Substituted phthalazin-1 (2H)-one derivatives as selective inhibitors of poly (ADP-ribose) polymerase-1

Patent metadata

Field	Value
Publication number	US-9598418-B2
Application number	US-201314647088-A
Country	US
Kind code	B2
Filing date	Dec 23, 2013
Priority date	Dec 31, 2012
Publication date	Mar 21, 2017
Grant date	Mar 21, 2017

Abstract

The present invention relates to novel compounds of general formula (I), their stereoisomers, regioisomers, tautomeric forms and novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them. The present invention also relates to a process of preparing novel compounds of general formula (I), their stereoisomers, regioisomers, their tautomeric forms, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutical compositions containing them, and novel intermediates involved in their synthesis.

First claim

We claim:

1. Compound having the structure of general formula (I)

wherein R 1 at each occurrence is independently selected from hydrogen, halogen, or the groups selected from (C 1 -C 6 )alkyl, haloalkyl, (C 3 -C 6 )cycloalkyl, alkylthio or the group (OSO 2 )alkyl;
R′ at each occurrence is independently selected from hydrogen, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxyl, haloalkyl, haloalkoxy, cyano, thioalkyl, (C 3 -C 6 )cycloalkyl groups;
m=1-4;
L=—O, —S, —NH;
n=0-4
R 2 is selected from hydrogen atom, hydroxyl, (C 1 -C 6 ) alkyl, (C 3 -C 6 )cycloalkyl, oxo, C(O)OR 5 , —C(O)R 5 , or —C(O)NR 6 R 7 , wherein said (C 1 -C 6 )alkyl and (C 3 -C 6 )cycloalkyl groups are further substituted by one or more substituents selected from halogen, hydroxyl, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy groups;
R 3 and R 4 are each independently selected from hydrogen atom, (C 1 -C 6 )alkyl, hydroxyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, —C(O)OR 5 , —OC(O)R 5 , —O(CH 2 ) p C(O)OR 5 , —C(O)R 5 , —NHC(O)R 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 or —C(O)NR 6 R 7 or alternatively, R 3 and R 4 together forms an oxo group;
each of the ring atoms ‘D’ and ‘E’ is independently selected from C or N atoms;
each of the ring atoms ‘F’, ‘G’ and ‘H’ is independently selected from C, N, O and S atoms
the ring formed by ‘D’, ‘E’, ‘F’, ‘G’ and ‘H’ represents a substituted or non-substituted five-membered bicyclic aromatic or non-aromatic heterocyclic ring;
R 5 at each occurrence is independently selected from hydrogen atom, optionally substituted groups selected from (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 )heterocyclyl, (C 6 -C 10 )aryl or (C 6 -C 10 )heteroaryl groups;
each of R 6 or R 7 at each occurrence are independently selected from (C 6 -C 10 )heterocyclyl, (C 6 -C 10 )aryl or (C 6 -C 10 )heteroaryl, optionally R 6 and R 7 are joined together with nitrogen atom to form a (C 6 -C 10 )heterocyclyl ring; wherein said heterocyclyl and heteroaryl ring contains one or more heteroatoms selected from N, O, S(O) n , n is 0, 1 or 2 and p is 0, 1 or 2.

2. The compound as claimed in claim 1 , wherein heterocycles representing

are selected from a member of the group consisting of

3. The compound as claimed in claim 1 , wherein the substituents on R 1 is selected from hydroxyl, oxo, halo, thio, nitro, amino, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, haloalkyl or haloalkoxy groups alone or in combination with other radicals.

4. The compound as claimed in claim 1 wherein the substituents on R 5 is selected from (C 1 -C 6 )alkyl, halogen, hydroxyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 ) heterocyclyl, (C 6 -C 10 )aryl, (C 6 -C 10 )heteroaryl, carboxylic acid or carboxylic acid ester substituents.

5. The compound as claimed in claim 1 wherein the substituents on R 6 & R 7 at each occurrence is independently selected from (C 1 -C 6 )alkyl, halogen, hydroxyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, (C 6 -C 10 )heteroaryl, carboxylic acid or carboxylic acid ester substituents.

6. The compound as claimed in claim 1 , wherein the substituents on substituted or non-substituted bicyclic aromatic or non-aromatic five membered heterocyclic ring is selected from halogen, hydroxyl, oxo, optionally substituted groups selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, (C 6 -C 10 )heteroaryl, benzyl, OR 5 , —C(O)OR 5 , —OC(O)R 5 , —O(CH 2 ) p C(O)OR 5 , C(O)R 5 , S(O) n R 5 , —NHC(O)R 5 , NR 6 R 7 , —OC(O)NR 6 R 7 or —C(ONR 6 R 7 , wherein each of R 5 , R 6 & R 7 are as defined in claim 1 and wherein the (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, (C 6 -C 10 )heteroaryl or benzyl group are each independently substituted further with one or more substituents selected from (C 1 -C 6 )alkyl, halogen, hydroxyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, (C 6 -C 10 )heteroaryl, oxo, —C(O)OR 5 , —OC(O)R 5 , O(CH 2 ) p C(O)OR 5 , —C(O)R 5 , —S(O)nR 5 , —NHC(O)R 5 , NR 6 R 7 , —OC(O)NR 6 R 7 or —C(O)NR 6 R 7 groups.

7. The compound as claimed in claim 1 , wherein aryl groups are selected from a member of the group consisting of phenyl, naphthyl, tetrahydronaphthyl, indenyl, dihydroindenyl, and biphenyl.

8. The compound as claimed in claim 1 , wherein the substituents on aryl groups are independently selected from hydrogen, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxyl, haloalkyl, haloalkoxy, cyano, thioalkyl, (C 3 -C 6 )cycloalkyl groups.

9. The compound as claimed in claim 1 , wherein the heteroaryl or heteroaromatic group is selected from pyridyl, thienyl, furyl, pyrrolyl, indolinyl, indolyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, purinyl groups.

10. The compound as claimed in claim 1 , where in the substitution on heteroaryl or heteroaromatic group is selected from hydrogen, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 ) alkoxy, hydroxyl, haloalkyl, haloalkoxy, (C 6 -C 10 )aryl, aralkyl, cyano, alkylthio, thioalkyl groups.

11. The compound as claimed in claim 1 , wherein the heterocyclyl group is selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thienopiperidinyl, groups.

12. The compound as claimed in claim 1 , wherein the substituents on heterocyclyl group is selected from hydrogen, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxyl, haloalkyl, haloalkoxy, (C 6 -C 10 )aryl, aralkyl, cyano, alkylthio, thioalkyl groups.

13. The compound as claimed in claim 1 selected from a member of the group consisting of:

Assignees

• Cadila Healthcare Ltd

Inventors

• Srivastava Brijesh K
• Desai Ranjit C
• Patel Pankaj R

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title