).

Another embodiment of the present invention is a method for preparation of a compound of formula (I) or i ntermediates as herei n descri bed i n Schemes 1 and 2. Another embodiment of the present invention provides a pharmaceutical composition comprising a compound of formula (I), optionally in admixture with a pharmaceutically acceptable excipient(s). Another embodiment of the present invention provides method for treating respiratory-tract disorders by administering a therapeutically effective amount of a compound of formula (I) to a mammal, including human being, in need thereof.

Another embodiment of the present invention provides method for treating respiratory-tract disorders such as asthma, chronic obstructive pulmonary disease, chronic bronchitis, acute respiratory distress syndrome (A RDS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema and allergic rhinitis, by administering a therapeutically effective amount of a compound of formula (I) to a mammal, including human being, in need thereof.

A nother embodi ment of the present i nventi on provi des method for treati ng chroni c obstructive pulmonary disease or asthma, by administering a therapeutically effective amount of a compound of formula (I) to a mammal, i ncl udi ng human bei ng, i n need thereof. Another embodiment of the present invention provides use of a compound of f ormul a (I) for the preparati on of a medi cament for treatment of respi ratory-tract di sorders.

Another embodiment of the present invention provides use of a compound of formula (I) for the preparation of a medi cament for treatment of respi ratory-tract disorders such as asthma, chronic obstructive pulmonary disease, chronic bronchitis, acute respiratory distress syndrome (A RDS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema and allergic rhinitis.

Another embodiment of the present invention provides the use of a compound of formula (I) for the preparation of a medicament for treatment of chronic obstructive pulmonary disease or asthma. FIGURES

Fig 1. Bronchoprotective effect of Compound no.1 in guinea pigs.

DETAILED DESCRIPTION OF THE INVENTION:

In one embodiment the present invention provides novel compounds of formula

(I),

(I)

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, Q, m, n and p are as defined above; or pharmaceutically acceptable salts, isomers, stereoisomers, atropisomers, conformers, tautomers, polymorphs, hydrates, N-oxide, S-oxide and solvates thereof.

In a preferred embodiment the present invention provides novel compounds of formula (I) as illustrated above, wherein

R¹ and R²are independently selected from (C3-C7)cycloalkyl, aryl and heteroaryl; R³ is selected from hydroxyl and (CrC6)alkyl;

R⁴ is hydrogen;

m is 1 or 2;

R⁵ and R⁶ are independently hydrogen or R⁵ and R⁶ on same carbon is gem dimethyl;

n is selected from 0-2;

R⁷ and R⁸ are independently hydrogen or R⁷ and R⁸ on same carbon is gem dimethyl;

p is 1 or 2;

R⁹ and R¹⁰are hydrogen;

R¹¹ is hydrogen or(Ci-C6)alkyl; Q is N(A)R¹²;

R¹² is hydrogen or (Ci-C6)alkyl;

R¹³ is hydrogen or O-R¹⁴;

R¹⁴ is selected from hydrogen and Si(Ci

R¹⁵ is (Ci-C₆)alkyl;

A is selected from

:/^" denotes point of attachment. A family of specific compounds of particular i nterest within the scope of present invention consists of compound and pharmaceutically acceptable salts thereof as follows: Table I:

C ompound. C hemical Name

No. 1 -{ 3-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- y I ) ethy I] ami no} methy I )-2, 3-di hy dro- 1 H - i ndol - 1 -y I ] -3- oxopropyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- y I ) ethy I] ami no} methy I )-2, 3-di hy dro- 1 H - i ndol - 1 -y I ] -2- oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate

1 -{ 3-[6-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl )-3,4-di hydroqui noli n-1(2H)-yl]-3- oxopropyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate

1 -{ 4-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- yl)ethyl]amino} methyl)-2,3-dihydro-1 H-indol-1-yl]-4- oxobutyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-{ 4-hydroxy-3-

[( methy I sulf ony l)ami no] phenyl} ethyl] ami no} methyl )-2, 3-di hydro- 1 H - i ndol-1 -yl] -2-oxoethyl} pi peridi n-4-yl hydroxy(dithi ophen-2-yl)acetate

1 -{ 2-[5-({ [( RS)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2-di hydroqui nol i n-5- yl)ethyl]amino} methyl)-2,3-dihydro-1 H-indol-1-yl]-2- oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate

1 -{ 3-[5-({ [(2R)-2-hydroxy-2-{ 4-hydroxy-3-

[( methy I sulf ony l)ami no] phenyl} ethyl] ami no} methyl )-2, 3-di hydro- 1 H - i ndol-1 -yl]-3-oxopropyl} pi peridin-4-yl hydroxy(dithiophen-2-yl)acetate

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- yl)ethyl]amino} methyl)-2,3-dihydro-1 H-indol-1-yl]-2- oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate hemifumarate salt

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2,3,4- tetrahydroqui nol in- 5-yl)ethyl]ami no} methyl)-2,3-dihydro-1 H-i ndol-1 - y I] -2-oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate

1 -{ 3-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- yl)ethyl]amino} methyl)-2,3-dihydro-1 H-indol-1-yl]-3- oxopropyl} piperidin-4-yl hydroxy(diphenyl)acetate 1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-oxo-l ,2-di hydroqui nol i n-5- y I ) ethy I] ami no} methy I )-2, 3-di hy dro- 1 H - i ndol - 1 -y I ] -2- oxoethyl} piperidin-4-yl hydroxy(diphenyl)acetate

1 -{ 3-[5-({ [(2R)-2-hydroxy-2-{ 4-hydroxy-3-

[( methy I sulf ony l)ami no] phenyl} ethyl] ami no} methyl )-2, 3-di hydro- 1 H - indol-1-yl]-3-oxopropyl} piperidin-4-yl hydroxy(diphenyl)acetate

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-oxo-l ,2-di hydroqui nol i n-5- yl)ethyl]amino} methyl)-2,3-dihydro-1 H-indol-1-yl]-2- oxoethyl} pyrrol i di n- 3-yl hydroxy(dithiophen-2-yl)acetate

1 -(2-{ 5-[({ (2R)-2-hydroxy-2-[4-hydroxy-3-

(hydroxymethyl)phenyl] ethyl} ami no)methyl]-2,3-di hydro-1 H-indol-1 - yl}-2-oxoethyl)pi peridin-4-yl hydroxy(dithiophen-2-yl)acetate

1 -{ 2-[5-({ ethyl [(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- di hydroqui nol i n-5-yl)ethyl] ami no} methyl)-2,3-di hydro-1 H-i ndol-1 -yl]-

2-oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-oxo-l ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl)-6- methyl-2, 3-di hydro-1 H-i ndol-1 -yl]-2- oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-oxo-l ,2-di hydroqui nol i n-5- yl)ethyl]amino} methyl)-2, 3-di hydro-1 H-i ndol-1-yl]-2-oxoethyl} -3,3- di methyl pi peri di n-4-y I hydroxy(di thi ophen-2-yl )acetate

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-oxo-l ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl)-2, 3-di hydro-1 H-i ndol-1-yl]-2-oxoethyl}-2,2- di methyl pi peri di n-4-y I hydroxy(di thi ophen-2-yl )acetate

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-3,4-di hydro-2H-1 ,4- benzoxazin-8-yl)ethyl]ami no} methyl)-2, 3-di hydro-1 H-indol-1 -yl]-2- oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate

1-(2-{ 5-[({(2R)-2-[3-(formylamino)-4-hydroxyphenyl]-2- hydroxy ethyl} ami no) methyl] -2,3-di hydro-1 H-i ndol-1 -yl} -2- oxoethyl ) pi peri di n-4-yl hydroxy(dithi ophen-2-yl )acetate 1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-di hydro-1 ,3- benzothiazol-7-yl)ethyl]amino} methyl)-2,3-dihydro-1 H-i ndol-1-yl]-2- oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-oxo-l ,2-di hydroqui nol i n-5- y I ) ethy I] ami no} methy I )-2, 3-di hy dro- 1 H - i ndol - 1 -y I ] -2- oxoethyl} piperidin-4-yl cyclopentyl( hydroxy) phenyl acetate

1 -{ 3-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-oxo-l ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl)-2, 3-di hydro-1 H - i ndol - 1 -y I ] -2, 2-di methyl -3- oxopropyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate

1 -{ 2-[5-({ [2-(8- hydroxy- 2-oxo-l ,2-di hydroqui nol i n-5- y I ) ethy I] ami no} methy I )-2, 3-di hy dro- 1 H - i ndol - 1 -y I ] -2- oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-{ 4-hydroxy-3-

[(methylsulfonyl)ami no] phenyl} ethyl]ami no} methyl)-2, 3-di hydro-1 H- indol-1-yl]-2-oxoethyl} piperidin-4-yl hydroxy(diphenyl)acetate

1 -{ 2-[5-({ [(2S)-2-hydroxy-2-(8- hydroxy- 2-oxo-l ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl)-2,3-di hydro-1 H-indol-1-yl]-2- oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-oxo-l ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl)-2,3-di hydro-1 H-indol-1-yl]-2- oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate acetate salt

(1 :1)

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-oxo-l ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl)-2,3-di hydro-1 H-indol-1-yl]-2- oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate butanedioate (hemi succinate salt)

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-oxo-l ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl)-2,3-di hydro-1 H-indol-1-yl]-2- oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate 2,3- di hydroxy butanedi oate (1 :1) 1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- y I ) ethy I] ami no} methy I )-2, 3-di hy dro- 1 H - i ndol - 1 -y I ] -2- oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl) acetate hemi ethane- 1 ,2-di sulfonic acid

1 -{ 2-[5-({ [2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2-di hydroqui nol i n-5- yl)ethyl]amino} methyl)-2,3-dihydro-1 H-indol-1-yl]-2- oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate hydrofluoride

(1 :1)

1 -{ 3-[6-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl )-3,4-di hydroqui noli n-1 (2H)-yl]-3- oxopropyl} piperidin-4-yl hydroxy(diphenyl)acetate

1 -{ 3-[6-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl )-3,4-di hydroqui noli n-1 (2H)-yl]-3-oxopropyl}-

2,2-di methyl pi peri di n-4-yl hydroxy(di phenyl )acetate

1 -{ 3-[6-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- yl)ethyl](2-methyl propyl )ami no} met hyl)-3,4-di hydroqui noli n-1(2H)- yl]-3-oxopropyl} piperidi n-4-yl hydroxy(di phenyl )acetate

1 -(2-{ 6-[({ (2R)-2-hydroxy-2-[4-hydroxy-3-

(hydroxymethyl)phenyl] ethyl} ami no)methyl]-3,4-di hydroqui nol i n-

1(2H)-yl}-2-ox oethy I ) pi peri d i n-4-y I hydroxy(diphenyl)acetate

1 -{ 2-[6-({ [(2R)-2-hydroxy-2-{ 4-hydroxy-3-

[(methylsulfonyl)amino]phenyl} ethyl]amino} methyl)-3,4- di hydroqui nol i n-1 (2H )-y I] -2-ox oethy I} pi peri di n-4-yl

hydroxy(diphenyl)acetate

1 -{ 2-[6-({ [(2R)-2-hydroxy-2-(6-hydroxy-3-oxo-3,4-di hydro-2H-1 ,4- benzoxazin-8-yl)ethyl]ami no} methyl)-3,4-di hydroqui nol i n-1 (2H)-yl]-2- oxoethyl} piperidin-4-yl hydroxy(diphenyl)acetate

1 -{ 3-[6-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-ox o-1 ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl )-3,4-di hydroqui noli n-1 (2H)-yl]-3- oxopropyl} piperidin-4-yl cyclopentyl(hydroxy)phenylacetate 1 -{ 3-[6-({ [(2R)-2-hydroxy-2-(6-hydroxy-3-oxo-3,4-di hydro-2H-1 ,4- benzoxazin-8-yl)ethyl]ami no} methyl)-3,4-di hydroqui nol i n-1 (2H)-yl]-

2,2-dimethyl-3-oxopropyl} piperidin-4-yl hydroxy(dithiophen-2- yl)acetate

1 -{ 2-[7-({ [(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-di hydro-1 ,3- benzothiazol-7-yl)ethyl]ami no} methyl )-3,4-di hydroqui noli n-1 (2H)-yl]-

2-oxoethyl} piperidin-4-yl 2,2-di(thiophen-2-yl)propanoate

1 -{ 2-[6-({ [(2R)-2-hydroxy-2-(6-hydroxy-3-oxo-3,4-di hydro-2H-1 ,4- benzoxazin-8-yl)ethyl]ami no} methyl)-2,3-di hydro-1 H-indol-1-yl]-2- oxoethyl} piperidin-4-yl 2,2-di(thiophen-2-yl)propanoate

1 -{ 2-[5-({ [(2R)-2-{ [tert- butyl (di methyl)si lyl] oxy} -2-(8-hydroxy-2-oxo-

1,2-di hydroqui nolin-5-yl)ethyl]ami no} methyl )-2,3-di hydro-1 H-indol-1 - yl]-2-oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate

1 -[3-(5-formyl-2,3-di hydro-1 H-indol-1 -yl)-3-oxopropyl] pi peridin-4-yl hydroxy(dithiophen-2-yl)acetate

1 -[3-(5-formyl-2,3-di hydro-1 H-indol-1 -yl)-3-oxopropyl] pi peridin-4-yl hydroxy(diphenyl)acetate

1 -[3-(5-f ormyl-2,3-di hydro-1 H - i ndol - 1 -y I ) -3-oxobuty 11 ] pi peri di n-4-yl hydroxy(dithiophen-2-yl)acetate

1 - [3-( 5-f ormy I -2, 3-di hy dro- 1 H - i ndol - 1 -y I ) -3-oxoethy I ] pi peri di n-4-y I hydroxy(diphenyl)acetate

1 -[3-(6-f ormyl-3,4-di hydroqui nol i n-1 (2H)-yl)-3-oxopropyl] pi peridi n-4- yl hydroxy(dithiophen-2-yl)acetate

1 -(3-chl oropropanoy I ) -2, 3- di hydro- 1 H - i ndol e-5-carbal dehyde

1 -(4-chl orobutanoyl )-2, 3-di hydro-1 H- i ndol e-5-carbal dehyde

1 -(3-chl oropropanoyl)-1 ,2,3,4- tetrahydroqui nol i ne-6-carbal dehyde

1-(chloroacetyl)-2,3-di hydro-1 H-i ndol e-5-carbal dehyde

1,2-di hydroqui nolin-5-yl)ethyl]ami no} methyl )-2,3-di hydro-1 H-indol-1 - yl]-2-oxoethyl} pi peridin-4-yl hydroxyl (diphenyl)acetate 53 1 - [2-( 5-f ormy I -2, 3-di hy dro- 1 H - i ndol - 1 -y I ) -2-oxoethy I ] pi peri di n-4-yl hydroxy(dithiophen-2-yl)acetate

DE FINITIONS:

The following definitions apply to the terms as used throughout this specification, unless otherwise limited i n specific instances:

The term ^"compound_, employed herein refers to any compound encompassed by the generic formula disclosed herein. The compounds described herein may contain one or more double bonds and therefore, may exist as isomers, stereoisomers, such as geometric isomers, E and Z isomers, and may possess asymmetric carbon atoms (optical centers) and therefore may exist as enantiomers, diastereoisomers. Accordingly, the chemical structures described herein encompasses all possible stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure) and stereoisomer! c mixtures (racemates). The compound described herein, may exist as conformational isomers such as chair or boat form The compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures described herein encompass all possible tautomeric forms of the illustrated compounds. The compounds described also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include, but are not limited to ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0, etc. Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, compounds may be hydrated or solvated. Certain compounds may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention.

The use of the terms ^"a_ and ^"an_ and ^"the_ and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

The nomenclature of the compounds of the present invention as indicated herein is according to ACD/Lab's ChemDraw with "logD Suite" (V ersion 12.0). ^"Pharmaceutically acceptable sal t_ refers to a salt of a compound, which possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with i norganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, trifluoroaceticacid, propionic acid, isobutyric acid, hexanoic acid, cyclopentanepropionic acid, oxalic acid, glycol ic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, suberic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, triphenylacetic acid, 3-(4- hydroxy benzoyl) benzoic acid, phthalic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2- ethanedi sulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3- phenyl propionic acid, tri methyl acetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glucuronic acid, galactunoric acid, glutamic acid, hydroxy naphthoic acid, salicylic acid, stearic acid, muconic acid, [(1S,4R)-7,7-dimethyl-2-oxo-norbornan-1- yl] methane sulfonic acid, 1,5-naphthalenedisulfonic acid and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanol amine, tri ethanol amine, N-methylglucamine and the like. Also included are salts of amino acids such as arginate and the like (see, for example, Berge, S.M., et al., ^" Pharmaceutical Salts_, J ournal of Pharmaceutical Science.1977; 66: 1-19). Compounds of present invention may form hemi, mono, di or tri salt

As used herein, the term ^"polymorph_, pertains to compounds having the same chemical formula, the same salt type and having the same form of hydrate/solvate but havi ng di ff erent crystal I ographi c properti es.

As used herein, the term ^"hydrate_, pertains to a compound having a number of water molecules bonded to the compound.

As used herein, the term ^"solvate_, pertains to a compound having a number of solvent molecules bonded to the compound.

The term "substituted", as used herein, includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution (includi ng multiple substitution at the same site) is chemical ly al lowed and which means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound, for example, when a substituent is keto, then the two hydrogens on the atom are replaced. All substituents iR¹, R², u .) and thei r further substituents described herein may be attached to the main structure at any heteroatom or carbon atom whi ch results i n f ormati on of stabl e compound.

As used herein, a ^"halogen_, substituent is a monovalent halogen radical chosen from chloro, bromo, iodo and fluoro.

T he term ^"al kyl _ used either al one or i n attachment with another group refers to an aliphatic hydrocarbon radical having the indicated number of carbon atoms and that is unsubstituted or substituted. When a subscript is used with reference to an alkyl, the subscri pt refers to the number of carbon atoms that group may contai n. For exampl e, a ^"C i - C6_ would refer to any alkyl group containing one to six carbons in the structure. Said ^"alkyl _ may be linear (for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl) or branched chain (for example, isopropyl, isobutyl, sec-butyl, tert-butyl) and it may contain one or two double or triple bonds to form corresponding alkenes or alkynes. The said ^"alkyl _ may also contain (C3-C₇)cycloalkyl ring in a spiro manner.

T he term ^"al koxy _ refers to any al kyl group as def i ned herei n above attached to the parent mol ecular moi ety through an oxygen bri dge.

The term ^" hydroxy I _ as used herein, refers to -OH group.

T he term ^"cycl oal kyl _ used either al one or i n attachment with another group refers to a cyclic ring system havi ng the indicated number of carbon atoms and that is unsubstituted or substituted with groups or substituents attached at any available atom to produce a stable compound. When a subscript is used with reference to a cycloalkyl, the subscript refers to the number of carbon atoms that group may contain. For example, the term "(C3-C₇)cycloalkyl _ would refer to a cyclic ring system having 3 to 7 carbon atoms and that is unsubstituted or substituted. The said "(C3-C₇)cycloalkyl _ means a cyclic ring system containing only carbon atom in the ring system backbone such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Cycloalkyl may include bi cyclic rings. Cycloalkyl may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The term "aryl" used either alone or in attachment with another group refers to an aromatic group for example, which is a 6 to 10 membered monocyclic or bicyclic carbon- containing ring systern which may be unsubstituted or substituted. The aryl groups include, but are not limited to, phenyl, naphthyl, bi phenyl, tetrahydronaphthyl and indane. Preferably, aryl is phenyl.

The term "heteroaryl" used either alone or in attachment with another group refers to an aromati c group for exampl e, whi ch is a 5 to 14 membered monocycl i c or bi cycl i c ri ng syster which has at least one heteroatom, which may be unsubstituted or substituted. The term "heteroatom" as used herein includes oxygen, sulfur and nitrogen. In bicyclic ring syster ri ng can be fused through a bridge heteroatom T he heteroaryl groups include, but are not limited to pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimdinyl, pyrazinyl, triazinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazol, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazoli nyl, quinoxalinyl, phthalazi nyl or naphthyridinyl.

The term "heterocycloalkyl" refers to a fully or partially saturated cyclic group, for example, which is a 3 to 14 membered monocyclic or bicyclic ring systenri which has at least one heteroatom. The term "heteroatom" as used herein includes O, N, S. In bicycl ic heterocyclic system, at least one ring is not aromatic and the rings can also be attached to each other in a spiro manner. The heterocyclic or heterocycle groups include, but are not limited to, oxiranyl, aziridinyl, oxetanyl, azetidinyl, pyrrolidinyl, dihydropyrrolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, di y drothi opheny I , pyrazol idinyl, imidazolidinyl, oxazolidinyl, isoxazoliidinyl, thiazol idinyl, triazol idinyl, oxadiazolidinyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, dioxanyl, morpholinyl, triazinanyl, azepanyl, diazepanyl, oxepanyl, dioxepanyl, oxazepanyl, indolinyl, benzomorpholinyl, tetrahydroquinolyl, tetrahydroisoquinolyl or thiomorpholinyl. As used herei n, ^"room temperature_, refers to a temperature between 20° C and 30°

C.

As used herei n, the term ^"mammal _ means a human or an ani mal such as monkeys, primates, dogs, cats, horses, cows, etc.

The terms ^"treating_, or ^"treatment_, of any disease or disorder as used herein to mean completely or partially preventing or delaying the onset of a disease or disorder or sign or symptom thereof; and/or partially or completely curing or ameliorating a disease or disorder and/or adverse effect attributable to the disorder.

The phrase "a therapeutically effective amount" means the amount of a compound that when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, mode of administration, the disease and its severity and the age, weight, etc., of the pati ent to be treated.

Throughout this specification and the appended claims, it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be i nterpreted inclusively, unless the context requires otherwi se. T hat i s, the use of these words may i mpl y the i nc I usi on of an el ement or el ements not specifically recited.

Also included within the scope of the invention are metabolites of compounds of formula (I), that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include following compounds. C ompound C hemical name

no.

^~54 8- hydroxy- 5-{(1 R)-1-hydroxy-2-[({ 1-[(4-hydroxypi peri din-1-yl)acetyl]-

2,3-dihydro-1 H-indol-5-yl} methyl)amino]ethyl} quinolin-2(1 H)-one 55 1 -{ 2-[5-(ami nomethyl)-2,3-di hydro-1 H-i ndol-1 -yl] -2- oxoethyl} pi peridi n-4-yl hydroxy(dithiophen-2-yl)acetate In another embodiment present invention provides the process for preparing the compounds of formula (I).

The followi ng reaction schemes are given to disclose the synthesis of the compounds accordi ng to the present i nventi on.

Accordingly, the compounds of formula (I) of the present invention may be prepared as descri bed in the given schemes.

Scheme - 1

PG= Protecting group such as Boc

Synthesis of compounds of formula .(wherein Q is N(A)R¹²; and R¹² is hydrogen) isshown in scheme 1. Compounds of formula I can be obtained from the reaction of compounds of formula II with suitable amine of formula A-NH₂ i n suitable solvent such as tol uene- methanol at elevated temperature, which is followed by reduction with suitable reducing agent such as sodium borohydride and further deprotection using tri ethyl amine- hydrogen fluoride complex in suitable solvent such as methylene chloride. Compounds of formula II is synthesized from the treatment of compound of formula VII-A with compounds of either formula III or formula IV or formula V orformula VI in the presence of suitable base such as triethylamine and suitable solvent such as tetrahydrofuran at reflux temperature. Deprotection of compounds of formula VII in the presence of IPA-HCI yields compounds of f ormul a V II-A . C ompound of f ormul a V II i s obtai ned from the reacti on of compound of formula VIII and IX in the presence of suitable base such as sodium hydride and solvent such as tol uene.

Scheme 2

Synthesis of compounds of formula III, IV, V and VI is described in scheme 2. Deacetylation of N-acetyl indoline compound of formula X, where p =1, was carried out using aqueous sodium hydroxide at elevated temperature and further reaction separately with compound of either formula VIII or formula IX in the presence of suitable base such as tri methyl amine and suitable solvent such as methylene chloride to furnish compounds of formula III or IV, respectively. Using similar condition as described for synthesis of compounds of formula III and IV, N-deacetylation of N-acetyl tetrahydroquinoline compound of formula XI, where p = 2, was carried out and which upon reaction with compounds of either formula V III or formula IX provided compounds of formula V and VI, respectively. Formylation reaction of N-acetyl indoline compound of formula XII or N-acetyltetrahydroquinoline compound of formula X III with hexamine in the presence of trifluroacteic acid at elevated temperature afforded respective aldehyde derivatives X or X I, respectively.

Substituted chloro acetyl chloride of formula VIII and chloro propanoyl chloride of formula IX, N-acetyl indol ine compound of formula X II, N-acetyl tetrahydroquinoline compound of formula X III, hydroxyl pyrrolidine, hydroxyl pi perdine of formula VIII and appropriate ester compound of formula IX are either commercially available or synthesized using conventional methods known to one of skill in the art.

Schemes 1 and 2 provide general method of preparation of compounds and intermediates according to present invention. One of ordinary skill wil l recognize to appropriately substitute various groups such as R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ in appropriately modified starting material to prepare desired compounds accordi ng to formula (I). A lternative to the given schemes, one of ordinary skill will readily synthesize the compounds according to the present invention using conventional synthetic organic techniques from suitable starting material which are either commercially available or may be readily prepared.

It would be obvious to one skilled in the art that variations in reaction time, temperature, solvents and/or reagents could increase the yields. The compounds of the present invention may have chiral centers and occur as racemates, racemic mixtures and as individual diastereomers or enantiomers with all isomeric forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers, substantially free of the other, are i ncluded within the scope of the invention; further included are all mixtures of the two enantiomers.

The novel compounds of the present invention were prepared according to the procedure of the schemes as described herein above, using appropriate materials and are further exemplified by the following specific examples. The examples are not to be consi dered or construed as I i mi ti ng the scope of the i nventi on set forth.

In present specification some general terms are used with their known intended meani ng whi ch are def i ned herei n bel ow:

Mass of compounds prepared according to present invention is measured using Single quadrupole mass spectrometer (Water ZQ 2000 instrument) using APCI ionization technique (E lectro spray chemical ionization Probe) or Finnigan LX Q, thermo instrument Technique using either ESI or APCIJH NM R Spectra of all the compounds is recorded by using Bruker TopSpin400 M Hz NMR Spectrometer.

EXAM PL E S:

E xample 1 :

Preparation of piperidin-4-yl hydroxy(dithiophen-2-yl)acetate hydrochloride

In a 3 litre four neck round bottom flask equipped with mechanical stirrer and Dean Stark apparatus, 60% suspension of sodium hydride (5.9 gm, 0.147 mol) was charged under nitrogen and then added toluene (1200 ml) followed by 1-Boc-4-hydroxy pi peridine (59.35 gm, 0.295 mol), and methylhydroxy[di(thiophen-2-yl)]acetate (75 gm, 0.295 mol) under stirring. The reaction mixture was refluxed for 3 to 4 hours and cooled down to room temperature. The toluene layer was separated and dried over sodium sulphate and evaporated under vacuum to get crude 109.0 gm of 1 - B oc- pi peri di n-4-y I hydroxy(dithiophen-2-yl) acetate as brownish semisolid, which was used as such for further reaction.

The above brownish semisolid was dissolved in isopropanol (400 ml) and added 7% isopropanol-HCI (650 ml). The reaction mixture was stirred at room temperature for 22 to 24 hours and further diluted with ethyl acetate (600 ml). The separated, solid was filtered and washed with ethyl acetate and dried undervacuum at 50 e5°C for 10 to 12 hours to get 62.0 gm of desired compound as pale yellow solid.

^! H NMR (DMSO-de) 7.47(2H, d), 7.08 (2H, s), 6.99-6.97 (2H, m), 4.90-4.86 (1 H, m), 2.81-2.77 (2H, m), 2.57-2.52 (2H, partially merged with solvent signal), 1.77-1.74 (2H, bs), 1.49-1.44 (2H, m)

ESMS: 323.85/324.92 [M H] ⁺

E xample 2:

Preparation of piperidin-4-yl hydroxy(di phenyl )acetate hydrochloride

The above compound was synthesized from methyl hydroxy(di phenyl)acetate using similar procedure as described for piperidin-4-yl hydroxy(dithiophen-2-yl)acetate hydrochloride in example- 1. E xample 3:

Preparation of 1-[2-(5-formyl-2,3-dihydro-1 H-indol-1-yl)-2-oxoethyl] piperidin-4-yl hydroxy(dithiophen-2-yl) ac

To a stirred suspension of piperidin-4-yl hydroxy(dithiophen-2-yl)acetate hydrochloride (100 gm 0.278 mol)in tetrahydrofuran (750 ml), 1 -(chloroacetyl)-2,3-dihydro-1 H-indole- 5-carbaldehyde (68.3 gm, 0.306) and tri ethyl amine (116 ml, 0.83 mol) were added and the reaction mixture was refluxed for 12 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (750 ml) and water (750 ml). The organic layer was separated, treated with charcoal, filtered and evaporated to dryness. The residue was suspended i n ethyl acetate (1000 ml) and stirred for 2 hours and the solid, thus obtained, was fi Itered, washed with ethyl acetate and dri ed under vacuum at 55 e5°C for 8 to 12 hours to get 108.0 gm desi red compound as col ored sol i d.

^! H NMR (DMSO-de) 9.86 (1 H, s), 8.21-8.19 (1 H, m), 7.76-7.73 (2H, m), 7.48-7.47 (2H, m), 7.28 (1 H, s), 7.12-7.11 (2H, m), 7.00-6.98(2H, m), 4.87-4.85 (1 H, m), 4.26-4.22 (2H, m), 3.21 (2H, s), 3.19-3.17 (2H, m), 2.55-2.50 (2H, partially merged with solvent signal), 2.46-2.43 (2H, partially merged with solvent signal), 1.86-1.85 (21-1, bs), 1.82-1.75 (21-1, bs)

ESMS: 510.80/511.87 [M H]⁺

E xample 4:

1-[3-(5-formyl-2,3-dihydro-1 H-indol-1-yl)-3-oxopropyl] piperidin-4-yl

hydroxy(dithiophen-2-yl) acetate E xample 5:

1-[3-(5-formyl-2,3-dihydro-1 H-indol-1-yl)-3-oxopropyl] piperidin-4-yl

hydroxy(di phenyl )acetate

E xample 6:

1 -[3-(5-f ormyl-2,3-di hydro-1 H-i ndol-1 -yl)-3-oxobutyl I] pi peridi n-4-yl

hydroxy(dithiophen-2-yl) acetate

E xample 7:

1 -[3-(5-f ormyl-2,3-di hydro-1 H-i ndol-1 -yl)-3-oxoethyl I] pi peri di n-4-yl

hydroxy(di phenyl )acetate

E xample 8:

1 -[3-(6-f ormyl-3,4-di hydroqui nol i n-1 (2H)-yl)-3-oxopropyl] pi peridi n-4-yl

hydroxy(dithiophen-2-yl) acetate

Compounds as described in examples 4-8 were synthesized using the same

condition as mentioned in example 3; with appropriate starting materials.

E xample 9:

Preparation of 1 -acetyl -2, 3- di hydro- 1 H-indole-5-carbaldehyde

To a stirred solution of 1-acetyl indoline (177 gm, 1.09 mol) in trifluoroacetic acid (900 ml), hexamine (170 gnri 1.20 mol) was added portion wise under sti rring at 8 e5°C and the R M was stirred at around 80 e5°Cfor 8 to 10 hours. The reaction mixture was cooled to RT, quenched with water and extracted with M DC, the organic layer was dried over sodi um sul phate and evaporated to dryness to get crude product. T he crude compound was purified by column chromatography using sil ica gel as stationary phase and 40% EtOAc in hexane as an el uent to get 147.0 gm desi red compound as sol i d. ^! H NMR (DMSO-de) 9.85 (1 H, s), 8.19-8.16 (1 H, m), 7.75-7.72 (2H, m), 4.18-4.03 (2H, m), 3.19-3.17 (2H, m), 2.20 (3H, s)

E xample 10:

Preparation of 1-(chloroacetyl)-2,3-dihydro-1 H-i ndole-5-carbaldehyde

The deacetylation reaction of 1 -acetyl -2, 3- di hydro- 1 H-indole-5-carbaldehyde (48 gm, 0.253 mol) in aqueous NaOH (20.31 gm 0.507 mol) (500 ml) was carried out at 75 e5°C for 1 to 2 hr. The reaction mixture was cooled to RT, extracted with MDC and the organic layer was dried over sodium sulphate, filtered and used as such for further reaction. To a stirred M DC layer, triethylamine (70 ml, 1.04 mol) was added and reaction mixture was cooled to 0-5°C and chloroacetyl chloride (22.5 ml, 0.55 mol) was now added dropwise over a peri od of 30 mi nutes. T he reacti on mi xture was sti rred for 1 hour at RT . T he reacti on mixture was quenched with water and extracted with MDC, the organic layer was dried over sodi um sul phate and evaporated to dryness to get 50.0 gm desi red compound as sol i d. ^! H NMR (DMSO-de) 10.09 (1 H, s), 8.20-8.18 (1 H, m), 7.80-7.76 (2H, m), 4.79 (2H, s), 4.23-4.18 (2H, m), 3.26-3.22 (2H, m). E xample 11:

1 -(3-chl oropropanoyl )-2,3-di hydro-1 H -i ndol e-5-carbal dehyde

E xample 12:

1 -(4-chl orobutanoy I )-2,3-di hydro-1 H -i ndol e-5-carbal dehyde

E xample 13:

1-(3-chloropropanoyl)-1,2,3,4-tetrahydroquinoline-6-carbaldehyde

Compounds as described in examples 11-13 were prepared using similar condition as mentioned in example 10; with appropriate starting materials. E xample 14:

Preparation of 1-{2-[5-({ [(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5- yl)ethyl]amino} methyl)-2,3-dihydro-1 H-indol-1-yl]-2-oxoethyl} piperidin-4-yl hydroxy (dithiophen-2-yl)acetate (Compound. No. 2)

To a stirred solution of 1-[2-(5-formyl-2,3-dihydro-1 H-indol-1-yl)-2-oxoethyl] piperidin-4- yl hydroxy(dithiophen-2-yl)acetate (100 gm, 0.196 mol), i n toluene (1000 ml) and methanol (500 ml), 5-[(1 R)-2-amino-1-{ [tert-butyl(dimethyl)silyl]oxy} ethyl]-8- hydroxyquinolin-2(1 H)-one diacetate (97.9 gm, 0.215 mol) was added and the reaction mixture was heated at 60 e5°C till to get clear solution. The reaction mixture was cooled down to room temperature and sodium borohydride (3.62 gm, 0.097 mol) was added porti on-wi se for 30 to 45 mi nutes at 0-5°C and reacti on mixture was sti rred for 30 mi nutes. The reaction mixture was quenched with aqueous saturated sodium hydrogen carbonate (750 ml) at room temperature, extracted with MDC (1000 ml), the organic layer was separated, dried over sodium sulphate and filtered to get 1-{2-[5-({ [(2R)-2-{ [tert- butyl(dimethyl)silyl]oxy}-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino} methyl)-2,3-dihydro-1 H-indol-1-yl]-2-oxoethyl} piperidin-4-yl hydroxy(dithiophen-2- yl)acetate in M DC layer.

To this , triethylamine hydrofl uoride (96.2 ml, 0.587 mol) was added at RT and the reaction mixture was sti rred at RT for 10 to 12 hours. T he obtai ned sol i d was f i Itered and washed with MDC. The solid was suspended in water and neutralized with saturated sodium hydrogen carbonate and was sti rred at R T for 8 to 10 hours. T he obtai ned sol i d was f i I tered, washed with plenty of water and dried under vacuum at 50 e5°C. Further, this solid was suspended in ethyl acetate (1000 ml) and stirred for 2 to 3 hours, filtered and dried under vacuum at around 50 e5°C to get 116.0 gm desi red compound as sol i d. Synthesis of 5-[(1 R)-2-amino-1-{ [tert-butyl(dimethyl)silyl]oxy}ethyl]-8- hydroxyquinolin-2(1 H)-one diacetate was prepared using the similar procedure as mentioned in US2006/0035931 and Organic Process Research & Development 2015, 19, 315-319.

E xample 15:

Preparation of 1-{2-[5-({ [(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5- yl)ethyl]amino} methyl)-2,3-dihydro-1 H-indol-1-yl]-2-oxoethyl} piperidin-4-yl hydroxy (diphenyl)acetate (Compound. No. 11)

To a sti rred solution of 1-[3-(5-formyl-2,3-dihydro-1 H-indol-1-yl)-3-oxoethyl] piperidin-4- yl hydroxy(diphenyl)acetate (0.8 gm, 0.0016 mol) i n methanol (15 ml), catalytic amount of acetic acid and 5-[(1 R)-2-amino-1-{ [tert-butyl(dimethyl)silyl]oxy} ethyl]-8- hydroxyquinolin-2(1 H)-one diacetate (0.8 gm, 0.00176 mol) were added and the reaction mixture was heated at 60 e5°C till to get clear solution. T he R M was cooled down to RT and sodium borohydride (43 mg, 0.00112 mol) was added portion wise for 5 minutes at 0- 5°C and R M was sti rred for 30 mi n. T he R M was quenched with aqueous saturated sodi um hydrogen carbonate (20 ml) at RT and was extracted i n ethyl acetate (100 ml x 3). The organic layer was separated, dried over sodium sulphate and evaporated to dryness to get 1 -{ 2-[5-({ [(2R)-2-{ [tert-butyl(di methyl)si lyl] oxy} -2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl]ami no} methyl)-2,3-dihydro-1 H-indol-1-yl]-2- oxoethyl} pi peri di n-4-yl hydroxyl (di phenyl)acetate.

The obtained compound was taken in methanol (10 ml), triethylamine hydrofluoride (788 mg, 0.00489 mol) was added at RT and the reacti on mixture was sti rred at RT for 10 to 12 hour. T he sol i d was f i Itered and washed with M DC . T he sol id was neutral i zed with aqueous saturated sodium hydrogen carbonate and stirred at RT for 6 to 8 hours. The solid was filtered, washed with water and dried under vacuum at 50 e5°C. The solid was suspended in ethyl acetate (15 ml) and sti rred f or 2 hours at RT, filtered and dried under vacuum at 50 e5°C to get 150 mg desi red compound as white sol i d.

E xample 16:

Preparation of 1-{2-[5-({ [(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5- yl)ethyl]amino} methyl)-2,3-dihydro-1 H-indol-1-yl]-2-oxoethyl} piperidin-4-yl hydroxy (dithiophen-2-yl)acetate hemifumarate salt (Compound. No. 8)

To a stirred solution of 1-{2-[5-({ [(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethyl]ami no} methyl)-2,3-dihydro-1 H-indol-1-yl]-2- oxoethy I} pi peri di n-4-y I hydroxy (dithiophen-2-yl)acetate (100 gm, 0.140 mol) in M eC N :T H F : E tO H ( 1 : 2: 1 ) (4000 ml ), f umari c aci d ( 16.22 gm, 0.139 mol ) sol uti on prepared in EtOH (1000 ml) and MeCN (1000 ml) was added under stirring over 5 to 10 minutes and the reaction mixture was stirred at RT for 20 to 24 hours. The obtained solid was filtered, washed with ethanol (100 ml), and dried under vacuum at 50 e5°C for 6 to 8 hours. Further, this sol id was suspended in EtOH (1600 ml) and ref I uxed f or 12 to 16 hours under sti rri ng and hot f i Itered to get 72.0 gm desi red compound as white sol i d.

Other representative compounds of the present invention were prepared in analogous manner by using the synthetic schemes as described above and characteristic data of prepared compounds is given below in Table II: Table II:

C omp ^rH -N M R (400 M H M ASS

. No.

1 (DMSO-d6) 8.11 (1H, d), 7.96 (1H, d), 7.47 (2H, d), 7.27 729.26/730.27 (1H, bs), 7.13-6.98 (7H, m), 6.91-6.89 (1H, m), 6.45 (1H, [MH]⁺ d), 5.05 (1 H, bs), 4.84 (1 H, bs), 4.10-4.06 (2H, m), 3.67 (2H,

s), 3.10-3.06 (2H, m), 2.68-2.57 (6H, m), 2.43-1.98 (4H,

partially merged with solvent signal), 1.79 (2H, bs), 1.61- 1.59 (2H, m)

2 (DMSO-d6) 8.10 (1H,d), 7.95(1 H, d), 7.48-7.46 (2H, m), 715.14/716.24 7.28-7.23 (1H, m), 7.16-6.98 (7H, m), 6.91-6.89 (1H, m), [MH] ⁺

6.45 (1H,d), 5.16 (1H, bs),4.85(1H, bs), 4.14-4.12 (2H, m),

3.67 (2H, s), 3.20 (2H, s), 3.07 (2H, m), 2.67-2.62 (2H, m),

2.49-2.43 (4H, partially merged with solvent signal), 1.98

(2H, bs), 1.82 (2H, bs)

3 (DMSO-d6) 8.08 (1H,d), 7.47 (2H, d), 7.09-7.03 (4H, m), 741.59/742.41 6.98 (2H, bs), 6.90-6.87 (2H, m), 6.78 (1H, bs), 6.48-6.44 [MH]^"

(2H, m), 5.02 (2H, bs), 3.54 (2H, s), 3.45-3.43 (5H, m), 3.20

(2H, bs), 2.66-2.61 (5H, m), 2.50 (2H, merged with solvent

signal), 1.89-1.81 (4H, m), 1.50 (2H, bs)

4 (DMSO-d6) 8.10 (1H,d), 7.97(1 H, d), 7.47-7.46 (2H, m), 743.23/744.23 7.25 (1H, bs), 7.14 (1H, s), 7.07-6.89 (8H, m), 6.47 (1H, d), [MH] ⁺

5.05 (1H, bs),4.81 (1H, bs),4.06(2H, m), 3.68 (2H,s), 3.08

(2H, t), 2.73-2.66 (2H, m), 2.40 (4H, partially merged with

solvent signal), 2.27-2.26 (4H, m), 1.75-1.71 (4H, m), 1.58

(2H, bs)

5 (DMSO-d6) 7.96(1H,d), 7.47 (2H,d), 7.16 (2H,d), 7.11- 741.02/742.60

7.06 (4H, m), 7.00-6.96 (3H, m), 6.81 (1H, d), 5.75 (1H, s), [MH] ⁺ 4.85 (1 H, bs), 4.53 (1 H, t), 4.15-4.13 (2H, m), 3.68 (2H, s),

3.20 (2H, s), 3.09 (2H, t), 2.91 (3H, s), 2.56 (2H, partially merged with solvent signal), 2.43 (3H, partially merged with

solvent signal), 1.82 (2H, bs), 1.63 (2H, bs)

(DMSO-d6) 8.10 (1 H, d), 7.96 (1 H, d), 7.47 (2H, d), 7.27 715.18/716.21 (1 H, s), 7.16 (1 H, bs), 7.10-6.98 (7H, m), 6.90 (1 H, d), 6.46 [M H] ⁺

(1 H, d), 5.07 (1 H, bs), 4.85 (1 H, bs), 4.15-4.02 (2H, m), 3.72

(2H, s), 3.20 (2H, partially merged with solvent signal ),

3.08 (2H, m), 2.71-2.67 (2H, m), 2.50 (4H, partially merged

with solvent signal), 1.82 (21-1, bs), 1.63 (21-1, bs)

(DMSO-d6) 7.97-7.95 (1 H, m), 7.46 (2H, d), 7.15 (2H, 755.23/756.30 bs), 7.10-7.10 (2H, m), 7.05 (1 H, d), 7.00-6.96 (3H, m), 6.80 [M H] ⁺

(1 H, d), 4.84 (1 H, bs), 4.52 (1 H, t), 4.10-4.02 (2H, m), 3.65

(2H, s), 3.12-3.08 (3H, m), 2.91-2.89 (4H, m), 2.57-2.54

(4H, partial ly merged with solvent signal ), 2.43 (2H,

partially merged with solvent signal), 2.32 (2H, bs), 1.79

(2H, bs), 1.61 (2H, bs)

(DMSO-d6) 8.11 (1 H, d), 7.98 (1 H, d), 7.48 (2H, bs), 7.28- 715.36/716.32 6.92 (9H, m), 6.52-6.46 (2H, m), 5.16 (1 H, bs), 4.85 (1 H, [M H] ⁺ bs), 4.15 (2H, bs), 3.84 (2H, s), 3.21 (2H, bs), 3.09 (2H, bs),

2.76 (2H, bs), 2.50 (4H, partially merged with solvent

signal), 1.82 (2H, bs), 1.63 (2H, bs)

(DMSO-d6+D20) 7.91 (1 H, bs), 7.43 (2H, s), 7.14-7.04 717.32/718.27 (4H, m), 6.98 (2H, s), 6.88-6.86 (1 H, m), 6.68-6.66 (1 H, m), [M H] ⁺

4.83 (1 H, bs), 4.75 (1 H, m) 4.09 (2H, bs), 3.67-3.58 (2H, m),

3.18-3.15 (2H, m), 3.07 (2H, bs), 2.87-2.81 (2H, m), 2.71

(2H, m), 2.42 (4H, partially merged with solvent signal),

2.37-2.35 (2H, m), 1.81 (2H, bs), 1.62 (21-1, bs)

(DMSO-d6) 8.11 (1 H, d), 7.97 (1 H, d), 7.34-7.28 (8H, m), 717.51/718.52 7.19 (2H, s), 7.12-7.05 (3H, m), 6.93-6.91 (1 H, m), 6.55 [M H] ⁺

(1 H, s), 6.48 (1 H, d), 5.12 (1 H, bs), 4.85 (1 H, bs), 4.09-4.05

(2H, m), 3.79 (2H, s), 3.09 (2H, m), 2.73 (2H, bs), 2.54 (2H, partially merged with solvent signal), 2.36-2.28 (6H, m),

1.75 (2H, bs), 1.54 (2H, bs)

(DMSO-d6) 8.10 (1 H, d), 7.95 (1 H, d), 7.34-7.27 (7H, m), 703.05/704.47 7.16 (2H, s), 7.09-7.04 (3H, m), 6.90 (1 H, d), 6.56 (1 H, s), [M H] ⁺

6.46 (1 H, d), 5.07 (1 H, t), 4.85 (1 H, bs), 4.13 (2H, t), 3.71

(2H, s), 3.16 (2H, s), 3.07 (2H, t), 2.69-2.67 (2H, m), 2.44- 2.38 (4H, partially merged with solvent signal), 1.79 (2H,

bs), 1.56 (2H, bs)

(DMSO-d6) 7.96 (1 H, d), 7.34-7.15 (10H, m), 7.08-7.06 743.38/744.39 (2H, m), 7.21 (1 H, d), 6.97 (1 H, d), 6.81 (1 H, d), 4.86 (1 H, [M H] ⁺ bs), 4.54 (1 H, t), 4.07 (2H, t), 3.69 (2H, s), 3.09 (2H, t), 2.91

(3H, s), 2.59-2.57 (2H, m), 2.49 (4H, merged with solvent

signal), 2.35-2.27 (4H, m), 1.76 (2H, bs), 1.54 (2H, bs)

(DMSO-d6) 9.25 (1 H, bs), 7.99-7.97 (1 H, m), 7.48-7.47 677.89/678.96 (2H, m), 7.29-7.22 (3H, m), 7.11 (3H, bs), 6.99 (3H, bs), [M H] ⁺ 6.71-6.69 (1 H, m), 4.86 (2H, m), 4.60 (1 H, bs), 4.45 (2H, s),

4.15 (2H, bs), 3.76 (2H, s), 3.20 (2H, s), 3.10 (2H, m), 2.73

(1 H, m), 2.61 (2H, m), 2.50-2.43 (4H, partially merged with

solvent signal), 1.82 (2H, bs), 1.63 (2H, bs)

(DMSO-d6) 8.00-7.93 (2H, m), 7.48-7.47 (2H, bs), 7.28 699.11/700.12 (1 H, s), 7.14-6.98 (7H, m), 6.84-6.83 (2H, m), 6.48-6.46 [M H] ⁺

(1 H, m), 485 (1 H, bs), 4.16-4.12 (2H, m), 3.64 (2H, s), 3.20

(2H, s), 3.07 (2H, m), 2.90-2.88 (2H, m), 2.65-2.63 (2H, m),

2.49 (4H, partially merged with solvent signal), 1.98 (2H,

bs), 1.82 (2H, bs)

(DMSO-d6) 7.95-7.93 (1 H, m), 7.34 (10H, m), 7.15 (2H, 729.04/730.11 bs), 7.06 (1 H, m), 6.97-6.95 (1 H, m), 6.81-6.79 (1 H, m), [M H] ⁺

4.85 (1 H, bs), 4.51 (1 H, bs), 4.12 (2H, bs), 3.65 (2H, s),

3.15-3.08 (4H, m), 2.90 (3H, s), 2.54 (2H, partially merged

with solvent signal), 2.50-2.37 (8H, partially merged with

solvent signal), 1.79 (2H, bs), 1.56 (2H, bs) (DMSO-d6) 8.11 (1 H, d), 7.95 (1 H, d), 7.48-7.46 (2H, m), 715.01/716.64 7.27 (1H, bs), 7.14-7.10 (3H, m), 7.07-7.04 (2H, m), 7.00- [MH] ⁺

6.98 (2H, m), 6.90 (1H, d), 6.47-6.44 (1H, d), 5.09 (1H, bs),

4.90 (1 H, bs), 4.14 (2H, m), 3.66 (2H, s), 3.20 (2H, s), 3.09- 3.07 (2H, m), 2.67-2.62 (2H, m), 2.49-2.43 (4H, partially

merged with solvent signal), 1.82(21-1, bs), 1.63(21-1, bs)

(DMSO-d6) 8.11 (1H, d), 7.95-7.94 (1H, m), 7.48-7.47 715.12/716.14 (2H, m), 7.28 (1H, bs), 7.14-6.99 (8H, m), 6.91-6.89 (1H, [MH] ⁺ m), 6.45 (1H, d), 5.03 (1H, bs), 4.85(1 H, bs), 4.14(21-1, m),

4.03-4.02 (1H, m), 3.66 (2H, s), 3.20 (2H, partially merged

with solvent signal), 3.07 (2H, partially merged with solvent

signal), 2.66-2.62 (2H, m), 2.49 (4H, merged with solvent

signal), 1.89 (3H, s), 1.98-1.82 (2H, bs), 1.63 (2H, bs)

(DMSO-d6) 8.11 (1H, d), 7.98-7.96 (1H, m), 7.48-7.46 715.25/716.21 (2H, m), 7.28 (1H, bs), 7.14-6.99 (8H, m), 6.48 (1H, d), [MH] ⁺ 5.10-5.07 (1H, m), 4.85 (1H, bs), 4.15 (2H, t), 3.76 (2H, s),

3.20 (2H, s), 3.08 (2H t), 2.75-2.68 (2H, m), 2.49 (2H,

merged with solvent signal), 2.43 (2H, partially merged with

solvent signal), 2.34 (2H, s), 1.82 (2H, bs), 1.63 (2H, bs)

(DMSO-d6) 8.11 (1H, d), 8.03 (1H, d), 7.48 (2H, d), 7.36 715.25/716.33 (1H, bs), 7.27 (1H, d), 7.12-7.09 (4H, m), 7.0-6.95 (3H, m), [MH] ⁺

6.53 (1H, d), 5.33-5.31 (1H, m), 4.86 (1H, bs), 4.17-4.15

(2H, m), 4.10-4.08(41-1, m), 3.24(21-1, s), 3.11 (2H, m), 2.98- 2.95 (1 H, m), 2.90-2.85 (1 H, m), 2.55 (2H, partially merged

with solvent signal), 2.45 (2H, partially merged with solvent

signal), 1.83 (2H, bs), 1.64 (2H, bs)

(DMSO-d6) 10.48 (1H, bs), 9.92 (1H, bs), 9.02 (1H, bs), 715.25/716.27 8.89(11-1, bs), 8.12(1 H, d), 8.04(1 H, d), 7.51-7.50 (1H, m), [MH] ⁺

7.46 (1 H, s), 7.37 (1 H, d), 7.15-7.06 (2H, m), 7.01-6.96 (2H,

m), 6.54 (1H, d), 5.35 (1H, d), 5.17 (1H, s), 5.02 (1H, bs),

4.39-4.34 (2H, m), 4.18 (2H, s), 4.11-4.09 (2H, m), 3.22- 3.16 (2H, bs), 3.02-2.95 (4H, m), 2.69 (2H, s), 1.98-1.95

(2H, m), 1.75 (2H, m)

31 (DMSO-d6) 8.14 (1 H, d), 8.10 (1 H, d), 7.48-7.46 (2H, m), 715.22/716.23 7.28-7.10 (6H, m), 7.05-7.07 (1 H, m), 7.0-6.98 (2H, m), [M H] ⁺

6.92-6.90 (1 H, d), 6.49-6.46 (1 H, d), 5.14-5.10 (1 H, m),

4.17-4.13 (2H, m), 4.85 (1 H, m), 3.21 (2H, s), 3.11-3.07

(2H, m), 2.84-2.80 (2H, m), 2.79-2.77 (2H, m), 2.50 (2H,

merged with solvent signal), 2.45-2.43 (2H, partially

merged with solvent signal), 1.82 (21-1, bs), 1.63 (21-1, bs)

C ombi nation T herapy

C ompounds of the present i nventi on may be admi ni stered i n combi nati on wi th other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula (I) are useful. Such other drugs may be administered contemporaneously or sequentially with a compound of Formula (I). When a compound of Formula (I) is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of Formula (I) is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula (I).

Pharmaceutical compositions

In another embodi ment of the invention, there is provided a pharmaceutical composition comprisi ng a therapeutical ly effective amount of one or more of a compound of formula (I). While it is possible to administer therapeutically effective quantity of compounds of formula (I) either individually or in combination, directly without any formulation, it is common practice to administer the compounds in the form of pharmaceutical dosage forms comprising pharmaceutically acceptable excipient(s) and at I east one active i ngredi ent T hese dosage forms may be admi ni stered by a vari ety of routes including intranasal, pulmonary, oral, topical, transdermal, subcutaneous, intramuscular, intravenous, intraperitoneal, etc. 0 ral composi ti ons may be i n the form of sol i d or I i qui d dosage form S ol i d dosage form may comprise pellets, pouches, sachets or discrete units such as tablets, multiparticulate units, capsules (soft & hard gelatin) etc. L iquid dosage forms may be i n the form of elixirs, suspensions, emulsions, sol utions, syrups etc. Composition intended for oral use may be prepared according to any method known in the art for the manufacture of the composition and such pharmaceutical compositions may contain in addition to active ingredients, excipients such as diluents, disintegrating agents, binders, solubilizers, lubricants, glidants, surfactants, suspending agents, emulsifiers, chelating agents, stabilizers, flavours, sweeteners, colours etc. Some example of suitable excipients include lactose, cellulose and its derivatives such as microcrystalline cel lulose, methyl cellulose, hydroxy propyl methyl cellulose & ethyl cellulose, di calcium phosphate, mannitol, starch, gelatin, polyvinyl pyrrolidone, various gums like acacia, tragacanth, xanthan, alginates & its derivatives, sorbitol, dextrose, xylitol, magnesium stearate, talc, colloidal silicon dioxide, mineral oi l, glyceryl mono stearate, glyceryl behenate, sodium starch glycolate, cross povidone, crossl inked carboxymethyl cellulose, various emulsifiers such as polyethylene glycol, sorbitol, fatty acid esters, polyethylene glycol alkyl ethers, sugar esters, polyoxyethylene polyoxypropyl block copolymers, poly ethoxy I ated fatty acid monoesters, di esters and mixtures thereof. Intranasal or pulmonary compositions according to present invention can be in the form of liquid or solid or semisolid composition suitable for nasal administration. L iquid composition can be aqueous, non-aqueous composition, suspension or emulsion, solid composition can be in the form of powder and the like and semi solid composition can be in form of gel and the like. Nasal /pulmonary compositions may also form in-situ gel. Said nasal or pulmonary composition comprises compounds of formula (I) optionally with one or more suitable excipients selected from in-situ gelling agent, mucoadhesive agent, polymer, humectant buff eri ng agent stabilizer, surfactant, preservative, thickening agent, solvents, co-solvents, permeation enhancer, chelating agent viscosity modifying agent, sweetener, taste masking agent, solubilizer, flavoring agent, and isotonicity agent.

Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, N - Methyl -2- Pyrrol i done, propylene glycol and other glycols, alcohols, a naturally occurring vegetable oil like sesame oi l, coconut oil, peanut oil, cotton seed oil or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, anti -oxidants, preservatives, complexing agents like cellulose derivatives, peptides, polypeptides and cycl odextri ns and the I i ke can be i ncorporated as requi red.

The dosage form can have a slow, delayed or controlled release of active ingredients i n addi ti on to i mmedi ate rel ease dosage forms. The amount of active ingredient which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment and the particular disorder or disease being treated.

The compounds of the invention may be administered by oral, inhalation or parenteral route at a dose of from 0.0005 to 100 mg/kg per day, preferably from 0.0005 to 50 mg/kg per day, more preferably from 0.001 to 20 mg/kg per day, most preferably from 0.001 to 10 mg/kg per day. The dose range for adult humans is generally from 5 ι g to 5 g per day and preferably 10 ι g to 2 g per day.

Dosage forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for exampl e units contai ni ng 5 1 g to 1000 mg.

In another embodiment present invention provides method of treating respiratory- tract disorders such as asthma and chronic obstructive pulmonary disease, chronic bronchitis, adult/acute respiratory distress syndrome (A R DS), chronic respi ratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema and allergic rhinitis by administering a therapeutically effective amount of a compound of formula (I) to a mammal, including human being, in need thereof.

A preferred embodiment of the present invention is a method for treating chronic obstructive pulmonary disease or asthma by administering a therapeutically effective amount of a compound of formula (I) to a mammal, i ncl udi ng human bei ng, i n need thereof. Biological testing:

In V itro test:

Assay to measure Adrenergic Beta2 receptor -mediated cA M P generation for confirming agonist activity:

C H 0 K 1 eel 1 1 i ne expressi ng human B eta( b2) A drenergi c R eceptor ( Perki nE I mer, E s-

033-C ) were employed. The LA NC E ^÷ U ltra cA M P measurement kit ( Perki n Elmer ), a homogeneous time-resolved fluorescence resonance energy transfer (T R-FRET) assay designed to measure cA M P was empl oyed. A 11 reagents were added i n 384 wel I opti plates as per Kit instruction. Test compounds were diluted as 2X concentration in assay buffer. Cells were incubated for 30 minutes with the indicated agonist concentrations. Time- resolved fluorescence was measured on Multimode Plate Reader (E nV ision^÷ , PerkinE lmer ).

Compounds of present invention exhibiting Beta 2 adrenergic receptor agonist activity showed increase in intracell ular cA MP levels. The results were expressed as percentage i ncrease of cA M P as compared with vehicle treated control.

Assay to measure inhibition of M uscarinic (M 3) receptor -mediated Calcium generation for confirming antagonist activity:

C HO eel Is expressing the human muscarinic (M 3) receptor ( Perki n E lmer ES- 212-C) were employed. The fluo-4 NW indicator (Invitrogen) was employed according to manufacturer s i nstructions for measurement of intracellular calcium levels. Cells were loaded with fl uo-4 NW for 30 minutes with at 37eC followed by 30 minutes incubation with vehicle or compounds. Cells were then stimulated with agonist, Carbachol. (Sigma).

Intracellular calcium levels were monitored upto 90 seconds after agonist treatment on Multimode Plate Reader (E nV ision^÷ ,PerkinEl mer ).

Compounds of present invention exhibiting muscarinic M3 receptor antagonistic activity showed inhibition of carbachol induced increase of intracellular calcium levels.

The results were expressed as percentage inhibition of increase in intracellular calcium as compared with vehicle treated control. Table III:

Criteria: + = <30%; ++ = ₄0-70%; +++ = 70-80%; ++++ = 80-90%; +++++ => 90-100 %; relativeto control O bservati on: I n-vi tro data shows that compounds of present i nventi on have anti muscari ni c as well as beta adrenergic agonist activity. In V ivo Bronchoprotection Studies:

The bronchoprotection activity of compound no. 1 was evaluated in an anesthetized guinea pig model using ventilation pressure as a surrogate measure of airway resistance (J Pharmacol Toxicol Methods. 2011 J an- Feb; 63(1): 89-95). In this model, efficacy and duration of effect were assessed by determining the protective effect of Compound no. 1 against methacholine induced bronchoconstriction at 1.5 hours and 24 hours after inhalation dosing.

Male Duncan- Hartley guinea pigs, weighing between 250 to 400 gram were used. V ehicle or solution of compound no. 1 (300 ι g/ml) was dosed by inhalation over a period of 15 minutes in a whole body exposure dosi ng chamber using 5 ml dosing solution. Omron, N E- C29 nebulizer was used to generate aerosol used for dosing. After 45 minutes of dosing, guinea pigs were anesthetized with an intraperitoneal injection of urethane (1 g/kg) and pentobarbital sodi um (20 mg/kg). After the animal achieved surgical plane of anesthesia, the jugular vein was isolated and cannulated using heparin saline filled polyethylene catheters to al I ow i ntravenous i nj ecti on of methachol i ne. T he trachea was then approached through a midline blunt incision, dissected free and cannulated. Upon completion of cannulation, the animals were venti lated at a stroke vol ume 1 ml/100 g body weight but not exceedi ng 2.5 ml vol ume and at rate of 100 strokes per mi nute usi ng smal I ani mal venti I ator (Columbus, U.S.A.). Ventilation pressure was measured in the expiratory tubing of ventilator using a MT L844 physiological pressure transducer coupled to a Powerlab-quad bridge-computer assembly (A DInstruments, Australia). Throughout the experiment the animals were maintained at 37 eC using a heating pad. Prior to initiating data collection, pentobarbital (10 mg/kg) was administered intraperitoneal I y to suppress spontaneous breathi ng and obtai n a stabl e basel i ne. After stabi I i zati on peri od and col I ecti on of basel i ne ventilation pressure values, guinea pigs were challenged intravenously with non- cumulatively incremental doses of the bronchoconstrictor methacholine. The changes in ventilation pressure were recorded using LabChart software (A DInstruments, Australia). After the completion of study, the animals were euthanized.

C hange i n venti I ati on pressure was measured in ^"cm of water_, whi ch represent difference in peak pressure after bronchoconstrictor challenge and baseline pressure. T he treatment induced percent inhibition of the bronchoconstrictor response to 8 ι g/kg of methacholine chal I enge i n compari son to vehi cl e treatment was cal cul ated.

The results of % Inhibition of methacholine induced bronchoconstriction by compound no. 1 at 300i g/ml after 1.5 hr and 24 hr of dosing has been represented graphically in Figure 1. (data expressed as mean e standard error of mean, n=6/group).***denotes p<0.001 versus vehicle control; statistical analysis performed usi ng Student s t- test

Observations:

It was observed that compound no. 1 produced potent and sustained bronchoprotective activity. Single admi nistration of compound no. 1 completely abolished methacholine induced bronchoconstriction at 1.5 hr post dosing. At 24 hrs post dosing, test compound elicited 87 % inhibition of methacholine- induced bronchoconstriction.

Claims

A compound of formula (I)

I

its pharmaceutically acceptable salts and isomers, stereoisomers, atropisomers, conformers, tautomers, polymorphs, hydrates, solvates, N-oxides or S-oxides thereof;

Wherein,

F^and R²are independently selected from (C3-C7)cycloalkyl, aryl and heteroaryl, the said (C3-C₇)cycloalkyl, aryl, and heteroaryl are optionally substituted by one or more (Ci- C6)alkyl, aryl, (C3-C₇)cycloalkyl, halogen, O-R¹⁴, SH, CN, (CH₂) -aryl, (CH₂) -heteroaryl, CH₂OH, CH₂-halogen, CH₂0-(CrC₆)alkyl, CH₂0-aryl, COOR¹²,CONR¹⁶R¹⁷or NHCOR¹²;

R³ is selected from hydrogen, hydroxyl, (Ci-C₄) alkoxy, CH₂OH, and (Ci-Ce)alkyl;

R⁴ is selected from hydrogen, (Ci-C6)alkyl, aryl, (CH₂)_p-aryl, (CH₂)_p-heteroaryl and (C3- C₇)cycloalkyl; m is 1or 2;

R⁵ and R⁶ are independently selected from hydrogen, (Ci-Ce)alkyl, halogen, (C3- C₇)cycloalkyl, heterocycloalkyi, (CH₂)_p-aryl and (CH₂)_p-heteroaryl or R⁵ and R⁶on same carbon form a 3-7 membered cycloalkyi or heterocycloalkyi ring in a spiro manner or is gem di methyl; n is selected from 0-4;

R⁷ and R⁸ is independently selected from hydrogen, (CrC6)alkyl and heterocycloalkyi or R⁷ and R⁸ on same carbon form a 3-7 membered cycloalkyi or heterocycloalkyi ring in a spi ro manner or is gem di methyl; p is 1 or 2;

R⁹ and R¹⁰ are independently selected from hydrogen, (CrC6)al kyl, (C₃- C7)cycloalkyl,)heterocycloalkyl and oxo or R⁹ and R¹⁰ on same carbon form a 3-7 membered cycloalkyi or heterocycloalkyi ring in a spiro manner or is gem dimethyl;

R¹¹ is selected from hydrogen, (Ci-Ce)alkyl, aryl, C H₂OH, C H₂-halogen, halogen, (C₃- C7)cycloalkyl, heteroaryl, heterocycloalkyi, O-R¹⁴, SH, C N, (C H₂)_p-aryl, (C H₂)_P- heteroaryl, CH₂0-(CrC₆)alkyl, CH₂0-aryl, COOR¹², CON R¹⁶R¹⁷and N HCOR¹²; Q is N(A)R¹²or O-A;

R¹² is selected from hydrogen, (Ci-Ce)alkyl, aryl, (C H₂)_p-aryl, (C H₂)_P- heteroaryl, (C₃- C7)cycloalkyl and heterocycloalkyi; R ¹³ i s sel ected from hydrogen, O- R ¹⁴ and

R¹⁴ is independently selected from hydrogen, (Ci-Ce)alkyl, aryl, heteroaryl, (CH₂)p-aryl, (C H₂) -heteroaryl, (C₃-C₇)cycloalkyl, Si(Ci-C6)alkyl, and

R¹⁵ is selected from (Ci-C₆)alkyl, (C₃-C₇)cycloalkyl, aryl, heteroaryl, (CH₂)p-aryl and (C H₂)p-heteroaryl;

R¹⁶ and R ¹⁷ are independently selected from hydrogen, (Ci-Ce)alkyl, (C₃-C₇)cycloalkyl and heterocycloalkyl or R¹⁶ and R¹⁷ together with nitrogen atom form a 3-10 membered heterocycloalkyl ring;

A is selected from

:/^" denotes point of attachment.

2. The compound of formula (I) according to claim 1, wherein

R¹ and R²are independently selected from (C₃-C₇)cycloalkyl, aryl and heteroaryl;

R³ is selected from hydroxyl and (Ci-C6)alkyl;

R⁴ is hydrogen;

m is 1 or 2;

R⁵ and R⁶ are i ndependently hydrogen or R ⁵ and R ⁶ on same carbon is gem dimethyl; n is selected from 0-2;

R⁷ and R⁸ are independently hydrogen or R⁷ and R⁸ on same carbon is gem dimethyl; p is 1 or 2;

R ⁹ and R ¹⁰ are hydrogen;

R¹¹ is hydrogen or (CrC6)alkyl;

Q is N(A)R¹²;

R¹² is hydrogen or (Ci-C6)alkyl;

R¹³ is hydrogen or O-R¹⁴;

R¹⁴ is selected from hydrogen and Si(Ci-C6)alkyl;

R¹⁵ is (Ci-C₆)alkyl;

A is selected from

: denotes point of attachment.

3. T he compound accordi ng to cl ai m 1 , whi ch i s sel ected from the group consi sti ng 1 -{ 3-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-OXO-1 ,2-di hydroqui nol i n-5- yl)ethyl]amino} methyl)-2,3-dihydro-1 H-indol-1-yl]-3-oxopropyl} piperidin-4-yl hydroxy(dithiophen-2-yl) acetate;

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- yl)ethyl]amino} methyl)-2,3-dihydro-1 H-indol-1-yl]-2-oxoethyl} pi peridin-4-yl hydroxy(dithiophen-2-yl) acetate;

1 -{ 3-[6-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- yl)ethyl] ami no} methyl )-3,4-di hydroqui nol i n-1 (2H)-yl]-3-oxopropyl} pi peri di n-4-yl hydroxy(dithiophen-2-yl) acetate; 1 -{ 4-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- yl)etlTyl]amino} methyl)-2 -dihydro-1 H-indol-1-yl]-^oxobutyl} pi peridi n-4-yl hydroxy(dithiophen-2-yl) acetate;

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-{ 4-hydroxy-3-

[(methylsulfonyl)ami no] phenyl} ethyl]ami no} methyl)-2,3-di hydro-1 H-indol-1-yl]-2- oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate;

1 -{ 2-[5-({ [( RS)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl )-2,3-di hydro-1 H-indol-1-yl]-2-oxoethyl} pi peridin-4-yl hydroxy(dithiophen-2-yl) acetate;

1-{ 3-[5-({ [(2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl} ethyl]ami no} methyl )-2,3-di hydro-1 H-indol-1-yl]-3-oxopropyl} pi peridin-4-yl hydroxy(dithiophen-2-yl) acetate;

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl )-2,3-di hydro-1 H-indol-1-yl]-2-oxoethyl} pi peridin-4-yl hydroxy(dithiophen-2-yl) acetate hemifumarate salt;

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2,3, 4-tetrahydroqui nol in- 5- yl)ethyl] ami no} methyl )-2,3-di hydro-1 H-i ndol-1 -yl]-2-oxoethyl} pi peri di n-4-yl hydroxy(dithiophen-2-yl) acetate;

1 -{ 3-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- yl)ethyl]amino} methyl)-2,3-dihydro-1 H-indol-1-yl]-3-oxopropyl} piperidin-4-yl hydroxy(di phenyl )acetate;

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl )-2,3-di hydro-1 H-indol-1-yl]-2-oxoethyl} pi peridin-4-yl hydroxy(di phenyl )acetate; 1 -{ 3-[5-({ [(2R)-2-hydroxy-2-{ 4-hydroxy-3-

[(methylsulfonyl)ami no] phenyl} ethyl]ami no} methyl)-2,3-di hydro-1 H-indol-1-yl]-3- oxopropyl} piperidin-4-yl hydroxy(diphenyl)acetate;

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-OXO-1 ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl )-2,3-di hydro-1 H-indol-1-yl]-2-oxoethyl} pyrrolidi n-3-yl hydroxy(dithiophen-2-yl) acetate;

1 -(2-{ 5-[({ (2R)-2-hydroxy-2-[4-hydroxy-3-

( hydroxymethyl ) phenyl] ethyl} ami no) methyl] -2,3-di hydro-1 H -i ndol -1 -y I} -2- oxoethyl)pi peri di n-4-yl hydroxy(dithi ophen-2-yl)acetate;

1 -{ 2-[5-({ ethyl [(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl )-2,3-di hydro-1 H-indol-1-yl]-2-oxoethyl} pi peridin-4-yl hydroxy(dithiophen-2-yl) acetate;

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- yl)ethyl]amino} methyl)-6-methyl-2,3-di hydro-1 H-indol-1-yl]-2-oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl) acetate;

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl )-2,3-di hydro-1 H-indol-1-yl]-2-oxoethyl} -3,3- dimethyl pi peridin-

4-yl hydroxy(dithiophen-2-yl)acetate;

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl )-2,3-di hydro-1 H-indol-1-yl]-2-oxoethyl}-2,2-di methyl pi peridin-

4-yl hydroxy(dithiophen-2-yl)acetate;

1-{2-[5-({ [(2R)-2-hydroxy-2-(5- hydroxy- 3-0X0-3, 4-di hydro-2H-1,4- benzoxazin-8- yl)ethyl]ami no} methyl )-2,3-di hydro-1 H-indol-1-yl]-2-oxoethyl} pi peridin-4-yl hydroxy(dithiophen-2-yl) acetate; 1-(2-{ 5-[({(2R)-2-[3-(fornnylamino)-4-hydroxyphenyl]-2- ydroxyethyl}ami no)methyl]- 2,3-di hydro-1 H-i ndol-1 -yl} -2-oxoethyl) pi peri di n-4-yl hydroxy(dithi ophen-2-yl)acetate;

1-{2-[5-({ [(2R)-2-hydroxy-2-(4- hydroxy- 2-oxo-2,3-di hydro-1, 3- benzothiazol-7- yl)ethyl]ami no} methyl )-2,3-di hydro-1 H-indol-1-yl]-2-oxoethyl} pi peridin-4-yl hydroxy(dithiophen-2-yl) acetate;

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-OXO-1 ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl )-2,3-di hydro-1 H-indol-1-yl]-2-oxoethyl} pi peridin-4-yl cycl opentyl ( hydroxy) phenyl acetate;

1 -{ 3-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- yl)ethyl]amino} methyl )-2,3-di hydro-1 H-indol-1-yl]-2,2-dimethyl-3-oxopropyl} pi peridin 4-yl hydroxy(dithiophen-2-yl)acetate;

1-{ 2-[5-({ [2-(8-hydroxy-2-ox o-1, 2-di hydroqui noli n-5-yl)ethyl]ami no} methyl)-2, 3- di hydro-1 H-indol-1-yl]-2-oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate;

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-{ 4-hydroxy-3-

[(methylsulfonyl)ami no] phenyl} ethyl]ami no} methyl)-2,3-di hydro-1 H-indol-1-yl]-2- oxoethy I} pi peri di n-4-y I hydroxy( di phenyl )acetate;

1 -{ 2-[5-({ [(2S)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl )-2,3-di hydro-1 H-indol-1-yl]-2-oxoethyl} pi peridin-4-yl hydroxy(dithiophen-2-yl) acetate;

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-0X0-1 ,2-di hydroqui nol i n-5- yl)ethyl]ami no} methyl )-2,3-di hydro-1 H-indol-1-yl]-2-oxoethyl} pi peridin-4-yl hydroxy( di thi ophen-2-y I ) acetate acetate; 1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-oxo-l ,2-di hydroqui nol i n-5- yl)ethyl]amino} methyl)-2,3-dihydro-1 H-indol-1-yl]-2-oxoethyl} pi peridin-4-yl hydroxy(dithiophen-2-yl) acetate butanedioate (hemi succinate salt);

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-oxo-l ,2-di hydroqui nol i n-5- yl)ethyl]amino} methyl)-2,3-dihydro-1 H-indol-1-yl]-2-oxoethyl} pi peridin-4-yl hydroxy(dithiophen-2-yl) acetate 2,3-dihydroxybutanedioate (1:1);

1 -{ 2-[5-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-oxo-l ,2-di hydroqui nol i n-5- yl)ethyl]amino} methyl)-2,3-dihydro-1 H-indol-1-yl]-2-oxoethyl} pi peridin-4-yl hydroxy(dithiophen-2-yl) acetate hemi ethane- 1 ,2-di sulfonic acid;

1 -{ 2-[5-({ [2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2-di hydroqui nol i n-5- yl)ethyl]amino} methyl)-2,3-dihydro-1 H-indol-1-yl]-2-oxoethyl} pi peridin-4-yl hydroxy(dithiophen-2-yl) acetate hydrofluoride (1 :1);

1 -{ 3-[6-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-oxo-l ,2-di hydroqui nol i n-5- yl)ethyl] ami no} methyl )-3,4-di hydroqui nol i n-1 (2H)-yl]-3-oxopropyl} pi peri di n-4-yl hydroxy(di phenyl )acetate;

1 -{ 3-[6-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-oxo-l ,2-di hydroqui nol i n-5- yl)ethyl] ami no} methyl )-3,4-di hydroqui nol i n-1 (2H)-yl]-3-oxopropyl} -2,2- di methyl pi peri di n-4-yl hydroxy(di phenyl)acetate;

1 -{ 3-[6-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-oxo-l ,2-di hydroqui nol i n-5-yl)ethyl] (2- methyl propyl)ami no} methyl)-3,4-di hydroqui nol i n-1 (2H )-yl]-3-oxopropyl} pi peridi n-4-yl hydroxy(di phenyl )acetate;

1 -(2-{ 6-[({ (2R)-2-hydroxy-2-[4-hydroxy-3-

( hydroxy methyl) phenyl] ethyl} ami no) methyl] -3, 4-di hydroqui noli n- 1(21-1 )-y 1} -2- oxoethy I) pi peri di n-4-yl hydroxy(di phenyl )acetate; 1 -{ 2-[6-({ [(2R)-2-hydroxy-2-{ 4-hydroxy-3-

[(methylsulf onyl)ami no] phenyl} ethyl] ami no} methyl)-3,4-di hydroqui nol i n-1 (2H)-yl] -2- oxoethy I} pi peri di n-4-y I hydroxy( di phenyl )acetate; 1-{2-[6-({ [(2R)-2-hydroxy-2-(6-hydroxy- 3-0X0-3, 4-dihydro-2H-1,4-benzoxazin-8- yl)ethyl]ami no} methyl )-3,4-di hydroqui noli n-1 (2H)-yl]-2-oxoethyl} pi peri di n-4-yl hydroxy(di phenyl )acetate;

1 -{ 3-[6-({ [(2R)-2-hydroxy-2-(8- hydroxy- 2-ox o-1 ,2-di hydroqui nol i n-5- yl)ethyl] ami no} methyl )-3,4-di hydroqui nol i n-1 (2H)-yl]-3-oxopropyl} pi peri di n-4-yl cycl opentyl ( hydroxy) pheny I acetate;

1-{3-[6-({ [(2R)-2-hydroxy-2-(6- hydroxy- 3-0X0-3, 4-dihydro-2H-1,4-benzoxazin-8- yl)ethyl] ami no} methyl )-3,4-di hydroqui nol i n-1 (2H)-yl]-2,2-di methyl-3- oxopropyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate;

1-{2-[7-({ [(2R)-2-hydroxy-2-(4- hydroxy- 2-oxo-2,3-dihydro-1, 3- benzothiazol-7- yl)ethyl]amino} methyl)-3,4-dihydroquinolin-1(2H)-yl]-2-oxoethyl} piperidin-4-yl 2,2- di (thi ophen-2-y I ) propanoate;

1-{2-[6-({ [(2R)-2-hydroxy-2-(6- hydroxy- 3-0X0-3, 4-di hydro-2H-1,4- benzoxazin-8- yl)ethyl]amino} methyl)-2,3-dihydro-1 H-indol-1-yl]-2-oxoethyl} piperidin-4-yl 2,2- di (thi ophen-2-y I ) propanoate; 1-{2-[5-({ [(2R)-2-{ [tert-butyl(dimethyl)silyl]oxy}-2-(8-hydroxy-2-oxo-1,2- di hydroqui noli n-5-yl)ethyl]ami no} methyl)-2,3-di hydro-1 H-indol-1-yl]-2- oxoethyl} piperidin-4-yl hydroxy(dithiophen-2-yl)acetate;

1 -{ 2-[5-({ [(2R)-2-{ [tert-butyl(di methyl)si lyl] oxy} -2-(8-hydroxy-2-oxo-1 ,2- di hydroqui noli n-5-yl)ethyl]ami no} methyl)-2,3-di hydro-1 H-indol-1-yl]-2- oxoethy I} pi peri di n-4-y I hydroxyl (diphenyl)acetate and pharmaceutically acceptable salts thereof.

4. A compound sel ected from the group consi sti ng of 1-[3-(5-formyl-2,3-di hydro-1 H-i ndol-1 -yl)-3-oxopropyl] pi peri din-4-yl hydroxy(dithiophen-2-yl) acetate;

1-[3-(5-formyl-2,3-di hydro-1 H-i ndol-1 -yl)-3-oxopropyl] pi peri din-4-yl hydroxy(di phenyl )ac etate;

1-[3-(5-formyl-2, 3-di hydro-1 H-i ndol-1 -yl)-3-oxobutyl] pi peri din-4-yl hydroxy(dithiophen-2-yl) acetate;

1 -[3-(5-f ormyl-2,3-di hydro-1 H-i ndol-1 -yl)-3-oxoethyl I] pi peri di n-4-yl hydroxy(di phenyl )ac etate;

1 -[3-(6-f ormyl-3,4-di hydroqui nol i n-1 (2H)-yl)-3-oxopropyl] pi peridi n-4-yl hydroxy(dithiophen-2-yl) acetate;

1 -(3-chl oropropanoyl )-2, 3-di hydro-1 H -i ndol e-5-carbal dehyde;

1 -(4-chl orobutanoy I )-2,3-di hydro-1 H -i ndol e-5-carbal dehyde;

1 -(3-chl oropropanoyl)-1 ,2,3,4- tetrahydroqui nol i ne-6-carbal dehyde;

1 -(chloroacetyl)-2, 3-di hydro-1 H-i ndol e-5-carbal dehyde;

1 -[2-(5-f ormyl-2,3-di hydro-1 H-i ndol-1 -yl)-2-oxoethyl] pi peri di n-4-yl hydroxy(dithiophen-2-yl) acetate and pharmaceutically acceptable salts thereof.

5. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds as claimed in in any of the claims 1 to 3, in admixture with a pharmaceutically acceptable excipient

6. A method of treating respi ratory- tract disorders in a mammal including human being, the method comprising administering a therapeutically effective amount of a compound as claimed in any of the claims 1 to 3 to a mammal in need thereof.

7. The method as c I ai med i n c I ai m 6, wherei n the respi ratory- tract di sorder i s sel ected from the group consisting of asthma, chronic obstructive pulmonary disease, chronic bronchitis, acute respiratory distress syndrome (A RDS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema and allergic rhinitis.

8. The method as claimed in claim 7, wherein the respi ratory- tract disorder is chronic obstructive pul monary di sease or asthma.

9. Use of a compound as claimed in in any of the claims 1 to 3, for the preparation of a medicament for treatment of respi ratory- tract disorders.

10. Use of a compound as claimed in claim 9, wherein the respiratory-tract disorder is selected from the group consisting of asthma, chronic obstructive pulmonary disease, chronic bronchitis, acute respiratory distress syndrome (AR DS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema and allergic rhinitis.

11. Use of a compound as clai med i n clai m 10, wherei n the respi ratory- tract disorder is chronic obstructive pulmonary disease or asthma.

12. A compound of formula (I), process for its preparation and pharmaceutical composition, as herein described with reference to the examples accompanying the specification.